Title of Invention

OLIGOSACCHARIDE DERIVATIVE

Abstract A compound represented by the general formula (I): wherein A represents the general formula (A1), (A2) or (A3): R1 and R2 are the same or different, and each represent a C1-C6 alkyl group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6 haloalkyl group, R3,R4,R5 and R6 are the same or different, and each represent a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6 haloalkyl group, amino group which amino group may optionally be substituted with one or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl groups, hydroxyl group, hydrogen atom or halogen atom, R7 represents a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6 haloalkyl group, hydroxyl group or hydrogen atom, and n represents an integer of 1 or 2; a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
Full Text DESCRIPTION
OLIGOSACCHARIDE DERIVATIVE
(TECHNICAL FIELD)
The present invention relates to a novel oligosaccharide
derivative, its pharmacologically acceptable salts and its
pharmacologically acceptable esters.
The present invention also relates to an oligosaccharide
derivative having actions including a-amylase inhibitory action,
blood glucose lowering action and lipid lowering action, its
pharmacologically acceptable salts and its pharmacologically
acceptable esters.
Moreover, the present invention relates to a therapeutic
drug and/or preventive drug for a disease such as, hyperglycemia,
post prandial hyperglycemia, impaired glucose tolerance (IGT),
diabetes mellitus, obesity, hyperlipemia, fatty liver,
hepatomegaly, diabetic complications, neuropathy,
arteriosclerosis, cataract or diabetic nephropathy (and
preferably a therapeutic drug and/or preventive drug for
hyperglycemia or diabetes mellitus) containing as its active
ingredient an oligosaccharide derivative, its pharmacologically
acceptable salts or its pharmacologically acceptable esters.
Moreover, the present invention relates to a preventive
drug or therapeutic drug for the aforementioned diseases
containing as its active ingredient the aforementioned compound,
a composition for preventing or treating the aforementioned
diseases containing as its active ingredient the aforementioned
compound, the use of the aforementioned compound to produce a
pharmaceutical for preventing or treating the aforementioned
diseases, or a prevention or treatment method for the
aforementioned diseases in which a pharmacologically effective
amount of the aforementioned compound is administered to a
mammal (and preferably to a human).
(BACKGROUND ART)

In the past, digestive enzyme inhibitors such as Basen
(Takeda Pharmaceutical), containing voglibose, and Glucobay
(Bayer), containing acarbose, have actually been used clinically
as effective therapeutic drugs for hyperglycemia. However,
since both compounds inhibit a-glucosidase, they have the
disadvantages of causing adverse side effects such as abdominal
distention, flatulence, increased abdominal wind, soft stools,
diarrhea and abdominal pain. Moreover, they have also been
reported to cause liver function disorders.
On the other hand, effects causing inhibition of the
absorption of nutrients are known to be obtainable by inhibiting
not only a-glucosidase, but a-amylase as well, and compounds are
known that lower blood glucose levels without causing the
aforementioned adverse side effects unique to a-glucosidase
inhibitors. However, the a-amylase inhibitory activity of these
compounds is weak, and there are no compounds known that have
adequate a-amylase inhibitory activity.
Compounds having a partial structure (sugar derivative)
that is in common with the oligosaccharide derivative of the
present invention that demonstrate a-amylase inhibitory activity
have been disclosed (see, for example, International Publication
WO 00/50434 and International Publication WO 01/94367). However,
these compounds differ from the compound of the present
invention in that they are required to have a deoxynojirimycin
backbone or a hexahydfo-3,5, 6-trihydroxy-1H-azepine backbone.
(DISCLOSURE OF THE INVENTION)
a-amylase inhibitors are required to be resistant to
degradation in the digestive tract (and particularly the small
intestine) and demonstrate stable action. However, since
previously reported a-amylase inhibitors cannot be said to
demonstrate adequate stability in the small intestine, there is
a possibility that they cannot demonstrate adequate
pharmacological effects stably. In addition, this instability
in the digestive tract (and particularly the small intestine)

results in the risk of having some form of effect on liver
function resulting from absorption of their degradation products.
Therefore, the inventors of the present invention
conducted extensive research for the purpose of developing a
therapeutic drug and/or preventive drug for diseases such as
hyperglycemia and diabetes mellitus that has superior a-amylase
inhibitory activity and high stability, and found that a novel
oligosaccharide derivative has superior a-amylase inhibitory
action, blood glucose lowering action and lipid lowering action,
improves diseases such as hyperglycemia, post prandial
hyperglycemia, hyperglycemia, impaired glucose tolerance (1GT),
diabetes mellitus, obesity, hyperlipemia, fatty liver,
hepatomegaly, diabetic complications, neuropathy,
arteriosclerosis, cataract and diabetic nephropathy, and has
high stability, thereby leading to completion of the present
invention.
Namely, the present invention provides an
oligosaccharide derivative, its pharmacologically acceptable
salts and its pharmacologically acceptable esters, which are
useful as therapeutic drugs or preventive drugs for diseases
such as hyperglycemia, post prandial hyperglycemia, impaired
glucose tolerance (IGT), diabetes mellitus, obesity,
hyperlipemia, fatty liver, hepatomegaly, diabetic complications
(such as retinopathy, nephropathy and neuropathy), neuropathy,
arteriosclerosis, cataract and diabetic nephropathy.
The present invention relates to a compound represented
by the following general formula (I):
(wherein A represents the following general formula (A1), (A2)
or (A3):


R1 and R2 may be the same or different and each represent a C1-C6
alkyl group, hydroxymethyl group, C1-C6 alkoxymethyl group or
C1-C6 haloalkyl group, R3, R4, R5 and R6 may be the same or
different and each represent a C1-C6 alkyl group, C1-C6 alkoxy
group, C1-C6 hydroxyalkyl group, C1-C6 haloalkyl group, amino
group (which amino group may be substituted with one or two C1-
C6 alkyl groups or C1-C6 hydroxyalkyl groups), hydroxyl group,
hydrogen atom or halogen atom, R7 represents a C1-C6 alkyl group,
C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6 haloalkyl
group, hydroxyl group or hydrogen atom, and n represents an
integer of 1 or 2),
its pharmacologically acceptable salts or its pharmacologically
acceptable esters.
In the present invention, a "C1-C3 alkyl group" refers
to a linear or branched alkyl group having 1 to 3 carbon atoms,
examples of which include methyl, ethyl, n-p.ropyl and isopropyl
groups. In R1, R2, R3, R4, R5 and R6, the C1-C3 alkyl group is
preferably a methyl group.
In the present invention, a "C1-C6 alkyl group" refers
to a linear or branched alkyl group having 1 to 6 carbon atoms,
examples of which include the groups indicated as examples of
the aforementioned "C1-C3 alkyl group" as well as n-butyl,
isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-
methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-
methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3, 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-
dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-
ethylbutyl groups. In the substituents of R1, R2, R3, R4, R5, R6,
R7 and the amino group of R3, R4, R5 and R6, the C1-C6 alkyl group
is preferably an alkyl group having 1 to 3 carbon atoms, and
most preferably a methyl group.

In the present invention, a "halogen atom" refers to a
fluorine atom, chlorine atom, bromine atom or iodine atom, and
is preferably a fluorine atom in R3, R4, R5, R6, r8, r9 and R11.
In the present invention, a "C1-C3 haloalkyl group" or
"C1-C6 haloalkyl group" respectively refer to groups in which
the aforementioned "C1-C3 alkyl group" or "C1-C6 alkyl group" is
substituted with the aforementioned "halogen atom(s)". Examples
of the "C1-C3 haloalkyl group" include trifluoromethyl,
trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,
fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-
bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-
chloropropyl and 2,2-dibromoethyl groups, and it is preferably a
fluoromethyl group in R1, R2, R3, R4, R5, R5, R7 and R10. Examples
of the "C1-C6 haloalkyl group" include the aforementioned
examples of the "C1-C3 haloalkyl group" as well as 4-iodobutyl,
4-fluorobutyl, 4-chlorobutyl, 5-iodopentyl, 5-fluoropentyl, 5-
chloropentyl, 6-iodohexyl, 6-fluorohexyl and 6-chlorohexyl
groups, and it is preferably a C1-C3 haloalkyl group and more
preferably a fluoromethyl group in R1, R2, R3, R4, R5, R6, R7 and
R10.
In the present invention, a "C1-C3 hydroxyalkyl group"
or "C1-C6 hydroxyalkyl group" respectively refers to a group in
which the aforementioned "C1-C3 alkyl group" or "C1-C6 alkyl
group" is substituted with a hydroxyl group. Examples of the
"C1-C3 hydroxyalkyl group" include hydroxymethyl, hydroxyethyl
and hydroxypropyl groups, and it is preferably a hydroxymethyl
group in R3, R4, R5, R6, R7, R10 and R11. Examples of the "C1-C6
hydroxyalkyl group" include the aforementioned examples of the
"C1-C3 hydroxyalkyl group" as well as hydroxybutyl,
hydroxypentyl and hydroxyhexyl groups, and it is preferably a
C1-C3 hydroxyalkyl group, and more preferably a hydroxymethyl
group, in R3, R4, R5, R6, R7, R10 and R11.
In the present invention, a "C1-C3 alkoxy group" or "C1-
C6 alkoxy group" respectively refers to a group in which a "Cl-
C3 alkyl group" or "C1-C6 alkyl group" is bonded to an oxygen
atom. Examples of the "C1-C3 alkoxy group" include methoxy,

ethoxy, n-propoxy and isopropoxy groups. Examples of the "C1-C6
alkoxy group" include the aforementioned examples of a "C1-C3
alkoxy group" as well as n-butoxy, isobutoxy, s-butoxy, tert-
butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-
hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,
3,3-dimethylbutoxy, 2,2-dimethylbutcxy, 1,1-dimethylbutoxy, 1,2-
dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy groups,
and it is preferably a C1-C3 alkoxy group, and more preferably a
methoxy group, in R3, R4, R5, R6 and R7.
In the present invention, a "C1-C3 alkoxymethyl group"
or "C1-C6 alkoxymethyl group" respectively refers to a group in
which the aforementioned "C1-C3 alkoxy group" or "C1-C6 alkoxy
group" is bonded to a methyl group. Examples of the "C1-C3
alkoxymethyl group" include methoxymethyl, ethoxymethyl, n-
propoxymethyl and isopropoxymethyl groups, and it is preferably
a methoxymethyl group in R1 and R2. Examples of a "C1-C6
alkoxymethyl group" include the aforementioned examples of the
"C1-C3 alkoxymethyl group" as well as n-butoxymethyl,
isobutoxymethyl, s-butoxymethyl, tert-butoxymethyl, n-
pentoxymethyl, isopentoxymethyl, 2-methylbutoxymethyl,
neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-
methylpentoxymethyl, 2-methylpentoxymethyl, 3,3-
dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-
dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-
dimethylbutoxymethyl and 2,3-dimethylbutoxymethyl groups, and it
is preferably a "C1-C3 alkoxymethyl group", and more preferably
a methoxymethyl group, in R1 and R2.
Oligosaccharide derivatives having the general formulas
(I), (Ia) and (Ib) of the present invention can be converted to
an acid addition salt in the case of having a basic group in
accordance with ordinary methods. Examples of such salts
include salts of halogenated hydroacids such as hydrofluoric
acid, hydrochloric acid, hydrobromic acid and hydroiodic acid;
inorganic acid salts such as nitrates, perchlorates, sulfates
and phosphates; salts of lower alkanesulfonic acids such as
methanesulfonic acid,

trifluoromethanesulfonic acid and ethanesulfonic acid; salts of
arylsulfonic acids such as benzenesulfonic acid and p-
toluenesulfonic acid; salts of amino acids such as glutamic acid
and aspartic acid; and, salts of carboxylic acids such as acetic
acid, fumaric acid, tartaric acid, oxalic acid, maleic acid,
malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic
acid, lactic acid, gluconic acid and citric acid. The
aforementioned salt is preferably a salt of a halogenated
hydroacid, and most preferably a hydrochloride.
Moreover, oligosaccharide derivatives having the
aforementioned general formulas (I), (Ia) and (Ib) can be
converted to a metal salt in accordance with ordinary methods
since they have a hydroxyl group. Examples of such salts
include salts of alkali metals such as lithium, sodium and
potassium; salts of alkaline earth metals such as calcium,
barium and magnesium; and, aluminium salts. The aforementioned
metal salt is preferably an alkali metal salt.
Oligosaccharide derivatives having the aforementioned
general formulas (I), (Ia) and (Ib) of the present invention can
be converted to pharmacologically acceptable esters in
accordance with ordinary methods. There are no particular
limitations on such esters provided they can be used medically
and their pharmacological acceptability is comparable to that of
the oligosaccharide derivatives of the aforementioned general
formulas (I), (Ia) and (Ib).
Examples of ester residues of oligosaccharide
derivatives having the aforementioned general formulas (I), (Ia)
and (Ib) of the present invention include C1-C6 alkyl groups
(wherein said alkyl groups may be substituted with a
trialkylsilyl group), C7-C16 aralkyl groups, C1-C5 alkyl croups
substituted with C1-C6 alkanoyloxy groups, C1-C5 alkyl grcups
substituted with C1-C6 alkyloxycarbonyloxy groups, C1-C5 alkyl
groups substituted with C5-C7 cycloalkyloxycarbonyloxy groups,
C1-C5 alkyl groups substituted with C6--C10 aryloxycarbonyloxy
groups, and 2-oxy-1,3-dioxolen-4-yl groups having a C1-C6 alkyl
group as a substituent at the 5-position.
FP0403s
Here, C1-C6 alkyl groups are preferably linear or
branched alkyl groups having 1 to 4 carbon atoms, and more
preferably are methyl, ethyl, propyl, isopropyl, butyl or
isobutyl groups, and most preferably are methyl groups or ethyl
groups.
C1-C5 alkyl groups refer to linear or branched alkyl
groups having 1 to 5 carbon atoms, preferably methyl, ethyl,
propyl, isopropyl, butyl or isobutyl groups, and most preferably
methyl or ethyl groups.
C5-C7 cycloalkyl groups refer to 5- to 7-member
saturated cyclic hydrocarbon groups, examples of which include
cyclopentyl, cyclohexyl and cyclobutyl groups, and preferably
cyclohexyl groups.
C6-C10 aryl groups refer to aromatic hydrocarbon groups
having 6 to 10 carbon atoms, examples of which include phenyl,
indenyl and naphthyl groups, and preferably phenyl groups.
C7-C16 aralkyl groups refer to groups in which the
aforementioned "C6-C10 aryl group" is bonded to the
aforementioned "C1-C6 alkyl group", examples of which include
benzyl, a-naphtylmethyl, p-naphthylmethyl, indenylmethyl,
phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl,
triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-
naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,
1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-
phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-
naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl,
1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl,
5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-
naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-
phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-
phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-
naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, and 6-
naphthylhexyl groups. They are preferably "aralkyl groups" in
which the number of carbons of the "alkyl group" is 1 to 4, and
more preferably benzyl groups in R1 and R2.
Specific preferable examples of ester residues include

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
benzyl, acetoxymethyl, 1-(acetoxy)ethyl, propionyloxymethyl, 1-
(propionyloxy)ethyl, butyryloxymethyl, 1-(butyryloxy)ethyl,
isobutyryloxymethyl, 1-(isobutyryloxy)ethyl, valeryloxymethyl,
1-(valeryloxy)ethyl, isovaleryloxymethyl, 1-(isovaleryloxy)ethyl,
pivaloyloxymethyl, 1-(pivaloyloxy)ethyl,
methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl,
ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl,
propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl,
isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl,
butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl,
isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, t-
butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl,
cyclopentanecarbonyloxymethyl, 1-(cyclopentanecarbonyloxy)ethyl,
cyclohexanecarbonyloxymethyl, 1-(cyclohexanecarbonyloxy)ethyl,
cyclopentyloxycarbonyloxymethyl, 1-
(cyclopentyloxycarbonyloxy)ethyl, cyclohexyloxycarbonyloxymethyl,
1-(cyclohexyloxycarbonyloxy)ethyl, benzoyloxymethyl, 1-
(benzoyloxy)ethyl, phenoxycarbonyloxymethyl, 1-
(phenoxycarbonyloxy)ethyl, (5-methyl-2-oxo-1,3-dioxolen-4-
yl)methyl or 2-trimethylsilylethyl group.
Furthermore, oligosaccharide derivatives having the
aforementioned general formulas (I), (Ia) and (Ib) have various
isomers. For example, optical isomers can be present in portion
A and the bonding portion of the sugar in oligosaccharide
derivatives having the aforementioned general formulas (I), (Ia)
and (Ib). In the aforementioned general formulas (I), (Ia) and
(Ib), these stereoisomers based on asymmetric carbons and the
racemic and non-racemic mixtures of these isomers are all
indicated with a single formula. Thus, the present invention
includes these isomers and mixtures of these isomers in various
proportions.
Moreover, in the case oligosaccharide derivatives having
the aforementioned general formulas (I), (Ia) and (Ib), their
salts or their esters form solvates (for example, hydrates), the

present invention includes these as well.
Moreover, compounds converted to oligosaccharide
derivatives having the aforementioned general formulas (I), (Ia)
and (Ib) that are metabolized in the living body, their salts or
their esters (for example, so-called pro-drugs such as amide
derivatives) are all included in the present invention.
In the present invention, (Al) is preferably the
following general formula (Ala) or (Alb):

and more preferably the following general formula (Ale):

(A2) is preferably the following general formula (A2a)
or (A2b):
and more preferably the following general formula (A2c):

(A3) is preferably the following general formula (A3a):


R1 is preferably a C1-C6 alkyl group or hydroxymethyl
group, and more preferably, a methyl group or hydroxymethyl
group, and particularly preferably a methyl group.
R2 is preferably a C1-C6 alkyl group or hydroxymethyl
group, more preferably a methyl group or hydroxymethyl group,
and particularly preferably a hydroxymethyl group.
R3 is preferably a C1-C6 hydroxyalkyl group, hydroxyl
group, halogen atom or hydrogen atom in general formulas (Al),
(Ale) and (Ala), more preferably a C1-C3 hydroxyalkyl group or
hydrogen atom, and particularly preferably a hydrogen atom. In
general formulas (A2), (A2a), (A2b) and (A2c), R3 is preferably
a C1-C6 hydroxyalkyl group, hydroxyl group, hydrogen atorr or
halogen atom, more preferably a C1-C3 hydroxyalkyl group or
hydrogen atom, and particularly preferably a hydroxymethyl group.
In general formulas (A3) and (A3a), R3 is preferably a C1-C6
hydroxyalkyl group, amino group, hydroxyl group, hydrogen atom
or halogen atom, more preferably a hydroxymethyl group, hydroxyl
group or amino group, and particularly preferably a hydroxyl
group.
R4 is preferably a C1-C6 hydroxyalkyl group, hydrogen
atom, hydroxyl group or halogen atom in general formulas (Al),
(Ale) and (Ala), more preferably a hydroxyl group or halogen
atom, particularly preferably a hydroxyl group or fluorine atom,
and most preferably a hydroxyl group. In general formulas (A2),
(A2a), (A2b) and (A2c), R4 is preferably a C1-C6 hydroxylalkyl
group, hydrogen atom, halogen atom or hydroxyl group, and more
preferably a hydroxyl group. In general formulas (A3) and (A3a),
R4 is preferably a C1-C6 hydroxyalkyl group, amino group,
hydroxyl group, halogen atom or hydrogen atom, more preferably a
hydroxyl group, halogen atom or hydrogen atom, and particularly
preferably a hydroxyl group.

R5 is preferably a hydroxyl group, halogen atom, C1-C6
hydroxyalkyl group, Cl-C6 haloalkyl group or hydrogen atom in
general formulas (Al), (A1c) and (Ala), more preferably a C1-C6
hydroxyalkyl group, particularly preferably a C1-C3 hydroxyaiky]
group, and most preferably a hydroxymethyl group. In general
formulas (A3) and (A3a), R5 is preferably a C1-C6 hydroxyalkyl
group, hydroxyl group, hydrogen atom, halogen atom or amino
group (and said amino group may be substituted with one or two
C1-C6 alkyl groups or C1-C6 hydroxyalkyl groups), more
preferably an amino group (and said amino group may be
substituted with one or two C1-C6 alkyl groups or C1-C6
hydroxyalkyl groups), and particularly preferably an anino group.
R6 is preferably a C1-C6 hydroxyalkyl group, amino group,
hydroxyl group, hydrogen atom or halogen atom in general
formulas (A3) and (A3a), more preferably a C1-C6 hydroxyalkyl
group, particularly preferably a C1-C3 hydroxyalkyl group, and
most preferably a hydroxymethyl group.
R7 is preferably a hydrogen atom, C1-C6 hydroxyalkyl
group or C1-C6 alkyl group, more preferably a hydrogen atom or
methyl group, and particularly preferably a hydrogen atom.
R8 and R9 are preferably C1-C3 hydroxyalkyl groups,
halogen atoms, hydrogen atoms or hydroxyl groups, and more
preferably hydrogen atoms or hydroxyl groups.
R10 is preferably a C1-C6 hydroxyalkyl group, more
preferably a C1-C3 hydroxyalkyl group, and particularly
preferably a hydroxymethyl group.
R11 is preferably a hydroxyl group,
n is preferably 1.
General formula (1) is preferably the following general
formula (IA) or (IB) :
and preferably (Al).
Specific examples of oligosaccharide derivatives having
the aforementioned general formulas (I), (Ia) and (Ib) of the
present invention, their pharmacologically acceptable salts and
their pharmacologically acceptable esters include the compounds
listed to follow. However, the present invention is not limited
to these exemplification compounds.
Furthermore, in the following Tables 1 to 5, "npr"
indicates an n-propyl group, "lPr" an i-propyl group, "aBu" an n-
butyl group, "tBu" a t-butyl group, "iBu" an i-butyl group, "aPn"
an n-pentyl group, and "nHex" an n-hexyl group.
In the above Tables, preferred compounds are 1-1, 1-115,
1-119, 1-155, 1-280, 1-354, 1-547, 1-556, 1-557, 3-1, 5-1, 5-3,
5-9, 5-22 or 5-28, more preferred are (2R,3R,4R)-4-hydroxy-2-
hydroxymethyl-pyrrolidin-3-yl 4-O-(6-deoxy-a-D-glucopyranosyl)-
a-D-glucopyranoside, (2R,3R,4R)-4-hydroxy-2-hydroxymethyl-
pyrrolidin-3-yl 4-O-(6-deoxy-p-D-glucopyranosyl)-a-D-
glucopyranoside, (2R,3R,4R)-4-hydroxy-2-hydroxymethyl-
pyrrolidin-3-yl 4-O-ß-D-glucopyranosyl-a-D-glucopyranoside,
(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-
fluoro-6-deoxy-p-D-glucopyranosyl)-D-glucopyranoside,
(1R,2S,3R,4R,5R)-1-amino-2,3-dihydroxy-5-hydroxymethyl-
cyclopent-4-yl 4-O-(6-deoxy-a-D-glucopyranosyl)-a-D-
glucopyranoside, (2R,3R,4R)-4-hydroxy-2-hydroxymethyl-
pyrrolidin-3-yl 4-O-(6-methoxy-6-decxy-p-D-glucopyranosyl)-D-
glucopyranoside, (2R, 3R, 4R)-4-hydroxy-2-hydroxymethyl-3, 4-
dihydro-2H-pyrrol-3-yl 4-O-(6-deoxy-a-D-glucopyranosyl)-a-D-
glucopyranoside, their pharmacologically acceptable salts and
their pharmacologically acceptable esters.
A compound having the general formula (I) can be
produced using, for example, a known compound for the starting
raw material according to the processes described below.

In the aforementioned formula and following description,
A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and n are the same as
previously defined. However, in the case R1, R2, R3, R4, R5, R6,
R7, R8, R9, R10 or R11 indicates a hydroxyl group or a group
having a hydroxyl group, said hydroxyl group may optionally be
protected.
In the aforementioned steps and following description, X1
to X25, Yal to Ya5 and Ycl to Yc3 are the same or different, and
each represents a hydrogen atom or hydroxyl group (said hydroxyl
group may optionally be protected by a protecting group), Ybl to
Yb5 are the same or different, and each represents a halogen atom,
hydrogen atom or hydroxyl group (said hydroxyl group may
optionally be protected by a protecting group), P1 represents a
protecting group of an amino group such as R6 or a C1-C6
alkoxycarbonyl group (preferably a t-butoxycarbonyl group) or

C7-C16 aralkyloxycarbonyl group (preferably a benzyloxycarbonyl
group), P2 and PJ are the same or different, and each represents
a protecting group of an amino group such as R7 or a C1-C6
alkoxycarbonyl group (preferably a t-butoxycarbonyl group) or a
C7-C16 aralkyloxycarbonyl group (preferably a benzyloxycarbonyl
group), and L1, L2, L3 and L4 represent a hydroxyl group (said
hydroxyl group may optionally be protected by a protecting group
or the hydrogen atom may optionally be substituted by a leaving
group) or a leaving group.
There are no particular limitations on the protecting
group used to protect a hydroxyl group provided the group is
typically used to protect a hydroxyl group, examples of which
include "aliphatic acyl groups" such as alkyl carbonyl groups,
e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-
methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-
dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,
tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-
methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-
dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl,
octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl
and heneicosanoyl groups, carboxylated alkyl carbonyl groups,
e.g. succinoyl, glutaroyl and adipoyl groups, halogeno lower
alkyl carbonyl groups, e.g. chloroacetyl, dichloroacetyl,
trichloroacetyl and trifluoroacetyl groups, lower alkoxy lower
alkyl carbonyl groups, e.g. methoxyacetyl groups, and
unsaturated alkyl carbonyl groups, e.g. (E)-2-methyl-2-butenoyl
groups; "aromatic acyl groups" such as aryl carbonyl groups, e.g.
benzoyl, a-naphthoyl and p-naphthoyl groups, halogenoaryl
carbonyl groups, e.g. 2-bromobenzoyl and 4-chlorobenzoyl groups,
lower alkylated aryl carbonyl groups, e.g. 2,4,6-
trimethylbenzoyl and 4-toluoyl groups, lower alkoxylated aryl
carbonyl groups, e.g. 4-anisoyl groups, carboxylated aryl
carbonyl groups, e.g. 2-carboxybenzoyl, 3-carboxybenzoyl and 4-
carboxybenzoyl groups, nitrated aryl carbonyl groups e.g. 4-
nitrobenzoyl and 2-nitrobenzoyl groups, lower alkoxycarbonylated

aryl carbonyl groups e.g. 2-(methoxycarbonyl) benzoyl groups,
and arylated aryl carbonyl groups, e.g. 4-phenylbenzoyl groups;
"tetrahydropyranyl or tetrahydrothiopyranyl groups" such as
tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-
methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-
methoxytetrahydrothiopyran-4-yl groups; "tetrahydrofurar.yl or
tetrahydrothiofuranyl groups" such as tetrahydrofuran-2-yl and
tetrahydrothiofuran-2-yl groups; "silyl groups" such as tri-
lower alkyl silyl groups, e.g. trimethylsilyl, triethylsilyl,
isopropyl dimethylsilyl, t-butyl dimethylsilyl, methyl
diisopropylsilyl, methyl di-t-butylsilyl and triisopropylsilyl
groups, and tri-lower alkyl silyl groups substituted with 1 to 2
aryl groups, e.g. diphenylmethylsilyl, diphenylbutylsilyl,
diphenylisopropylsilyl and phenyldiisopropylsilyl groups;
"alkoxymethyl groups" such as lower alkoxymethyl groups, e.g.
methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,
propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl
groups, lower alkoxylated lower alkoxymethyl groups, e.g. 2-
methoxyethoxymethyl groups, and halogeno lower alkoxymethyl
groups, e.g. 2,2,2-trichloroethoxymethyl and bis (2-
chloroethoxy)methyl groups; "substituted ethyl groups" such as
lower alkoxylated ethyl groups, e.g. 1-ethoxyethyl and 1-
(isopropoxy)ethyl groups and halogenated ethyl groups, e.g.
2,2,2-trichloroethyl groups; "aralkyl groups" such as lower
alkyl groups substituted with 1 to 3 aryl groups, e.g. ben2yl,
a-naphthylmethyl, ß-naphthylmethyl, diphenylmethyl,
triphenylmethyl, a-naphthyldiphenylmethyl and 9-anthrylmethyl
groups, and lower alkyl groups substituted with 1 to 3 aryl
groups in which an aryl ring is substituted with a lower alkyl,
lower alkoxy, halogen or cyano group e.g. 4-methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl,
4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-
chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl and piperonyl
groups; "alkoxycarbonyl groups" such as lower alkoxycarbonyl
groups, e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl
and isobutoxycarbonyl groups, and lower alkoxycarbonyl groups
substituted with halogen or tri-lower alkylsilyl groups, e.g.
2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl
groups; "alkenyloxy carbonyl groups" such as vinyloxycarbonyl
and allyloxycarbonyl groups; and, "aralkyloxy carbonyl croups"
in which an aryl ring may or may not be substituted with 1 to 2
lower alkoxy or nitro groups, e.g. benzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-
nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.
There are no particular limitations on reagents used to protect
diols provided they are normally used to protect diols, and
preferable examples include aldehyde derivatives such as
benzaldehyde, ketone derivatives such as acetone, and dimethoxy
compounds such as 2,2-dimethoxypropane and dimethoxybenzyl.
The process for producing Compound (I) of the present
invention is comprised of the following three steps.
(1) Step A is a step wherein the left side portion of
Compound (I) in the form of intermediate (iii) is produced.
(2) Step B is a step wherein the right side portion of
Compound (I) in the form of Intermediate (vii) is produced, and
process a, b or c can be selected corresponding to the desired
Compound (I).
(3) Step C is a step wherein Compound (I) of the present
invention is produced by condensing Intermediate (iii) obtained
in Step A and Intermediate (vii) obtained in Step B.
The following provides an explanation of each step.
(Process A)
Raw material compound (i) can be produced by protecting
and deprotecting a hydroxyl group of a known compound in
accordance with known processes. In addition, protection and
deprotection of a hydroxyl group can also be carried out in this
step as necessary.
Protection and deprotection of a hydroxyl group can be
carried in compliance with commonly known processes such as the
process described in "Protective Groups in Organic Synthesis" by
Green-Watts (Wiley-Interscience, USA).

