Title of Invention	A PROCESS FOR THE TRANSFORMATION OF TRICYCLOPENTABENZENE TO 12-HYDROXY-16-OXATETRACYCLO [10.3.1.01,5.07,11] HEXADEC-7 (11)-EN-2,6-DIONE
Abstract	A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.0110 '"] hexadec - 7(11) -en-2,6-diene by ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry CFbCb admixed with dimethyl sulfide at a temperature in the range of-70 to -90°C to obtain 12 - hydroxyl-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7( 11 )-en-2.6-diene of formula 2.

Title of Invention

A PROCESS FOR THE TRANSFORMATION OF TRICYCLOPENTABENZENE TO 12-HYDROXY-16-OXATETRACYCLO [10.3.1.01,5.07,11] HEXADEC-7 (11)-EN-2,6-DIONE

Abstract

A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.0110 '"] hexadec - 7(11) -en-2,6-diene by ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry CFbCb admixed with dimethyl sulfide at a temperature in the range of-70 to -90°C to obtain 12 - hydroxyl-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7( 11 )-en-2.6-diene of formula 2.

Full Text	A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.015.07.11]hexadec- 7(11)-en-2,6-diene Field of the invention The present invention relates to the transformation of tricyclopentabenzene (trindane) to 12-hydroxy-16-oxatetracyclo [10.3.1.015.07.11] hexadec-7(ll)-en-2,6-dione of the formula 2 an important natural product analogue. (Formula Removed) Background of the invention The development of novel and shortest synethetic routes towards natural products and their analogs having immense importance as drug candidates continues to be a challenge in organic chemistry. Although many interesting synthetic strategies have been developed towards this (eg. M.H. Jose Ignacio, R.F. Maria del Rosario, C.L. Jose Ignacio, Nicolas Birlirakis, and Simeon Arseniyadis, Tet. Asymm.2.000, 11,4,951-973; Gary A. Sulikowski, Fabio Agnelli, and R. Michael Carbett, J. Org. Chem, 2000, 65,337-342 and the references therein), the main drav/back in many cases is the large number of reaction steps and relatively poor yields of the target molecule. Many reagents employed in such synthesis ae costly which makes the strategy less economic. Earlier efforts towards the synthesis of clathrin models (E. Ungewickell, Current Biol., 1999.9.1.R32-35) has resulted in the RuVIII mediated transformation of trindane to 4-[(1R, 2S. 4R. 5S)-i,2,5-trihydroxy-3- ioxabicyclo [3.3.0] octane-4 spiro-l'-(2'-oxocyclopentan)-2-yl] butanoic acid (S. Ranganathan, K.M. Muraleedharan, P. Bhardwaj, and K.P. Madhusudanan, J. Chem. Soc. Chem. Commun., 1998, 2239-2240). The exclusive  oxidation observed here at once suggested a high reactivity for the double bonds, which is confined within the closed framework of peripheral methylenes. Accordingly, it is important to develop a process for the development of synthetic routes for natural product analogues that is cheap and at the same time provides a high yield. Objects of the invention The main objective of the present invention is to transform tridane (1), a readily available hydrocarbon, to a highly functionalized and condensed tetracyclic system 2 having structural resemblance to natural products (J.S. Clark, A.G. Dossetter, A.J. Blake, W.S. Li, and W.G. Whittingham, J. Chem. Soc. Chem. Commun., 1999, 749-750; J.S. Clark, and Y.S. Wong, J. Chem. Soc. Chem. Cornmun., 1999, 1079-1080), in one step by ozonolysis. It is another objective of the invention to provide a process for the synthetic production of natural product analogues that is cheap and still results in high yield. It is a further objective of the invention to provide a synthetic route for the production of natural product analogues that overcomes the drawbacks associated with the prior art above. Summary of the invention Accordingly, the present invention provides a process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.01.5.07.11] hexadec - 7(11) -en-2.6-diene of the formula 2, (Formula Removed) said process comprising ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry Cl-^Cb admixed with dimethyl sulfide at a temperature in the range of -70 to -90°C to obtain 12 -hydroxyl-16-oxatetracyclo [10.3.1.015.07.11] hexadec -7(ll)-en-2,6-diene of formula 2. In a further embodiment of the invention, the reaction is carried out as a one pot reaction. Detailed description of the invention