In addition, deprotection can also be carried out in the
manner described below.
In the case of using a silyl group for the hydroxyl
group deprotecting group, it can normally be removed by treating
either with a compound that forms a fluorine anion such as
tetrabutyl ammonium fluoride, hydrofluoric acid, hydrofluoric
acid-pyridine or potassium fluoride, or an organic acid, such as
acetic acid, methanesulfonic acid, paratoluene sulfonic acid,
trifluoroacetic acid or trifluoromethanesulfonic acid, or an
inorganic acid such as hydrochloric acid.
Furthermore, in the case of removal by a fluorine anion,
the reaction may be promoted by adding an organic acid such as
formic acid, acetic acid or propionic acid.
There are no particular limitations on the solvent used
provided it dissolves the starting substance to a certain extent
without inhibiting the reaction, and preferable examples include
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and diethylene glycol dimethyl ether;
nitriles such as acetonitrile and isobutyronitrile; water;
organic acids such as acetic acid and mixed solvents thereof.
There are no particular limitations on the reaction
temperature or reaction time, and the reaction is normally
carried out at 0°C to 100°C (and preferably 10°C to 30°C) for 1
to 24 hours.
In the case the hydroxyl group protecting group is an
aralkyl group or aralkyloxy carbonyl group, normally a process
in which it is removed by contacting with a reducing agent in a
solvent (and preferably contact reduction at normal temperature
in the presence of a catalyst) or a process in which it is
removed using an oxidizing agent, is used preferably.
There are no particular limitations on the solvent used
during removal by catalytic reduction provided it is not
involved in the present reaction, and preferable examples
include alcohols such as methanol, ethanol and isopropanol;
ethers such as diethyl ether, tetrahydrofuran and dioxane;
aromatic hydrocarbons such as toluene, benzene and xylene;

aliphatic hydrocarbons such as hexane and cyclohexane; esters
such as ethyl acetate and propyl acetate; amides such as
formarnide, diinethylf ormamide, dimethylacet.amide, N-methyl-2-
pyrrolidone and hexamethylphosphorotriamide; fatty acids such as
formic acid and acetic acid; water and mixed solvents thereof,
while more preferable examples include alcohols, fatty acids,
mixed solvents of alcohols and ethers, mixed solvents of
alcohols and water and mixed solvents of fatty acids and water.
There are no particular limitations on the catalyst used
provided it is normally used in catalytic reduction reactions,
and preferable examples of catalysts used include palladium
carbon, palladium black, Rainey nickel, platinum oxide, platinum
black, rhodium-aluminium oxide, triphenylphosphine-rhociium
chloride and palladium-barium sulfate.
There are no particular limitations on the pressure, and
the reaction is normally carried out at a pressure of 1 to 10
atmospheres.
Although reaction temperature and reaction time vary
depending on the types of starting substance, solvent, catalyst
and so forth, they are normally 0°C to 100°C (and preferably 20°C
to 70°C) and 5 minutes to 48 hours (and preferably 1 hour to 24
hours).
There are no particular limitations on the solvent used
during removal by oxidation provided it is not involved in the
present reaction, and water-containing organic solvents are
preferable.
Preferable examples of such organic solvents include
ketones such as acetone, halogenated hydrocarbons such as
methylene chloride, chloroform and carbon tetrachloride,
nitriles such as acetonitrile, ethers such as diethyl ether,
tetrahydrofuran and dioxane, amides such as dimethylformamide,
dimethylacetamide and hexamethylphosphorotriamide, and
sulfoxides such as dimethyl sulfoxide.
There are no particular limitations on the oxidizing
agent used provided it is a compound normally used for oxidation,
and potassium persulfate, sodium persulfate, cerium ammonium

nitrate (CAN) or 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ)
is used preferably.
Although reaction temperature and reaction time vary
depending on the types of starting substance, solvent, catalyst
and so forth, they are normally 0°C to 150°C and 10 minutes to 24
hours.
In addition, the protecting group can also be removed by
allowing an alkali metal such as lithium metal or sodium metal
to act at -78°C to -20°C in liquid ammonia or an alcohol such as
methanol or ethanol.
Moreover, it can also be removed by using an alkyl silyl
halide such as aluminium chloride-sodium iodide or
trimethylsilyl iodide in a solvent.
There are no particular limitations on the solvent used
provided it is not involved in the present reaction, and
nitriles such as acetonitrile, halogenated hydrocarbons such as
methylene chloride and chloroform, or mixed solvents thereof are
used preferably.
Although reaction temperature and reaction time vary
depending on the types of the starting substance, solvent and so
forth, the reaction temperature and reaction time are normally
0°C to 50°C and 5 minutes to 3 days.
Furthermore, in the case the reaction substrate has a
sulfur atom, aluminium chloride-sodium iodide is used preferably.
In the case the hydroxyl group protecting group is an
aliphatic acyl group, aromatic acyl group or alkoxycarbonyl
group, it is removed by treating with base in a solvent.
There are no particular limitations on the base used
provided it does not have an effect on the other parts of the
compound, and examples of bases that are used preferably include
metal alkoxides such as sodium methoxide; alkaline metal
carbonates such as sodium carbonate, potassium carbonate and
lithium carbonate; alkaline metal hydroxides such as sodiun
hydroxide, potassium hydroxide, lithium hydroxide and barium
hydroxide; and ammonias such as aqueous ammonia and concentrated

ammonia-methanol.
There are no particular limitations on the solvent used
provided it is normally used in hydrolysis reactions, preferable
examples of which include water; organic solvents such as
alcohols e.g. methanol, ethanol and n-propanol, and ethers e.g.
tetrahydrofuran and dioxane; and mixed solvents of water and the
aforementioned organic solvents.
Although there are no particular limitations on the
reaction temperature and reaction time, and they vary according
to the starting substance, solvent, base used and so forth, the
reaction is normally carried out at 0°C to 150°C for 1 hour to 10
hours to suppress side reactions.
In the case the hydroxyl group protecting group is an
alkoxy methyl group, tetrahydropyranyl group,
tetrahydrothiopyranyl group, tetrahydrofuranyl group,
tetrahydrothiofuranyl group or substituted ethyl group, the
protecting group is normally removed by treating with acid in a
solvent.
There are no particular limitations on the acid used
provided it is normally used as a Bronsted acid or Lewis acid,
and although preferable examples include Bronsted acids such as
hydrogen chloride; inorganic acids e.g. hydrochloric acid,
sulfuric acid and nitric acid; and, organic acids e.g. acetic
acid, trifluoroacetic acid, methane sulfonic acid and p-toluene
sulfonic acid; as well as Lewis acids such as boron trifluoride,
a strongly acidic cation exchange resin such as Dowex 50W can
also be used.
There are no particular limitations on the solvent used
provided it dissolves the starting substance to a certain extent
without inhibiting the reaction, and preferable examples include
aliphatic hydrocarbons such as hexane, heptane, ligroin and
petroleum ether; aromatic hydrocarbons such as benzene, toluene
and xylene; halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene
and dichlorobenzene; esters such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; ethers such

as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; alcohols
such as methanol, ethanol, n-propanoi, isopropanol, n-butanol,
isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol,
glycerin, octanol, cyclohexanol and methyl cellusorb; ketones
such as acetone, methyl ethyl ketone, methyl isobutyl ketone,
isophorone and cyclohexanone; water and mixed solvents thereof,
while more preferable examples include halogenated hydrocarbons,
esters and ethers.
Although reaction temperature and reaction time vary
depending on the types, concentrations and so forth of the
starting substance, solvent and acid used, they are normally -
10°C to 100°C (and preferably -5°C to 50°C) and 5 minutes to 48
hours (and preferably 30 minutes to 10 hours).
In the case the hydroxyl group protecting group is an
alkenyloxy carbonyl group, removal is normally achieved by
treating with base under similar conditions as the removal
reaction in the case the hydroxyl group protecting group is an
aforementioned aliphatic acyl group, aromatic acyl group or
alkoxycarbonyl group.
Furthermore, in the case of an allyloxycarbonyl group, a
process in which it is removed using palladium in particular as
well as triphenylphosphine or bis(methyldiphenylphosphine) (1,5-
cyclooctadiene) iridium (I). hexafluorophosphate is simple and
can be carried out with few side reactions.
In the case the hydroxyl group protecting group is a
formyl group, it is removed by treating with base in a solvent.
There are no particular limitations on the base used
provided it does not have an effect on other parts of the
compounds, and an alkaline metal hydrogen carbonate such as
potassium hydrogen carbonate, is used preferably.
There are no particular limitations on the solvent used
provided is normally used in hydrolysis reactions, and
preferable examples include water; organic solvents such as
alcohols e.g. methanol, ethanol and n-propanol, or ethers e.g.
tetrahydrofuran and dioxane; and, mixed solvents of water and
the aforementioned organic solvents.
Although reaction temperature and reaction time vary
depending on the types of the starting substance, solvent and
base used and there are no particular limitations on them, the
reaction is normally carried out at 0°C to 150°C for 1 hour to 10
hours to suppress side reactions.
In the case the hydroxyl group protecting group is a
halogen-substituted acetamide group such as a trifluoroacetamide
group, it is removed by treating with base in a solvent.
There are no particular limitations on the base used
provided it does not have an effect on other parts of the
compound, and a basic resin such as Dowex 1x4 (OH") is used
preferably.
There are no particular limitations on the solvent used
provided it is normally used in hydrolysis reactions, and
preferable examples include water; and, alcohols such as
methanol, ethanol and n-propanol, with water being more
preferable.
A deprotecting group of an allyl group at the anomer
position is preferably a palladium catalyst such as palladium
chloride or an iridium catalyst.
There are no particular limitations on the solvent used
provided it is normally used in catalytic reactions, and
preferable examples include alcohol-based solvents such as
methanol, ether-based solvents such as tetrahydrofuran, and
water, with methanol and tetrahydrofuran being more preferable.
(Step A1)
This step is a step in which compound (ii) is produced,
and is achieved by introducing a leaving group to a hydroxyl
group at a desired location as necessary, followed by carrying
out a nucleophilic substitution reaction with a reagent
corresponding to the R1 and R2 groups introduced.
In the case the leaving group is a halogen atom, there
are no particular limitations on the solvent used provided it
dissolves the starting substance without inhibiting the reaction,

with preferable examples including ethers such as diethyl ether,
tetrahydrofuran and dioxane, amides such as dimethylformamide,
dimethylacetamide and hexamethylphosphotriamide, halogenated
hydrocarbons such as dichloromethane, chloroform and 1,2-
dichloroethane, nitriles such as acetonitrile and propionitrile,
esters such as ethyl formate and ethyl acetate and mixed
solvents thereof, more preferable examples being halogenated
hydrocarbons and ethers, and particularly preferable examples
being dichloromethane and tetrahydrofuran.
There are no particular limitations on the halogenation
agent used provided it is normally used in reactions between
hydroxyl groups and halogen atoms, examples of which include
dialkylaminosulfatrihalides such as diethylaminosulfa-
trifluoride (DAST), thionyl halides such as thionyl chloride,
thionyl bromide and thionyl iodide, sulfuryl halides such as
sulfuryl chloride, sulfuryl bromide and sulfuryl iodide,
phosphorus trihalides such as phosphorus trichloride, phosphorus
tribromide and phosphorus triiodide, phosphorus pentahalides
such as phosphorus pentachloride, phosphorus pentabromide and
phosphorus pentaiodide, and phosphorus oxyhalides such as
phosphorus oxychloride, phosphorus oxybromide and phosphorus
oxyiodide.
The reaction temperature is 0ºC to the heating
temperature (boiling point of the solvent used), and preferably
room temperature to the heating temperature (boiling point of
the solvent used).
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
In the case the leaving group is a sulfonyl group, there
are no particular limitations on the sulfonylation agent used
provided it is normally used in hydroxyl group sulfonylation
reactions, examples of which include alkane sulfonyl halides
such as ethane sulfonyl chloride, aryl sulfonyl halides such as
p-toluene sulfonyl chloride, and sulfonic acid anhydrides such
as methane sulfonic acid anhydride, benzene sulfonic acid
anhydride and trifluoromethane sulfonic acid anhydride.

Preferable examples include methanesulfonyl chloride, p-
toluenesulfonyl chloride and trifluoromethanesulfonic acid
anhydride.
There are no particular limitations on the solvent used
provided it dissolves the starting substance to a certain extent
without inhibiting the reaction, examples of which include
aliphatic hydrocarbons such as hexane, heptane, ligroin and
petroleum ether; aromatic hydrocarbons such as benzene, toluene
and xylene; halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene
and dichlorobenzene; esters such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; and, ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and diethylene glycol dimethyl ether.
Preferable examples include halogenated hydrocarbons, esters and
ethers, with tetrahydrofuran being more preferable.
There are no particular limitations on the base used
provided it is used as a base in normal reactions, preferable
examples of which include organic bases such as triethylamine,
tripropylamine, tributylamine, diisopropylethylamine,
dicyclohexylamine, N-methylpiperidine, pyridine, 4-
pyrrolidinopyridine, picoline, 4-(N,N-dimethylarnino) pyridine,
2,6-di (t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazbicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), with triethylamine and
pyridine being more preferable.
The reaction temperature is 0°C to the heating
temperature (boiling point of the solvent used), and preferably
0°C to room temperature.
The reaction time is 10 minutes to 24 hours, and
preferably 10 minutes to 1 hour.
Examples of the reagent used for the reagent
corresponding to groups R1 and FT include commercially available
reducing agents and halogenation agents.
Preferable examples of the reducing agent used include

alkaline metal borohydrides such as sodium borohydride and
lithium borohydride, hydrogenated aluminium compounds such as
lithium aluminium hydride and aluminium triethoxide lithium
hydride, and hydride reagents such as sodium tellurium hydride.
There are no particular limitations on the solvent used
provided it dissolves the starting substance without inhibiting
the reaction, and preferable examples include alcohols such as
methanol and ethanol, ethers such as ether and tetrahydrofuran,
and mixed solvents thereof.
There are no particular limitations on the halogenation
agent used provided it is normally used in halogenation
reactions, and preferable examples include
dialkylaminosulfatrihalides such as diethylaminosulfa-
trifluoride (DAST), thionyl halides such as thionyl chloride,
thionyl bromide and thionyl iodide, sulfuryl halides such as
sulfuryl chloride, sulfuryl bromide and sulfuryl iodide,
phosphorus trihalides such as phosphorus trichloride, phosphorus
tribromide and phosphorus triiodide, phosphorus pentahalides
such as phosphorus pentachloride, phosphorus pentabromice and
phosphorous pentaiodide, and phosphorous oxyhalides such as
phosphorous oxychloride, phosphorous oxybromide and phosphorous
oxyiodide, with diethylaminosulfatrifluoride being more
preferable.
There are no particular limitations on the solvent used
provided it dissolves the starting substance to a certain extent
without inhibiting the reaction, and examples include ethers
such as ether and tetrahydrofuran, with tetrahydrofuran being
preferable.
The reaction temperature is 0°C to the heating
temperature (boiling point of the solvent used), and preferably
room temperature to the heating temperature (boiling point of
the solvent used).
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
(Step A2)
This step is a step in which intermediate (iii) is

produced, and is achieved by introducing a leaving group at
position 1 of compound (ii) following the process of step Al.
(Step B)
(Process Ba)
Raw material compound (iv) can be produced following the
process described in Tetrahedron, Vol. 26, 1985, p. 1469.
Moreover, raw material compound (v) can be produced by
protecting and deprotecting a hydroxyl group of a known compound
according to a known process. In addition, hydroxyl group
protection and deprotection can also be carried out as necessary
in the present step in the same manner as Process A. Moreover,
in the case of having a halogen atom for a substituent, a
halogen atom can be introduced according to the halogenation
reaction of step A1.
(Step Bal)
This step is a step in which a bicyclic compound (v) is
produced, and is achieved by reducing the azide group of
compound (iv) followed by heating.
There are no particular limitations on the solvent used
provided it dissolves the starting substance, and examples
include water-soluble ethers such as tetrahydrofuran and dioxane,
water, and mixed solvents thereof, with a mixed solvent of water
and tetrahydrofuran being preferable.
Examples of azide group reducing agents include
phosphines and aqueous ammonia. Although examples include
trialkyl phosphines such as trimethyl phosphine and triethyl
phosphine and aqueous ammonia, and triaryl phosphines such as
triphenyl phosphine and aqueous ammonia, a triaryl phosph:.ne
such as triphenyl phosphine and aqueous ammonia are preferable.
In addition, a catalyst can also be used for the
reducing agent. There are no particular limitations on the
catalyst used provided it is normally used in catalytic
reduction reactions, and examples include palladium carbonate,
palladium black, palladium carbon, palladium hydroxide, Rainey
nickel, platinum oxide, platinum black, rhodium-aluminium

hydroxide, triphenyl phosphine-rhodium chloride and palladium-
barium sulfate, with palladium carbon and palladium hydroxide
being preferable.
In the case of using a catalyst for the reducing agent,
there are no particular limitations on the solvent used provided
it dissolves the starting substance without inhibiting the
reaction, and preferable examples include alcohols such as
methanol and ethanol, ethers such as tetrahydrofuran and dioxane,
fatty acids such as acetic acid, and esters such as ethyl
acetate, with methanol being more preferable.
The reaction temperature is 0ºC to 50°C, and preferably
0°C to room temperature.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
(Step Ba2)
This step is a step in which compound (vi) having a
protected amino group is produced, and is achieved by protecting
the amino group of compound (v) with a suitable protecting group.
There are no particular limitations on the solvent used
provided it dissolves the starting substance without inhibiting
the reaction, and preferable examples include ethers such as
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol,
alcohols such as methanol and ethanol, ketones such as acetone
and methyl ethyl ketone, amides such as N, N-dimethylformamide
and N,N-dimethylacetamide, and sulfoxides such as dimethyl
sulfoxide.
There are no particular limitations on the reagent used
provided it is normally used in reactions in which a protecting
group is introduced to a free amino group, and preferable
examples include di-t-butyl dicarbonate, benzyloxycarbonyl
chloride and p-nitrobenzyloxycarbonyl chloride, with di-t-butyl
carbonate being more preferable.
There are no particular limitations on the base used
provided it is used as a base in normal reactions, and
preferable examples include alkaline earth carbonates, alkaline
earth hydrogen carbonates and organic bases, with alkaline metal

hydrogen carbonates being more preferable.
The reaction temperature is 0°C to 50°C, and preferably
0°C to room temperature.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 10 hours.
(Step Ba3)
This step is a step in which pyrrolidine compound (viia)
is produced, and is achieved by opening one of the rings of
bicyclic compound (vi), protecting the hydroxyl group as
necessary, and deprotecting the hydroxyl group at the site that
glycosylates with intermediate (iii).
There are no particular limitations on the reducing
agent used provided it is normally used in reduction reactions,
and examples include alkali metal borohydrides such as sodium
borohydride and lithium borohydride, hydrogenated aluminium
compounds such as lithium aluminium hydride and aluminium
triethoxide lithium hydride, and hydride reagents such as sodium
tellurium hydride, with sodium borohydride being preferable.
There are no particular limitations on the solvent used
provided it dissolves the starting substance to a certain extent
without inhibiting the reaction, and examples include alcohols
such as methanol and ethanol, ethers such as dioxane, ether and
tetrahydrofuran, water and mixed solvents thereof, with methanol
or tetrahydrofuran being preferable.
The reaction temperature is 0°C to the boiling point of
the solvent used, and preferably 50°C to the boiling poirt of
the solvent used.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
(Process Bb)
Raw material compound (viii) can be produced according
to the process described in Carbohydrate Research, Vol. 169,
1987, p. 23. Moreover, raw material compound (viii) can be
produced by protecting and deprotecting a hydroxyl group of a
known compound according to a known process. In addition, the
hydroxyl group can also be protected and deprotected as
necessary in the present step in the same manner as Process A.
Moreover, in the case of having a halogen atom for a substituent,
a halogen atom can be introduced according to the halogenation
reaction of step A1.
(Step Bb1)
The present step is a step in which compound (ix) is
produced, and is achieved by introducing a leaving group at the
6-position of raw material compound (viii) under the same
conditions as step A1. In addition, the leaving group can be
further converted to a different leaving group as necessary.
(Step Bb2)
The present step is a step in which compound (x) having
an olefin terminal is produced, and is achieved by heating
compound (ix) in a solvent in the presence of a catalyst.
There are no particular limitations on the solvent used
provided it dissolves the starting substance without inhibiting
the reaction, and preferable examples include alcohols such as
methanol, ethanol and isopropanol, water, and mixed solvents
thereof, with a mixed solvent of water and isopropanol being
more preferable.
There are no particular limitations on the catalyst used
provided it is normally used in reactions in which a double bond
is reduced, and examples include zinc, palladium carbon,
platinum, Rainey nickel, alkali metal borohydrides such as
sodium borohydride and lithium borohydride, hydrogenated
aluminium compounds such as such as lithium aluminium hydride
and aluminium triethoxide lithium hydride, and hydride reagents
such as sodium tellurium hydride, with zinc being preferable.
The reaction temperature is 0°C to the boiling point of
the solvent used, and preferably 50°C to the boiling point of
the solvent used.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
(Step Bb3)
The present step is a step in which compound (xi) having
a hydroxylamino group is produced, and is achieved by treating
compound (x) with a hydroxylamine hydrochloride.
There are no particular limitations on the solvent used
provided it dissolves the starting substance without inhibiting
the reaction, and preferable examples include mixed solvents of
alcohols such as methanol, ethanol and isopropanol, and organic
bases such as pyridine, with a mixed solvent of ethanol and
pyridine being particularly preferable.
The reaction temperature is 0°C to the boiling point of
the solvent used, and preferably 0°C to 60°C.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
(Step Bb4)
The present step is a step in which bicyclic compound
(xii) is produced, and is achieved by cyclizing compound (xi) by
heating in a solvent.
There are no particular limitations on the solvent used
provided it is inactive, and preferable examples include
aromatic hydrocarbons such as benzene, toluene and xylene, with
toluene being particularly preferable.
The reaction temperature is 0°C to the boiling point of
the solvent used, and preferably 50°C to the boiling point of
the solvent used.
The reaction time is 10 minutes to 24 hours, and

preferably 1 hour to 5 hours.
(Step Bb5)
The present step is a step in which intermediate
compound (viib) is produced, and is achieved by deprotecting the
hydroxyl group at the site that glycosylates with intermediate
(iii), and protecting the secondary amine of compound (xii)
under similar conditions to step Al.
(Process Bc)
Raw material compound (xiii) can be produced according
to the process described in the Chemical Pharmaceutical Bulletin,
Vol. 39, 1991, p. 2807. Moreover, raw material compound (xiii)
can be produced by protecting and deprotecting the hydroxyl
group of a known compound according to a known process. In
addition, protection and deprotection of the hydroxyl group can
also be carried out as necessary in the present step in the same
manner as Process A. Moreover, in the case of having a halogen
atom for a substituent, a halogen atom can be introduced
according to the halogenation reaction of Step Al.
(Step Bel)
The present step is a step in which intermediate
compound (viic) is produced, and is achieved by deprotecting the
hydroxyl group protecting group of raw material compound (xiii).
(Process C)
(Step CI)
The present step is a step in which desired compound (I)
is produced, and is achieved by carrying out a glycosylation
reaction with intermediate compounds (iii) and (vii), and
deprotecting the hydroxyl group and amino group as necessary in
accordance with established methods.
Preferable examples of the deprotecting group at the
anomer position of compound (iii) include fluorine, bromine,
chlorine, trichloroimidate, diphenyl phosphate, diethyl
phosphite, thiomethyl and phenylthio groups.
There are no particular limitations on the solvent used
provided it is inactive, and preferable examples include

halogenated hydrocarbons such as methylene chloride and
chloroform, ethers such as ether and tetrahydrofuran, and
aromatic hydrocarbons such as benzene, toluene and xylene, with
more preferable examples including halogenated hydrocarbons and
ethers, and particularly preferable examples including methylene
chloride and ether.
There are no particular limitations on the catalyst used
provided it is normally used in glycosylation reactions, and
preferable examples include trimethylsilyl
trifluoromethanesulfonic acid, trifluoromethanesulfonic acid,
boron trifluoride ether complex, toluenesulfonic acid, silver
trifluoromethanesulfonic acid and tetrabutyl ammonium iodide.
The reaction temperature is 0ºC to the boiling point of
the solvent used, and preferably room temperature.
The reaction time is 10 minutes to 24 hours, and
preferably 1 hour to 5 hours.
In addition, compound (I) can also be produced by
deprotecting the hydroxyl group after the glycosylation reaction
with intermediate compounds (iii) and. (viic), and then
additionally subjecting to basic conditions.
In addition, in the case n = 2, compound (I) can oe
produced using a trisaccharide derivative for the raw material
compound in a process similar to processes A and C.
In addition, in the case of having a basic group, the
desired compound (I) can be converted to an acid addition salt,
preferably a hydrochloride, in accordance with ordinary rrethods.
Following completion of the reactions of each of the
aforementioned steps, the desired compound is collected from the
reaction mixture in accordance with ordinary methods. For
example, the desired compound is obtained by suitably
neutralizing the reaction mixture, or in the case of the
presence of insoluble matter, removing the insoluble matter by
filtration, followed by adding water and an immiscible organic
solvent such as ethyl acetate, washing with water and so forth,
and then separating the organic phase containing the desired

compound, drying with anhydrous magnesium sulfate, for example,
and finally distilling off the solvent.
The resulting desired compound can be separated and
purified as necessary by suitably combining ordinary methods
such as recystallization, reprecipitation or other methods
normally routinely used for the separation and purification of
organic compounds, examples of which include adsorption column
chromatography, distribution column chromatography and ether
methods using a synthetic adsorbent, methods using ion exchange
chromatography, and forward and/or reverse phase chromatography
using silica gel or alkylated silica gel, followed by eluting
with a suitable eluent.
Oligosaccharide derivatives of the present invention
having the aforementioned general formulas (I), (Ia) and (Ib),
their pharmacologically acceptable salts and their
pharmacologically acceptable esters are administered in various
forms. There are no particular limitations on the
administration form, and each type of preparation form is
determined according to the formulation, the age, gender and
other conditions of the patient, the degree of the disease and
so forth. Examples of formulations in the case of oral
administration include tablets, pills, powders, granules, syrups,
liquids, suspensions, emulsions, granules and capsules.
Administration is performed intrarectally in the case of
suppositories. Administration is preferably performed orally.
Each of these formulations can be formulated in
accordance with ordinary methods using known adjuvants that can
normally be used in known pharmaceutical fields, examples of
which include vehicles, binders, disintegration agents,
lubricants, dissolving agents, correctives and coating agents.
When forming into the form of tablets, a wide range of
carriers conventionally known in this field can be used for the
carrier, examples of which include vehicles such as lactose,
sucrose, sodium chloride, glucose, urea, starch, calcium
carbonate, kaolin, crystalline cellulose and silicic acid,
binders such as water, ethanol, propanol, simple syrup, liquid

glucose, liquid starch, liquid gelatin, carboxymethyl cellulose,
shellac, methyl cellulose, potassium phosphate and polyvinyl
pyrrolidone, disintegration agents such as dry starch, sodium
alginate, powdered agar, powdered laminarin, sodium bicarbonate,
calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
sodium lauryl sulfate, monoglyceride stearate, starch and
lactose, disintegration inhibitors such as sucrose, stearine,
cocoa butter and hydrogenated oils, absorption promoters such as
quaternary ammonium salts and sodium lauryl sulfate,
moisturizers such as glycerin and starch, adsorbents such as
starch, lactose, kaolin, bentonite and colloidal silicic acid,
and lubricants such as refined talc, stearates, powdered boric
acid and polyethylene glycol. Moreover, tablets can be tablets
provided with an ordinary coating as necessary, examples of
which include sugar-coated tablets, gelatin-sealed tablets,
enteric coated tablets and film-coated tablets, tablets provided
with two layers of coatings or multilayer tablets.
When forming into the form of pills, a wide range of
carriers conventionally known in this field can be used for the
carrier, examples of which include vehicles such as glucose,
lactose, starch, cocoa butter, hardened vegetable oils, kaolin
and talc, binders such as powdered gum Arabic, powdered
tragacanth, gelatin and ethanol, and disintegration agents such
as laminaran agar.
When forming into the form of suppositories, a wide
range of carriers conventionally known in this field can be used
for the carrier, examples of which include polyethylene glycol,
cocoa butter, higher alcohols, esters of higher alcohols,
gelatin and semi-synthetic glycerides.
Moreover, other pharmaceuticals such as colorants,
preservatives, fragrances, flavorings and sweeteners may also be
included as necessary.
Although there are no particular limitations on the
amount of active ingredient compound contained in the
aforementioned pharmaceutical preparations, and it can be
suitably selected over a wide range, it is suitable to normally

contain an amount of 1 to 70% by weight, and preferably 1 to 30%
by weight, in the total composition.
Although varying according to symptoms, age, body weight,
administration method, drug form and so forth, the normal daily
adult dosage has a lower limit of 0.001 mg (preferably 0.01 mg
and more preferably 0.1 mg), and an upper limit of 2,000 mg
(preferably 200 mg and more preferably 100 mg), and this dosage
can be administered in a single administration or in multiple
administrations.
(Best mode for carrying out the invention)
Next, the present invention is explained in more detail
by way of Examples, Reference examples, Test examples and
Preparation examples, but the present invention is not limited
thereto.
D-Maltose monohydrate (36.0 g, 100 mmol) was dissolved
in pyridine (200 mL) and acetic anhydride (100 mL) and 4-
dimethylaminopyridine (0.6 g, 4.90 mol) were added thereto,
followed by stirring of the mixture at room temperature for 12
hours. The reaction mixture was ice-cooled and ice (30 g) was
added thereto, followed by stirring of the mixture for 30
minutes. The reaction mixture was extracted with ethyl acetate