Earlier effonts towards the synthesis of clathrin models (E. Ungewickell, Current Biol., 1999, 9, l,R32-35)has resulted in the Ru VIII mediated transformation of trindane to 4-[lR,2S,4R, 5S)-1,2,5—trihydroxy-3-oxabicyclo [3.3.0] octane-4 spiro-l'-(2'-oxocyclopentan)-2-yl] butanoic acid (S.Ranganathan, D.M. Amuraleedharan, P. Bharadwaj, and K. P. Madhusudanan, J. Chem. Soc. Chem. Comnmn., 1998, 2239 - 2240). The exclusive  oxidation observed here indicated a high reactivity for the double bonds, which is confined within the closed framework of peripheral methylenes. As a result, the reactivity of the aromatic  system in trindane towards ozone was studied. The synthetic route for the preparation of 12-hydroxy-16-oxatetracyclo [l0.3.l.01.5.O7.11] hexadec - 7(11) - en -2,6-dione (2) by the ozonolysis of trindane (1) is given below and scheme 1 represents the mechanism for this transformation. (Formula Removed) The following example is given by way of illustration only and therefore should not be construed to limit the scope of the present invention. Example: Ozonolysis of trindane: isolation of 12 - hydroxy - 16 - oxatetracyclo [10.3.1.O'-'.O7'11] hexadec - 7(11) - en -2,6-dione (2) Ozonized oxygen was bubbled through a solution of Trindane (3.1 g, 15.65 mmol) in dry CH2C12 (150 mL) at - -70 to - 80°C for 2.5 h, admixed with Dimethyl sulfide (5.2 mL). left stirred for 2h. treated with saturated. NaHCOj (20 mL), and stirred for an additional 1 h. The organic layer was separated and the aqueous layer washed with additional CH2Cl2 (3 x 25 mL). The organic layers were combined, washed with distilled water (1 x 10 mL), dried (MgSO4), evaporated under vacua and the residue chromatographed on silica gel. Elution with hexane-EtOAc (2:1) afforded 2 as a crystalline solid. The reaction in addition gave 19% yield of monobenzylic oxidation product of trindane (3), together with 2 g of unreacted trindane. The percentage yields of the products were calculated based on the amount of trindane reacted. 2) Yield: 0. 2g (14%); Mp. : 138 - 140°C IR (neat): 3400 (br), 2944, 1752, 1680, 1440, 1040 1H NMR (CDCls) δ 1.38 -2.2 (m, CH2-CH2:, CH2-CH2-OO & CH2 of pyran ring), 2.3 -3.0 (m, -CH2-C=O, 2 x CH2-C=C), 3.23 (m, 1H, -(CO)-CH(CH2)2-C=O) 13C NMR (CDC13) δ 17.93 - 35.3 (8 x CH2), 58.36 (-CH), 81.20 (quaternary carbon) 98.50 (C-OH), 140.84, 154.60 (-OC-), 198.58 (C=O, conjugated), 212.96 (C=O, non-conjugated) FAB MS (m/z) (%): 263 (56%) (MH)+, 285 (30%) (M+Na)+, El MS: 262. The proposed structure of this compound has been confirmed by X-ray crystallography. 3)Yield:0.23g(19%) IR (neat): 3424 (br, enolization), 2944, 1712, 1600, 1400, 1272, 1120. 1H NMR (CDC13) δ 2.19 (rn, 4H, 2 x CH2), 2.64 - 3.00 (m, 10H, benzylic CH2s), 3.2 (t, 2H, CH2-CO) 13C NMR (CDC13) δ 24.52 - 36.82 (8 x CH2), 139.1 - 149.4 (6 x C aromatic), 207.67 (OO) FAB MS (m/z) (%): 213 (100%) (MH)" The main advantages of the present invention are 1 The present compound, 12 - hydroxy - 16 - oxatetracyclo [lOJ.l.O^.O7'11] hexadec -7(11) - en -2,6-dione, a potentially important natural product analogue (2) which is highly functionalized and condensed tetracyclic system, is synthesized in one step. 2. The starting material trindane is a readily available hydrocarbon, which makes the synthesis more economic. 3. The only reagents used to effect the transformation are ozone and dimethyl sulfide, which also makes the synthesis more economic. 4. The reaction is a one-pot reaction without requiring isolation of intermediates, making the process more convenient. 5. The various functional groups present in 2 (ie. hydroxyl, carbonyl and olefinic) could be used for its transformation to various structural analogs or other natural products of therapeutic importance. We claim: A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.015.07.11] hexadec - 7(11) -en-2,6-diene of the formula 2, (Formula Removed) said process comprising ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry CH2C12 admixed with dimethyl sulfide at a temperature in the range of -70 to -90°C to obtain 12 - hydroxyl-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7(1 l)-en-2,6-diene of formula 2. 2. A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7(ll)-en-2,6-dione substantially as described hereinbefore and with reference to the foregoing example