(500 mL) and the organic layer was washed with diluted
hydrochloric acid (IN, 200 mL), saturated aqueous sodium
hydrogencarbonate (100 mL) and saturated brine (100 mL). After
it was dried with anhydrous sodium sulfate, the solvent was
distilled off under reduced pressure. The residue was dissolved
in methylene chloride (700 mL) and allyl alcohol (34 mL, 500
mol) and trimethylsilyl trifluoromethanesulfonate (18.1 mL, 100
mmol) were added thereto, followed by stirring of the mixture at
room temperature for 2 hours. The reaction mixture was added to
saturated aqueous sodium hydrogencarbonate (1 L) and after it
was extracted with methylene chloride (500 mL), the organic
layer was washed with saturated brine (300 mL) and dried with
anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (ethyl acetaterhexane,
2:3, V/V) to obtain the desired title compound (30.0 g, yield
31%) as pale yellow amorphous matter.
1H NMR (400 MHz, CDC13) : d 1.99 (3H, s), 2.00 (3H, s), 2,31 (6H,
s), 2.03 (3H, s), 2.09 (3H, s), 2.14 (3H, s), 3.65-3.69 (1H, m),
3.93-4.14 (4H, m), 4.20-4.26 (2H, m), 4.30 (1H, dd, J=13.2, 5.1
Hz), 4.47 (1H, dd, J=12.4, 2.9 Hz), 4.57 (1H, d, J=8.1 Hz),
4.83-4.87 (2H, m) , 5.04 (1H, t, J=9.5 Hz), 5.18-5.28 (3H,. m) ,
5.35 (1H, t, J=9.5 Hz), 5.41 (1H, d, J=3.7 Hz), 5.79-5.88 (1H,
m) ;
MS (FAB) m/z: 677 (M+H)+, 699 (M+Na)+.
(Ib) Allyl 4-O-(4, 6-O-benzylidene-a-D-glucopyranosyl)-D-
glucopyranoside
The compound (17.0 g, 25.1 mmol) synthesized in Example
1 (Ia) was dissolved in methanol (250 mL) and sodium methoxide
(2 mL, 9.8 mol) was added thereto under ice-cooling, followed by
stirring of the mixture at room temperature for 1 hour. After
Dowex 50w x 8 was added to the mixture until the reaction
mixture became neutral and was filtered, the solvent was
distilled off under reduced pressure. The residue was dissolved
in N,N-dimethylformamide (200 mL) and benzaldehyde
dimethylacetal (4.65 mL, 31.0 mmol) and p-toluenesulfonic acid
monohydrate (226 mg, 1.19 mmol) were added thereto, followed by
stirring of the mixture at 20 mmHg and 50°C for 5 hours. After
triethylamine (1 mL) was added to the reaction mixture, the
solvent was distilled off under reduced pressure. The residue
was purified using silica gel flash column chromatography (ethyl
acetate:hexane:methanol, 5:5:1, V/V/V) to obtain the desired
title compound (10.0 g, yield 85%) as pale yellow amorphous
matter.
1H NMR (400 MHz, CD3OD) : d 3.16 (1H, t, J=9.5 Hz), 3.28-3.32 (1H,
m) , 3.35 (1H, t, J=9.5 Hz), 3.42 (1H, t, J=9.5 Hz), 3.47 (1H, dd,
J=9.5, 3.6 Hz), 3.54 (1H, t, J=9.5 Hz), 3.61-3.66 (2H, m), 3.71
(1H, t, J=9.5 Hz), 3.74-3.81 (2H, m) , 4.02-4.07 (1H, m) , 4.12
(1H, dd, J=10.3, 5.1 Hz), 4.22-4.29 (2H, m), 5.06 (1H, d, J=10.2
Hz), 5.10 (1H, d, J=4.4 Hz), 5-23 (1H, d, J=17.5 Hz), 5.81-5.91
(1H, m) , 7.22-7.24 (3H, m), 7.38-7.40 (2H, m);
MS (FAB) m/z: 471 (M+H)+, 493 (M+Na)+.
(1c) Allyl 4-O-(4,6-O-benzylidene-2,3-di-O-benzyl-a-D-
glucopyranosyl)-2,3,6-tri-O-benzyl-D-glucopyranoside
The compound (10.0 g, 21.3 mmol) synthesized in Example
1 (Ib) was dissolved in N,N-dimethylformamide (300 mL) and
sodium hydride (9.28 g, 213 mmol) was added thereto under ice-
cooling, followed by stirring of the mixture under ice-cooling
for 30 minutes. After benzyl bromide (25 mL, 213 mmol) was
added thereto and the mixture was stirred at room temperature
for 3 hours, water (100 mL) was added to the reaction mixture
and the mixture was extracted with ethyl acetate (500 mL). The
extract was washed with water (100 mL) and saturated brine (100
mL) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 9:1, V/V) to obtain the
desired title compound (18.5 g, yield 94%) as a pale yellow
solid.
1H NMR (400 MHz, CDCl3) : d 3.49-3.68 (4H, m) , 3.76-3.90 (3H, m) ,
3.93-4.03 (2H, m), 4.09-4.19 (3H, m) , 4.42-4.78 (10H, m), 4.84-
5.07 (3H, m), 5.23 (1H, t, J=9.8 Hz), 5.35 (1H, dd, J=17.5, 8.8
Hz), 5.54 (1H, d, J=3.9 Hz), 5.74 (1H, dd, J=24.5, 3.9 Hz),
5.92-6.02 (1H, m) , 7.17-7.51 (5H, m) ;
MS (FAB) m/z: 922 (M+H)+, 944 (M+Na)".
(1d) Allyl 2,3, 6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-a-D-
glucopyranosyl)-D-glucopyranoside
The compound (30.0 g, 32.5 mmol) synthesized in Example
1 (1c) was dissolved in diethyl ether (300 mL) and methylene
chloride (150 mL) and lithium aluminium hydride (1.85 g, 48.8
mmol) and aluminium chloride (III) (6.93 g, 52.0 mmol) were
added thereto, followed by heating of the mixture under reflux
for 2 hours. After the reacti.on mixture was diluted with
diethyl ether (500 mL), IN aqueous sodium hydroxide solution
(5.6 mL) was added to the reaction mixture, followed by stirring
of the mixture for 1 hour. After it was extracted with ethyl
acetate, the organic layer was washed with 10% aqueous
hydrochloric acid solution (100 mL), saturated aqueous sodium
hydrogencarbonate solution (150 mL) and saturated brine (100 mL)
and dried with anhydrous sodium sulfate,- followed by distilling
off of the solvent under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate, 4:1-3:1-2:1, V/V) to obtain the desired
title compound (21.1 g, yield 71%) as a pale yellow solid.
1H NMR (400 MHz, CDCl3) : d 3.40-3.71 (6H, m), 3.74-3.85 (2H, m),
3.90 (2H, m), 3.99-4.07 (1H, m), 4.10-4.20 (3H, m), 4.42-4.70
(7H, m), 4.76-5.08 (6H, m), 5.23 (1H, t, J=10.7 Hz), 5.35 (1H,
dd, J=18.6, 8.8 Hz), 5.64 (1H, dd, J=13.7, 3.9 Hz), 5.93-6.02
(1H, m), 7.18-7.34 (30H, m);
MS (FAB) m/z: 946 (M+Na)+, 924 (M+H)+.
(1e) Allyl 2,3, 6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy-
a-D-glucopyranosyl)-D-glucopyranoside
The compound (15.2 g, 16.5 rrmol) synthesized in Example
1 (Id) was dissolved in pyridine (300 mL) and p-toluenesulfonyl
chloride (12.5 g, 66.0 mmol) and 4-dimethylaminopyridir.e (2.01 g,
16.4 mmol) were added thereto, followed by stirring of the
mixture at room temperature for 13 hours. After the solvent was
distilled off under reduced pressure, the residue was poured
into 10% aqueous hydrochloric acid solution (50 mL) and ethyl
acetate (200 mL). The organic layer was washed with 10% aqueous
hydrochloric acid solution (50 mL), saturated aqueous sodium
hydrogencarbonate solution (20 mL) and saturated brine (20 mL)
and dried with anhydrous sodium sulfate, followed by distilling
off of the solvent under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate, 5:1-3:1, V/V) to obtain tosylate (13.5 g,
yield 76%) as a yellow oil. The tosylate (13.5 g, 12.5 mol) was
dissolved in diethyl ether (300 mL) and lithium aluminium
hydride (950 mg, 25 mol) was added to the reaction mixture,
followed by heating of the mixture under reflux for 1 hour. IN
aqueous NaOH solution (1.0 mL) and water (1.0 mL) were added
thereto and the mixture was stirred for 30 minutes. After
celite filtration, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 6:1, V/V) to obtain
the desired title compound (10.2 g, yield 90%) as a colorless
solid.
1H NMR (400 MHz, CDCl3) : d 1.08 (3H, d, J=5.8 Hz), 3.01 (1H, t,
J=9.5 Hz), 3.35 (1H, dd, J=9.5, 3.7 Hz), 3.44-3.50 (2H, m) ,
3.66-3.72 (5H, m), 3.78 (1H, t, J=9.5 Hz), 3.93 (1H, t, J=9.5
Hz), 4.07 (1H, dd, J=12.8, 5.9 Hz), 4.35 (1H, dd, J=13.1, 5.1
Hz), 4.39-4.57 (7H, m), 4.69 (2H, d, J=11.7 Hz), 4.77-4.88 (3H,
m), 5.13 (1H, d, J=10.0 Hz), 5.26 (1H, d, J=16.9 Hz), 5.47 (1H,
d, J=3.7 Hz), 5.84-5.92 (1H, m) , 7.09-7.26 (30H, m);
MS (FAB) m/z: 907 (M+H)+.
(1f) 4-O-(6-Deoxy-2,3,4-tri-o-benzyl-a-D-glucopyranosyl)-2,3, 6-
tri-O-benzyl-D-glucopyranoside
The compound (10.2 g, 11.2 mmol) synthesized in example
1 (1e) was dissolved in methanol (40 mL) and tetrahydrofuran
(100 mL) and palladium chloride (II) (400 mg, 2.24 mmol) was
added thereto, followed by stirring of the mixture at room
temperature for 14 hours. After the reaction mixture was
subjected to celite filtration, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 5:1-4:1,
V/V) to obtain the desired title compound (8.17 g, yield 84%) as
pale yellow amorphous matter.
1H NMR (400 MHz, CDCl3): d 1.14 (3H, d, J=6.6 Hz), 3.09 (1H, t,
J=9.5 Hz), 3.41-3.47 (2H, m), 3.62-3.81 (4H, m), 3.96-4.C5 (2H,
m) , 4.01-4.14 (1H, m), 4.49-4.68 (6H, m) , 4.74-4.78 (2H, m) ,
4.84-4.96 (4H, m), 5.22 (1H, d, J=3.6 Hz), 5.51 (1H, d, J=3.7
Hz), 7.19-7.34 (30H, m) ;
MS (FAB) m/z: 889 (M+Na)+.
(1g) Methyl 3-O-benzoyl-N-benzoyloxycarbonyl-2, 5-dideoxy-2, 5-
imino-a-D-lyxofuranoside
Methyl N-benzoyloxycarbonyl-2,5-dideoxy-2,5-imino-a-D-
lyxofuranoside (Tetrahedron, 1986, vol. 42, p.5685-5692) (13.9 g,
49.8 mmol) was dissolved in methylene chloride (200 mL) and
pyridine (20 mL, 249.0 mmol) and benzoyl chloride (11.6 mL, 99.6
mmol) were added thereto, followed by stirring of the mixture at
room temperature for 2 hours. After IN hydrochloric acid (200
mL) was added to the reaction mixture at 0°C and the mixture was
extracted with methylene chloride (100 mL), the organic layer
was washed with saturated aqueous sodium hydrogencarbonate (200
mL) and saturated brine (200 mL) and dried with anhydrous sodium
sulfate, followed by distilling off of the solvent under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to
obtain the desired title compound (15.82 g, yield 83%) as a

colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.42-3.46 (4H, 3s), 3.60 (1H, dd,
3=32.2, 10.8 Hz), 4.54 (1H, d, J=34.2 Hz), 4.64 (1H, br, d,
J=7.9 Hz), 4.85 (1H, d, J=36.2 Hz), 5.13-5.22 (2H, m), 3.47 (1H,
s), 7.29-7.35 (5H, m), 7.41-7.45 (2H, m), 7.59 (1H, t, J=7.8 Hz)
7.95 (2H, t, J=7.8 Hz);
MS (FAB) m/z: 406 (M+Na)+, 384 (M+H)+,
(1h) Benzyl {2R,3R, 4R)-3-benzoyloxy-4-hydroxy~2-
(hydroxymethyl)pyrrolidine-1-carboxylate
The compound (15.8 g, 41.3 mmol) synthesized in Example
1 (1g) was dissolved in trifluoroacetre acid:water (4:1, 160 mL)
and the mixture was stirred at room temperature for 15 minutes.
After water (200 mL) was added to the reaction mixture at 0°C
and the mixture was extracted with methylene chloride (300 mL),
the organic layer was washed with saturated aqueous sodium
hydrogencarbonate (200 mL) and saturated brine (200 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was
dissolved in ethanol (150 mL) and the compound obtained by
dissolving sodium borohydride (0.78 g, 20.7 mmol) in water (15
mL) was added thereto, followed by stirring of the mixture at
0°C for 20 minutes. After saturated aqueous ammonium chloride
(20 mL) was added to the reaction mixture at 0°C, ethanol was
distilled off under reduced pressure. After water (100 mL) was
added thereto and the mixture was extracted with ethyl acetate
(100 mL), the organic layer was washed with saturated brine (100
mL) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the
desired title compound (14.2 g, yield 89%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d 3.68 (1H, d, J=11.7 Hz), 3.86 (1H, dd,
J=11.7, 4.4 Hz), 3.93-4.04 (2H, m) , 4.25-4.32 (2H, m) , 5.09-5.32
(3H, m), 7.32-7.46 (7H, m), 7.59 (1H, t, J=7.4 Hz), 7.99 (2H, d,

J=8.8 Hz);
MS (FAB) m/z: 372 (M+H)+,
(1i) Benzyl (2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-
hydroxypyrrolidine-1-carboxylate
The compound (4.26 g, 11.5 mrnol) synthesized in Example
1 (1h) was dissolved in dichloromethane:cyclohexane (1:2, 180
mL) and benzyl trichloroacetoimidate (10.6 mL, 57.5 mrnol) and
trifluoromethanesulfonic acid (0.15 mL, 1.7 mrnol) were added
thereto, followed by stirring of the mixture at room temperature
for 3 hours. After saturated aqueous sodium hydrogencarbonate
(10 mL) was added to the reaction mixture at 0°C and the mixture
was diluted with ethyl acetate (200 mL), it was washed with
water (300 mL) and saturated brine (300 mL) and dried with
anhydrous sodium sulfate, followed by distilling of the solvent
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 10:1-5:1,
V/V) to obtain 7.85 g of a pale yellow oil. Thus obtained 7.85
g of pale yellow oil was dissolved in methanol (100 mL) and 1M
aqueous potassium carbonate solution (4 mL) was added thereto,
followed by stirring of the mixture at room temperature for 5
hours. After methanol was distilled off under reduced pressure,
water (100 mL) was added thereto and the mixture was extracted
with ethyl acetate (100 mL) and then, the organic layer was
washed with saturated brine (100 mL). After it was dried with
anhydrous sodium sulfate, the solvent was distilled off under
reduced pressure. The residue was purified using silica gel
flash column chromatography hexane:ethyl acetate, 2:1, V/V) to
obtain the desired title compound (4.06 g, yield 64%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.35 (1H, dc, J=11.7, 3.7 Hz), 3.51-
3.72 (1H, m), 3.66-3.89 (4H, m), 4.37-4.52 (5H, m) , 4.98-5.07
(2H, m), 7.09-7.26 (15H, m);
MS (FAB) m/z: 448 (M+H)+.
(1j) Benzyl (2R,3R, 4R)-4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-

tri-O-benzyl~4-O-(2,3,4-tri-O-benzyl-6-deoxy-a-D-
glucopyranosyl)-a-D-glucopyranosyl]oxy}pyrrolidine-1-carboxylate
Benzyl(2R,3R,4R)-4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-
benzyl-4-O- (2, 3, 4-tri-O-benzyl-6-deoxy-a-D-glucopyranosyl) -ß-D-
glucopyranosyl]oxy}pyrrolidine-1-carboxylate
The compound (13.5 g, 15.57 mmol) synthesized in Example
1 (If) was dissolved in methylene chloride (250 mL) and
trichloroacetonitrile (10 mL, 134.3 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 40
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (13.0 g, 82%) as a yellow oil. The
compound (5.48 g, 12.2 mmol) synthesized in Example 1 (li) was
dissolved in diethyl ether (4 00 mL) and imidate (13.0 g, 13.0
mmol) was added thereto. A solution of trimethylsilyl
trifluoromethanesulfonate (222 µL, 1.22 mmol) in diethyl ether
(2 mL) was added thereto and the mixture was stirred at room
temperature for 45 minutes. After triethylamine (1 mL) was
added to the reaction mixture, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 4:1, V/V)
to obtain the desired title compound a isomer (11.6 g, 56%) as a
pale yellow oil and further the ß isomer (3.7 g, 18%) as a pale
yellow oil.
a isomer: 1H NMR (400 MHz, CDCl3) : d 1.20 (3H, d, J=5.9 Hz),
3.10-3.22 (2H, m), 3.30-3.38 (2H, m), 3.42 (1H, t, J=8.8 Hz),
3.50-3.70 (5H, m), 3.76-3.87 (5H, m), 4.01-4.10 (1H, m), 4.26-
4.51 (9H, m), 4.61 (1H, d, J=11.0 Hz), 4.69-4.88 (8H, m), 4.96-
5.16 (3H, m), 7.19-7.34 (43H, m), 7.43 (2H, d, J=7.3 Hz);
MS (FAB) m/z: 1318 (M+Na)+.
(3 isomer: 1H NMR (400 MHz, CDCl3) : d 1.17 (3H, d, J=6.5 Hz), 3.10
(1H, t, J=9.1 Hz), 3.41-3.48 (3H, m), 3.54-3.63 (3H, m), 3.69-
3.78 (4H, m), 3.81-3.92 (2H, m), 4.02 (1H, s, J=8.79 Hz), 4.25

(1H, d, J=4.39 Hz), 4.40-4.63 (13H,m), 4.73-4.79 (3H,m), 4.86-
4.95 (4H,m), 5.09-5.19 (lH,m), 5.53 (1H, d, J=3.67 Hz), 7.18-
7.30 (45H,m);
MS (FAB) m/z: 1296 (M+H)+,
(1k) (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-
(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (5.60 g, 4.32 mmol) synthesized in Example
1 (1j) was dissolved in methanol (350 mL) and hydrochloric acid
(4.8 mL) and 20% palladium hydroxide-carbon (2.8 g) were added
thereto, followed by stirring of the mixture at room temperature
under a hydrogen atmosphere for 4 hours. After celite
filtration, 18% ammonia water (6 mL) was added thereto and the
solvent was distilled off under reduced pressure. The residue
was purified by ion exchange resin (Dowex 50w x 8) column (water
- 5% ammonia water). Further, it was purified using silica gel
flash column chromatography (ethyl acetate:methanol:water, 2:2:1,
V/V) to obtain the desired title compound (1.20 g, 63%) as a
colorless solid.
[a]D20 +145.7 (c 0.36, H20) ;
1H NMR (400 MHz, D20) : d 1.28 (3H, d, J=6.6 Hz), 2.93 (1H, dd,
J=12.4, 3.0 Hz), 3.12-3.20 (3H, m), 3.57-3.65 (4H, m), 3.71-3.87
(6H, m), 3.92-3.98 (2H, m), 4.32-4.34 (1H, m), 5.13 (1H, d,
J=3.6 Hz), 5.34 (1H, d, J=3.0 Hz);
13CNMR (125.70 MHz, D,0) : 5 16.72, 51.62, 60.64,61.62, 64.84,
68.79, 70.94, 71.07, 72.13, 72.83, 73.48, 74.96, 75.64, 77.13,
84.01, 97.44, 99,88;
MS (FAB) m/z: 442 (M+H)+, 464 (M+Na)+.

(2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-
deoxy-p-D-glucopyranosyl)-a-D-glucopyranoside (Exemplification
compound No. 1-1)
(2a) Allyl 4-O-P-D-glucopyranosyl-D-glucopyranoside
a-D-cellobiose octacetate (48.59 g, 71.6 mmol) was
dissolved in methylene chloride (600 mL), and allyl alchol (29
mL, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16
mL, 86.0 mmol) were added thereto under ice-cooling, followed by
stirring of the mixture at room temperature for 1.5 hours.
Water (200 mL) was added to the reaction mixture and the mixture
was extracted with methylene chloride (200 mL). After the
extract was washed with saturated brine (100 mL) and dried with
anhydrous sodium sulfate, the solvent was distilled off under
reduced pressure. The residue was dissolved in methanol (300
mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto
under ice-cooling, followed by stirring of the mixture at room
temperature for 2 hours. After Dowex 50w x 8 was added thereto
until the reaction mixture became neutral and it was filtered,
the solvent was distilled off under reduced pressure. The
residue was purified using silica gel flash column
chromatography (ethyl acetate :methanol:water, 8:2:1, V/V) to
obtain the desired title compound (24.8 g, yield 91%) as pale
yellow amorphous matter.
2H NMR (400 MHz, CDCl3) : d 3.20-3.40 (9H, m), 3.40-3.65 (4H, m),
4.00-4.40 (3H, m), 5.18 (1H, d, J= 11.7 Hz), 5.35 (1H, d, J=17.6
Hz), 5.95 (1H, ddd, J=17.6, 11.7, 5.9 Hz) ;
MS (FAB) m/z: 383 (M+H)+,
(2b) Allyl 2,3, 6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-4,6-O-
benzylidene-p-D-glucopyranosyl)-D-glucopyranoside
The compound (24.8 g, 64.9 mmol) synthesized in Example
2 (2a) was dissolved in N,N-dimethylformamide (300 mL) and
benzaldehyde dimethylacetal (13 mL, 84.4 mmol) and p-

toluenesulfonic acid monohydrate (617 mg, 3.24 mmol) were added
thereto, followed by stirring of the mixture at 20mmH g and 50°C
for 5 hours. After triethylamine (900 |iL) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure. Water (100 mL) was added to the residue and the
mixture was extracted with ethyl acetate (200 mL x 5). After
the extract was washed with saturated brine (100 mL) and dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure. The residue was dissolved in N,N-
dimethylformamide (400 mL) and sodium hydride (20 g, 0.45 mmol)
was added thereto under ice-cooling, followed by stirring of the
mixture at the same temperature for 10 minutes. Benzyl bromide
(54 mL, 0.45 mmol) was added thereto and the mixture was stirred
at room temperature for 2.5 hours. Water (100 mL) was added to
the reaction mixture and the mixture was extracted with ethyl
acetate (500 mL). After the extract was washed with water (100
mL) and saturated brine (50 mL) and dried with anhydrous sodium
sulfate, the solvent was distilled off under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 10:1-7:1, V/V) to obtain
the desired title compound (46.6 g, yeild 78%) as a pale yellow
solid.
1H NMR (400 MHz, CDCl3) : d 3.10-5.00 (26H, m), 5.18 (1H, d,
J=11.7 Hz), 5.35 (1H, d, J=17. 6 Hz), 5.60 (1H, s), 5.95 (1H, ddd,
J=17.6, 11.7, 5.9 Hz), 7.20-7.60 (30H, m) ;
MS (FAB) m/z: 922 (M+H)+,
(2c) Allyl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-p~D-
glucopyranosyl)-D-glucopyranoside
The compound (63.0 g, 68.4 mmol) synthesized in Example
2 (2b) was dissolved in diethyl ether (800 mL) and methylene
chloride (400 mL) and lithium aluminium hydride (10.4 g, 0.27
mol) and aluminium chloride (III) (36.4 g, 0.27 mol) were added
thereto, followed by heating of the mixture under reflux for 1
hour. After the reaction mixture was diluted with diethyl ether

(500 mL). IN aqueous sodium hydroxide solution (21.0 mL) was
added to the reaction mixture and the mixture was stirred for 1
hour. After extraction with ethyl acetate, the organic layer
was washed with 10% aqueous hydrochloric acid solution (500 mL),
saturated aqueous sodium hydrogencarbonate solution (500 mL) and
saturated brine (300 mL) and dried with anhydrous sodium sulfate,
followed by distilling off of the solvent reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1-3:1-2:1, V/V) to
obtain the desired title compound (37.8 g, yield 60%) as a pale
yellow solid.
1H NMR (400 MHz, CDCl3) : d 3.10-5.00 (29H, m), 5.18 (1H, d,
J=10.8 Hz), 5.35 (1H, d, J=22.5 Hz), 5.95 (1H, ddd, J=22.5, 10.8,
5.9 Hz), 7.20-7.60 (30H, m);
MS (FAB) m/z: 924 (M+H)+.
(2d) Allyl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-
toluenesulfonyl-ß-D-glucopyranosyl)-D-glucopyranoside
The compound (37.8 g, 41.0 mmol) synthesized in Example
2 (2c) was dissolved in pyridine (300 mL) and p-toluenesulfonyl
chloride (15.6 g, 82.0 mmol) and 4-dimethylaminopyridine (1.0 g,
0.82 mmol) were added thereto, followed by stirring of the
mixture at room temperature for 13 hours. After the solvent was
distilled off under reduced pressure, the residue was poured to
10% aqueous hydrochloric acid solution (50 mL) and ethyl acetate
(200 mL) and the organic layer was washed with 10% aqueous
hydrochloric acid solution (50 mL), saturated aqueous sodium
hydrogencarbonate solution (20 mL) and saturated brine (20 mL)
and dried with anhydrous sodium sulfate, followed by distilling
off of the solvent under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate, 5:1-3:1, V/V) -;o obtain the desired title
compound (32.6 g, yield 74%) as a yellow oil.
1H NMR (400 MHz, CDCl3) : d 2.35 (3H, s), 3.10-5.00 (28H, m), 5.18
(1H, d, J=10.8 Hz), 5.35 (1H, d, J=22.5 Hz), 5.95 (1H, ddd,
J=22.5, 10.8, 5.9 Hz), 7.10-7.65 (34H, m);
MS (FAB) m/z: 1078 (M+H)+.
(2e) Allyl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-deoxy~
ß-D-glucopyranosyl)-D-glucopyranoside
The compound (32.6 g, 30.3 mol) synthesized in Example 2
(2d) was dissolved in diethyl ether (600 mL) and lithium
aluminium hydride (1.72 g, 45.4 mol) was added thereto, followed
by heating of the mixture under reflux for 1 hour. After the
reaction mixture was diluted with diethyl ether (200 mL), IN
aqueous NaOH solution (2.0 mL) and water (2.0 mL) were added
thereto, followed by stirring of the mixture for 30 minutes.
After celite filtration, the solvent was distilled off under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 7:1-6:1, V/V)
to obtain the desired title compound (15.0 g, yield 55%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 1.20 (3H, d, J=6.0 Hz), 3.10-5.00 (26H,
m), 5.20 (1H, d, J=10.8 Hz), 5.35 (1H, d, J=22.5 Hz), 5.95 (1H,
ddd, J=22.5, 10.8, 5.9 Hz), 7.10-7.65 (30H, m);
MS (FAB) m/z: 908 (M+H)*.
(2f) 2, 3, 6-tri-O-Benzyl-4-O- (2, 3, 4-tri-O-benzyl-6-deoxy-|3-D-
glucopyranosyl)-D-glucopyranoside
The compound (15.0 g, 16.5 mmol) synthesized in Example
2 (2e) was dissolved in methanol (150 mL) and tetrahydrofuran
(30 mL) and palladium chloride (II) (586 mg, 3.31 mmol) was
added thereto, followed by stirring of the mixture at room
temperature for 14 hours. After the reaction mixture was
subjected to celite filtration, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 5:1-4:1-
3:1, V/V) to obtain the desired title compound (12.0 g, yield
84%) as pale yellow amorphous matter.
1H NMR (400 MHz, CDCl3) : d 1.19-1.22 (3H, m), 2.96-3.66 (8H, m),
3.77-4.02 (3H, m), 4.34-4.37 (2H, m), 4.54-4.89 (10H, m), 5.00-
5.19 (2H, m), 7.23-7.45 (30H, m);
MS (FAB) m/z: 868 (M+H)+.
(2g) Benzyl (2R, 3R, 4R) -4-benzyloxy-2-benzyloxymethyl-3-{[2, 3, 6-
tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl~6-deoxy-ß-D-
glucopyranosyl)-a-D-glucopyranosyl]oxy}pyrrolidine-1-carboxylate
The compound (18.8 g, 21.8 mmol) synthesized in Example
2(2f) was dissolved in methylene chloride (400 mL) and
trichloroacetonitrile (10.9 mL, 109 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (0.33 mL, 2.18 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 15 minutes. After the solvent was distilled off under
reduced pressure, the residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1, 1%
triethylamine, V/V) to obtain imidate (19.8 g, 90%) of colorless
oil. The compound (9.5 g, 21.2 mmol) synthesized in Example 1
(li) was dissolved in diethyl ether (480 mL) and trimethylsilyl
trifluoromethanesulfonate (0.38 mL, 2.12 mmol) was dissolved in
diethyl ether (20 mL) under a nitrogen atmosphere and the
mixture was added thereto. A solution of imidate in diethyl
ether (100 mL) was added to the reaction mixture and the mixture
was stirred at room temperature for 3 hours. After
triethylamine (0.35 mL, 2.54 mmol) was added to the reaction
mixture and the solvent was distilled off under reduced pressure,
the mixture was diluted with ethyl acetate (200 mL) and washed
with saturated aqueous sodium hydrogencarbonate (200 mL) and
saturated brine (200 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 3:1, V/V)
to obtain the desired title compound (13.3 g, 47%) and its ß
isomer (4.5 g, 16%) as a colorless oil.
JH NMR (400 MHz, CDCl3) : d 1.20 (3H, d, J=5.9 Hz), 3.10-3.22 (2H,
m), 3.30-3.38 (2H, m), 3.42 (1H, t, J=8.8 Hz), 3.50-3.70 (5H, m),

3.76-3.87 (5H, m), 4.01-4.10 (1H, m), 4.26-4.51 (9H, m), 4.61
(1H, d, J=11.0 Hz), 4.69-4.88 (8H, m), 4.96-5.16 (3H, m), 7.19-
7.34 (43H, m), 7.43 (2H, d, J=7.3 Hz);
MS (FAB) m/z: 1318 (M+Na)+.
(2h) (2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-
(6-deoxy-ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (13.3 g, 10.3 mmol) synthesized in Example
2 (2 g) was dissolved in 1% hydrochloric acid methanol solution
(250 mL) and 20% palladium hydroxide-carbon (4 g) was added
thereto, followed by stirring of the mixture under a hydrogen
atmosphere for 2 hours. After the catalyst was removed by
celite filtration, 28% ammonia water (5 mL) was added thereto
and the mixture was stirred for 10 minutes. After the solvent
was distilled off under reduced pressure and the residue was
passed through ion exchange resin (Dowex 50w x 8) column with
water (200 mL), 1% ammonia water (200 mL) was flowed through.
The ammonia water containing the desired compound was
concentrated under reduced pressure and was purified using
silica gel flash column chromatography (ethyl
acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired
title compound (1.6 g, 35%) as a colorless solid.
[a]D20 +88.8 (c 0.52, H20) ;
1H NMR (500 MHz, D20) : d 1.22 (3H, d, J=6.8 Hz), 2.88 (1H, m),
3.07-3.16 (3H, m), 3.21 (1H, dd, J=7.8, 7.8 Hz), 3.36 (1H, dd,
J=9.8, 9.8 Hz), 3.42 (1H, m), 3.49-3.55 (2H, m), 3.61-3.72 (5H,
m), 3.75-3.83 (2H, m), 3.89 (1H, m), 4.24(1H, m), 4.38 (1H, d,
J=7.9 Hz), 5.02 (1H, d, J=3.9 Hz);
13C NMR (D20) : d 16.9, 51.7, 60.0, 61.8, 64.7, 71.0, 71.1, 71.6,
72.2, 73.6, 75.0, 75.5, 75.9, 79.2, 84.3, 97.4, 102.7;
MS (FAB) m/z: 442 (M+H)+.