Full Text

A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.015.07.11]hexadec- 7(11)-en-2,6-diene Field of the invention
The present invention relates to the transformation of tricyclopentabenzene (trindane) to 12-hydroxy-16-oxatetracyclo [10.3.1.015.07.11] hexadec-7(ll)-en-2,6-dione of the formula 2 an important natural product analogue.
(Formula Removed)
Background of the invention
The development of novel and shortest synethetic routes towards natural products and their analogs having immense importance as drug candidates continues to be a challenge in organic chemistry. Although many interesting synthetic strategies have been developed towards this (eg. M.H. Jose Ignacio, R.F. Maria del Rosario, C.L. Jose Ignacio, Nicolas Birlirakis, and Simeon Arseniyadis, Tet. Asymm.2.000, 11,4,951-973; Gary A. Sulikowski, Fabio Agnelli, and R. Michael Carbett, J. Org. Chem, 2000, 65,337-342 and the references therein), the main drav/back in many cases is the large number of reaction steps and relatively poor yields of the target molecule. Many reagents employed in such synthesis ae costly which makes the strategy less economic.
Earlier efforts towards the synthesis of clathrin models (E. Ungewickell, Current Biol., 1999.9.1.R32-35) has resulted in the RuVIII mediated transformation of trindane to 4-[(1R, 2S. 4R. 5S)-i,2,5-trihydroxy-3- ioxabicyclo [3.3.0] octane-4 spiro-l'-(2'-oxocyclopentan)-2-yl] butanoic acid (S. Ranganathan, K.M. Muraleedharan, P. Bhardwaj, and K.P. Madhusudanan, J. Chem. Soc. Chem. Commun., 1998, 2239-2240). The exclusive  oxidation observed here at once suggested a high reactivity for the double bonds, which is confined within the closed framework of peripheral methylenes.
Accordingly, it is important to develop a process for the development of synthetic routes for natural product analogues that is cheap and at the same time provides a high yield. Objects of the invention

The main objective of the present invention is to transform tridane (1), a readily available hydrocarbon, to a highly functionalized and condensed tetracyclic system 2 having structural resemblance to natural products (J.S. Clark, A.G. Dossetter, A.J. Blake, W.S. Li, and W.G. Whittingham, J. Chem. Soc. Chem. Commun., 1999, 749-750; J.S. Clark, and Y.S. Wong, J. Chem. Soc. Chem. Cornmun., 1999, 1079-1080), in one step by ozonolysis.
It is another objective of the invention to provide a process for the synthetic production of natural product analogues that is cheap and still results in high yield.
It is a further objective of the invention to provide a synthetic route for the production of natural product analogues that overcomes the drawbacks associated with the prior art above. Summary of the invention
Accordingly, the present invention provides a process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.01.5.07.11] hexadec - 7(11) -en-2.6-diene of the formula 2,
(Formula Removed)

said process comprising ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry Cl-^Cb admixed with dimethyl sulfide at a temperature in the range of -70 to -90°C to obtain 12 -hydroxyl-16-oxatetracyclo [10.3.1.015.07.11] hexadec -7(ll)-en-2,6-diene of formula 2.
In a further embodiment of the invention, the reaction is carried out as a one pot reaction. Detailed description of the invention
Earlier effonts towards the synthesis of clathrin models (E. Ungewickell, Current Biol., 1999, 9, l,R32-35)has resulted in the Ru VIII mediated transformation of trindane to 4-[lR,2S,4R, 5S)-1,2,5—trihydroxy-3-oxabicyclo [3.3.0] octane-4 spiro-l'-(2'-oxocyclopentan)-2-yl] butanoic acid (S.Ranganathan, D.M. Amuraleedharan, P. Bharadwaj,