(2R,3R,4R)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-ß-D-
glucopyranosyl-a-D-glucopyranoside (Exemplification compound No.

(3a) Allyl 2, 3, 6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyi-p-D-
glucopyranosyl)-D-glucopyranoside
a-D-Cellobiose octaacetate (4.15 g, 6.12 mmol) was
dissolved in methylene chloride (50 mL) and allyl alcohol (2.09
mL, 30.6 mmol) and trimethylsilyl trifluoromethanesulfonate
(1.11 mL, 6.12 mmol) were added thereto under ice-cooling,
followed by stirring of the mixture at room temperature for 4
hours. After water (20 mL) was added to the reaction mixture
and the mixture was extracted with methylene chloride (50 mL),
the organic layer was washed with saturated brine (20 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was
dissolved in methanol (40 mL) and sodium methoxide (2.36 mL,
12.2 mmol) was added thereto under ice-cooling, followed by
stirring of the mixture at room temperature for 1 hour. After
Dowex 50w x 8 was added until the reaction mixture became
neutral and the mixture was filtered, the solvent was distilled
off under reduced pressure. The residue was dissolved in N,N-
dimethylformamide (60 mL) and sodium hydride (2.67 g, 61.2 mmol)
was added thereto under ice-cooling, followed by stirring of the
mixture at the same temperature for 10 minutes. Benzyl bromide
(8.01 mL, 67.3 mmol) was added thereto and the mixture was
stirred at room temperature for 2 hours. After water (40 mL)
was added thereto and the mixture was extracted with ethyl
acetate (200 mL), the organic layer was washed with water (40
mL) and saturated brine (20 mL) and dried with anhydrous sodium
sulfate, followed by distilling off of the solvent under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane: ethyl acetate, 20:1-10:1-8:1.. V/V)
to obtain the desired title compound (4.85 g, yield 78%) as a
pale yellow solid.
1H NMR (400 MHz, CDCl3) : d 3.29-3.71 (10H, m), 3.80-4.15 (3H, m),
4.36-4.61 (8H, m), 4.67-4.89 (8H, m), 5.04-5.11 (1H, m), 5.17-
5.22 (1H, m), 5.29-5.34 (1H, m), 5.91-5.98 (1H, m), 7.07-7.41
(35H, m);
MS (FAB) m/z: 1014 (M+H)+.
(3b) 2, 3, 6-tri-O-Benzyl-4-O- (2, 3, 4, 6-tetra-O-benzyl-(3-D-
glucopyranosyl)-D-glucopyranoside
The compound (4.85 g, 4.79 mmol) synthesized in Example
3 (3a) was dissolved in dimethylsulfoxide (40 mL) and potassium
t-butoxide (2.15 g, 19.2 mmol) was added thereto, followed by
stirring of the mixture at 110°C for 1 hour. After water (30 mL)
was added to the reaction mixture and. the mixture was extracted
with ethyl acetate (150 mL), the organic layer was washed with
saturated brine (20 mL) and dried with anhydrous sodium sulfate,
followed by distilling off of the solvent under reduced pressure.
The residue was dissolved in 1,4-dioxane (36 mL) and 16% aqueous
sulfuric acid solution (3 mL) was added thereto, followed by
stirring of the mixture at 100°C for 1 hour. After water (30 mL)
was added to the reaction mixture and the mixture was extracted
with ethyl acetate (150 mL), the organic layer was washed with
saturated brine (20 mL) and dried with anhydrous sodium sulfate,
followed by distilling off of the solvent under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1 3:1, V/V) to obtain
the desired title compound (3.15 g, yield 68%) as a browr. oil.
1H NMR (400 MHz, CDCl3) : d 2.96-3.95 (9H, m), 4.30-4.38 (3H, m),
4.45-4.81 (7H, m), 4.98-5.10 (1H, m), 7.09-7.32 (35H, m);
MS (FAB) m/z: 974 (M+H)+.
(3c) (2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4,6-
tetra-O-benzyl-p-D-glucopyranosyl)-a-D-glucopyranoside

The compound (537 mg, 0.55 mmol) synthesized in Example
3 (3b) was dissolved in methylene chloride (15 mL) and
trichloroacetonitrile (277 µL, 2.76 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 40
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (611 mg, 99%) as a yellow oil. The
compound (223 mg, 0.50 mmol) synthesized in Example 1 (1i) was
dissolved in diethyl ether (10 mL) and trimethylsilyl
trifluoromethanesulfonate (9 µL, 0.05 mmol) was added thereto.
A solution of imidate (611 mg, 0.55 mmol) in diethyl ether (4
mL) was added dropwise thereto and the mixture was stirred at
room temperature for 4 5 minutes. After triethylamine (4 drops)
was added to the reaction mixture, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 2:3, V/V)
to obtain the desired title compound (395 mg, 57%) as a pale
yellow oil.
1H NMR (400 MHz, CDCl3) : d 3.24-3.36 (17H, m), 4.00-4.10 (2H, m),
4.25-4.54 (11H, m), 4.66-4.87 (8H, m), 4.95-5.12 (3H, m), 7.12-
7.39 (50H, m);
MS (FAB) m/z: 1402 (M+H)+.
(3d) (2R, 3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
ß-D-glucopyranosyl-a-D-glucopyranoside
The compound (611 mg, 0.55 mmol) synthesized in Example
3 (3c) was dissolved in methanol (8 mL) and ethyl acetate (2 mL)
and hydrochloric acid-methanol solution (2 mL) and 20% palladium
hydroxide-carbon (400 mg) were added thereto, followed by
stirring of the mixture at room temperature under a hydrogen
atmosphere for 4 hours. After the celite filtration, the
solvent was distilled off under reduced pressure and methanol (2
mL) and 28% ammonia water (300 µl) were added thereto, followed

by stirring of the mixture at room temperature for 10 minutes.
After the solvent was distilled off under reduced pressure, the
residue was purified by ion exchange resin (Dowex 50w x 8)
column (water - 1.4% ammonia water). Further, it was purified
using silica gel flash column chromatography (ethyl
acetate:methanol:water, 1:1:1, V/V) to obtain the desired title
compound (54 mg, 42%) as colorless amorphous matter.
[a]D20 +91.9 (c 0.38, D20);
1H NMR (400 MHz, D20) : d 2.90 (1H, dd, J=12.5, 2.2 Hz), 3.11 (1H,
dd, J=12.5, 5.1 Hz), 3.16-3.22 (2H, m), 3.28-3.43 (3H, m), 3.49-
3.82 (10H, m), 3.88-3.91 (1H, m), 4.23-4.27 (1H, m), 4.40 (1H, d,
J=8.1 Hz), 5.01 (1H, d, J=4.4 Hz);
MS (FAB) m/z: 458 (M+H)+.
(4a) Allyl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-
6-deoxy-p-D-glucopyranosyl) -a-D-glucopyranoside
The compound (6.43 g, 6.97 mmol) synthesized in Example
2 (2c) was dissolved in 1,2-dimethoxyethane (130 mL) and
diethylaminosulfur trifluoride (2 mL, 20.50 mmol) was added
thereto, followed by stirring of the mixture at 60°C for 1 hour.
Methanol (10 mL) was added to the reaction mixture under ice-
cooling and the mixture was stirred for 30 minutes. After ethyl
acetate (50 mL) was added thereto and the organic layer was
washed with saturated aqueous sodium hydrogencarbonate solution
(50 mL) and saturated brine (50 mL) and dried with anhydrous
sodium sulfate, the solvent was distilled off under reduced

pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 6:1, V/V) to obtain
the desired title compound (5.06 g, yield 78%) as a yellow solid.
1H NMR (400 MHz, CDCl3) : d 3.00-5.20 (28H, m), 5.25 (1H, d, J=8.0
Hz), 5.40 (1H, d, J=16.0 Hz), 6.00 (1H, m), 7.20-7.60 (30H, m);
MS (FAB) m/z: 926 (M+H)+.
(4b) Allyl 2,3, 6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-fluoro-
6-deoxy-p-D-glucopyranosyl)-D-glucopyranoside
The compound (5.06 g, 5.47 mmol) synthesized in Example
4 (4a) was dissolved in methanol (75 mL) and tetrahydrofuran (15
mL) and palladium chloride (II) (190 mg, 1.09 mmol) was added
thereto, followed by stirring of the mixture at room temperature
for 14 hours. After the reaction mixture was subjected to
celite filtration, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 4:1-3:1-2:1, V/V)
to obtain the desired title compound (3.07 g, yield 63%) as pale
yellow amorphous matter.
1H NMR (400 MHz, CDCl3) : d 3.10-5.20 (27H, m), 7.20-7.60 (30H,
m);
MS (FAB) m/z: 886 (M+H)+,
(4c) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
(benzyloxymethyl)pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-
tri-O-benzyl-6-fluoro-6-deoxy-p-D-glucopyranosyl)-a-D-
glucopyranoside
The compound (646.0 mg, 0.73 mmol) synthesized in
Example 4 (4b) was dissolved in methylene chloride (12 mL) and
trichloroacetonitrile (0.38 mL, 3.66 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (1 drop) were added thereto,
followed by stirring of the mixture at room temperature for 30
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane: ethyl acetate, 4:1, 1% triethylamine,

V/V) to obtain imidate (740.2 mg, 98.5%) of yellow oil. The
compound (326.7 mg, 0.73 mmol) synthesized in Example 1 (li) was
dissolved in diethyl ether (13 mL) and trimethylsilyl
trifluoromethanesulfonate (6.6 µL, 0.037 mmol) was dissolved in
diethyl ether (2 mL) under a nitrogen atmosphere and the mixture
was added thereto. A solution of imidate (740.2 mg) in diethyl
ether (5 mL) was added to the reaction mixture and the mixture
was stirred at room temperature for 2 hours. After
triethylamine (5.0 µL, 0.036 mmol) was added to the reaction
mixture and the solvent was distilled off under reduced pressure,
the residue was diluted with ethyl acetate (20 mL) and washed
with saturated aqueous sodium hydrogencarbonate (20 mL) and
saturated brine (20 mL). After the organic layer was dried with
anhydrous sodium sulfate, the solvent was distilled off under
reduced pressure and the residue containing a, ß-mixture was
purified using silica gel flash column chromatography
(hexanerethyl acetate, 6:1, V/V) to isolate the desired title
compound a form (126.0 mg, 13%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.00-5.20 (39H, m), 7.00-7.60 (45H,
m);
MS (FAB) m/z: 1315 (M+H)+.
(4d) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
(6-fluoro-6-deoxy -ß-D-glucopyranosyl)-oc-D-glucopyranoside
The compound (126.0 mg, 0.096 mmol) synthesized in
Example 4 (4c) was dissolved in methanol (10 mL) containing 1%
aqueous hydrochloric acid solution and 20% palladium hydroxide-
carbon (100 mg) was added thereto, followed by stirring of the
mixture under a hydrogen atmosphere for 2 hours. After the
solvent was removed by celite filtration, 28% ammonia water (0.5
mL) was added thereto, followed by stirring of the mixture for
10 minutes. After the solvent was distilled off under reduced
pressure and the aqueous solution (100 mL) was subjected to ion
exchange resin (Dowex 50w x 8), it was eluted with 1% ammonia
water (100 mL). The ammonia water containing the desired

compound was concentrated under reduced pressure and the residue
was purified using silica gel flash column chromatography (ethyl
acetate:methanol:water, 5:2:1-1:1:1, v/V) to obtain the desired
title compound (23.1 mg, 52%) as colorless amorphous matter.
[a]D20 +49.6 (c 0.30, H20);
1H NMR (400 MHz, D20) : d 3.00-3.07 (1H, m), 3.20-3.27 (2H, m),
3.30-3.80 (21H, m), 3.95 (1H, s), 4.29 (1H, brs), 4.43 (1H, d,
J=8.0 Hz), 4.50-4.80 (2H, m), 5.00 (1H, d, J=4.0 Hz);
MS (FAB) m/z: 460 (M+H)+.

The compound (7.76 g, 20.30 mmol) synthesized in Example
2 (2a) was dissolved in N,N-dimethylformamide (160 mL) and t-
butyldimethylsilyl chloride (7.65 mL, 50.75 mmol) and imidazole
(4.15 g, 60.90 mmol) were added thereto, followed by stirring of
the mixture at room temperature for 1 hour. After water (50 mL)
was added to the reaction mixture and the mixture was extracted
with ethyl acetate (100 mL), it was washed with a saturated
brine (50 mL) and dried with anhydrous sodium sulfate, followed
by distilling off of the solvent under reduced pressure. The
residue was dissolved in N,N-dimethylformamide (120 mL) and
sodium hydride (4.0 g, 91.67 mmol) was added thereto under ice-
cooling, followed by stirring of the mixture at the same
temperature for 10 minutes. Benzyl bromide (11 mL, 92.48 mmol)

was added thereto and the mixture was stirred at room
temperature for 3 hours. After water (50 mL) was added to the
reaction mixture and the mixture was extracted with ethyl
acetate (150 mL), the organic layer was washed with water (50
mL) and saturated brine (50 mL) and dried with anhydrous sodium
sulfate, followed by distilling off of the solvent under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 12:1, V/V) to
obtain the desired title compound (3.67 g, yield 89%) as a
colorless oil.
1H NMR (400 MHz, CDCl3) : d 0.00-0.20 (12H, m), 0.90-1.0C (18H, m),
3.00-5.20 (26H, m), 5.20 (1H, d, J=8.0 Hz), 5.35 (1H, d. J=16.0
Hz), 6.00 (1H, m), 7.20-7.60 (25H, m);
MS (FAB) m/z: 1062 (M+H)+.
(5b) Allyl 2,3-di-O-benzyl-4-O-(2,3,4-tri-O-benzyl-ß-D-
glucopyranosyl)-D-glucopyranoside
The compound (8.67 g, 8.17 mmol) synthesized in Example
5 (5a) was dissolved in tetrahydrofuran (150 mL) and a solution
of 1.0 M tetrabutyl ammonium fluoride in THF (20 mL, 20 mmol)
was added thereto, followed by stirring of the mixture at room
temperature for 5 hours. After the solvent was distilled off
under reduced pressure, the residue v/as purified using silica
gel flash column chromatography (methylene chloride:methanol,
50:1, V/V) to obtain the desired title compound (4.19 g, yield
62%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d 3.00-5.20 (28H, m), 5.20 (1H, d,
J=12.0 Hz), 5.30 (1H, d, J=18.0 Hz), 5.98 (1H, m), 7.20-7.40
(25H, m);
MS (FAB) m/z: 833 (M+H)+.
(5c) Allyl 2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O-(2,3,4-tri-O-
benzyl-6-fluoro-6-deoxy-ß-D-glucopyranosyl) -D-glucopyranoside
The compound (4.19 g, 5.03 mmol) synthesized in Example
5 (5b) was dissolved in 1,2-dimethoxyethane (85 mL) and

diethylaminosulfur trifluoride (2.5 mL, 25.61 mmol) was added
thereto, followed by stirring of the mixture at 60°C for 1 hour.
Methanol (10 mL) was added to the reaction mixture under ice-
cooling and the mixture was stirred for 30 minutes. After ethyl
acetate (50 mL) was added thereto and the organic layer was
washed with saturated aqueous sodium hydrogencarbonate solution
(50 mL) and saturated brine (50 mL) and dried with anhydrous
sodium sulfate, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 5:1-4:1, V/V) to
obtain the desired title compound (2.23 g, yield 53%) as a
yellow solid.
1H NMR (400 MHz, CDCl3): d 3.00-5.10 (26H, m), 5.23 (1H, m), 5.33
(1H, m), 5.95 (1H, m), 7.20-7.40 (25H, m);
MS (FAB) m/z: 837 (M+H)+,
(5d) Allyl 2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O-(2,3,4-tri-O-
benzyl-6-fluoro-6-deoxy -ß-D-glucopyrar.osyl)-D-glucopyranoside
The compound (2.23 g, 2.66 mmol) synthesized in Example
5 (5c) was dissolved in acetic acid (20 mL) and water (1 mL) and
palladium chloride (II) (0.47 g, 2.65 mmol) and sodium acetate
(0.87 g, 10.61 mmol) were added thereto, followed by stirring of
the mixture at room temperature for 14 hours. After the
reaction mixture was subjected to celite filtration, the solvent
was distilled off under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate 3:1, V/V) to obtain the desired title
compound (0.73 g, yield 34%) as pale yellow amorphous matter.
1H NMR (400 MHz, CDCl3) : d 3.00-5.10 (25H, m), 7.20-7.60 (25H,
m);
MS (FAB) m/z: 797 (M+H)+.
(5e) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
(benzyloxymethyl)pyrrolidin-3-yl 2,3-di-O-benzyl-6-fluoro-6-
deoxy-4-O- (2,3, 4-tri~0-benzyl-6-fluoro-6-deoxy-(3-D-

glucopyranosyl) -a-D-glucopyranoside
The compound (730.0 mg, 0.92 mmol) synthesized in
Example 5 (5d) was dissolved in methylene chloride (13.5 mL) and
trichloroacetonitrile (0.46 mL, 4.60 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (1 drop) were added thereto,
followed by stirring of the mixture at room temperature for 30
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1, 1% triethylamine,
V/V) to obtain imidate (675.3 mg, 78%) of yellow oil. The
compound (412.3 mg, 0.92 mmol) synthesized in Example 1 (li) was
dissolved in diethyl ether (13 mL) and trimethylsilyl
trifluoromethanesulfonate (8.3 µL, 0.046 mmol) was dissolved in
diethyl ether (2 mL) under a nitrogen atmosphere and the mixture
was added. Subsequently, a solution of imidate (675.3 mg) in
diethyl ether (5 mL) was added to the reaction mixture and the
mixture was stirred at room temperature for 2 hours. After
triethylamine (7.0 µL, 0.050 mmol) was added to the reaction
mixture and the solvent was distilled off under reduced pressure,
the residue was diluted with ethyl acetate (20 mL) and the
mixture was washed with saturated aqueous sodium
hydrogencarbonate (20 mL) and saturated brine (20 mL). After
the organic layer was dried with anhydrous sodium sulfate, the
solvent was distilled off under reduced pressure. The residue
containing a,p-mixture was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 6:1, V/V) to
isolate the desired title compound a form (122.6 mg, 11%)
thereof as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.00-5.20 (37H, m), 7.00-7.60 (40H,
m);
MS (FAB) m/z: 1227 (M+H)+.
(5f) (2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
(6-f luoro-6-deoxy-(3-D-glucopyranosyl) -6-fluoro-6-deoxy-a-D-
glucopyranoside

The compound (122.6 mg, 0.10 mmol) synthesized in
Example 5 (5e) was dissolved in methanol (10 mL) containing 1%
aqueous hydrochloric acid solution and 20% palladium hydroxide-
carbon (100 mg) was added thereto, followed by stirring of the
mixture under a hydrogen atmosphere for 2 hours. After the
catalyst was removed by celite filtration, 28% ammonia water
(0.5 mL) was added thereto and the mixture was stirred for 10
minutes. After the solvent was distilled off under reduced
pressure and the aqueous solution (100 mL) was subjected to ion
exchange resin (Dowex 50w x 8) column, it was eluted with 1%
ammonia water (100 mL). The ammonia water containing the
desired compound was concentrated under reduced pressure and the
residue was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1., V/V)
to obtain the desired title compound (25.9 mg, 56%) as a
colorless solid.
1H NMR (400 MHz, D20) : d 3.20-3.90 (22H, m), 4.10 (1H, sj, 4.41
(1H, d, J=8.1 Hz), 4.50-4.80 (4H, m), 5.05 (1H, d, J=6.3 Hz);
MS (FAB) m/z: 462 (M+H)+.
(6a) Methyl 4,6-O-benzylidene-3-O-benzyl-2-deoxy-D-
glucopyranoside
2-Deoxy-D-glucose (10.1 g, 61.5 mmol) was dissolved in
methanol (100 mL) and hydrochloric acid-methanol solution (50
mL) was added thereto, followed by heating of the mixture under
reflux for 3 hours. After cooling to room temperature,
triethylamine was added thereto until the reaction mixture
became basic and the solvent was distilled off under reduced
pressure. The residue was dissolved in N, N-dimethylforma.mide
(100 mL) and benzaldehyde dimethylacetal (12.9 mL, 86.1 mmol)
and p-toluenesulfonic acid monohydrate (585 mg, 3.08 mmol) were
added thereto, followed by stirring of the mixture at 20 mmHg
and 50°C for 3 hours. After cooling to room temperature, water
(50 mL) was added to the reaction mixture and the mixture was
extracted with ethyl acetate (200 mL). The organic layer was
washed with water (50 mL) and saturated brine (30 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was dissolved in
N,N-dimethylformamide (100 mL) and 55% sodium hydride (3.99 g,
92.3 mmol) was added thereto under ice-cooling, followed by
stirring of the mixture at the same temperature for 10 minutes.
Benzyl bromide (11.0 mL, 92.3 mmol) was added thereto and the
mixture was stirred at room temperature for 19 hours. After
water (50 mL) was added to the reaction mixture and the mixture
was extracted with ethyl acetate (200 mL), the organic layer was
washed with water (50 mL) and saturated brine (30 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
20:1-10:1, V/V) to obtain the desired title compound (16.0 g,
yield 73%) as a yellow solid.
1H NMR (400 MHz, CDCl3): d 1.66-1.83 (1H, m), 2.24-2.34 (1H, m),
3.33 (3H, s), 3.65-3.85 (3H, m), 3.98-4.04 (1H, m), 4.22-4.35
(1H, m), 4.66-4.84 (3H, m), 5.60-5.62 (1H, m), 7.23-7.40 (8H, m),
7.49-7.52 (2H, m);
MS (FAB) m/z: 357 (M+H)+.
(6b) Methyl 3-O-benzyl-2-deoxy-D-glucopyranoside
The compound (2.00 g, 5.62 mmol) synthesized in Example
6 (6a) was dissolved in acetic acid (1.5 mL) and water (5 µL) and

the mixture was stirred at 60°C for 2 hours and 30 minutes.
After cooling to room temperature, the solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 2:1-1:2,
V/V) to obtain the desired title compound (1.33 g, yield 88%) as
a pale yellow oil.
1H NMR (400 MHz, CDCl3): d 1.49-1.64 (1H, m), 2.11 (1H, brs),
2.25-2.36 (1H, m), 2.62 (1H, brs), 3.33 (3H, s), 3.44-3.65 (2H,
m), 3.76-3.87 (3H, m), 4.41-4.52 (1H, m), 4.65-4.71 (1H, m),
4.81-4.82 (1H, m), 7.26-7.37 (5H, m);
MS (FAB) m/z: 267 (M-H)+.
(6c) Methyl 3-O-benzyl-2-deoxy-6-O -ß-toluenesulfonyl-D-
glucopyranoside
The compound (12.2 g, 45.3 mmol) synthesized in Example
6 (6b) was dissolved in pyridine (100 mL) and p-toluenesulfonyl
chloride (13 g, 68.0 mmol) and 4-dimethylaminopyridine (553 mg,
4.53 mmol) were added thereto, followed by stirring of the
mixture at room temperature for 12 hours. The reaction mixture
was poured to 10% aqueous hydrochloric acid solution (80 mL)
under ice cooling, and ethyl acetate (200 mL) and the organic
layer was washed with 10% aqueous hydrochloric acid solution (80
mL), saturated aqueous sodium hydrogencarbonate solution (80 mL)
and saturated brine (50 mL) and dried with anhydrous sodium
sulfate, followed by distilling off of the solvent under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to
obtain the desired title compound (16.9 g, yield:88%) as pale
yellow amorphous matter.
1H NMR (400 MHz, CDCl3) : d 1.54-1.61 (1H, m), 2.20-2.28 (1H, m),
2.44 (3H, s), 3.27 (3H, s), 3.41-3.48 (2H, m), 3.70-3.76 (2H, m),
4.22-4.41 (2H, m), 4.47-4.57 (1H, m), 4.63-4.68 (1H, m), 4.75-
4.76 (1H, m), 7.26-7.36 (7H, m), 7.79-7.84 (2H, m);
MS (FAB) m/z: 421 (M-H)+.
(6d) Methyl 4-O-benzoyl-3-O-benzyl-2-deoxy-6-O -ß-
toluenesulfonyl-D-glucopyrancside
The compound (16.9 g, 40.0 mmol) synthesized in Example
6 (6c) was dissolved in methylene chloride (150 mL) and
triethylamine (22 mL, 0.16 mol), benzoyl chloride (14 mL,. 0.12
mol) and 4-dimethylaminopyridine (48S mg, 4.00 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 18 hours. After water (80 mL) was added to the reaction
mixture and the mixture was extracted with methylene chloride
(100 mL), the organic layer was washed with saturated brine (50
mL) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) to obtain
the desired title compound (20.8 g, yield 99%) as a yellow oil.
1H NMR (400 MHz, CDCl3) : d 1.71-1.78 (1H, m), 2.26-2.31 (1H, m),
2.33 (3H, s), 3.32 (3H, s), 3.94-4.14 (4H, m), 4.40-4.44 (1H, m),
4.52-4.59 (1H, m), 4.80-4.81 (1H, m), 5.03-5.08 (1H, m), 7.09-
7.20 (6H, m), 7.40-7.49 (3H, m), 7.57-7.62 (1H, m), 7.66-7.71
(2H, m), 7.87-7.96 (2H, m);
MS (FAB) m/z: 527 (M+H)+.
(6e) Methyl 4-O-benzoyl-3-O-benzyl-2,6-dideoxy-6-iode-D-
glucopyranoside
The compound (2.53 g, 4.81 mmoL) synthesized in Example
6 (6d) was dissolved in toluene (30 mL) and sodium iodide (3.6 g,
24.0 mmol) and 18-crown-6~ether (254 mg, 0.96 mmol) were added
thereto, followed by stirring of the mixture at 100°C under a
nitrogen atmosphere for 3 hours. After cooling to room
temperature, water (30 mL) was added to the reaction mixture and
the mixture was extracted with ethyl acetate (100 mL). The
organic layer was washed with saturated brine (30 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
15:1 - 10:1, V/V) to obtain the desired title compound (2.11 g,
FP0403S
yield 91%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): d 1.72-1.86 (1H, m), 2.31-2.41 (1H, m),
3.17-3.26 (1H, m), 3.33-3.40 (1H, m), 3.45 (3H, s), 3.69-3.86
(1H, m), 3.99-4.31 (1H, m), 4.44-4.48 (1H, m), 4.57-4.62 (1H, m),
4.90-4.91 (1H, m), 5.03-5.18 (1H, m), 7.13-7.26 (5H, m), 7.43-
7.49 (2H, m), 7.58-7.62 (1H, m), 8.02-8.04 (2H, m);
MS (FAB) m/z: 483 (M+H)+.
(6f) 4-O-Benzoyl-3-O-benzyl-2,5,6-trideoxy-D-xylo-hex-5-enose
oxime
The compound (2.11 g, 4.38 mmol) synthesized in Example
6 (6e) was dissolved in isopropanol (50 mL) and water (2 mL) and
zinc powder (2 g) washed with 5% aqueous hydrochloric acid
solution was added thereto, followed by heating of the mixture
under reflux for 25 minutes. After cooling to room temperature,
it was subjected to celite filtration and the solvent was;
distilled off under reduced pressure. The residue was dissolved
in ethanol (50 mL) and hydroxylamine hydrochloride (913 mg, 13.1
mmol) and pyridine (1.06 mL, 13.1 mmol) were added thereto,
followed by stirring of the mixture at 60°C for 50 minutes.
After cooling to room temperature, the solvent was distilled off
under reduced pressure and water (20 mL) was added thereto.
After the mixture was extracted with ethyl acetate (100 µL), the
organic layer was washed with saturated brine (20 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
6:1-5:1-4:1-3:1, V/V) to obtain the desired title compound (1.14
g, yield 77%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 2.47-2.55 (1H, m), 2.61-2.79 (1H, m),
3.88 (0.5H, dt, J=8.1, 5.1 Hz), 3.94 (0.5H, dt, J=8.1, 4.4 Hz),
4.65 (0.5H, d, J=11.7 Hz), 4.67 (0.5H, d, J=11.7 Hz), 4.74 (0.5H,
d, J=11.7Hz), 4.75 (0.5H, d, J=11.7 Hz), 5.33-5.36 (1H, m),
5.41-5.47 (1H, m), 5.74-5.77 (1H, m), 6.01 (1H, ddd, J=16.8, 5.9,
5.1 Hz), 6.84 (0.5H, t, J=5.1 Hz), 7.26-7.33 (5H, m), 7.43-7.48
(2.5H, m), 7.56-7.60 (1H, m), 8.06-8.08 (2H, m);
MS (FAB) m/z: 340 (M+H)+.
(6g) (3aR,4R,5R,6aS)-4-Benzoyloxy-5-benzyloxy-hexahydro-
cyclopenta[c]isoxazole (3aS, 4R,5R,6aR)-4-benzoyloxy-5-benzyloxy-
hexahydro-cyclopenta[c]isoxazole
The compound (5.0 g, 14.7 mmol) synthesized in Example 6
(6f) was dissolved in toluene (100 ml) and the mixture was
heated under reflux for 40 hours. After cooling to room
temperature, the solvent was distilled off under reduced
pressure and the residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 2:1-1:1, V/V) to
obtain the desired title compound (mixture) (4.08 g, yield 82%)
as an orange-color oil.
1H NMR (400 MHz, CDCl3): d 1.92 (0.3H, ddd, J=10.2, 5.1, 5.1 Hz),
2.00-2.13 (1.4H, m), 2.28-2.35 (0.3H, m), 2.99-3.01 (0.3H, m),
3.37 (0.7H, dd, J=8.8, 7.3 Hz), 3.43-3.49 (0.7H, m), 3.99-4.22
(4.3H, m), 4.63 (0.3H, d, J=11.7 Hz), 4.63 (1.4H, s), 4.67 (0.3H,
d, J=9.5 Hz), 5.21 (0.3H, t, J=3.7 Hz), 5.28 (0.7H, d, J=3.7Hz),
7.25-7.35 (5H, m), 7.43-7.47 (2H, m), 7.54-7.60 (1H, m), 7.99-
8.08 (2H, m);
MS (FAB) m/z: 340 (M+H)+.
(6h) (3aR, 4R, 5R, 6aS)-5-Benzyloxy-1-benzyloxycarbonyl-4-hydroxy-
hexahydro-cyclopenta[c]isoxazole
The compound (4.08 g, 12.0 mmol) synthesized in Example
6 (6 g) was dissolved in methanol (40 mL) and sodium methoxide
(696 µl. 3.61 mmol) was added thereto, followed by stirring of
the mixture at room temperature for 2 hours. After Dowex 50W x
8 was added thereto until the reaction mixture became neutral
and it was filtered, the solvent was distilled off under reduced
pressure. The residue was dissolved in ethyl acetate (40 mL)
and saturated aqueous sodium hydrogencarbonate solution (20 mL)
and benzyloxy chloroformate (2.4 mL, 16.8 mmol) were added
thereto under ice-cooling, followed by stirring of the mixture
at the same temperature for 1 hour and 30 minutes. The organic
layer was washed with saturated brine (50 mL) and dried with
anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
2:1-1:1, V/V) to obtain the desired title compound (789 mg,
yield 18%) as a pale yellow solid and its diastereomer (1.62 g,
yield 36%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) : d 1.57-1.63 (1H, m), 2.47 (1H, brs),
2.50-2.56 (1H, m), 2.73-2.77 (1H, m), 3.61-3.69 (2H, m), 3.88-
3.92 (1H, m), 4.01 (1H, d, J=8.8 Hz), 4.49 (1H, d, J=11.7 Hz),
4.48-4.55 (1H, m), 4.60 (1H, d, J=11.7 Hz), 5.18 (2H, s);
MS (FAB) m/z: 370 (M+H)+.
(6i) (3aR,4R,5R,6aS)-5-Benzyloxy-1-benzyloxycarbonyl-hexahydro-
cyclopenta[c]isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-
benzyl-6-deoxy -ß-D-glucopyranosyl)-D-glucopyranoside
The compound (751 mg, 0.87 mmol) synthesized in Example
2 (2f) was dissolved in methylene chloride (15 mL) and
trichloroacetonitrile (435 µL, 4.33 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 1
hour. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 6:1-5:1, 1% triethylamine,
V/V) to obtain imidate (734 mg, 84%) as a yellow oil. The
compound (244 mg, 0.66 mmol) synthesized in Example 6 (6h) was
dissolved in diethyl ether (12 mL) and trimethylsilyl
trifluoromethanesulfonate (12 µl. 0.07 mmol) was added thereto.
A solution of imidate (734 mg, 0.73 mmol) in diethyl ether (3
mL) was added dropwise thereto, followed by stirring of the
mixture at room temperature for 1 hour. After triethylamine (4
drops) was added to the reaction mixture, the solvent was
distilled off under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:diethyl

ether, 2:1-1:1, V/V) to obtain the desired title compound (a, (3
mixture) (516 mg, yield 64%) as colorless amorphous matter.
1H NMR (400 MHz, CDCl3): d 1.19 (1.5H, d, J=2.9Hz), 1.20 (1.5H, d,
J=2.9 Hz), 1.62-1.68 (0.5H, m), 1.79-1.84 (0.5H, m), 2.39-2.45
(0.5H, m), 2.48-2.53 (0.5H, m), 2.73-2.77 (0.5H, m), 2.85-2.86
(0.5H, m), 3.10-3.60 (8H, m), 3.69-4.02 (6H, m), 4.10-4.14 (1H,
m), 4.32-4.64 (8H, m), 4.69-4.87 (7H, m), 5.00 (0.5H, d, J=10.7
Hz), 5.12 (0.5H, d, J=3. 9 Hz), 5.18 (1H, d, J=10.7 Hz), 7.18-
7.43 (50H, m);
MS (FAB) m/z: 1217 (M)+.
(6j ) (3aR,4R,5R,6aS)-5-Benzyloxy-1-methyloxycarbonyl-hexahydro-
cyclopenta[c]isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-
benzyl-6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (516 mg, 0.42 mmol) synthesized in Example
6 (6i) was dissolved in methanol (6 mL) and toluene (6 mL) and
sodium methoxide (221 µl. 1.15 mmol) was added thereto, followed
by stirring of the mixture at 50°C for 40 minutes. After cooling
to room temperature, Dowex 50W x 8 was added thereto until the
reaction mixture became neutral and it was filtered, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:diethyl ether, 1.5:1-1:1, v/v) to cbtain
the desired title compound (173 mg, yield 47%) as colorless
amorphous matter.
1H NMR (400 MHz, CDCl3): d 1.61-1.69 (1H, m), 2.48-2.55 (1K, m),
2.72-2.78 (1H, m), 3.13 (1H, dd, J=9.5, 8.8 Hz), 3.21 (1H, dd,
J=9.5, 5.9 Hz), 3.31 (1H, dd, J=8.1, 7.3 Hz), 3.36-3.54 (5H, m),
3.59-3.62 (1H, m), 3.79 (3H, s), 3.74-3.94 (5H, m), 3.99 (1H, d,
J=8.8 Hz), 4.32-4.38 (2H, m), 4.50-4.67 (7H, m), 4.76-5.00 (5H,
m), 5.01 (1H, d, J=11.0 Hz), 5.12 (1H, d, J=3.7 Hz), 7.14-7.44
(35H, m);
MS (FAB) m/z: 1141 (M)+.
(6k) (3aR,4R,5R,6aS)-5-Benzyloxy-hexahydro-

cyclopenta[c]isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-
benzyl-6-deoxy-(3-D-glucopyranosyl) -a-D-g] ucopyranoside
The compound (363 mg, 0.32 mmol) synthesized in Example
6 (6j) was dissolved in methanol (8 mL) and IN aqueous potassium
hydroxide solution (4 mL) was added thereto, followed by
stirring of the mixture at 80ºC for 8 hours. After cooling to
room temperature, saturated aqueous ammonium chloride solution
(15 mL) was added to the reaction mixture and the mixture was
extracted with ethyl acetate (100 mL). After the organic layer
was washed with saturated brine (10 mL) and dried with anhydrous
sodium sulfate, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 1.5:1-1:1, V/V) to
obtain the desired title compound (313 mg, yield 91%) as pale
yellow amorphous matter.
1H NMR- (400 MHz, CDCl3) : d 1.20 (3H, d, J=5.9 Hz), 1.56-1.64 (1H,
m), 2.26-2.36 (1H, m), 2.76-2.86 (1H, m), 3.13 (1H, dd, J=9.5,
8.8 Hz), 3.19-3.25 (2H, m), 3.32 (1H, dd, J=8.8, 8.1 Hz), 3.43-
3.53 (3H, m), 3.67-3.69 (2H, m), 3.81-3.95 (6H, m), 4.35-4.40
(2H, m), 4.51-4.67 (7H, m), 4.74-4.87 (6H, m), 5.01 (1H, d,
J=10.3 Hz), 7.15-7.44 (35H, m);
MS (FAB) m/z: 1084 (M+H)+.
(61) (1S, 3R,4R,5S)-1-Amino-3-hydroxy-5-hydroxymethyl-
cyclopenta-4-yl 4-O- (6-deoxy -ß-D-glucopyranosyl) -a-D-
glucopyranoside
The compound (313 mg, 0.29 mmol; synthesized in Example
6 (6k) was dissolved in methanol (8 mL) and ethyl acetate (4 mL)
and hydrochloric acid (5 drops) and 20% palladium hydroxide-
carbon (300 mg) were added thereto, followed by stirring of the
mixture at room temperature under a hydrogen atmosphere for 6
hours. After the celite filtration, the solvent was distilled
off under reduced pressure and methanol (3 mL) and 28% ammonia
water (300 µL) were added thereto, followed by stirring of the
mixture at room temperature for 10 minutes. After the solvent was

distilled off under reduced pressure, the residue was purified
by ion exchange column (Dowex 50W x 8) (water-2.8% ammonia
water). Further, it was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to
obtain the desired title compound (137 mg, yield 81%) as a pale
yellow solid.
1H NMR (500 MHz, D20) : d 1.19 (1H, d, J=5.9 Hz), 1.53 (1H, dt,
J=13.7, 6.8 Hz), 2.18-2.23 (1H, m), 2.27-2.33 (1H, m), 3.07 (1H,
dd, J=9.8, 8.8 Hz), 3.19 (1H, dd, J=9.8, 7.8 Hz), 3.34 (1H, dd,
J=9.8, 8.8 Hz), 3.37-3.41 (1H, m), 3.47-3.51 (2H, m), 3.58 (1H,
dd, J=14.7, 6.8 Hz), 3.66-3.80 (6H, m), 3.86 (1H, dd, J=6.8, 4.9
Hz), 4.11-4.14 (1H, m), 4.36 (1H, d, J=7.8 Hz), 5.06 (1H, d,
J=3.9 Hz);
13C NMR (125 MHz, D20) : d 16.89, 38.27, 47.74, 49.85, 59.41,
60.05, 70.97, 71.19, 71.56, 72.22, 73.64, 74.96, 75.45, 75.51,
79.24, 84.26, 97.34, 102.68;
MS (FAB) m/z: 456 (M+H)+.
Azide epoxide (Tetrahedron, 26, 1985, 1469) (2.03 g,
6.97 mmol) was dissolved in ethanol (40 mL) and Lindlar catalyst
(0.4 g) was added thereto, followed by stirring of the mixture
under a hydrogen atmosphere for 2 hours. After the catalyst was
removed by celite filtration, it was dissolved in ethanol (40
mL) and the mixture was heated under reflux for 1 hour. After

the solvent was distilled off under reduced pressure, the
residue was purified using silica gel flash column
chromatography (methylene chloride:ethanol, 20:1-10:1, V/V) to
obtain the desired title compound (1.21 g, yield 65%) as a brown
solid.
1H NMR (400 MHz, CDCl3): d 2.15-2.35 (2H, br), 3.19 (1H, dd,
J=5.8, 5.9 Hz), 3.35 (3H, s), 3.41 (1H, s), 3.65 (1H, dd.. J=5.8,
11.7 Hz), 3.73 (1H, dd, J=5.8, 11.7 Hz), 4.11 (1H, s), 4.18 (1H
s), 4.54 (1H, d, J=11.7 Hz), 4.61 (1H, d, J=11.7 Hz), 4.64 (1H,
s), 7.29-7.38 (5H, m);
MS (FAB) m/z: 266 (M+H)+.
(7b) (1R,3R,4S,6R, 7R)-7-Hydroxy-6-hydroxymethyl-3-methoxy-2-
oxa-5-aza-bicyclo[2,2,1]heptane-5-carboxylic acid benzyl ester
The compound (930 mg, 3.51 mmol) synthesized in Example
7 (7a) was dissolved in methanol (20 mL) and 20% palladium
hydroxide-carbon (280 mg) was added thereto, followed by
stirring of the mixture under a hydrogen atmosphere for 6 hours.
After the catalyst was removed by celite filtration, the solvent
was distilled off under reduced pressure. The residue was
dissolved in ethyl acetate:saturated aqueous sodium
hydrogencarbonate solution (2:1, 20 mL) and benzyl chloroformate
(0.75 mL, 5.27 mmol) was added thereto, followed by stirring of
the mixture at 0°C for 2 hours. After water (20 mL) was added
thereto at 0°C and the mixture was extracted with ethyl acetate,
the organic layer was washed with saturated brine (20 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:ethyl
acetate, 1:1-3:1, V/V) to obtain the desired title compound (759
mg, yield 70%) as a colorless solid.
1H NMR (400 MHz, CDCl3): d 3.33 (3H, s), 3.50-4.00 (3H, m), 4.10-
4.25 (3H, m), 4.61 (1H, brs), 4.60-4.74 (2H, m), 5.10-5.25 (2H,
m), 7.25-7.45 (5H, m);
MS (FAB) m/z: 310 (M+H)+.

(7c) (1R, 3S, 4S, 6R, 7R)-7-Benzyloxy-6-t-
butyldimethylsilyloxymethyl-3-methoxy-2-oxa-5-aza-
bicyclo[2,2,1]heptane-5-carboxylic acid benzyl ester
The compound (152 mg, 0.49 mmol) synthesized in Example
7 (7b) was dissolved in pyridine (4 mL) and t-butyldimethylsilyl
chloride (82 mg, 0.54 mmol) was added thereto, followed by
stirring of the mixture at 0°C for 3 hours. After it was
confirmed by TLC that the raw material was no longer present,
benzoyl chloride (86 µl. 0.74 mmol) was added and the mixture
was stirred at 0°C for 1 hour. After water (20 mL) was added
thereto at 0°C and the mixture was extracted with ethyl acetate,
the organic layer was washed with saturated brine (20 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:ethyl
acetate, 10:1, V/V) to obtain the desired title compound (218 mg,
yield 84%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d -0.24 — 0.04 (6H, m), 0.72 (4.5H, s),
0.77 (4.5H, s), 3.34 (1.5H, s), 3.38 (1.5H, s), 3.67-3.80 (2H,
m), 3.91 (0.5Hm), 4.10 (0.5H, m), 4.40 (0.5H, s), 4.46 !0.5H,
m), 4.66 (0.5H, s), 4.69 (1H, m), 4.78 (0.5H, m), 5.15 (2H, m),
5.44 (1H, m), 7.39-7.36 (5H, m), 7.41 (2H, m), 7.55 (1H, m),
7.95 (2H, m);
MS (FAB) m/z: 528 (M+H)+.
(7d) (2R,3R, 4R, 5R)-N-Benzyloxycarbonyl-3-benzoyl-2,5-
dihydroxymethyl-4-hydroxypyrrolidine
The compound (997 mg, 1.89 mmol) synthesized in Example
7 (7c) was dissolved in trifluoroacetic acid:water (4:1, 12 mL)
and the mixture was stirred at room temperature for 15 minutes.
After water (20 mL) was added to the reaction mixture at 0°C and
the mixture was extracted with dichloromethane (30 mL), the
organic layer was washed with saturated aqueous sodium
hydrogencarbonate (20 mL) and saturated brine (20 mL) and dried

with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was dissolved in
ethanol (15 mL) and the compound obtained by dissolving sodium
borohydride (35.7 mg, 0.10 mmol) in water (5 mL) was added
thereto, followed by stirring of the mixture at 0°C for 20
minutes. After saturated aqueous ammonium chloride (2 mL) was
added to the reaction mixture at 0°C, ethanol was distilled off
under reduced pressure. After water (15 mL) was added thereto
and the mixture was extracted with ethyl acetate (15 mL), the
organic layer was washed with saturated brine (15 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
2:1, V/V) to obtain the desired title compound (643 mg, yield
85%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.60-3.38 (9H, m), 4.98-5.19 (4H, m),
7.20-7.30 (5H, m), 7.36. (2H, m), 7.50 (1H, m), 7.89 (2H, d,
J=7.3 Hz);
MS (FAB) m/z: 402 (M+H)+.
(7e) (2R,3R,4R,5R)-N-Benzyloxycarbonyl-3-hydroxy-2,5-
dibenzyloxymethyl-4-benzyloxypyrrolidine
The compound (64 3 mg, 1.60 mmol) synthesized in Example
7 (7d) was dissolved in dichloromethane:cyclohexane (1:2, 18 mL)
and benzyl tricloroacetoimidate (2.7 mL, 14.4 mmol) and
trifluoromethanesulfonic acid (29 µL, 0.32 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 2 hours. After saturated aqueous sodium hydrogencarbonate
(5 mL) was added to the reaction mixture at 0°C and the mixture
was diluted with ethyl acetate (200 mL), it was washed with
water (30 mL) and saturated brine (30 mL) and dried with
anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
20:1-10:1, V/V) to obtain 1080 mg of colorless oil. The thus

obtained 1080 mg of colorless oil was dissolved in
methanol:tetrahydrofuran (4:1, 25 mL) and potassium carbonate
(44 mg, 0.32 mmol) was added thereto, followed by stirring of
the mixture at room temperature for 2.5 hours. After methanol
was distilled off under reduced pressure, water (15 mL) was
added thereto and the mixture was extracted with ethyl acetate
(15 mL). The organic layer was washed with saturated brine (15
mL) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1, V/V) to obtain the
desired title compound (715 mg, yield 78%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.40-3.49 (2H, m), 3.62 (1H, dd, J=4.4,
8.8 Hz), 3.79-4.12 (4H, m), 4.19 (1H, dd, J=3.7, 10.3 Hz), 4.26-
4.61 (6H, m), 5.01 (1H, d, J=16.8 Hz), 5.03 (1H, d, J=16.8 Hz),
5.51 (1H, m), 7.15-7.38 (20H, m);
MS (FAB) m/z : 568 (M+H)+.
(7f) (2R, 3R, 4R, 5R)-N-Benzyloxycarbonyl-2,5-dibenzyloxymethyl-4-
benzyloxypyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-
benzyl-6-deoxy -ß-D-glucopyranosyl) -a-D-glucopyranoside
The compound (426 mg, 0.49 mmol) synthesized in Example
2 (2f) was dissolved in methylene chloride (8 mL) and
trichloroacetonitrile (0.25 mL, 2.45 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (7 µL, 0.05 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 15 minutes. After the solvent was distilled off under
reduced pressure, the residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1, 1%
triethylamine, V/V) to obtain imidate (398 mg, 80%) of colorless
oil. The compound (248 mg, 0.44 mmol) synthesized in Example 7
(7e) was dissolved in diethyl ether (8 mL) and trimethylsilyl
trifluoromethanesulfonate (7 µl. 44 µmmol) was added thereto
under a nitrogen atmosphere. A solution of imidate in diethyl
ether (5 mL) was added to the reaction mixture and the mixture

was stirred at room temperature for 1.5 hours. After
triethylamine (12 µL, 88 µmol) was added to the reaction mixture
and the solvent was distilled off under reduced pressure, it was
diluted with ethyl acetate (20 mL) and washed with saturated
aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20
mL). After the organic layer was dried with anhydrous sodium
sulfate, the solvent was distilled off under reduced pressure
and the residue was purified using silica gel flash column
chromatography (hexane:diethyl ether, 4:1, V/V) to obtain the
desired title compound (218 mg, 31%) as a colorless oil.
1H NMR (500 MHz, CDCl3) : d 1.23 (3H, d, J=5. 9 Hz), 2.92-3.19 (4H,
m), 3.26-3.73 (13H, m), 3.85 (1H, dd, J=5.1, 5.1 Hz), 3.93 (1H,
dd, J=5.1, 5.1 Hz), 4.31 (1H, d, J=8.0 Hz), 5.03 (1H, d, J=3. 6
Hz);
MS (FAB) m/z: 4 72 (M+H)+.
(7g) (2R,3R,4R,5R)-2,5-Dihydroxymethyl-4-hydroxypyrrolidin-3-yl
4-O-(6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (218 mg, 0.15 mmol) synthesized in Example
7 (7f) was dissolved in 1% hydrochloric acid methanol solution
(5 mL) and 20% palladium hydroxide-carbon (110 mg) was added
thereto, followed by stirring of the mixture under a hydrogen
atmosphere for 2 hours. After the catalyst was removed by
celite filtration, 28% ammonia water (0.8 mL) was added thereto,
followed by stirring of the mixture for 10 minutes. After the
solvent was distilled off under reduced pressure and it was
passed through ion exchange resin column with water (30 rrL), 1%
ammonia water (30 mL) was flowed through. The ammonia water
containing the desired compound was concentrated under reduced
pressure and was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V)
to obtain the desired title compound (47 mg, 64%) as a colorless
solid.
1H NMR (400 MHz, D20) : d 1.15 (3H, d, J=5.9 Hz), 2.92-3.19 (4H,
m), 3.26-3.73 (13H, m), 3.85 (1H, dd, J=5.1, 5.1 Hz), 3.93 (1H,

dd, J=5.1, 5.1 Hz), 4.31 (1H, d, J=8.0 Hz), 5.03 (1H, d, J=3.6
Hz);
MS (FAB) m/z: 472 (M+H)+.

The compound (2.19 g, 2.37 mmol) synthesized in Example
2 (2c) was dissolved in N,N-dimethylformamide (45 mL) and sodium
hydride (0.12 g, 2.75 mmol) was added thereto under ice-cooling,
followed by stirring of the mixture for 10 minutes. Methyl
iodide (0.3 mL, 4.82 mmol) was added thereto and the mixture was
stirred at room temperature for 5 hours. Methanol (5 mL) was
added to the reaction mixture under ice-cooling and the mixture
was stirred for 30 minutes. Ethyl acetate (20 mL) was added
thereto and the organic layer was washed with water (20 mL) and
saturated brine (20 mL) and dried with anhydrous sodium sulfate,
followed by distilling off of the solvent under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 6:1-5:1, V/V) to obtain
the desired title compound (1.80 g, yield 81%) as a colorless
oil.
1H NMR (400 MHz, CDCl3) : d 3.21 (3H, s), 3.30-5.00 (28H, m), 5.10
(1H, m), 5.20 (1H, m), 5.95 (1H, m), 7.20-7.40 (30H, m);
MS (FAB) m/z: 938 (M+H)+.
(8b) Allyl 2,3, 6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-

methoxy-6-deoxy -ß-D-glucopyranosyl)-D-glucopyranoside
The compound (1.80 g, 1.92 mmol) synthesized in Example
8 (8a) was dissolved in methanol (30 mL) and tetrahydrofuran (6
mL) and palladium chloride (II) (67.4 mg, 0.38 mmol) was added
thereto, followed by stirring of the mixture at room temperature
for 14 hours. After the reaction mixture was subjected to
celite filtration, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane :ethyl acetate, 5 :1-4:1-3:1, V/V)
to obtain the desired title compound (1.43 g, yield 83%) as
colorless amorphous matter.
1H NMR (400 MHz, CDCl3) : d 3.20 (3H, s), 3.25-5.00 (27H, m), 5.10
(1H, m), 7.20-7.40 (30H, m);
MS (FAB) m/z: 898 (M+H)+.
(8c) (2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
(benzyloxymethyl)pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-
tri-O-benzyl-6-methoxy-6-deoxy -ß-D-glucopyranosyl)-a-D-
glucopyranoside
The compound (762.6 mg, 0.85 mmol) synthesized in
Example 8 (8b) was dissolved in methylene chloride (14 mL) and
trichloroacetonitrile (0.43 mL, 4.29 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (1 drop) were added thereto,
followed by stirring of the mixture at room temperature; for 30
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1, 1% triethylamine,
V/V) to obtain imidate (567.8 mg, €4%) of colorless oil. The
compound (380.8 mg, 0.85 mmol) synthesized in Example 1 (1i) was
dissolved in diethyl ether (13 mL) and trimethylsilyl
trifluoromethanesulfonate (8.0 pL, 0.044 mmol) was dissolved in
diethyl ether (2 mL) under a nitrogen atmosphere and it was
added. A solution of imidate (5 67.8 mg) in diethyl ether (5 mL)
was added to the reaction mixture and the mixture was stirred at
room temperature for 2 hours. After triethylamine (8.0 µl.

0.057 mmol) was added to the reaction mixture and the solvent
was distilled off under reduced pressure, it was diluted with
ethyl acetate (20 mL) and the mixture was washed with saturated
aqueous sodium hydrogencarbonate solution (20 mL) and saturated
brine (20 mL). After the organic layer was dried with anhydrous
sodium sulfate, the solvent was distilled off under reduced
pressure and the residue containing the a, p mixture was
purified using silica gel flash column chromatography
(hexane:diethyl ether, 3:1, V/V) to isolate the desired title
compound a form (150.1 mg, 13%) thereof as colorless amorphous
matter.
2H NMR (400 MHz, CDCl3): d 3.20 (3H, s), 3.25-5.20 (39H, m),
7.20-7.40 (45H, m);
MS (FAB) m/z: 1327 (M+H)+.
(8d) (2R, 3R, 4R) -4-Hydroxy-2-hydroxyitiethyl-pyrrolidin-3-yl 4-O-
(6-methoxy-6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyrahoside
The compound (150.1 mg, 0.11 mmol) synthesized in
Example 8 (8c) was dissolved in methanol (10 mL) containing 1%
aqueous hydrochloric acid solution and 20% palladium hydroxide-
carbon (100 mg) was added thereto, followed by stirring of the
mixture under a hydrogen atmosphere for 2 hours. After the
catalyst was removed by celite filtration, 28% ammonia water
(0.5 mL) was added thereto and the mixture was stirred for 10
minutes. After the solvent was distilled off under reduced
pressure and the aqueous solution (100 mL) was subjected to ion
exchange resin (Dowex 50w x 8) column, it was eluted with 1%
ammonia water (100 mL). The ammonia water containing the
desired compound was concentrated under reduced pressure and the
residue was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V)
to obtain the desired title compound (49.1 mg, 95%) as a
colorless solid.
1 HNMR (400 MHz, CDCl3) : d 3.00-4.20 (19H, m), 3.27 (3H, s), 4.37
(1H, d, J=8.0 Hz), 4.98 (1H, d, J=3.7 Hz);

MS (FAB) m/z: 472 (M+H)+.
The compound (3.37 g, 9.07 mmol) synthesized in Example
1 (1h) was dissolved in methylene chloridercyclohexane (1:2, 180
mL) and benzyl trichloroacetoimidate (2.0 mL, 10.88 mmol) and
trifluoromethanesulfonic acid (2.57 mL, 15.3 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 1 hour. After saturated aqueous sodium hydrogencarbonate
solution (20 mL) was added to the reaction mixture at 0ºC and
the mixture was diluted with ethyl acetate (200 mL), it was
washed with water (300 mL) and saturated aqueous sodium
hydrogencarbonate solution (300 mL) and dried with anhydrous
sodium sulfate, followed by distilling off of the solvent under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1-2:1, V/V)
to obtain 4.71 g of pale yellow oil.
lH NMR (400 MHz, CDCl3) : d 3.50-4.20 (4H, m), 4.45-4.80 (3H, m),
5.00-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 (1H, m), 7.99 (2H,
m);
MS (FAB) m/z: 462 (M+H)+.
(9b) (2R,3R,4S)-3-Benzoyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-4-hydroxy-pyrrolidine
The compound (183 mg, 0.40 mmol) synthesized in Example

9 (9a) was dissolved in methylene chloride (4 mL) and pyridine
(96 µl. 1.20 mmol) and trifluoromethanesulfonic acid anhydride
(0.10 mL, 0.60 mmol) were added thereto, followed by stirring of
the mixture at 0°C for 20 minutes. After water (10 mL) was added
thereto at 0°C and the mixture was extracted with methylene
chloride, the organic layer was washed with saturated brine (10
mL) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 2:1, V/V) to obtain the
desired title compound (92 mg, yield 50%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) : d 3.25-4.20 (4H, m), 4.25-4.75 (3H, m),
5.10-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 (1H, t, J=7.4 Hz),
7.99 (2H, d, J=8.8 Hz);
MS (FAB) m/z: 462 (M+H)+.
(9c) (2R,3R,4R)-N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-
pyrrolidine
The compound (980 mg, 2.12 mmol) synthesized in Example
9 (9b) was dissolved in 1,2-dimethoxyethane (20 mL) and
diethylaminosulfur trifluoride (0.84 mL, 6.36 mmol) was added
thereto at -20°C. The temperature of the mixture was gradually
raised and the mixture was stirred at 60°C for 1 hour. After
saturated aqueous sodium hydrogencarbonate solution was added
thereto at 0°C until foaming did not occur, the mixture was
extracted with ethyl acetate and the organic layer was washed
with saturated brine (20 mL) and dried with anhydrous sodium
sulfate, follwed by distilling off of the solvent under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 4:1, V/V) to obtain
a pale yellow oil (545 mg). The thus obtained pale yellow oil
(545 mg) was dissolved in methanol (1C mL) and potassium
carbonate (50 mg) was added thereto, followed by stirring of the
mixture at room temperature for 20 minutes. After the solvent
was distilled off under reduced pressure, water (20 mL) was

added thereto and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine (20 mL). The
solvent was distilled off under reduced pressure and the residue
was purified using silica gel flash column chromatography
(hexane:ethyl acetate, 2:1, V/V) to obtain the desired title
compound (263 mg, yield 34%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.10-4.20 (4H, m), 4.25-4.75 (3H, m),
4.80-5.20 (5H, m), 7.30-7.45 (10H, m);
MS (FAB) m/z: 360 (M+H)+.
(9d) (2R,3R,4R)-N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-
pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-benzyl-6-
deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (657 mg, 0.76 mmol) synthesized in Example
1 (If) was dissolved in methylene chloride (12 mL) and
trichloroacetonitrile (0.38 mL, 3.8 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (11 µl. 76 µmol) were added
thereto, followed by stirring of the mixture at room temperature
for 15 minutes. After the solvent was distilled off under
reduced pressure, the residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1, 1%
triethylamine, V/V) to obtain imidate (767 mg, 100%) of
colorless oil. The compound (263 mg, 0.73 mmol) synthesized in
Example 9 (9c) was dissolved in diethyl ether (12 mL) and
trimethylsilyl trifluoromethanesulfonate (13 µL 73 µmol) was
added thereto under a nitrogen atmosphere. A solution of
imidate in diethyl ether (8 mL) was added to the reaction
mixture and the mixture was stirred at. room temperature for 1.5
hours. After triethylamine (20 µl. 14 6 µmol) was added tc the
reaction mixture and the solvent was distilled off under reduced
pressure, the residue was diluted with ethyl acetate (20 mL) and
the mixture was washed with saturated aqueous sodium
hydrogencarbonate (20 mL) and saturated brine (20 mL). After
the organic layer was dried with anhydrous sodium sulfate, the
solvent was distilled off under reduced pressure and the residue

was purified using silica gel flash column chromatography
(hexane:diethyl ether, 4:1, V/V) to obtain the desired title
compound a isomer (109 mg, 12%) and ß isomer (52 mg, 6%) as a
colorless oil.
1H NMR (400 MHz, CDCl3): d 1.09 (3H, d, J=4.2 Hz), 3.00-5.60 (35H,
m), 7.10-7.40 (40H, m);
MS (FAB) m/z: 1209 (M+H)+.
(9e) (2R, 3R, 4R)-4-Fluoro-2-hydroxymethyl-pyrrolidin-3-y:. 4-O-
(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (109 mg, 90.2 µmol) synthesized in Example 9
(9d) was dissolved in 1% hydrochloric acid methanol solution (5
mL) and 20% palladium hydroxide-carbon (55 mg) was added thereto,
followed by stirring of the mixture under a hydrogen atmosphere
for 1 hour. After the catalyst was removed by celite filtration,
28% ammonia water (0.2 mL) was added thereto and the mixture was
stirred for 10 minutes. After the solvent was distilled off
under reduced pressure and it was passed through ion exchange
resin (Dowex 50w x 8) column with water (30 mL), 1% ammonia
water (30 mL) was flowed through. The ammonia water containing
the desired compound was concentrated under reduced pressure and
the residue was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V)
to obtain the desired title compound (26 mg, 65%) as a colorless
solid.
1H NMR (500 MHz, CDCl3): d 1.18 (3H, d, J=5.9 Hz), 2.98-3.16 (4H,
m), 3.47-3.77 (12H, m), 4.11 (1H, dd, J=4.9, 20.5 Hz), 5.02 (1H,
m), 5.23 (1H, m);
MS (FAB) m/z: 444 (M+H)+.

(2R,3R,4R)-4-Hydroxy-2-fluoromethyl-pyrrolidin-3-yl 4-O-[6-
deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside (Exemplification
compound No. 1-119)
t
The compound (257 mg, 0.69 mmol) synthesized in Example
1 (lh) was dissolved in 1,2-dimethoxyethane (5 mL) and
diethylaminosulfur trifluoride (0.11 mL, 0.83 mmol) was added
thereto at -20°C. The temperature of the mixture was gradually
raised and the mixture was stirred at 60ºC for 1 hour. After
saturated aqueous sodium hydrogencarbonate solution was added
thereto at 0°C until foaming did not occur, the mixture was
extracted with ethyl acetate (15 mL) and the organic layer was
washed with saturated brine (15 mL) and dried with anhydrous
sodium sulfate, followed by distilling off of the solvent under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to
obtain a colorless oil (113 mg, 44%).
1H NMR (400 MHz, CDCl3) : d 3.50-4.25 (4H, m), 4.50-5.55 (3H, m),
5.40-5.60 (2H, m), 7.20-7.50 (7H, m), 7.60 (]H, m), 8.00-3.10
(2H, m);
MS (FAB) m/z: 374 (M+H)+.
(10b) (2R, 3R,4S)-3-Benzoyloxy-N-benzyloxycarbonyl-4-benzyloxy-
2-fluoromethyl-pyrrolidine
The compound (344 mg, 0.92 mmol) synthesized in Example
10 (10a) was dissolved in methylene chloride:cyclohexane (1:2,
10 mL) and benzyl trichloroacetoimidate (0.68 mL, 3.68 mmol) and
trifluoromethane sulfonic acid (16 µl. 0.18 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 4 hours. After saturated aqueous sodium hydrogencarbonate
(1 mL) was added to the reaction mixture at 0°C and the mixture
was diluted with ethyl acetate (20 mL), the mixture was washed

with water (20 mL) and saturated brine (20 mL) and dried with
anhydrous sodium sulfate, followed by distilling off of "he
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl ace:ate,
8:1-5:1, V/V) to obtain a colorless oil (307 mg, 68%).
1H NMR (400 MHz, CDCl3) : d 3.50-5.25 (7H, m), 5.50-5.75 (4H, m),
7.20-7.50 (12H, m), 7.60 (1H, m), 8.00-8.10 (2H, m);
MS (FAB) m/z: 464 (M+H)+.
(10c) (2R,3R,4S)-N-Benzyloxycarbonyl-4-benzyloxy-2-
fluoromethyl-pyrrolidine
The compound (307 mg, 0.66 mmol) synthesized in Example
10 (10b) was dissolved in methanol (6 mL) and potassium
carbonate (27 mg, 0.20 mmol) was added thereto, followed by
stirring of the mixture at room temperature for 2.5 hours.
After methanol was distilled off under reduced pressure, water
(15 mL) was added thereto and the mixture was extracted with
ethyl acetate (15 mL). The organic layer was washed with
saturated brine (15 mL) and dried with anhydrous sodium sulfate,
followed by distilling off of the solvent under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain the
desired title compound (176 mg, yield. 74%) as a colorless oil.
1 NMR (400 MHz, CDCl3) : d 3.35-4.80 (7H, m), 5.50-5.75 (4H, m),
7.20-7.50 (10H, m);
MS (FAB) m/z: 360 (M+H)+.
(10 (2R, 3R, 4R)-N-Benzyloxycarbonyl-4-benzyloxy-2-
fluoromethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-
O-benzyl-6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (398 mg, 0.46 mmol) synthesized in Example
2 (2f) was dissolved in methylene chloride (8 mL) and
trichloroacetonitrile (0.23 mL, 2.30 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (7 µL, 0.05 mmol) were added
thereto, followed by stirring of the mixture at room temperature

for 15 minutes. After the solvent was distilled off under
reduced pressure, the residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1, 1%
triethylamine, V/V) to obtain imidate of colorless oil. The
compound (165 mg, 0.46 mmol) synthesized in Example 10 (10c) was
dissolved in diethyl ether (8 mL) and trimethylsilyl
trifluoromethanesulfonate (8 µl. 46|jmol) was added thereto under
a nitrogen atmosphere. A solution of imidate in diethyl ether
(4 mL) was added to the reaction mixture and the mixture was
stirred at room temperature for 2.5 hours. After triethylamine
(13 (J.L, 92 (jmol) was added to the reaction mixture and the
solvent was distilled off under reduced pressure, the residue
was diluted with ethyl acetate (15 mL) and the mixture was
washed with saturated aqueous sodium hydrogencarbonate (15 mL)
and saturated brine (15 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 4:1, V/V)
to obtain the desired title compound (53 mg, 10%) as a colorless
oil.
1 NMR (400 MHz, CDCl3): d 1.10 (3H, d, J=4.2 Hz), 3.00-5.60 (35H,
m), 7.10-7.40 (40H, m);
MS (FAB) m/z: 1209 (M+H)+.
(10e) (2R,3R,4R)-4-Hydroxy-2-fluoromethyl-pyrrolidin-3-yl 4-O-
(6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (53 mg, 43.9 µmol) synthesized in Example 10
(10d) was dissolved in 1% hydrochloric acid methanol solution (5
mL) and 20% palladium hydroxide-carbon (30 mg) was added thereto,
followed by stirring of the mixture under a hydrogen atmosphere
for 3 hours. After the catalyst was removed by celite
filtration, 28% ammonia water (0.2 mL) was added thereto and the
mixture was stirred for 10 minutes. After the solvent was
distilled off under reduced pressure and it was passed through
ion exchange resin column with water (30 mL), 1% ammonia water

(30 mL) was flowed through. The ammonia water containing the
desired compound was concentrated under reduced pressure and the
residue was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V)
to obtain the desired title compound (1.6 mg, 8%) as a colorless
solid.
1H NMR (500 MHz, CDCl3) : d 1.18 (3H, d, J=4. 0 Hz), 2.98-4.25 (16H,
m), 4.50 (2H, m), 5.83 (1H, m);
MS (FAB) m/z: 444 (M+H)+.
The compound (815 mg, 1.77 mmol) synthesized in Example
9 (9b) was dissolved in dichloromethane:cyclohexane (1:2, 45 mL)
and benzyltrichloroacetoimidate (0.66 mL, 3.54 mmol) and
trifluoromethanesulfonic acid (24 µl. 0.27 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 1.5 hours. After saturated aqueous sodium hydrogencarbonate
solution (5 mL) was added to the reaction mixture at 0°C and the
mixture was diluted with ethyl acetate (200 mL), the mixture was
washed with water (50 mL) and saturated aqueous sodium
hydrogencarbonate solution (50 mL) and dried with anhydrous
sodium sulfate, followed by distilling off of the solvent under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 4:1, V/V) to
obtain a pale yellow oil (866 mg). Thus obtained pale yellow

oil (866 mg) was dissolved in methanol (15 mL) and potassium
carbonate (65 mg) was added thereto, followed by stirring of the
mixture at room temperature for 1 hour. After the solvent was
distilled off under reduced pressure, water (20 mL) was added
thereto and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine (20 mL). The
solvent was distilled off under reduced pressure and the residue
was purified using silica gel flash column chromatography
(hexane:ethyl acetate, 5:1-2:1, V/V) to obtain the desired title
compound (233 mg, yield 30%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.35-4.25 (6H, m), 4.25-4.70 (4H, m),
5.00-5.30 (4H, m), 7.09-7.26 (15H, m);
MS (FAB) m/z: 448 (M+H)+.
(11b) (2R,3R,4S)-N-Benzyloxycarbonyl-2-benzyloxymethyl-4-
benzyloxy-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-(2,3,4-tri-O-
benzyl-6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (513 mg, 0.59 mmol) synthesized in Example
1 (1f) was dissolved in methylene chloride (10 mL) and
trichloroacetonitrile (0.3 mL, 2.95 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (9 µl. 0.06 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 15 minutes. After the solvent was distilled off under
reduced pressure, the residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 5:1, 1%
triethylamine, V/V) to obtain imidate (447 mg, 75%) of colorless
oil. The compound (233 mg, 0.52 mmol; synthesized in Example 11
(11a) was dissolved in diethyl ether (10 mL) and trimethylsilyl
trifluoromethanesulfonate (9 µl. 59 µmol) was added thereto
under a nitrogen atmosphere. A solution of imidate in diethyl
ether (5 mL) was added to the reaction mixture and the mixture
was stirred at room temperature for 1.5 hours. After
triethylamine (16 µl. 118 µmol) was added to the reaction
mixture and the solvent was distilled off under reduced pressure,
it was diluted with ethyl acetate (20 mL) and the mixture was

washed with saturated aqueous sodium hydrogencarbonate (20 mL)
and saturated brine (20 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 5:1-4:1,
V/V) to obtain the desired title compound a isomer (58 mg, 8%)
and (3 isomer (51 mg, 7%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 1.15 (3H, d, J=5.6 Hz), 3.10-5.20 (36H,
m), 1.15 (1H, d, J=6.3 Hz), 7.20-7.39 (45H, m);
MS (FAB) m/z: 1297 (M+H)+.
(11e) (2R,3R,4S)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (58 mg, 44.7 µmol) synthesized in Example 11
(lib) was dissolved in 1% hydrochloric acid methanol solution (5
mL) and 20% palladium hydroxide-carbon (30 mg) was added thereto,
followed by stirring of the mixture under a hydrogen atmosphere
for 1.5 hours. After the catalyst was removed by celite
filtration, 28% ammonia water (0.2 mL) was added thereto and the
mixture was stirred for 10 minutes. After the solvent was
distilled off under reduced pressure and it was passed through
ion exchange resin (Dowex 50w x 8) column with water (30 mL), 1%
ammonia water (30 mL) was flowed through. The ammonia water
containing the desired compound was concentrated under reduced
pressure and the residue was purified using silica gel flash
column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1,
V/V) to obtain the desired title compound (13 mg, 68%) as a
colorless solid.
1H NMR (400 MHz, D20) : d 1.19 (3H, d, J=4.1 Hz), 2.80-4.60 (17H,
m), 5.00 (1H, d, J=3.6 Hz), 5.24 (1H, d, J=3.0 Hz);
MS (FAB) m/z: 442 (M+H)+.

(2R,3R,4R)-2-Hydroxymethyl-3-hydroxy-pyrrolidin-4-yl 4-O-(6-
deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside) (Exemplification

compound No. 1-556)

The compound (607 mg, 0.70 mmol) synthesized in Example
2 (2f) was dissolved in methylene chloride (10 mL) and
trichloroacetonitrile (500 µL, 4.98 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 4 0
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (630 mg, 89%) as a yellow oil. The
compound (323 mg, 0.700 mmol) synthesized in Example 9 (9a) was
dissolved in diethyl ether (10 mL) and imidate (630 mg, 0.623
mmol) was added thereto. Trimethylsilyl
trifluoromethanesulfonate (6.3 µL, 34.8 µmol) was dropwise
thereto and the mixture was stirred at room temperature for 4 5
minutes. After triethylamine (4 drops) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:diethyl ether, 6:1, V/V) to obtain
the desired title compound (610 mg, 75%) as a pale yellow oil.
Subsequently the pale yellow oil (610 mg, 0.465 mmol) was
dissolved in methanol (10 mL) and potassium carbonate water (1M,
1 mL, 1 mmol) was added thereto, followed by stirring of the
mixture at room temperature for 3 hours. The solvent was
distilled off under reduced pressure and the residue was
purified using silica gel flash column chromatography
(hexane:diethyl ether, 2:1, V/V) to obtain the desired title

compound (280 mg, yield 50%) as a colorless solid.
1H NMR (400 MHz, D20): d 1.19 (3H, d, J=5.8 Hz), 2.83 (1H, brs),
3.12 (1H, t, J=9.3 Hz), 3.17-3.23 (1H, m), 3.29-3.37 (2H, m),
3.39-3.45 (2H, m), 3.51 (1H, dd, J=9.76, 2.93 Hz), 3.60 (1H, brt,
J=7.8 Hz), 3.72-4.01 (7H, m), 4.27-4.56 (6H, m), 4.60-4.63 (2H,
m), 4.73-4.75 (4H, brm), 4.78 (1H, d, J=10.75 Hz), 4.85 (1H, d,
J=10.74 Hz), 4.87 (1H, d, J=9.77 Hz), 4.92 (1H, d, J=2.93 Hz),
5.01-5.12 (3H, m), 7.21-7.34 (38H, m), 7.43 (2H, d, J=6.83 Hz);
MS (FAB) m/z: 1207 (M+H)+.
(12b) (2R, 3R,4R)-2-Hydroxymethyl-3-hydroxy-pyrrolidin-4-yl 4-O-
(6-deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (90 mg, 74.6 µmol) synthesized in Example 12
(12a) was dissolved in methanol (10 mL) and hydrochloric acid
(140 µL) and 20% palladium hydroxide-carbon (90 mg) were added
thereto, followed by stirring of the mixture at room temperature
under a hydrogen atmosphere for 2 hours. After the celite
filtration, ammonia water (5%) was added thereto until the pH
became neutral. The solvent was distilled off under reduced
pressure and the residue was purified by ion exchange resin
(Dowex 50w x 8) column (water-5% ammonia water). Further, it
was purified using silica gel flash column chromatography (ethyl
acetate:methanol:water, 1:1:1, V/V) to obtain the desired title
compound (26 mg, 79%) as a colorless solid.
1H NMR (400 MHz, D20) : d 1.32 (3H, d, J=5.8 Hz), 3.17-3.22 (2H,
m), 3.30-3.38 (2H, m), 3.44-3.55 (2H, m), 3.60-3.64 (2H, m),
3.74-3.86 (6H, m), 3.92 (1H, brd, J=ll,72 Hz), 4.13 (1H, brs),
4.24 (1H, brs), 4.48 (1H, d, J=7.81 Hz), 5.11 (1H, d, J=2.93
Hz);
MS (FAB) m/z: 442 (M+H)+.

(2R,3R,4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-
deoxy-a-D-glucopyranosyl) -ß-D-glucopyranoside (Exemplification
compound No. 1-1)


The compound P form (60 mg, 4 6.3 µmol) synthesized in
Example 1 (lj) was dissolved in methanol (4 mL) and hydrochloric
acid (56 µL) and 20% palladium hydroxide-carbon (60 mg) were
added thereto, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere for 4 hours. After the
celite filtration, 18% ammonia water (3 drops) was added thereto
and the solvent was distilled off under reduced pressure. The
residue was purified by ion exchange resin (Dowex 50w x £:)
column (water-5% ammonia water). Further, it was purified using
silica gel flash column chromatography (ethyl
acetate:methanol:water, 3:2:1, V/V) to obtain the desired title
compound (10 mg, 49%) as a colorless solid.
1H NMR (400 MHz, D20) : d 1.29 (3H, d, J=5.8 Hz), 2.93 (1H, dd,
J=11.7, 3.6Hz), 3.15-3.35 (4H, m), 3.51-3.65 (5H, m), 3.74-3.80
(5H, m), 3.93-4.00 (2H, m), 4.40 (1H, br, s), 4.56 (1H, cl, J=7.3
Hz), 5.34 (1H, br, s);
MS (FAB) m/z: 464 (M+Na)+, 442 (M+H)+.
a-D-glucopyranoside
Methyl 2,3-di-O-benzyl-6-O -ß-toluenesulfonyl-a-D-
glucopyranoside (J. Org. Chem., 2001, 66, 5965-5975) (163.9 g,
310 mmol) was dissolved in methylene chloride (1.5 L) and 4-
dimethylaminopyridine (43.5 g, 352 mmol) and triethylamine (49.0
mL, 352 mmol) were added thereto. Benzoyl chloride (43.2 mL,
372 mmol) was dropwise thereto and the mixture was stirred at
0°C for 1 hour. After diluted hydrochloric acid (2N, 500 mL) was
added to the reaction mixture and the mixture was extracted with
methylene chloride (1L), the organic layer was washed with
saturated aqueous sodium hydrogencarbonate (1L) and saturated
brine (1L) and dried with anhydrous sodium sulfate, followed by
distilling off of the solvent under reduced pressure. The
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the
desired title compound(196 g, yield 99%) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.34 (3H, s), 3.40 (3H, s), 3.58 (1H,
dd, J=9.3, 3.4 Hz), 3.98-4.10 (4H, m), 4.57-4.65 (3H, m), 4.79
(1H, d, J=10.8 Hz), 5.06 (1H, dd, J=9.8, 9.8 Hz), 7.08-7.10 (5H,
m), 7.18 (2H, d, J=7.8 Hz), 7.29-7.35 (5H, m), 7.41-7.45 (2H, m),
7.57-7.61 (1H, m), 7.67 (2H, d, J=7.8 Hz), 7.89 (2H, d, J=8.8
Hz);
MS (FAB) m/z: 633 (M+H)+.
(14b) Methyl 4-O-benzoyl-2,3-di-O-benzyl-6-deoxy-6-iode-a-D-
glucopyranoside
The compound (196 g, 310 mmol) synthesized in Example 14
(14a) was dissolved in toluene (2L) and sodium iodide (235 g,
1.57mol) and 18-crown-6-ether (16.6 g, 62.8 mmol) were added
thereto under a nitrogen atmosphere, followed by stirring of the
mixture at 100°C for 2 hours. The reaction mixture was cooled to
room temperature and was filtered and the filtered product was
washed with toluene. The filtrate and the washing liquid were
washed with saturated aqueous sodium hydrogencarbonate (1L) and
saturated brine (1L) and dried with anhydrous sodium sulfate,

followed by distilling off of the solvent under reduced pressure
to obtain the desired title compound (181 g, yield 99%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.12 (1H, dd, J=11.0, 8.8 Hz), 3.29
(1H, dd, J=11.0, 2.2 Hz), 3.51 (3H, s), 3.64 (1H, dd, J=9.6, 3.7
Hz), 3.82-3.89 (1H, m), 4.06 (1H, dd, J=9.6, 8.8 Hz), 4.50-4.68
(3H, m), 4.82 (1H, d, J=11.0 Hz), 4.82 (1H, d, J=12.8 Hz), 5.06
(1H, dd, J=9.5, 9.5 Hz), 7.08-7.10 (5H, m), 7.29-7.38 (5H, m),
7.42-7.47 (2H, m), 7.57-7.61 (1H, m), 7.98 (2H, d, J=8.0 Hz);
MS (FAB) m/z: 589 (M+H)+.
(14c) 4-O-Benzoyl-2, 3-di-O-benzyl-5,6-dideoxy-D-xylo-hex-5-
enose oxime
The compound (181 g, 307 mmol) synthesized in Example 14
(14b) was dissolved in isopropanol (1.5 L) and distilled water
(50 mL) and zinc powder (180 g) washed with diluted hydrochloric
acid was added thereto, followed by stirring of the mixture at
100°C for 1 hour. The reaction mixture was subjected to celite
filtration, the filtered product was washed with ethanol and the
filtrate and the washing liquid were distilled off under reduced
pressure. The residue was dissolved in ethanol (500 mL) and
hydroxylamine hydrochloride (42.7 g, 615 mmol) and pyridine
(49.7 mL, 615 mmol) were added thereto, followed by stirring of
the mixture at 80°C for 40 minutes. The solvent was distilled
off under reduced pressure and the residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
5:1, V/V) to obtain the desired title compound (126 g, yield
921) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.83 (0.7H, dd, J=5.8, 4.9 Hz), 3.99
(0.3H, dd, J=6.2, 3.9 Hz), 4.23 (0.7H, dd, J-7.8, 4.9 Hz), 4.42
(1H, dd, J=11.8, 3.9 Hz), 4.65 (1H, d, J=11.7 Hz), 4.68-4.76 (3H,
m), 4.97 (0.3H, dd, J=5.8, 3.9 Hz), 5.23 (1H, dd, J=10.7, 5.9
Hz), 5.31-5.37 (1H, m), 5.78-5.94 (2H, m), 7.20-7.38 (9H, m),
7.40-7.48 (3H, m), 7.53-7.59 (1H, m), 8.00-8.07 (2H, m);
MS (FAB) m/z: 446 (M+H]+.

(14d) (3aR,4R,5R,GS,6aR)-4-Benzoyloxy-5,6-dibenzyloxy-
hexahydro-cyclopenta[c]isoxasole
The compound (126 g, 282 mmol) synthesized in Example 14
(14c) was dissolved in toluene (800 mL) and the mixture was
stirred at 120°C for 8 hours. The solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V)
to obtain the desired title compound (59.7 g, yield 48%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.83-2.91 (1H, m), 3.45-3.60 (1H, m),
3.89-3.95 (2H, m), 4.11-4.18 (1H, m), 4.55 (1H, m), 4.75-4.87
(4H, m), 5.01 (1H, dd, J=7.8, 6.8 Hz), 5.09-5.13 (1H, m), 7.22-
7.40 (10H, m), 7.43-7.47 (2H, m), 7.57-7.61 (1H, m), 7.97-8.00
(2H, m);
MS (FAB) m/z: 446 (M+H)+.
(14e) (3aR,4R,5S,6S,6aR)-1-Benzyloxycarbonyl-5,6-dibenzyloxy-4-
hydroxy-hexahydro-cyclopenta[c]isoxazole
The compound (59.7 g, 134 mmol) synthesized in Example
14 (14d) was dissolved in methanol (1L) and sodium methoxide (10
mL, 4 9 mmol) was added thereto, followed by stirring of the
mixture at room temperature for 15 minutes. After saturated
aqueous ammonium chloride solution (500 mL) was added to the
reaction mixture at 0°C and the mixture was extracted with ethyl
acetate (1.5 L), the organic layer was washed with saturated
brine (50 mL). Saturated aqueous sodium hydrogencarbonate (500
mL) and benzyloxychloroformate (22.9 mL, 160 mmol) were added to
the organic layer at 0°C and the mixture was stirred at 0ºC for 1
hour. After the organic layer was washed with saturated brine
(500 mL) and dried with anhydrous sodium sulfate, the solvent
was distilled off under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate, 1:1, V/V) to obtain the desired title
compound (61.3 g, yield 96%) as a colorless solid.

1H NMR (400 MHz, CDCl3) : d 2.30 (1H, brd, J=3. 7 Hz, OH), 2.91 (1H,
ddd, J=8.9, 8.9, 5.7 Hz, H-3a), 3.58 (1H, dd, J=9.0, 5.7 Hz, H-
3), 3.73 (1H, dd, J-8.6, 8.4 Hz, H-5), 3.82 (1H, ddd, J=8.9, 8.6,
3.7 Hz, H-4), 3.84 (1H, dd, J=8.4, 5.. 6 Hz, H-6), 3.98 (1H, d,
J=9.0 Hz, H-3), 4.54 (1H, d, J=11.3 Hz), 4.54 (]H, dd, J=8.9,
5.6 Hz, H-6a), 4.63 (1H, d, J=11.7 Hz), 4.84 (1H, d, J=11.3 Hz),
4.87 (1H, d, J=11.7 Hz), 5.20 (1H, d, J=12.J Hz), 5.27 (1H, d,
J=12.1 Hz), 7.23-7.40 (15H, m).
MS (FAB) m/z: 476 (M+H)+.
(14f) (3aR,4R,5R,6S,6aR)-1-Benzyloxycarbonyl-5,6-dibenzyloxy-
hexahydro-cyclopenta[c]isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O-(6-
deoxy-2,3,4-tri-O-benzyl-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (215 mg, 0.248 mmol) synthesized in Example
1 (If) was dissolved in methylene chloride (5 mL) and
trichloroacetonitrile (460 µl. 4.61 mmol) and 1, 8-diazabicyclo
[5.4.0]-7-undecene (2 drops) were added thereto, followed by
stirring of the mixture at room temperature for 40 minutes.
After the solvent was distilled off under reduced pressure, the
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (250 mg, 99%) as a yellow oil. The
compound (100 mg, 0.21 mmol) synthesized in Example 14 (14e) was
dissolved in diethyl ether (10 mL) and imidate (250 mg, 0.248
mmol) was added thereto. Trimethylsilyl
trifluoromethanesulfonate (3.8 µL, 0.021 mmol) was added
dropwise thereto and the mixture was stirred at room temperature
for 4 5 minutes. After triethylamine (4 drops) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:diethyl ether, 2:1, V/V) to obtain
the desired title compound (55 mg, 17%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): d 1.15 (3H, d, J=6.8 Hz), 3.01-3.12 (2H,
m), 3.14 (1H, dd, J=9.8, 3.9 Hz), 3.50-3.62 (3H, m), 3.64-3.80
(2H, m), 3.80-3.96 (5H, m), 3.99-4.10 (2H, m), 4.43 (1H, d,

J=11.7 Hz), 4.47 (1H, d, J=11.7 Hz), 4.50-4.62 (7H, m), 4.68-
4.93 (8H, m), 5.06 (1H, d, J=11.7 Hz), 5.18-5.29 (3H, m), 5.61
(1H, d, J=3.9 Hz), 7.05-7.41 (45H, m);
MS (FAB) m/z: 1324 (M+H)+.
(14g) (1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-
cyclopent-4-yl 4-O-(6-deoxy-a-D-glucopyranosyl)-a-D-
glucopyranoside
The compound (53 mg, 40.4 µmol) synthesized in Example 14
(14f) was dissolved in methanol (10 mL) and hydrochloric acid
(10 µL) and 20% palladium hydroxide-carbon (53 mg) were added
thereto, followed by stirring of the mixture at room temperature
under a hydrogen atmosphere for 4 hours. After celite
filtration, the solvent was distilled off under reduced pressure
and the residue was purified by ion exchange resin (Dowex 50w x
8) column (water-5% ammonia water). Further, it was purified
using silica gel flash column chromatography (ethyl
acetate:methanol:water, 1:1:1, V/V) to obtain the desired title
compound (5 mg, 26%) as a colorless solid.
1H NMR (400 MHz, D20) : d 1.18 (3H, d, J=6.8 Hz), 2.00-2.08 (1H,
m), 2.15-2.22 (1H, m), 3.03-3.09 (1H, m), 3.16-3.22 (1H, m),
3.45-3.57 (5H, m), 3.58-3.78 (8H, m), 3.81-3.89 (3H, m), 5.10
(1H, d, J=2.9 Hz), 5.23 (1H, d, J=2. 9 Hz);
MS (FAB) m/z: 472 (M+H)+.

(1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-
cyclopent-4-yl 4-O-(6-deoxy -ß-D-glucopyranosyl)-a-D-
glucopyranoside (Exemplification compound No. 5-1)
(15a) (3aR,4R,5R,6S,6aR)-1-Benzyloxycarbonyl-5, 6-dibenzyloxy-
hexahydro-cyclopenta[c]isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O-(6-
deoxy-2,3,4-tri-O-benzyl -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (1.0 g, 1.15 mmol) synthesized in Example 2
(2f) was dissolved in methylene chloride (30 mL) and
trichloroacetonitrile (460 j µL, 4.61 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 40
minutes. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane: ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (970 mg, 84%) as a yellow oil. The
compound (508 mg, 1.06 mmol) synthesized in Example 14 (14e) was
dissolved in diethyl ether (20 mL) and imidate (970 mg, 0.97
mmol) was added thereto. Trimethylsilyl
trifluoromethanesulfonate (17 µL, 0.097 mmol) was added dropwise
thereto and the mixture was stirred at room temperature for 45
minutes. After triethylamine (4 drops) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure..The residue was purified using silica gel flash
column chromatography (hexane:diethyl ether, 1:1, V/V) tc obtain
the desired title compound (125 mg, 9%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): d 1.22 (3H, d, J=6.8 Hz), 2.81-2.87 (1H,
m), 3.15 (1H, dd, J=9.8, 8.7 Hz), 3.19-3.24 (1H, m), 3.28-3.36
(2H, m), 3.40-3.45 (1H, m), 3.52 (1H, dd, J=8.8, 3.9 Hz), 3.55-
3.59 (1H, m), 3.75 (1H, dd, J=10.7, 3..9 Hz), 3.79-3.84 (2H, m),
3.86-3.91 (1H, m), 3.93-4.01 (2H, m), 4.31 (1H, d, J=11.7 Hz),
4.35 (1H, d, J=7.8 Hz), 4.50 (1H, d, J=11.7 Hz), 4.52-4.59 (2H,

m), 4.60-4.64 (3H, m), 4.70-4.87 (10H, m), 4.89 (1H, d, J=12.7
Hz), 5.00 (1H, d, J=10.7 Hz), 5.07 I.1H, d, J=3.9 Hz), 5.21 (1H,
d, J=11.7 Hz), 5.28 (1H, d, J= 12.7 Hz), 7.10-7.43 (45H, m);
MS (FAB) m/z: 1324 (M+H)+.
(15b) (1R,2S,3R,4R,5R)-1-Amino-2,3-dihydroxy-5-hydroxymethyl-
cyclopent-4-yl 4-O-(6-deoxy-3-D-glucopyranosyl)-a-D-
glucopyranoside
The compound (115 mg, 86.8 µmol) synthesized in Example
15 (15a) was dissolved in methanol (20 mL) and ethyl acetate (1
mL) and hydrochloric acid (10 µL) and 20% palladium hydroxide-
carbon (115 mg) were added thereto, followed by stirring of the
mixture at room temperature under a hydrogen atmosphere for 4
hours. After celite filtration, the solvent was distilled off
under reduced pressure and the residue was purified by ion
exchange resin (Dowex 50w x 8) column (water-5% ammonia water).
Further, it was purified using silica gel flash column
chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to
obtain the desired title compound (30 mg, 73%) as a colorless
amorphous.
[a]D20 +60.9 (c 0.11, H20);
1H NMR (400 MHz, D20): d 1.21 (3H, d, J=6.8 Hz), 2.17-2.25 (1H,
m), 3.05-3.10 (1H, m), 3.18-3.27 (2H, m), 3.30-3.92 (14H, m),
4.38 (1H, d, J=7.8 Hz), 5.08-5.10 (1H, m);
MS (FAB) m/z: 472 (M+H)+.

(1R,2S,3R,4R,5R)-1-(2-Hydroxy-1-hydroxymethyl-ethylamino)-2,3-
dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O-(6-deoxy -ß-D-
glucopyranosyl)-a-D-glucopyranoside (Exemplification compound No.
5-22)
(16a) (3aR,4R,5R,6S, 6aR)-4-Benzoyloxy-5,6-dibenzyloxy-1-(1,3-
dihydroxyprop-2-yl)-hexahydro-cyclopenta[c]isoxazole
The compound (3.07 g, 6.89 mmol) synthesized in Example
14 (14d) was dissolved in methanol (10 mL) and tetrahydrofuran
(10 mL) and 1,3-dihydroxyacetone (1.86 g, 20.7 mmol) and acetic
acid (1 mL) were added thereto, followed by stirring of the
mixture at 70°C for 30 minutes. Sodium cyanoborohydride (1.30 g,
20.67 mmol) was added thereto and the mixture was stirred at
70°C for 10 hours. The solvent was distilled off under reduced
pressure and the residue was purified using silica gel flash
column chromatography (methylene chloride:methanol, 20:1, V/V)
to obtain the desired title compound (1.20 g, yield 33%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.35 (1H, dd, J=6.8, 4.9 Hz), 2.39 (1H,
t, J=5.9 Hz), 2.77-2.82 (1H, m), 2.93-3.00 (1H, m), 3.74-3.84
(3H, m), 3.88-3.94 (1H, m), 3.96-4.08 (3H, m), 4.21-4.26 (2H, m),
4.74-4.86 (4H, m), 5.05 (1H, d, J=7.8, 5.9 Hz), 7.26-7.38 (10H,
m), 7.45-7.50 (2H, m), 7.59-7.64 (1H, m), 7.98-8.02 (2H, m);
MS (FAB) m/z: 520 (M+H)+.
(16b) (3aR,4R,5S,6S,6aR)-5,6-Dibenzyloxy-1-(2,2-dimethyl-
[1,3]dioxan-5-yl)-4-hydroxy-hexahydro-cyclopenta[c]isoxazole
The compound (1.20 g, 2.31 mmol) synthesized in Example
16 (16a) was dissolved in acetone (30 mL) and 2,2-dimethcxy
propane (2.27 mL, 18.5 mmol) and p-toluenesulfonic acid
monohydrate (660 mg, 3.47 mmol) were added thereto, followed by
stirring of the mixture at room temperature for 15 minutes.

After saturated aqueous sodium hydrogencarbonate (50 mL) was
added to the reaction mixture at 0°C and the mixture was
extracted with ethyl acetate (50 mL), the organic layer was
washed with saturated brine (50 mL). The solvent was distilled
off under reduced pressure and the residue was dissolved in
methanol. Sodium methoxide (0.4 mL, 1.96 mmol) was added
thereto and the mixture was stirred at room temperature for 20
minutes. After saturated aqueous ammonium chloride (50 mL) was
added to the reaction mixture at 0°C and the mixture was
extracted with ethyl acetate (50 mL), the organic layer was
washed with saturated brine (50 mL) and dried with anhydrous
sodium sulfate, followed by distilling off of the solvent under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to
obtain the desired title compound (840 mg, yield 80%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 1.39 (3H, s), 1.47 (3H, s), 2.06 (1H,
d, J=3.9 Hz), 2.85-2.96 (2H, m), 3.49 (1H, dd, J=9.8, 6.8 Hz),
3.67-3.72 (1H, m), 3.75-3.85 (6H, m), 3.89-3.97 (2H, m), 4.67
(1H, d, J=11.7 Hz), 4.68 (1H, d, J=11.7 Hz), 4.76 (1H, d, J=11.7
Hz), 4.85 (1H, d, J=11.7 Hz), 7.26-7.38 (10H, m);
MS (FAB) m/z 456: (M+H)+.
(16c) (3aR,4R,5S,6S,6aR)-5,6-Dibenzyloxy-1-(2, 2-dimethyl-
[1, 3]dioxan-.5-yl) -hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-
tri-O-benzyl-4-O-(6-deoxy-2,3,4-tri-O-benzyl -ß-D-
glucopyranosyl)-a-D-glucopyranoside
The compound (600 mg, 0.692 mmol) synthesized in Example
2 (2f) was dissolved in methylene chloride (20 mL) and
trichloroacetonitrile (277 µL, 2.76 mmol) and 2,8-
diazabicyclo[5.4.0]-7-undecene (2 drops) were added thereto,
followed by stirring of the mixture at room temperature for 40
minutes. After the solvent was distilled, off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,

V/V) to obtain imidate (550 mg, 80%) as a yellow oil. The
compound (230 mg, 0.501 mmol) synthesized in Example 16;i6b)
was dissolved in diethyl ether (10 ml.) and imidate (550 ng,
0.551 mmol) was added thereto. Trimethylsilyl
trifluoromethanesulfonate (45 µl. 0.250 mmol) was added dropwise
thereto and the mixture was stirred at room temperature for 4 5
minutes. After triethylamine (4 drops) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain
the desired title compound (140 mg, 20%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) : d 1.22 (3H, d, J=5.8 Hz), 1.43 (3H, s),
1.49 (3H, s), 2.70-2.80 (2H, m), 3.11-3.17 (1H, m), 3.19-3.27
(1H, m), 3.30-3.54 (6H, m), 3.61-3.95 (12H, m), 4.34 (1H, d,
J=11.7 Hz), 4.38 (1H, d, J=7.3 Hz), 4.52 (1H, d, J=12.5 Hz),
4.58-4.73 (5H, m), 4.73-4.90 (8H, m), 5.00 (1H, d, J=3.7 Hz),
5.03 (1H, d, J=11.0 Hz), 7.17-7.38 (38H, m), 7.43-7.47 (2H, m).
MS (FAB) m/z: 1304 (M+H)+.
(16d) (1R,2S,3R,4R,5R)-1-(2-Hydroxy-1-hydroxymethyl-
ethylamino)-2, 3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O-(6-
deoxy -ß-D-glucopyranosyl)-a-D-glucopyranoside
The compound (146 mg, 113 µmol) synthesized in Example 16
(16c) was dissolved in acetic acid (10 mL) and distilled water
(2.5 mL) and the mixture was stirred at 50°C for 1 hour. The
solvent was distilled off under reduced pressure and the residue
was purified using silica gel flash column chromatography
(hexanerethyl acetate, 1:1, V/V) to obtain diol (128 mg, 101
µmol) as a colorless crystal. The diol (118 mg, 93.3 µmol) was
dissolved in methanol (20 mL) and ethyl acetate (1 mL) and
hydrochlo ric acid (30 µL) and 20% palladium hydroxide—carbon
(118 mg) were added thereto, followed by stirring of the mixture
at room temperature under a hydrogen atmosphere for 4 hours.
After celite filtration, the solvent was distilled off under
reduced pressure and the residue was purified by ion exchange

resin (Dowex 50w x 8) column (water-5% ammonia water). Further,
it was purified using silica gel flash column chromatography
(ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired
title compound (43 mg, 841) as a colorless solid.
1H NMR (400 MHz, D20) : d 1.32 (3H, d, J=6.8 Hz), 2.34-2.41 (1H,
m), 2.88-2.94 (1H, m), 3.16-3.22 (1H, m), 3.29-3.38 (2H, m),
3.42-3.50 (1H, m), 3.49-3.97 (16H, m), 4.48 (1H, d, J=7.8 Hz),
5.18 (1H, d, J=7.8 Hz);
13C NMR (100 MHz, D20): 816.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6,
61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5,
81.9, 97.8, 102.7;
MS (FAB) m/z: 546 (M+H)+.
1,3,4,6-tetra-O-Acetyl-2-deoxy-2-fluoro-P-D-glucopyranose
(Carbohydr. Res., 153, 1986, 168-170) (13.4 g, 38.3 mmol) was
dissolved in methanol (150 mL) and Dowex 50w x 8 (19 g) was
added thereto, followed by stirring of the mixture at 80°C for
12 hours. The reaction mixture was subjected to celite
filtration and the filtered product was washed with methanol.
The filtrate and the washing liquid were combined and distilled
off under reduced pressure. The residue was purified using
silica gel flash column chromatography (methylene
chloride:methanol, 10:1-5:1, V/V) to obtain the desired title

compound (3.37 g, yield 45%) as a colorless solid.
1H NMR (400 MHz, CD30D) : d 3.32-3.36 (1H, m), 3.43 (1.5H, s),
3.52-3.64 (2H, m), 3.54 (1.5H, s), 3.65-3.70 (1H, m), 3.80-3.92
(2.5H, m), 4.16-4.29 (0.5H, m), 4.43 (0.5H, dd, J=7.8, 2.9 Hz),
4.88 (0.5H, d, J=3.9 Hz).
MS (FAB) m/z: 197 (M+H)+.
(17b) Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-D-
glucopyranoside
The compound (3.5 g, 17.9 mmol) synthesized in Example
17 (17a) was dissolved in dimethylformamide (70 mL) and
benzaldehyde dimethylacetal (3.75 mL, 25.0 mmol) and p-
toluenesulfonic acid monohydrate (170 mg, 0.892 mmol) were added
thereto, followed by stirring of the mixture at 50°C under
reduced pressure for 2 hours. Triethylamine (2 mL) was added to
the reaction mixture and the solvent was distilled off under
reduced pressure. The residue was purified using silica gel
flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to
obtain the desired title product (3.36 g, yield 66%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.42-3.58 (1H, m), 3.48 (2H, s), 3.60
(1H, s), 3.70-3.90 (1.33H, m), 3.98-4.08 (0.66H, m), 4.16-4.40
(2H, m), 4.48-4.54 (1H, m), 4.94 (0.66H, d, J=4.4 Hz), 5.02-5.06
(0.33H, m), 5.52-5.54 (1H, m), 7.36-7.41 (3H, m), 7.46-7.51 (2H,
m);
MS (FAB) m/z: 285 (M+H)+.
(17c) Methyl 4-O-benzoyl-3-O-benzyl-2-deoxy-2-fluoro-6-O -ß-
toluenesulfonyl-D-glucopyranoside
The compound (3.36 g, 11.8 mmol) synthesized in Example
17 (17b) was dissolved in dimethylformamide (50 mL) and sodium
hydride (741 mg, 17.7 mmol) was added thereto under a nitrogen
atmosphere, followed by stirring of the mixture at room
temperature for 30 minutes. The reaction mixture was ice-cooled
and benzyl bromide (1.68 mL, 14.1 mmol) was added thereto,

followed by stirring of the mixture at room temperature for 2
hours. After saturated aqueous ammonium chloride solution (50
mL) was added to the reaction mixture at 0°C and the mixture was
extracted with ethyl acetate (100 mL), the organic layer was
washed with saturated brine (100 mL) and dried with anhydrous
sodium sulfate, followed by distilling off of the solvent under
reduced pressure. Acetic acid (16 mL) and distilled water (4
mL) were added to the residue and the mixture was stirred at
60°C for 3 hours. The solvent was distilled off under reduced
pressure and the reaction mixture was azeotroped with toluene.
The residue was dissolved in pyridine (10 mL) and p-
toluenesulfonic acid chloride (1.75 g, 9.20 mmol) and 4-
dimethylaminopyridine (101 mg, 0.83 mmol) were added thereto
under ice-cooling, followed by stirring of the mixture at room
temperature for 6 hours. The reaction mixture was ice-cooled
and diluted hydrochloric acid (2N, 80 mL) was added thereto.
After the mixture was extracted with ethyl acetate (100 mL), the
organic layer was washed with saturated aqueous sodium
hydrogencarbonate (200 mL) and saturated brine (200 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was
dissolved in methylene chloride (40 mL) and 4-
dimethylaminopyridine (1.28 g, 10.5 mmol), benzoyl chloride
(1.30 mL, 11.2 mmol) and triethylamine (1.46 mL, 10.5 mmol) were
added thereto under ice-cooling, followed by stirring of the
mixture at 0°C for 3 hours. The reaction mixture was ice-cooled
and diluted hydrochloric acid (2N, 80 mL) was added thereto.
After the mixture was extracted with methylene chloride (100 mL),
the organic layer was washed with saturated aqueous sodium
hydrogencarbonate (200 mL) and saturated brine (100 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:ethyl
acetate, 3:1, V/V) to obtain the desired title compound (4.16 g,
yield 65%) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.35 (3/2H, s), 2.36 (3/2H, s), 3.47
(3/2H, s), 3.55 (3/2H, s), 3.79-3.88 (1H, m), 4.01-4.15 (3H, m),
4.28-4.62 (3.5H, m), 4.77 (1H, dd, J=11.7, 5.1 Hz), 4.91 (0.5H,
d, J=4.4 Hz), 5.05-5.12 (1H, m), 7.06-7.10 (5H, m), 7.18-7.22
(2H, m), 7.42-7.48 (2H, m), 7.58-7.65 (1H, m), 7.66-7.71. (2H, m),
7.89-7.93 (2H, m);
MS (FAB) m/z: 545 (M+H)+.
(17d) Methyl 4-O-benzoyl-3-O-benzyl-2,6-dideoxy-2-fluoro-6-
iode-D-glucopyranoside
The compound (3.83 g, 7.03 mmol) synthesized in Example
17 (17c) was dissolved in toluene (120 mL) and sodium iodide
(5.27 g, 39.2 mmol) and 18-crown-6-ether (370 mg, 1.40 mmol)
were added thereto under a nitrogen atmosphere, followed by
stirring of the mixture at 100°C for 2 hours. The reaction
mixture was cooled to room temperature and filtered and the
filtered product was washed with toluene. The filtrate and the
washing liquid were washed with saturated aqueous sodium
hydrogencarbonate (100 mL) and saturated brine (100 mL) and
dried with anhydrous sodium sulfate, followed by distilling off
of the solvent under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:ethyl
acetate, 5:1, V/V) to obtain the desired title compound (3.38 g,
yield 96%) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.12-3.21 (1H, m), 3.27-3.32 (1H, m),
3.57-3.62 (1H, m), 3.58 (3/2H, s), 3.65 (3/2H, s), 3.82-3.91 (1H,
m), 4.38-4.68 (5/2H, m), 4.79 (1H, dd, J=11.7, 6.8 Hz), 4.99
(1/2H, dd, J=3.9 Hz), 5.06-5.13 (1H, m), 7.07-7.18 (5H, m),
7.43-7.48 (2H, m), 7.59-7.64 (1H, m), 7.95-8.00 (2H, m);
MS (FAB) m/z: 501 (M+H)+.
(17e) 4-O-Benzoyl-3-O-benzyl-2-fluoro-2, 5,6-trideoxy-D-xylo-
hex-5-enose oxime
The compound (3.37 g, 6.74 mmol) synthesized in Example
17 (17d) was dissolved in isopropanol (40 mL) and distilled
water (1.3 mL) and zinc powder (4 g) washed with diluted
hydrochloric acid was added thereto, followed by stirring of the
mixture at 100°C for 1 hour. The reaction mixture was subjected
to celite filtration, the filtered product was washed with
ethanol and the filtrate and the washing liquid were distilled
off under reduced pressure. The residue was dissolved in
ethanol (80 mL) and hydroxylamine hydrochloride (1.18 g, 17.1
mmol) and pyridine (1.38 mL, 17.1 mmol) were added thereto,
followed by stirring of the mixture at 60°C for 40 minutes. The
solvent was distilled off under reduced pressure and the residue
was purified using silica gel flash column chromatography
(hexanerethyl acetate, 5:1, V/V) to obtain the desired title
compound (1.31 g, yield 54%) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 3.87-3.94 (0.7H, m), 4.13-4.22 (0.3H,
m), 4.64-4.82 (2H, m), 5.22 (0.7H, ddd, J=46.9, 6.8, 4.9 Hz),
5.34-5.55 (2H, m), 5.75-5.88 (1.3H, m), 5.98-6.07 (1H, m), 7.24-
7.62 (8H, m), 8.03-8.08 (2H, m);
MS (FAB) m/z: 358 (M+H)+.
(17f) (3aR,4R,5S,6S,6aR)-4-Benzoyloxy-5-benzyloxy-6-fluoro-
hexahydro-cyclopenta[c]isoxazole
The compound (1.31 g, 3.66 mmol) synthesized in Example
17 (17e) was dissolved in toluene (30 mL) and the mixture was
stirred at 120°C for 8 hours. The solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexanerethyl acetate, 3:1, V/V)
to obtain the desired title compound (965 mg, yield 74%) as a
colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.91-2.98 (1H, m), 3.50-3.58 (1H, m),
4.00-4.10 (1H, m), 4.21-4.28 (1H, m), 4.54 (1H, brd, J=7.8 Hz),
4.72 (1H, d, J=12.7 Hz), 4.83 (1H, d, J=12.7 Hz), 4.84 (1H, ddd,
J=52.7, 7.8, 5.8 Hz), 4.98-5.02 (1H, m), 5.11-5.15 (1H, m),
7.28-7.36 (5H, m), 7.45-7.49 (2H, m), 7.59-7.63 (1H, m), 7.97-
8.00 (2H, m);
MS (FAB) m/z 358: (M+H)-.

(17g) (3aR,4R,5S,6S,6aR)-5-Benzyloxy-1-benzyloxycarbonyl-6-
fluoro-4-hydroxy-hexahydro-cyclopenta[c]isoxazole
The compound (950 mg, 2.66 mmol) synthesized in Example
17 (17f) was dissolved in methanol (10 mL) and sodium methoxide
(270 µL, 1.30 mmol) was added thereto, followed by stirring of
the mixture at room temperature for 15 minutes. After saturated
aqueous ammonium chloride solution (50 mL) was added to the
reaction mixture at 0°C and the mixture was extracted with ethyl
acetate (50 mL), the organic layer was washed with saturated
brine (50 mL) and dried with anhydrous sodium sulfate, followed
by distilling off of the solvent under reduced pressure. The
residue was dissolved in ethyl acetate (100 mL) and saturated
aqueous sodium hydrogencarbonate (50 mL) and benzyl
oxychloroformate (570 µl. 4.00 mmol) were added thereto at 0°C,
followed by stirring of the mixture at 0°C for 1 hour. The
organic layer was washed with saturated brine (50 mL) and dried
with anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
1:1, V/V) to obtain the desired title compound (1.00 g, yield
97%) as a colorless solid.
1H NMR (400 MHz, CDCl3) : d 2.29 (1H, brd, J=3.3 Hz, OH), 2.92-
2.99 (1H, m, H-3a), 3.60 (1H, dd, J=9.0, 5.8 Hz, H-3), 3.82-3.91
(2H, m, H-5, H-4), 3.98 (1H, d, J=8.8 Hz, H-3), 4.61 (1H, d,
J=12.7 Hz, CH2Ph), 4.62-4.70 (1H, m, H-6a), 4.72-4.76 (1/2H, m,
H-6), 4.84 (1H, d, J=12.7 Hz, CH2Ph), 4.82-4.86 (1/2H, m, H-6),
5.21 (2H, s), 7.23-7.40 (10H, m);
MS (FAB) m/z: 388(M+H)+.
(17h)(3aR,4R,5S,6S,6aR)-5-Benzyloxy-1-benzyloxycarbonyl-6-
fluoro-hexahydro-cyclopentafc]isoxazol-4-yl 2,3,6-tri-O-benzyl-
4-O-(6-deoxy-2,3,4-tri-O-benzyl -ß-D-glucopyranosyl)-a-D-
glucopyranoside
The compound (840 mg, 0.969 mmol) synthesized in Example

2 (2f) was dissolved in methylene chloride (10 mL) and
trichloroacetoni trile (460 µl. 4.61 mmol) and 1,8-diazabicyclo
[5.4.0]-7-undecene (2 drops) were added thereto, followed by
stirring of the mixture at room temperature for 40 minutes.
After the solvent was distilled off under reduced pressure, the
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (830 mg, 85%) as a yellow oil. The
compound (300 mg, 0.756 mmol) synthesized in Example 17 (17g)
was dissolved in diethyl ether (15 mL) and imidate (830 mg,
0.832 mmol) was added thereto. Trimethylsilyl
trifluoromethanesulfonate (13 (iL, 0.0756 mmol) was added
dropwise thereto and the mixture was stirred at room temperature
for 4 5 minutes. After triethylamine (4 drops) was added to the
reaction mixture, the solvent was distilled off under reduced
pressure. The residue was purified using silica gel flash
column chromatography (hexane:diethyl ether, 2:1, V/V) to obtain
the desired title compound (86 mg, 9%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) : d 1.20 (3H, d, J=5.9 Hz), 2.87-2.94 (1H,
m), 3.10-3.16 (1H, m), 3.19-3.24 (1H, m), 3.28-3.38 (3H, m),
3.42-3.46 (1H, m), 3.51 (1H, dd, J=9.8, 3.9 Hz), 3.55-3.59 (1H,
m), 3.74 (1H, dd, J=10.7, 3.9 Hz), 3.79-3.84 (2H, m), 3.84-3.89
(1H, m), 3.94 (1H, d, J=9.8 Hz), 4.00-4.06 (1H, m), 4.31 (1H, d,
J=12.7 Hz), 4.35 (1H, d, J=7.8 Hz), 4.49 (1H, d, J=12.7 Hz),
4.58-4.88 (13H, m), 5.01 (1H, d, J=10.8 Hz), 5.05 (1H, d, J=3.9
Hz), 5.18-5.26 (2H, m), 7.15-7.43 (40H, m);
MS (FAB) m/z: 1236 (M+H)+.
(17i) (1R,2S,3S,4R,5R)-1-Amino-2-fluoro-3-hydroxy-5-
hydroxymethyl-cyclopent-4-yl 4-O-(6-deoxy -ß-D-glucopyrancsyl) -a-
D-glucopyranoside
The compound (85 mg, 68.8 pmol) synthesized in Example 17
(17h) was dissolved in methanol (20 mL) and ethyl acetate (1 mL)
and hydrochloric acid (30 µL) and 20% palladium hydroxide-carbon
(85 mg) were added thereto, followed by stirring of the mixture

at room temperature under a hydrogen atmosphere for 4 hours.
After celite filtration, the solvent was distilled off under
reduced pressure and the residue was purified by ion exchange
resin (Dowex 50w x 8) column (water-5% ammonia water). Further,
it was purified using silica gel flash column chromatography
(ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired
title compound (28mg, 861) as colorless amorphous matter.
1H NMR (400 MHz, D20) : d 1.21 (3H, d, J=5.9 Hz), 2.23-2.33 (1H,
m), 3.04-3.10 (1H, m), 3.18-3.25 (2H, m), 3.28-3.61 (6H, m),
3.64-3.80 (5H, m), 3.86-3.91 (1H, m), 4.11-4.18 (1H, m), 4.37
(1H, d, J=8.8 Hz), 4.41-4.46 (1/2H, m), 4.52-4.57 (1/2H, m),
5.06-5.08 (1H, m);
13C NMR (100 MHz, D20) : 516.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6,
61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5,
81.9, 97.8, 102.7;
MS (FAB) m/z: 474 (M+H)+.

2-O-Benzyl-4-deoxy-3-O-formyl-4-trifluoroacetamido-D-
arabinoside (Chem. Pharm. Bull., 1991, 39, 2807-2812) (0.80 g,
2.20 mmol) was dissolved in methylene chloride (50 mL) and
benzyl trichloroacetoimidate (0.82 mL, 4.40 mmol) and
trifluoromethanesulfonic acid (40 µL, 0.22 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 3 hours. After saturated aqueous sodium hydrogencarbonate

(30 mL) was added to the reaction mixture at 0°C and the mixture
was diluted with ethyl acetate (100 mL), the mixture was; washed
with water (50 mL) and saturated brine (50 mL) and dried with
anhydrous sodium sulfate, followed by distilling off of the
solvent under reduced pressure. The residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
6:1, V/V) to obtain the desired title compound (0.73 g, yield
74%) as pale yellow amorphous matter.
1H NMR (CDCl3) : d 3.55 (1H, dd, J=12.5, 2.2 Hz), 3.63 (1H, dd,
J=10.3, 3.7 Hz), 4.13 (1H, d, J=13.9 Hz), 4.50 (1H, d, J=11.0
Hz), 4.53 (1H, d, J=12.5 Hz), 4.61 (1H, d, J=11.7 Hz), 4.62 (1H,
br, s), 4.75 (1H, d, J=12.5 Hz), 4.90 (1H, d, J=2.9 Hz), 5.44
(1H, dd, J=10.3, 4.4 Hz), 6.69 (1H, d, J=7.33 Hz), 7.13-7.38
(10H, m), 8.00 (1H, s);
MS (FAB) m/z: 476 (M+Na)+.
(18b) 1,2-di-O-Benzyl-4-deoxy-4-trifluoroacetamido-a-D-
arabinoside
The compound (0.73 g, 1.61 mmol) synthesized in Example
18 (18a) was dissolved in methanol (30 mL) and water (5 mL) and
potassium hydrogencarbonate (1.00 g, 10.0 mmol) was added
thereto, followed by stirring of the mixture at room temperature
for 15 hours. Ethyl acetate (50 mL) was added thereto and the
organic layer was washed with saturated brine (20 mL). After it
was dried with anhydrous sodium sulfate, the solvent was
distilled off under reduced pressure. The residue was purified
using silica gel flash column chromatography (hexane:ethyl
acetate, 6:1, V/V) to obtain the desired title compound (205 mg,
yield 41%) as colorless amorphous matter.
1H NMR (CDCl3) : d 2.84 (1H, d, J=2.2Hz), 3.44 (1H, dd, J=9.5, 2.9
Hz), 3.76 (1H, dd, J=12.5, 1.5 Hz), 3.92 (1H, dd, J=12.5, 1.5
Hz), 4.20-4.28 (2H, m), 4.47 (1H, d, J=11.7 Hz), 5.53 (2H, s),
4.72 (1H, d, J=12.5 Hz), 4.91 (1H, d, J=3.7 Hz), 6.67 (1H, br, d,
J=5.86 Hz), 7.12-7.38 (10H, m);
MS (FAB) m/z: 426(M+H)+. 448 (M+Na)+.

(18c) 1, 2-di-O-Benzyl-4-deoxy-4-trifluoroacetamido-3-O-[2,3,6-
tri-O-benzyl-4-O- (2, 3, 4-tri-O-benzyl-6-deoxy-(3-D-
glucopyranosyl)-a-D-glucopyranosyl}-a-D-arabinoside
The compound (0.70 g, 0.81 mmol) synthesized in Elxample
2 (2f) was dissolved in methylene chloride (20 mL) and
trichloroacetonitrile (1.00 mL, 10.0 mmol) and 2 drops of 1,8-
diazabicyclo[5.4.0]-7-undecene were added thereto, followed by
stirring of the mixture at room temperature for 30 minutes.
After the solvent was distilled off under reduced pressure, the
residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 5:1, 1% triethylamine,
V/V) to obtain imidate (0.75 g, 92%) of colorless oil. The
compound (205 mg, 0.48 mmol) synthesized in Example 18 (18b) and
imidate (0.75 g, 0.74 mmol) were dissolved in diethyl ether (30
mL) and trimethylsilyl trifluoromethanesulfonate (8.7 µl. 0.074
mmol) was added thereto under a nitrogen atmosphere, followed by
stirring of the mixture at room temperature for 3 hours. After
triethylamine (0.1 mL) was added to the reaction mixture and the
solvent was distilled off under reduced pressure, the residue
was diluted with ethyl acetate (30 mL) and the mixture was
washed with saturated aqueous sodium hydrogencarbonate (20 mL)
and saturated brine (20 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure and the residue was purified using silica
gel flash column chromatography (hexane:diethyl ether, 3:1, V/V)
to obtain the desired title compound (185 mg, 31%) and its ß
isomer (250 mg, 41%) as colorless amorphous matter.
1H NMR (CDCl3) : d 1.17 (3H, d, J=5.9 Hz), 3.12 (1H, t, J=9.5 Hz),
3.19-3.25 (1H, m), 3.36 (1H, t, J=9.5 Hz), 3.44-3.50 (2H, m),
3.54-3.64 (3H, m), 3.75 (1H, t, J=9.5 Hz), 3.81-3.98 (4H, m),
4.19 (1H, dd, J=8.8, 4.4 Hz), 4.35-4.39 (3H, m), 4.45 (1H, d,
J=11.7 Hz), 4.49-4.54 (3H, m), 4.59-4.61 (2H, m), 4.67-4.80 (6H,
m), 4.84 (1H, d, J=11.0 Hz), 4.90 (1H, d, J=1.0 Hz), 4.94 (1H, d,
J=11.7 Hz), 5.02 (1H, d, J=11.0 Hz), 5.18 (1H, d, J=3.7 Hz),

6.88 (1H, br, d, J=7.3 Hz), 7.10-7.40 (40H, m);
MS (FAB) m/z: 1296 (M+Na)+.
(18d) 4-Deoxy-4-trifluoroacetamido-3-O-{4-O- (6-deoxy-ß-D-
glucopyranosyl)-a-D-glucopyranosyl}-D-arabinoside
The compound (180 mg, 0.14 mmol) synthesized in Example
18 (18c) was dissolved in methanol (10 mL) and 20% palladium
hydroxide-carbon (120 mg) was added thereto, followed by
stirring of the mixture under a hydrogen atmosphere for 3 hours.
After the catalyst was removed by celite filtration, the solvent
was distilled off under reduced pressure. The residue was
purified using silica gel flash column chromatography (ethyl
acetate:methanol, 4:1, V/V) to obtain the desired title compound
(69 mg, 88.5%) as a colorless solid.
1H NMR (D20) : d 1.32 (3H, d, J=5.9 Hz), 3.19 (1H, t, J=9.5 Hz),
3.30-3.34 (2H, m), 3.46 (1H, t, J=9.5 Hz), 3.52 (1H, br, t,
J=7.4 HZ), 3.59-3.67 (3H, m), 3.72-3.88 (3H, m), 3.97-4.07 (2H,
m), 4.19-4.29 (1H, m), 4.48 (1H, d, J=8.0 Hz), 4.58-4.66 (2H, m),
5.24 (1H, br, s);
MS (FAB) m/z: 576 (M+Na)".
(18e) (2R, 3R, 4R)-4-Hydroxy-2-hydroxymethyl-3,4-dihydro-2H-
pyrrol-3-yl 4-O-(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside
The compound (47 mg, 0.085 mmol) synthesized in Example
18 (18d) was dissolved in water (10 mL) and ion exchange resin
Dowex-lx4 (OH-) (3.0 g) was added thereto, followed by stirring
of the mixture at room temperature for 1.5 hours. The ion
exchange resin was removed and the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (chloroform:methanol:water,
6:4:1, V/V) to obtain the desired title compound (8.0 mg, yield
21.4%) as colorless amorphous matter.
1H NMR (D20) : d 1.32 (3H, d, J=5.9 Hz), 3.16-3.21 (1H, m), 3.31-
3.33 (1H, m), 3.45-3.52 (2H, m), 3.63-3.69 (2H, m), 3.80-3.96
(5H, m), 4.08 (1H, br, s), 4.25 (1H, d, J=4. 9 Hz), 4.49 (1H, d,

J=6.8 Hz), 4.94 (1H, d, J=4.9 Hz), 5.17 (1H, d, J=4.0 Hz), 7.68
(1H, br, s);
MS (FAB) m/z: 462 (M+Na)+.
4-O-Acetyl-2,3,6-tri-O-benzyl-glucopyranoside (Agric.
Biol. Chem, 1986, 50, 2261-2272) (2.21 g, 4.49 mmol) was
dissolved in methylene chloride (45 mL) and
trichloroacetonitrile (2.3 mL, 22.44 mmol) and 1,8-
diazabicyclo[5.4.0]-7-undecene (65 µL, 0.44 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 1 hour. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 2:1, 1% triethylamine,
V/V) to obtain imidate (2.06 g, 72.0%) as a yellow oil. The
compound (2.00 g, 4.47 mmol) synthesized in Example 1 (li) was
dissolved in diethyl ether (100 mL) and imidate (2.06 g, 3.23
mmol) was added thereto. A solution of trimethylsilyl
trifluoromethanesulfonate (40 µl. 0.22 mmol) in diethyl ether (2
mL) was added dropwise thereto and the mixture was stirred at
room temperature for 2 hours. After triethylamine (50 µL] was
added to the reaction mixture and the solvent was distilled off
under reduced pressure, the residue was diluted with ethyl

acetate (20 mL) and the mixture was washed with saturated
aqueous sodium hydrogencarbonate (20 mL) and saturated brine (10
mL). After the organic layer was dried with anhydrous sodium
sulfate, the solvent was distilled off under reduced pressure
and the residue containing the a, ß mixture was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
5:1, V/V) to isolate the desired title compound a form (1.93 g,
46.6%) thereof as a colorless oil.
1H NMR (400 MHz, CDCl3) d 1.82 (3H, s>, 3.20-5.20 (26H, m), 7.10-
7.40 (30H, m);
MS (FAB) m/z: 922 (M+H)+.
(19b) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-a-D-
glucopyranoside
The compound (1.57 g, 1.70 mmol) synthesized in Example
19 (19a) was dissolved in methanol (30 mL) and potassium
carbonate (235 mg, 1.70 mmol) was added thereto, followed by
stirring of the mixture at room temperature for 14 hours. The
reaction mixture was diluted with ethyl acetate (10 mL) and the
mixture was washed with saturated aqueous sodium
hydrogencarbonate (10 mL) and saturated brine (10 mL). After
the organic layer was dried with anhydrous sodium sulfate, the
solvent was distilled off under reduced pressure. The residue
was purified using silica gel flash column chromatography
(hexane:ethyl acetate, 3:1, V/V) to obtain the desired title
compound (1.41 g, 94.0%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.40-5.20 (26H, m), 7.10-7.40 (30H,
m);
MS (FAB) m/z: 880 (M+H)+.
(19c) Allyl 2, 3, 6-O-tri-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl -ß-
D-glucopyranosyl)-D-glucopyranoside
The compound (4.0 g, 10.46 mmol) synthesized in Example
2 (2a) was dissolved in pyridine (30 mL) and benzoyl chloride

(12.1 mL, 104.24 mmol) was added thereto under ice-cooling,
followed by stirring of the mixture at room temperature for 14
hours. The reaction mixture was poured to 10% aqueous
hydrochloric acid solution (20 mL) and methyl chloride (20 mL)
and the organic layer was washed with 10% aqueous hydrochloric
acid solution (20 mL), saturated aqueous sodium
hydrogencarbonate solution (20 mL) and saturated brine (20 mL)
and dried with anhydrous sodium sulfate, followed by distilling
off of the solvent under reduced pressure. The residue was
purified using silica gel flash column chromatography
(hexane:ethyl acetate, 5:1-5:2, V/V) to obtain the desired title
compound (8.10 g, yield 70%) as a colorless oil.
1H NMR (400 MHz, CDCl3) : d 3.71-4.27 (6H, m), 4.44-4.51 (1H, m),
4.58-4.63 (1H, m), 4.72 (1H, d, J=6.4Hz), 4.93-5.81 (10H, m),
7.17-8.11 (35H, m);
MS (FAB) m/z: 1111 (M+H)+.
(19d) 2,3,6-O-tri-Benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl -ß-D-
glucopyranosyl)-D-glucopyranoside
The compound (8.10 g, 7.29 mmol) synthesized in Example
19 (19c) was dissolved in methanol (75 mL) and tetrahydrofuran
(15 mL) and palladium chloride (II) (258 mg, 1.45 mmol) was
added thereto, followed by stirring of the mixture at room
temperature for 14 hours. After the reaction mixture was
subjected to celite filtration, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 3:1-2:1,
V/V) to obtain the desired title compound (5.10 g, yield 66%) as
a pale yellow solid.
1H NMR (400 MHz, CDCl3) : d 2.96-3.13 (1H, m), 3.79-3.92 (2H, m),
4.05-4.25 (2H, m), 4.33-4.40 (1H, m), 4.47-4.50 (1H, m), 4.60-
4.63 (1H, m), 4.89-6.15 (7H, m), 7.21-8.01 (35H, m);
MS (FAB) m/z: 1071 (M+H)+.
(19e) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-{2, 3, 6,-
tri-O-benzoyl-4-O-(2,3,4,C-tetra-O-benzoyl -ß-D-glucopyranosyli-
ß-D-glucopyranosyl} -a-D-gi ucopyranoside
The compound (414.4 mg, 0.3 9 mmol) synthesized in
Example 19 (19d) was dissolved in methylene chloride (8 mL) and
trichloroacetonitrile (200 µl. 1.99 mmol) and 1,8-diazabicyclo
[5.4.0] -7-undecene (6 µl. 0.04 mmol) were added thereto,
followed by stirring of the mixture at room temperature for 1
hour. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 2:1, 1% triethylamine,
V/V) to obtain imidate (255.1 mg, 53.8%) as colorless amorphous
matter. The compound (185.3 mg, 0.21 mmol) synthesized in
Example 19 (19b) was dissolved in diethyl ether (8 mL) and
imidate (225.1 mg, 0.21 mmol) was added thereto. A solution of
trimethylsilyl trifluoromethanesulfonate (38 µL, 0.21 mmol) in
diethyl ether (2 mL) was added dropwise thereto and the mixture
was stirred at room temperature for 2 hours. After
triethylamine (35 µL) was added to the reaction mixture and the
solvent was distilled off under reduced pressure, the residue
was diluted with ethyl acetate (10 mL) and washed with saturated
aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10
mL). After the organic layer was dried with anhydrous sodium
sulfate, the solvent was distilled off under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) to isolate
the desired title compound (295.8 mg, 72.9%) as colorless
amorphous matter.
1H NMR (400 MHz, CDCl3) : d 3.20-5.60 (40H, m), 7.10-7.40 (65H,
m);
MS (FAB) m/z: 1932 (M+H)+.
(19f) (2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3, 6-tri-O-benzyl-4-O-{4-O-(P~
D-glucopyranosyl) -ß-D-glucopyranosyl}-a-D-glucopyranoside

The compound (295.8 mg, 0.15 mmol) synthesized in
Example 19 (19e) was dissolved in methanol (6 mL) and potassium
carbonate (20 mg, 0.14 mmol) was added thereto, followed by
stirring of the mixture at room temperature for 6 hours. The
reaction mixture was diluted with ethyl acetate (10 mL) and
washed with saturated aqueous sodium hydrogencarbonate (10 mL)
and saturated brine (10 mL). The mixture was neutralized with
methanol-hydrochloric acid and the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (methylene chloride:methanol,
30:1-20:1-10:1, V/V) to obtain the desired title compound (100.7
mg, 55.8%) as a colorless solid.
1H NMR (400 MHz, CD30D) : d 3.20-5.60 (40H, m), 7.10-7.40 (30H,
m);
MS (FAB) m/z: 1204 (M+H)+.
(19g) (2R, 3R, 4R)-4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
{ 4-O- (ß-D-glucopyranosyl) -ß-D-glucopyranosyl} -a-D-
glucopyranoside
The compound (100.7 mg, 0.084 mmol) synthesized in
Example 19 (19f) was dissolved in methanol (10 mL) and 36%
hydrochloric acid (280 µL) and palladium hydroxide (100 mg) were
added thereto, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere for 4 hours. After
celite filtration, 18% ammonia water (1 mL) was added thereto
and the solvent was distilled off under reduced pressure. The
residue was purified by ion exchange resin (Dowex 50w x 8)
column (water - 1% ammonia water). Further, it was purified
using silica gel flash column chromatography (ethyl
acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired
title compound (10.0 mg, 19.21) as a colorless solid.
1H NMR (400 MHz, D20) : d 3.00-3.95 (25H, m), 4.38 (1H, d, J=8.1
Hz), 4.42 (1H, d, J=8.0 Hz), 5.00 (1H, d, J=2.6 Hz);
MS (FAB) m/z: 620 (M+H)+.
(20a) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 4-O-acetyl-2,3,6-tri-O-benzyl-a-
D-galactopyranoside
4-O-Acetyl-2,3,6-O-tri-benzyl-D-galactopyranoside (BCSJ,
1989, 62, 3549-3566) (1.60 g, 3.25 mmol) was dissolved in
methylene chloride (30 mL) and trichloroacetonitrile (1.6 mL,
15.96 mmol) and 1, 8-diazabicyclo [5. 4. 0] -7-undecene (50 µL, 0.33
mmol) were added thereto, followed by stirring of the mixture at
room temperature for 1 hour. After the solvent was distilled
off under reduced pressure, the residue was purified using
silica gel flash column chromatography (hexane:ethyl acetate,
6:1, 1% triethylamine, V/V) to obtain imidate (1.37 g, 66%) as a
yellow oil. The compound (0.96 g, 2.01 mmol) synthesized in
Example 1 (li) was dissolved in diethyl ether (50 mL) and
imidate (1.37 g, 2.15 mmol) was added thereto. A solution of
trimethylsilyl trifluoromethanesulfonate (20 µl. 0.11 mmol) in
diethyl ether (2 mL) was added dropwise thereto, followed by
stirring of the mixture at room temperature for 2 hours. After
triethylamine (10 µL) was added to the reaction mixture and the
solvent was distilled off under reduced pressure, the residue
was diluted with ethyl acetate (20 mL) and the mixture was
washed with saturated aqueous sodium hydrogencarbonate (20 mL)
and saturated brine (10 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure and the residue containing the a, (3
mixture was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 6:1-4:1, V/V) to isolate
the desired title compound a isomer (0.98 g, 50%) thereof as a
colorless oil.
1H NMR (400 MHz, CDCl3) : d 2.02 (3H, s),5.15-3.38 (25H, m), 5.61
(1H, m), 7.16-7.35 (30H, m);
MS (FAB) m/z:922(M+H)+.
(20b) (2R, 3R, 4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-a-D-
galactopyranoside
The compound (0.98 g, 1.06 mmol) synthesized in Example
20 (20a) was dissolved in methanol (20 mL) and potassium
carbonate (147 mg, 1.06 mmol) was added thereto, followed by
stirring of the mixture at room temperature for 14 hours. The
reaction mixture was diluted with ethyl acetate (10 mL) and
washed with saturated aqueous sodium hydrogencarbonate (10 mL)
and saturated brine (10 mL). After the organic layer was dried
with anhydrous sodium sulfate, the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (hexane:ethyl acetate, 4:1, V/V)
to obtain the desired title compound (772.4 mg, 83%) as a
colorless oil.
1H NMR (400 MHz, CDCl3) : d 2.70-2.81 (1H, m), 3.46-5.15 (26H, m),
7.15-7.37 (30H, m);
MS (FAB) m/z: 880 (M+H)+.
(20c) (2R,3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-{2,3,6-
tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl -ß-D-glucopyranosyl)-
ß-D-glucopyranosyl} -a-D-galactopyranoside
The compound (516.8 mg, 0.48 mmol) synthesized in
Example 20 (20b) was dissolved in methylene chloride (10 mL) and
trichloroacetonitrile (240 µl. 2.39 mmol) and 1,8-

diazabicyclo [5. 4. 0] -7-undecene (7.5 µl. 0.05 mmol) were added
thereto, followed by stirring of the mixture at room temperature
for 1 hour. After the solvent was distilled off under reduced
pressure, the residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1, 1% triethylamine,
V/V) to obtain imidate (376.9 mg, 651) as colorless amorphous
matter. The compound (270.0 mg, 0.31 mmol) synthesized in
Example 20 (20b) was dissolved in diethyl ether (15 mL) and
imidate (376.9 mg, 0.31 mmol) was added thereto. A solution of
trimethylsilyl trifluoromethanesulfonate (56 µl. 0.31 mmol) in
diethyl ether (2 mL) was added dropwise thereto and the mixture
was stirred at room temperature for 2 hours. After
triethylamine (50 µL) was added to the reaction mixture and the
solvent was distilled off under reduced pressure, the residue
was diluted with ethyl acetate (20 mL) and washed with saturated
aqueous sodium hydrogencarbonate (20 mL) and saturated brine (10
mL). After the organic layer was dried with anhydrous sodium
sulfate, the solvent was distilled off under reduced pressure.
The residue was purified using silica gel flash column
chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) to isolate
the desired title compound (390.8 mg, 65%) as colorless
amorphous matter.
3H NMR (400 MHz, CDCl3) : d 3.20-5.70 (40H, m), 7.10-7.40 (65H,
m);
MS (FAB) m/z: 1932 (M+H)+.
(20d) (2R, 3R,4R)-4-Benzyloxy-N-benzyloxycarbonyl-2-
benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O-{4-O-(ß-
D-glucopyranosyl) -ß-D-glucopyranosyl}-a-D-galactopyranoside
The compound (390.8 mg, 0.20 mmol) synthesized in
Example 20 (20c) was dissolved in methanol (8 mL) and potassium
carbonate (27.6 mg, 0.20 mmol) was added thereto, followed by
stirring of the mixture at room temperature for 6 hours. The
reaction mixture was diluted with ethyl acetate (10 mL) and
washed with saturated aqueous sodium hydrogencarbonate (10 mL)

and saturated brine (10 mL). The mixture was neutralized with
methanol-hydrochloric acid and the solvent was distilled off
under reduced pressure. The residue was purified using silica
gel flash column chromatography (methylene chloride:methanol,
30:1-20:1-10:1, V/V) to obtain the desired title compound (146.5
mg, 61%) as a colorless solid.
1H NMR (400 MHz, CD3OD) : d 1.13 3.20-4.70 (37H, m), 4.97 (1H, d,
J=3.6Hz), 5.07 (2H, s), 7.23-7.39 (30H, m);
MS (FAB) m/z: 1226 (M+Na)+.
(20e) (2R, 3R, 4R) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-
{4-O- (ß-D-glucopyranosyl) -ß-D-glucopyranosyl } -a-D-
galactopyranoside
The compound (146.5 mg, 0.12 mmol) synthesized in
Example 20 (20d) was dissolved in methanol (15 mL) and 36%
hydrochloric acid (420 µL) and palladium hydroxide (150 mg) were
added thereto, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere for 4 hours. After
celite filtration, 18% ammonia water (1 mL) was added thereto,
the solvent was distilled off under reduced pressure and the
residue was purified by ion exchange resin (Dowex 50w x 8)
column (water - 1% ammonia water). Further, it was purified
using silica gel flash column chromatography (ethyl
acetate methanol:water, 5:2:1-1:1:1, V/V) to obtain acetate
(23.6 mg, 32%) of the desired title compound as a colorless
solid.
1H NMR (400 MHz, D20) : d 3.17-3.87 (22H, m), 4.01 (1H, s), 4.11
(1H, s), 4.36 (lH,m), 4.38 (1H, d, J=8.0 Hz), 4.56 (1H, c, J=8.0
Hz), 5.04 (1H, s);
MS (FAB) m/z: 620 (M+H)+.

a-Amylase Inhibitory Action
(1) Preparation of Human a-Amylase Solution
"Caribzyme AMY" (International Reagents) was used for

the human pancreatic a-amylase (HPA). Purified water was added
to the commercially available HPA and dissolved to a
concentration of 200 IU/1 to prepare an a-amylase solution. The
activity of the a-amylase was measured using a commercially
available a-amylase assay reagent ("Neo-Amylase Test Daiichi",
Daiichi Pure Chemicals).
(2) Preparation of Inhibitory Solutions
Each test compound was prepared with distilled water to
a final concentration of 0.1 to 30 µg/ml, respectively.
(3) Measurement of Human a-Amylase Inhibitory Activity of
Inhibitory Solutions
3.78 to 3.9 ml of distilled water and 0 to 120 µl of
inhibitory solution were added to 100 µl of HPA solution and
adjusted to a total volume of A ml. After incubating for 10
minutes at 37°C, a blue starch tablet ("Neo-Amylase Test
Daiichi", Daiichi Pure Chemicals) was added followed by stirring
for about 10 seconds with a mixer and heating for 30 minutes at
37°C. Subsequently, 1.0 ml of 0.5 N aqueous sodium hydroxide
solution was added followed by stirring to stop the reaction,
after which the mixture was centrifuged (1,500 G, 5 minutes) and
the absorbance of the resulting supernatant was measured at 620
nm. A mixture to which inhibitory solution had not been added
was used as a control. In addition, distilled water was added
instead of a-amylase for use as a blank. The inhibition rate
was calculated according to the following formula, and the final
concentration of test compound required to inhibit the activity
of the HPA solution by 50% (µg/ml) was taken to be the IC50
value. Those values are shown in Table 6.
Inhibition rate (%) = [l-{(Absorbance of control) - (absorbance
of blank)}/{(absorbance when inhibitor added) - (absorbance of
blank)}] x 100
It was found from Table 6 that compounds of the present
invention have superior a-amylase inhibitory action.

Postprandial Hyperglycemia Inhibitory Action
(1) Test Animals
Commercially available normal mice (ddY mice, males, age
8 weeks at the time of testing, supplied by Japan SLC).
(2) Experimental Methods and Results
For the dose group, a test compound and commercially
available cornstarch were mixed well with 0.5% carboxymethyl
cellulose to prepare a suspension that was orally administered
at 0.3 mg (test compound)/2 g (cornstarch)/kg (body weight) to
five mice that had been fasted in advance for 20 hours. The
control group was administered with a similar suspension in the
same manner with the exception of not containing the test
compound.

Blood samples were collected from a tail vein of the
mice before dosing and at 0.5, 1, 2 and 3 hours after dosing
followed by measurement of blood glucose levels and calculation
of the inhibition rate (%) according to the following formula
from the area under the curve (AUC) of the increase in blood
glucose levels (area under the curve of the change in increases
in blood glucose levels, mg/dlxhr). Blood glucose levels were
measured using a blood glucose analyzer (Glucoloader GXT, A & T)
Inhibition rate (%) = [l-(dose group AUC/control group blood
glucose increase AUC)] x 100
According to Table 7, compounds of the present invention
were determined to have superior action in inhibiting increases
in blood glucose levels. Thus, compounds of the present
invention are considered to be useful as postprandial
hyperglycemia therapeutic agents.

Blood Glucose Lowering Action
(1) Test Animals
Commercially available, genetically obese diabetic mice
(C57BL/KsJ-db/db mice, males, age 16 weeks at the time of
testing, supplied by Clea Japan).
(2) Experimental Methods and Results
A test compound was mixed into a refined laboratory
animal diet (carbohydrate content: 65.95% (w/w), Oriental Yeast)
to a test compound concentration of 0.305% (w/w) and allowed to
be freely ingested by diabetic mice for 1 week in groups of 5
mice per group. A control group was allowed similar
unrestricted access to the same feed with the exception of not
containing the test compound.
Blood glucose levels were measured before the start of
dosing and one week after the start of dosing. Blood samples
were collected from a tail vein and blood glucose levels were
measured using a blood glucose analyzer (Glucoloader GXT, A & T)
to calculate the blood glucose lowering rate (%) according to
the following formula.
Blood glucose lowering rate (%) = [1-(compound dose group blood
glucose level/control group blood glucose level)] x 100
According to Table 8, compounds of the present invention
were determined to have superior blood glucose lowering action.
Thus, compounds of the present invention are considered to be
useful as diabetes mellitus therapeutic agents.

Powders of each of the ingredients listed above are
mixed well and passed through a 60 mesh sieve (the sieve mesh is
based on the Tyler mesh). 180 mg of the resulting powder is
weighed out and filled into gelatin capsules (No. 3) to prepare
capsule preparations.

Powders of each of the ingredients listed above are
mixed well and compressed and molded into tablets having a

weight of 150 mg each. These tablets may be coated with sugar
or a film as necessary.

Powders of each of the ingredients listed above are
mixed well, wetted purified water and granulated with a basket-
type granulator followed by drying to obtain granules.
(INDUSTRIAL APPLICABILITY)
Compounds of the present invention in the form of a
novel oligosaccharide derivative, its pharmacologically
acceptable salts and its pharmacologically acceptable esters
demonstrate superior a-amylase inhibitory action, blood glucose
lowering action and lipid lowering action, and are useful as
therapeutic drugs and/or preventive drugs for hyperglycemia,
postprandial hyperglycemia, impaired glucose tolerance, diabetes
mellitus, obesity, hyperlipemia, fatty liver, hepatomegaly,
diabetic complications, neuropathy, arteriosclerosis, cataract
or diabetic nephropathy (and preferably as therapeutic drugs
and/or preventive drugs for hyperglycemia or diabetes mellitus).
WE CLAIM:
1. A compound represented by the general formula (I):

wherein
A represents the general formula (A1), (A2) or (A3):

R1 and R2 are the same or different, and each represent a C1-C6 alkyl
group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6
haloalkyl group,
R3,R4,R5 and R6 are the same or different, and each represent a C1-C6
alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6
haloalkyl group, amino group which amino group may optionally be
substituted with one or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl
groups, hydroxyl group, hydrogen atom or halogen atom,
R7 represents a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6
hydroxyalkyl group, C1-C6 haloalkyl group, hydroxyl group or
hydrogen atom, and
n represents an integer of 1 or 2;
a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
2. A compound as claimed in claim 1, wherein R1 and R2 are the same or
different and each represent a C1-C3 alkyl group, hydroxymethyl
group, C1-C3 alkoxymethyl group or C1-C3 haloalkyl group; a
pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
3. A compound as claimed in Claim 1 or Claim 2, wherein R3, R4, R5 and
R6 are the same or different and each represent a C1-C3 alkyl group,
C1-C3 hydroxyalkyl group, C1-C3 haloalkyl group, amino group which
amino group may optionally be substituted with one or two C1-C6
hydroxyalkyl groups, hydroxyl group, hydrogen atom or halogen atom a
pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
4. A compound as claimed in any one of Claims 1 to 3, wherein R7
represents a hydrogen atom; or a pharmacologically acceptable salt
thereof or a pharmacologically acceptable ester thereof.
5. A compound as claimed in Claim 1, represented by the general formula
(Ia):

wherein
R1 and R2 are the same or different, and each represent a C1-C6 alkyl
group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6
haloalkyl group,
R7 represents a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6
hydroxyalkyl group, C1-C6 haloalkyl group, hydroxyl group or a hydrogen
atom,
R10 represents a hydrogen atom, hydroxyl group, C1-C6 hydroxyalkyl
group or C1-C6 haloalkyl group,
R8 and R9 are the same or different and each represent a hydroxyl group,
C1-C6 hydroxyalkyl group, hydrogen atom or halogen atom,
and
n represents an integer of 1 or 2;
or a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
6. A compound as claimed in claim 5, wherein R1 is a C1-C3 alkyl group,
hydroxymethyl group, C1-C3 alkoxymethyl group or C1-C3 haloalkyl
group; a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
7. A compound as claimed in Claim 5 or Claim 6, wherein R1 is a methyl
group or hydroxymethyl group; a pharmacologically acceptable salt
thereof or a pharmacologically acceptable ester thereof.
8. A compound as claimed in any one of Claims 5 to 7, wherein R2 is a
hydroxymethyl group or C1-C3 haloalkyl group; a pharmacologically
acceptable salt thereof or a pharmacologically acceptable ester thereof.
9. A compound as claimed in Claim 8, wherein R2 is a hydroxymethyl group;
a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
10. A compound as claimed in any one of Claims 5 to 9, wherein R7 is a
hydrogen atom; a pharmacologically acceptable salt thereof or a
pharmacologically acceptable ester thereof.
11.A compound as claimed in any one of Claims 5 to 10, wherein R10 is a
hydrogen atom, C1-C3 hydroxyalkyl group or C1-C3 haloalkyl group; a
pharmacologically acceptable salt thereof of a pharmacologically
acceptable ester thereof.
12. A compound as claimed in Claim 11, wherein R10 is a C1-C3 hydroxyalkyl
group; a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
13. A compound as claimed in any one of Claims 5 to 12, wherein R8 and R9
are the same or different and each represent a hydroxyl group or
hydrogen atom; a pharmacologically acceptable salt thereof or a
pharmacologically acceptable ester thereof.
14. A compound as claimed in Claim 1, represented by the general formula
(Ib):
wherein
R1 and R2 are the same or different, and each represent a CVC6 alkyl
group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6
haloalkyl group,
R11 represents a hydroxyl group, C1-C6 hydroxyalkyl group,
hydrogen atom or halogen atom, and
n represents an integer of 1 or 2;
a pharmacologically acceptable salt thereof or a
pharmacologically acceptable ester thereof.
15. A compound as claimed in Claim 14, wherein R11 is a hydroxyl group; a
pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
16. A compound as claimed in Claim 14 or Claim 15, wherein R1 is a C1-C3
alkyl group, R2 is a hydroxymethyl group and n is 1; a pharmacologically
acceptable salt thereof or a pharmacologically acceptable ester thereof.
17. A compound as claimed in Claim 1, wherein said compound is
(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-deoxy-a-D-
glucopyranosyl)-a-D-glucopyranoside,
(2R, 3R, 4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-deoxy -ß-D-
glucopyranosyl)-a-D-glucopyranoside,
(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O -ß-D-
glucopyranosyl-a-D-glucopyranoside,
(2R,3R,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-fluoro-6-
deoxy-ß-D-glucopyranosyl-D-glucopyranoside,
(1R,2S,3R,4R,5R)-1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl
4-O-(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside,
(2R,3R,4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-(6-methoxy-6-
deoxy-P-D-glucopyranosyl-D-glucopyranoside, or
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrro-3-yl 4-O-
(6-deoxy-a-D-glucopyranosyl)-a-D-glucopyranoside,
a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.
18. A pharmaceutical composition comprising a compound, a
pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof as claimed in any one of claims 1 to 17.
19. An a-amylase inhibitor comprising a compound, a pharmacologically
acceptable salt thereof or a pharmacologically acceptable ester thereof as
claimed in any one of claims 1 to 17.
20.A hypoglycemic agent comprising a compound, a pharmacologically
acceptable salt thereof or a pharmacologically acceptable ester thereof as
claimed in any one of Claims 1 to 17.
21. A pharmaceutical composition for preventing or treating hyperglycemic,
postprandial hyperglycemia, or diabetes mellitus, comprising a compound,
a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof as claimed in any one of claims 1 to 17.

A compound represented by the general formula (I):

wherein
A represents the general formula (A1), (A2) or (A3):

R1 and R2 are the same or different, and each represent a C1-C6 alkyl
group, hydroxymethyl group, C1-C6 alkoxymethyl group or C1-C6
haloalkyl group,

R3,R4,R5 and R6 are the same or different, and each represent a C1-C6
alkyl group, C1-C6 alkoxy group, C1-C6 hydroxyalkyl group, C1-C6
haloalkyl group, amino group which amino group may optionally be
substituted with one or two C1-C6 alkyl groups or C1-C6 hydroxyalkyl
groups, hydroxyl group, hydrogen atom or halogen atom,
R7 represents a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6
hydroxyalkyl group, C1-C6 haloalkyl group, hydroxyl group or
hydrogen atom, and
n represents an integer of 1 or 2;
a pharmacologically acceptable salt thereof or a pharmacologically
acceptable ester thereof.

Documents:

1447-kolnp-2005-granted-abstract.pdf

1447-kolnp-2005-granted-claims.pdf

1447-kolnp-2005-granted-correspondence.pdf

1447-kolnp-2005-granted-description (complete).pdf

1447-kolnp-2005-granted-examination report.pdf

1447-kolnp-2005-granted-form 1.pdf

1447-kolnp-2005-granted-form 13.pdf

1447-kolnp-2005-granted-form 18.pdf

1447-kolnp-2005-granted-form 2.pdf

1447-kolnp-2005-granted-form 3.pdf

1447-kolnp-2005-granted-form 5.pdf

1447-kolnp-2005-granted-gpa.pdf

1447-kolnp-2005-granted-reply to examination report.pdf

1447-kolnp-2005-granted-specification.pdf

1447-kolnp-2005-granted-translated copy of priority document.pdf


Patent Number 233848
Indian Patent Application Number 1447/KOLNP/2005
PG Journal Number 16/2009
Publication Date 17-Apr-2009
Grant Date 16-Apr-2009
Date of Filing 26-Jul-2005
Name of Patentee SANKYO COMPANY, LIMITED
Applicant Address 5-1, NIHONBASHI HONCHO 3-CHOME, CHUO-KU, TOKYO 103-8426
Inventors:
# Inventor's Name Inventor's Address
1 XIAOLIU LI C/O SANKYO COMPANY LIMITED, 2-58, HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
2 TAKESHI HONDA C/O SANKYO COMPANY LIMITED, 2-58, HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
3 AKIRA OKUNO C/O SANKYO COMPANY LIMITED, 2-58, HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
4 MASANORI IZUMI C/O SANKYO COMPANY LIMITED, 2-58, HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
PCT International Classification Number C07H 15/203
PCT International Application Number PCT/JP2004/000879
PCT International Filing date 2004-01-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2003-022800 2003-01-30 Japan