and K. P. Madhusudanan, J. Chem. Soc. Chem. Comnmn., 1998, 2239 - 2240). The exclusive  oxidation observed here indicated a high reactivity for the double bonds, which is confined within the closed framework of peripheral methylenes. As a result, the reactivity of the aromatic  system in trindane towards ozone was studied.
The synthetic route for the preparation of 12-hydroxy-16-oxatetracyclo [l0.3.l.01.5.O7.11] hexadec - 7(11) - en -2,6-dione (2) by the ozonolysis of trindane (1) is given below and scheme 1 represents the mechanism for this transformation.
(Formula Removed)
The following example is given by way of illustration only and therefore should not be construed to limit the scope of the present invention.
Example: Ozonolysis of trindane: isolation of 12 - hydroxy - 16 - oxatetracyclo [10.3.1.O'-'.O7'11] hexadec - 7(11) - en -2,6-dione (2)
Ozonized oxygen was bubbled through a solution of Trindane (3.1 g, 15.65 mmol) in dry CH2C12 (150 mL) at - -70 to - 80°C for 2.5 h, admixed with Dimethyl sulfide (5.2 mL). left stirred for 2h. treated with saturated. NaHCOj (20 mL), and stirred for an additional 1 h.
The organic layer was separated and the aqueous layer washed with additional CH2Cl2 (3 x 25 mL). The organic layers were combined, washed with distilled water (1 x 10 mL), dried (MgSO4), evaporated under vacua and the residue chromatographed on silica gel. Elution with hexane-EtOAc (2:1) afforded 2 as a crystalline solid. The reaction in addition gave 19% yield of monobenzylic oxidation product of trindane (3), together with 2 g of unreacted trindane. The percentage yields of the products were calculated based on the amount of trindane reacted.
2) Yield: 0. 2g (14%); Mp. : 138 - 140°C IR (neat): 3400 (br), 2944, 1752, 1680, 1440, 1040
1H NMR (CDCls) δ 1.38 -2.2 (m, CH2-CH2:, CH2-CH2-OO & CH2 of pyran ring), 2.3 -3.0 (m, -CH2-C=O, 2 x CH2-C=C), 3.23 (m, 1H, -(CO)-CH(CH2)2-C=O) 13C NMR (CDC13) δ 17.93 - 35.3 (8 x CH2), 58.36 (-CH), 81.20 (quaternary carbon) 98.50 (C-OH), 140.84, 154.60 (-OC-), 198.58 (C=O, conjugated), 212.96 (C=O, non-conjugated) FAB MS (m/z) (%): 263 (56%) (MH)+, 285 (30%) (M+Na)+, El MS: 262. The proposed structure of this compound has been confirmed by X-ray crystallography. 3)Yield:0.23g(19%)
IR (neat): 3424 (br, enolization), 2944, 1712, 1600, 1400, 1272, 1120. 1H NMR (CDC13) δ 2.19 (rn, 4H, 2 x CH2), 2.64 - 3.00 (m, 10H, benzylic CH2s), 3.2 (t, 2H, CH2-CO)
13C NMR (CDC13) δ 24.52 - 36.82 (8 x CH2), 139.1 - 149.4 (6 x C aromatic), 207.67 (OO) FAB MS (m/z) (%): 213 (100%) (MH)" The main advantages of the present invention are
1 The present compound, 12 - hydroxy - 16 - oxatetracyclo [lOJ.l.O^.O7'11] hexadec -7(11) - en -2,6-dione, a potentially important natural product analogue (2) which is highly functionalized and condensed tetracyclic system, is synthesized in one step.
2. The starting material trindane is a readily available hydrocarbon, which makes the
synthesis more economic.
3. The only reagents used to effect the transformation are ozone and dimethyl sulfide,
which also makes the synthesis more economic.
4. The reaction is a one-pot reaction without requiring isolation of intermediates, making
the process more convenient.
5. The various functional groups present in 2 (ie. hydroxyl, carbonyl and olefinic) could
be used for its transformation to various structural analogs or other natural products of therapeutic importance.

We claim:
A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.1.015.07.11] hexadec - 7(11) -en-2,6-diene of the formula 2,
(Formula Removed)

said process comprising ozonolysing two out of three double bonds of tricyclopentabenzene by passing ozonised oxygen through a solution of tricyclopentabenzene in dry CH2C12 admixed with dimethyl sulfide at a temperature in the range of -70 to -90°C to obtain 12 - hydroxyl-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7(1 l)-en-2,6-diene of formula 2.
2. A process for the transformation of tricyclopentabenzene to 12-hydroxy-16-oxatetracyclo [10.3.1.01.5.07.11] hexadec -7(ll)-en-2,6-dione substantially as described hereinbefore and with reference to the foregoing example

Documents:

339-del-2001-abstract.pdf

339-del-2001-claims.pdf

339-del-2001-correspondence-others.pdf

339-del-2001-correspondence-po.pdf

339-del-2001-description (complete).pdf

339-del-2001-form-1.pdf

339-del-2001-form-18.pdf

339-del-2001-form-2.pdf

339-del-2001-form-3.pdf

339-del-2001-petition-137.pdf

339-del-2001-petition-138.pdf

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Patent Number

231769

Indian Patent Application Number

339/DEL/2001

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

09-Mar-2009

Date of Filing

23-Mar-2001

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SUBRAMANIA RANGANATHAN	INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD-500007, ANDHRA PRADESH, INDIA.
2	KANNOTH MANJHERI MURALEEDHARAN	INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD-500007, ANDHRA PRADESH, INDIA.

PCT International Classification Number

C07D 313/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA