Title of Invention	ASYMMETRIC SYNTHESIS OF Y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST
Abstract	The present invention relates to a proccess for preparation of γ-nitrophosphonate of general formula (4), The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocataysis with complete stereochemical control by uisng a particular enantiomer of the products as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction moxture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking) and in the absence of any catayst (absolute asymmetric synthesis).

Title of Invention

ASYMMETRIC SYNTHESIS OF Y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST

Abstract

The present invention relates to a proccess for preparation of γ-nitrophosphonate of general formula (4), The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocataysis with complete stereochemical control by uisng a particular enantiomer of the products as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction moxture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking) and in the absence of any catayst (absolute asymmetric synthesis).

Full Text	FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention: ASYMMETRIC SYNTHESIS OF g-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST 2. Applicant(s) (a) NAME : (b) NATIONALITY (c) ADDRESS : INDIAN INSTITUTE OF TECHNOLOGY Created by an act of Parliament, Institute of Technologies Act, 1961 Indian Institute of Technology, Bombay, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF THE INVENTION The present invention relates to a process for preparing g-nitrophosphonates. More particularly, the invention relates to process of preparation of g-nitrophosphonates reacting phosphonate stabilized carbanion to nitroalkenes selectively comprising steps of asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric induction, i.e. without using any chiral source. BACKGROUND AND PRIOR ART Last few decades have seen development of chiral catalysis to an extent where it can be thought of biomimicking. However, source of pure enantiomer still beholds in the technique of classic resolution, biochemical and biological methods. This is due to the fact that most of the asymmetric reactions are not absolute in the sense of selectivity. The present invention envisages that the autocatalytic amplification can be critical leading to the utilization of general reactions where enantiomeric excess is anything but absolute. The exclusion of external ligand for catalysis save costs to a great extent and also removes the necessity to separate the product from catalyst which could further prove economical in commercial applications. The origin of homochirality and the chemical routes mimicking the process leading to high enantiomeric enrichment of organic compounds generated great interest in the past few years. Soai reaction was pivotal which led to utilization of several chiral initiators including product itself in these reactions [Chirality 2006, 18, 469-478]. However, only a rare set of reactions with very limited substrate scope is known to show asymmetric autocatalytic amplification (AAA). A recent report demonstrated Mannich reaction of acetone with (E)-ethyl 2-(4-methoxyphenylimino)acetate [Angew. Chem., Int. Ed. 2007, 46, 393-396]. Another report shows the phenomenon with moderate amplification in Mannich and aldol reactions [Chirality 2007, 19, 816-825]. The milestone of breaking the symmetry and absolute asymmetric synthesis are even rarer [Mirror symmetry breaking: Chem. Rev. 2003, 103, 3369-3400; Absolute asymmetric synthesis (3 papers, 1 patent): Tetrahedron: Asymmetry 2003, 14, 185-188; Org. Lett. 2003, 5, 4337-4339; J. Am. Chem. Soc. 2002, 124, 10010-10011; Japan Kokai Tokkyo Koho 9,268,179,1997]. The Soai reaction, i.e. addition of organozinc compounds to aldehydes, works with only a few substrates and the report on Mannich reaction is based on only one example of substrates (references; vide supra). These reactions are generally based on weak interactions which are very sensitive to minor change in electronic and steric factors. On practical hand, the best condition [Angew. Chem., Int. Ed. 2003, 42, 315-317] takes at least three steps for amplification upto >99% ee after addition of product of low ee's as the chiral catalyst. The main disadvantage with the prior art is that the projected speculations for these reactions in the presence of product as the chiral catalyst require three steps to attain such enantioselectivities and in the absence of any catalyst for which the prior art is also limited to a specific reaction, i.e. addition of dialkyl zinc to an aromatic aldehyde, the selectivities are only moderate. The existing process for preparation of aminophosphonates requires addition of other chiral catalysts such as cinchonine [Tetrahedron:Asymmetry,,2001',18, 2719]. Such types of processes are cumbersome and costly. Thus, there is a need for development in terms of a process for preparation of nitrophosphonates, more particularly, y-nitrophosphonates which would be first and cost effective. The present inventors have found a process which by adopting selectively asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis in Michael addition produces an amplification of greater than 99% enantiomeric excess (ee) in one step which is about three times superior to that of Soai reaction in literature. The products synthesized and their derivatives are possible drug candidates and their asymmetric synthesis was highly desirable. OBJECTS OF THE INVENTION Accordingly, one object of the present invention is to provide a process for preparing y-nitrophosphonates with high stereoselectivity and chemical yields. Yet another object of the present invention is to develop a methodology which can serve the above purpose by autocatalysis in the presence/absence of any chiral/achiral ligand. This provides a highly commercially viable process for y-nitrophosphonates giving an access to several well known biologically active molecules (e.g. y-aminophosphonic acid, [Bioorganic and Medicinal Chemistry Letters 1991, /, 501]) in enantiopure form. Further object of the present invention is to take this field a step ahead so that the plethora of asymmetric reactions can also gain practical importance by contributing to pool of pure enantiomers. SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a process for preparation of y-nitrophosphonate of general formual (4), said process steps comprising: (i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4CI solution and (v) extracting by ethyl acetate after saturating with brine Another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4), said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities and (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine Yet another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4), EtCk ^0 EtO"° N02 said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst and (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine DETAILED DESCRIPTION OF THE INVENTION The present invention pertains to asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis (i.e. achieving enantioselectivity without any catalyst or additive) in the Michael addition of alkyl and benzyl phosphonates to nitroalkenes. A typical procedure involves the following steps: (i) mixing of phosphonate at low temperature (-78 °C) in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of nitroalkene (with the same product, non-racemic, in the case of asymmetric autocatalysis, racemic, in the case of mirror symmetry breaking and none in the case of absolute asymmetric synthesis) and (iii) further mixing till completion of the reaction (iv) quenching the reaction mixture by saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine. In case of solid product, the product is washed by isopropanol/hexane (1:10) after trituration and further recrystallization with CH2Cl2/hexane (1:10) to afford chemically pure product. In case of liquid product, the residue is purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution). The methodology proved to be general after screening various phosphonates (benzyl, naphthyl, p-chlorobenzyl and methyl) and nitroalkenes (p-chloronitrostyrene and p-methoxynitrostyrene). Non-racemic catalysts with enantiomeric excess (R,R) or (S,S) provides the same enantiomers as products in excellent yields. The substrates undergo >50% conversion within a minute of reaction in high ee's. The rate of reaction is greater in the mirror symmetry breaking experiment by using racemic catalyst as compared to that of absolute asymmetric synthesis. The stereoselectivity may vary according to the solvent/mixture concentration (e.g. 1/4-1/8 molar), but the preferred concentration is 1/6 molar. The reaction mixture can be brought to ambient temperature after addition of all the reagents to give the product in good yields without much depletion in stereoselectivity, but a common procedure best suited to all the substrates needs 8 h of low temperature with 10 h of stirring at room temperature. The reaction is sensitive to additives and solvent, but the best solvent is found to be THF. The invention is now illustrated with a few but non-limiting examples (See Tables 1-3). Example 1 Preparation of diethyl 2-(4-chlorophenyl)-3-nitro-l-phenylpropylphosphonate 3a A solution of LDA (1.5 mmol) was prepared by dropwise addition of w-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2a (114 mg, 0.5 mmol) in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3a (21 mg, 0.05 mmol, non-racemic, racemic or none, see Tables 1, 2 and 3, respectively) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4C1 (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was triturated, washed by isopropanol/hexane (1:10, 3 x 1 ml) and recrystallized from CH2Cl2/hexane (1:10) to afford the pure product. Notably, the product can be prepared with high purity without involvement of column chromatography in case of solid products. Example 2 Preparation of diethyl 2-(4-chlorophenyl)-3-nitropropylphosphonate 3e EtCk 3e A solution of LDA (1.5 mmol) was prepared by dropwise addition of «-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2d (0.075 mg, 0.5 mmol)in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3e (17 mg, 0.05 mmol, non-racemic, racemic or none) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4CI (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution). Table 1 Asymmetric autocatalysis and amplification in the Michael addition of phosphonate 2a to nitroalkene la O OEt Jr^p P-OEt 2a -78°C(8h) to rt (10 h) entry catalyst 3a ee (%)m yield (%)[bJ dr® ee (%)LcJ 1 99 (&J?) 2 75 (££) 3 50 (R,R) 4 25 (i?,i?) 5 10 (R,R) 6 10 (5,5) 7 25 (S,S) 8 50 (5,S) 85 100:0 >99 (R,R) 82 99:01 >99 (R,R) 82 95:05 >99 (&£) 77 93:07 >99 (£) 79 92:08 >99 (R,R) 75 98:02 98 (5.S) 76 99:01 >99 (S,S) 78 >99:01 >99 (5,S) [a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane). Table 2 Mirror symmetry breaking in the Michael addition of phosphonate 2a to nitroalkene la. EtCk ^.0 i-P ci la NO, (3 OEt P-OEt O^ 2a LDA(3 equiv),THF -78°C(8h) to rt(10h) Entry conditions W yield (%)[b] w ee (%) W 1 3 equiv LDA, rac 3a, 10 mol % 2 3 equiv LDA, rac 3a, 5 mol % 3 3 equiv LDA, rac 3a, 1 mol % 4 2 equiv LDA, rac 3a, 1 mol % 5 1 equiv LDA, rac 3a, 1 mol % 6 3 equiv LDA, no catalyst 7 3 equiv LDA, rac 3a, 1 mol %[d] 72 98:02 99 68 99:01 >99 64 98:02 98 12 98:02 84 2 70:30 40 54 99:01 99 64 98:02 98 [a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane); [d] Ambient temperature after addition. Table 3 Absolute asymmetric induction in the Michael addition of phosphonates 2 to nitroalkenes l.[a] NO, R'- o OEt P-OEt LDA (3 equiv), THF -78°C(8h) tort (10 h) NO, EtOs. ^.O ^r\ ^R EtO"P Entry 1,R 2,R' 3,yield (%)[b] dr[ci ee (%)[cJ 1 la, CI 2a, Ph 3a,55 99:01 99 (S,S) 2 lb, OMe 2a, Ph 3b,63 89:11 89 (R,R) 3 la, CI 2b, Naphthyl 3c,73 75:25 60 (R,R) 4 la, CI 2c, 4-Cl-Ph 3d,54 54:46 91e 5 la, CI 2d,H 3e,64 - 88f [a] Conditions were kept constant though ideal conditions for each case may differ; [b] Isolated yield after purification by silica gel column chromatography and/or recrystallization; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane); [d] One in four cases (16 experiments) gave (R,R) enantiomer; [e] (S,R) or (R,S); [f] Absolute configuration not determined. WE CLAIM: 1. A process for preparation of g-nitrophosphonate of general formula (4), said process steps comprising : (i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities and (iii) further mixing till completion of the reaction (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine 2. A process for preparation of g-nitrophosphonate having general formula, said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities; (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine. 3. A process for preparation of y-nitrophosphonate having general formula (4), said process steps comprising: (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst; (iii) further mixing till completion of the reaction. (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine 4. Process as claimed in any one of claims 1,2 or 3 wherein the low temperature for mixing the phosphonate is -78°C. 5. Process as claimed in any one of claims 1, 2 or 3 wherein said saturated aqueous solution is NH4CI. 6. Process as claimed in any preceding claims comprising optionally adding additives in the reaction of a phosphonate stabilized carbanion to nitroalkenes. 7. Process as claimed in claim 6, wherein the additives are selected from chiral, achiral and mixture thereof. 8. Process as claimed in any preceding claims comprising controlling of reaction of phosphonate stabilized carbanion to nitroalkenes by control factors selectively concentration of reaction mixture, reaction time and reaction temperature or combination thereof. 9. Process as claimed in claim 8 wherein the concentration of the mixture ranges from 1/4 to 1/8 molar. 10. Process as claimed in claims 8 and 9 wherein the concentration of the mixture is preferably 1/6 molar. 11. Process as claimed in claim 8 wherein the reaction temperature ranges from -100°Cto+50°C. 12. Process as claimed in claim 11 wherein the reaction temperature is preferably -78°C to 25 °C. Dated this the 30th day of November 2007 ABSTRACT Title: ASYMMETRIC SYNTHESIS OF y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST The present invention relates to a process for preparation of y-nitrophosphonate of general formula (4), The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction mixture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking)and in the absence of any catalyst (absolute asymmetric synthesis). FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention: ASYMMETRIC SYNTHESIS OF g-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST 2. Applicant(s) (a) NAME : (b) NATIONALITY (c) ADDRESS : INDIAN INSTITUTE OF TECHNOLOGY Created by an act of Parliament, Institute of Technologies Act, 1961 Indian Institute of Technology, Bombay, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF THE INVENTION The present invention relates to a process for preparing g-nitrophosphonates. More particularly, the invention relates to process of preparation of g-nitrophosphonates reacting phosphonate stabilized carbanion to nitroalkenes selectively comprising steps of asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric induction, i.e. without using any chiral source. BACKGROUND AND PRIOR ART Last few decades have seen development of chiral catalysis to an extent where it can be thought of biomimicking. However, source of pure enantiomer still beholds in the technique of classic resolution, biochemical and biological methods. This is due to the fact that most of the asymmetric reactions are not absolute in the sense of selectivity. The present invention envisages that the autocatalytic amplification can be critical leading to the utilization of general reactions where enantiomeric excess is anything but absolute. The exclusion of external ligand for catalysis save costs to a great extent and also removes the necessity to separate the product from catalyst which could further prove economical in commercial applications. The origin of homochirality and the chemical routes mimicking the process leading to high enantiomeric enrichment of organic compounds generated great interest in the past few years. Soai reaction was pivotal which led to utilization of several chiral initiators including product itself in these reactions [Chirality 2006, 18, 469-478]. However, only a rare set of reactions with very limited substrate scope is known to show asymmetric autocatalytic amplification (AAA). A recent report demonstrated Mannich reaction of acetone with (E)-ethyl 2-(4-methoxyphenylimino)acetate [Angew. Chem., Int. Ed. 2007, 46, 393-396]. Another report shows the phenomenon with moderate amplification in Mannich and aldol reactions [Chirality 2007, 19, 816-825]. The milestone of breaking the symmetry and absolute asymmetric synthesis are even rarer [Mirror symmetry breaking: Chem. Rev. 2003, 103, 3369-3400; Absolute asymmetric synthesis (3 papers, 1 patent): Tetrahedron: Asymmetry 2003, 14, 185-188; Org. Lett. 2003, 5, 4337-4339; J. Am. Chem. Soc. 2002, 124, 10010-10011; Japan Kokai Tokkyo Koho 9,268,179,1997]. The Soai reaction, i.e. addition of organozinc compounds to aldehydes, works with only a few substrates and the report on Mannich reaction is based on only one example of substrates (references; vide supra). These reactions are generally based on weak interactions which are very sensitive to minor change in electronic and steric factors. On practical hand, the best condition [Angew. Chem., Int. Ed. 2003, 42, 315-317] takes at least three steps for amplification upto >99% ee after addition of product of low ee's as the chiral catalyst. The main disadvantage with the prior art is that the projected speculations for these reactions in the presence of product as the chiral catalyst require three steps to attain such enantioselectivities and in the absence of any catalyst for which the prior art is also limited to a specific reaction, i.e. addition of dialkyl zinc to an aromatic aldehyde, the selectivities are only moderate. The existing process for preparation of aminophosphonates requires addition of other chiral catalysts such as cinchonine [Tetrahedron:Asymmetry,,2001',18, 2719]. Such types of processes are cumbersome and costly. Thus, there is a need for development in terms of a process for preparation of nitrophosphonates, more particularly, y-nitrophosphonates which would be first and cost effective. The present inventors have found a process which by adopting selectively asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis in Michael addition produces an amplification of greater than 99% enantiomeric excess (ee) in one step which is about three times superior to that of Soai reaction in literature. The products synthesized and their derivatives are possible drug candidates and their asymmetric synthesis was highly desirable. OBJECTS OF THE INVENTION Accordingly, one object of the present invention is to provide a process for preparing y-nitrophosphonates with high stereoselectivity and chemical yields. Yet another object of the present invention is to develop a methodology which can serve the above purpose by autocatalysis in the presence/absence of any chiral/achiral ligand. This provides a highly commercially viable process for y-nitrophosphonates giving an access to several well known biologically active molecules (e.g. y-aminophosphonic acid, [Bioorganic and Medicinal Chemistry Letters 1991, /, 501]) in enantiopure form. Further object of the present invention is to take this field a step ahead so that the plethora of asymmetric reactions can also gain practical importance by contributing to pool of pure enantiomers. SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a process for preparation of y-nitrophosphonate of general formual (4), said process steps comprising: (i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4CI solution and (v) extracting by ethyl acetate after saturating with brine Another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4), said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities and (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine Yet another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4), EtCk ^0 EtO"° N02 said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst and (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine DETAILED DESCRIPTION OF THE INVENTION The present invention pertains to asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis (i.e. achieving enantioselectivity without any catalyst or additive) in the Michael addition of alkyl and benzyl phosphonates to nitroalkenes. A typical procedure involves the following steps: (i) mixing of phosphonate at low temperature (-78 °C) in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of nitroalkene (with the same product, non-racemic, in the case of asymmetric autocatalysis, racemic, in the case of mirror symmetry breaking and none in the case of absolute asymmetric synthesis) and (iii) further mixing till completion of the reaction (iv) quenching the reaction mixture by saturated aqueous NH4C1 solution and (v) extracting by ethyl acetate after saturating with brine. In case of solid product, the product is washed by isopropanol/hexane (1:10) after trituration and further recrystallization with CH2Cl2/hexane (1:10) to afford chemically pure product. In case of liquid product, the residue is purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution). The methodology proved to be general after screening various phosphonates (benzyl, naphthyl, p-chlorobenzyl and methyl) and nitroalkenes (p-chloronitrostyrene and p-methoxynitrostyrene). Non-racemic catalysts with enantiomeric excess (R,R) or (S,S) provides the same enantiomers as products in excellent yields. The substrates undergo >50% conversion within a minute of reaction in high ee's. The rate of reaction is greater in the mirror symmetry breaking experiment by using racemic catalyst as compared to that of absolute asymmetric synthesis. The stereoselectivity may vary according to the solvent/mixture concentration (e.g. 1/4-1/8 molar), but the preferred concentration is 1/6 molar. The reaction mixture can be brought to ambient temperature after addition of all the reagents to give the product in good yields without much depletion in stereoselectivity, but a common procedure best suited to all the substrates needs 8 h of low temperature with 10 h of stirring at room temperature. The reaction is sensitive to additives and solvent, but the best solvent is found to be THF. The invention is now illustrated with a few but non-limiting examples (See Tables 1-3). Example 1 Preparation of diethyl 2-(4-chlorophenyl)-3-nitro-l-phenylpropylphosphonate 3a A solution of LDA (1.5 mmol) was prepared by dropwise addition of w-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2a (114 mg, 0.5 mmol) in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3a (21 mg, 0.05 mmol, non-racemic, racemic or none, see Tables 1, 2 and 3, respectively) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4C1 (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was triturated, washed by isopropanol/hexane (1:10, 3 x 1 ml) and recrystallized from CH2Cl2/hexane (1:10) to afford the pure product. Notably, the product can be prepared with high purity without involvement of column chromatography in case of solid products. Example 2 Preparation of diethyl 2-(4-chlorophenyl)-3-nitropropylphosphonate 3e EtCk 3e A solution of LDA (1.5 mmol) was prepared by dropwise addition of «-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2d (0.075 mg, 0.5 mmol)in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3e (17 mg, 0.05 mmol, non-racemic, racemic or none) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4CI (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution). Table 1 Asymmetric autocatalysis and amplification in the Michael addition of phosphonate 2a to nitroalkene la O OEt Jr^p P-OEt 2a -78°C(8h) to rt (10 h) entry catalyst 3a ee (%)m yield (%)[bJ dr® ee (%)LcJ 1 99 (&J?) 2 75 (££) 3 50 (R,R) 4 25 (i?,i?) 5 10 (R,R) 6 10 (5,5) 7 25 (S,S) 8 50 (5,S) 85 100:0 >99 (R,R) 82 99:01 >99 (R,R) 82 95:05 >99 (&£) 77 93:07 >99 (£) 79 92:08 >99 (R,R) 75 98:02 98 (5.S) 76 99:01 >99 (S,S) 78 >99:01 >99 (5,S) [a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane). Table 2 Mirror symmetry breaking in the Michael addition of phosphonate 2a to nitroalkene la. EtCk ^.0 i-P ci la NO, (3 OEt P-OEt O^ 2a LDA(3 equiv),THF -78°C(8h) to rt(10h) Entry conditions W yield (%)[b] w ee (%) W 1 3 equiv LDA, rac 3a, 10 mol % 2 3 equiv LDA, rac 3a, 5 mol % 3 3 equiv LDA, rac 3a, 1 mol % 4 2 equiv LDA, rac 3a, 1 mol % 5 1 equiv LDA, rac 3a, 1 mol % 6 3 equiv LDA, no catalyst 7 3 equiv LDA, rac 3a, 1 mol %[d] 72 98:02 99 68 99:01 >99 64 98:02 98 12 98:02 84 2 70:30 40 54 99:01 99 64 98:02 98 [a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane); [d] Ambient temperature after addition. Table 3 Absolute asymmetric induction in the Michael addition of phosphonates 2 to nitroalkenes l.[a] NO, R'- o OEt P-OEt LDA (3 equiv), THF -78°C(8h) tort (10 h) NO, EtOs. ^.O ^r\ ^R EtO"P Entry 1,R 2,R' 3,yield (%)[b] dr[ci ee (%)[cJ 1 la, CI 2a, Ph 3a,55 99:01 99 (S,S) 2 lb, OMe 2a, Ph 3b,63 89:11 89 (R,R) 3 la, CI 2b, Naphthyl 3c,73 75:25 60 (R,R) 4 la, CI 2c, 4-Cl-Ph 3d,54 54:46 91e 5 la, CI 2d,H 3e,64 - 88f [a] Conditions were kept constant though ideal conditions for each case may differ; [b] Isolated yield after purification by silica gel column chromatography and/or recrystallization; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane); [d] One in four cases (16 experiments) gave (R,R) enantiomer; [e] (S,R) or (R,S); [f] Absolute configuration not determined. WE CLAIM: 1. A process for preparation of g-nitrophosphonate of general formula (4), said process steps comprising : (i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities and (iii) further mixing till completion of the reaction (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine 2. A process for preparation of g-nitrophosphonate having general formula, said process steps comprising : (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities; (iii) further mixing till completion of the reaction; (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine. 3. A process for preparation of y-nitrophosphonate having general formula (4), said process steps comprising: (i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; (ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst; (iii) further mixing till completion of the reaction. (iv) quenching the reaction mixture by a saturated aqueous solution and (v) extracting by ethyl acetate after saturating with brine 4. Process as claimed in any one of claims 1,2 or 3 wherein the low temperature for mixing the phosphonate is -78°C. 5. Process as claimed in any one of claims 1, 2 or 3 wherein said saturated aqueous solution is NH4CI. 6. Process as claimed in any preceding claims comprising optionally adding additives in the reaction of a phosphonate stabilized carbanion to nitroalkenes. 7. Process as claimed in claim 6, wherein the additives are selected from chiral, achiral and mixture thereof. 8. Process as claimed in any preceding claims comprising controlling of reaction of phosphonate stabilized carbanion to nitroalkenes by control factors selectively concentration of reaction mixture, reaction time and reaction temperature or combination thereof. 9. Process as claimed in claim 8 wherein the concentration of the mixture ranges from 1/4 to 1/8 molar. 10. Process as claimed in claims 8 and 9 wherein the concentration of the mixture is preferably 1/6 molar. 11. Process as claimed in claim 8 wherein the reaction temperature ranges from -100°Cto+50°C. 12. Process as claimed in claim 11 wherein the reaction temperature is preferably -78°C to 25 °C. Dated this the 30th day of November 2007 ABSTRACT Title: ASYMMETRIC SYNTHESIS OF y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST The present invention relates to a process for preparation of y-nitrophosphonate of general formula (4), The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction mixture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking)and in the absence of any catalyst (absolute asymmetric synthesis).

Full Text

FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: ASYMMETRIC SYNTHESIS OF g-NITROPHOSPHONATES
IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

INDIAN INSTITUTE OF TECHNOLOGY
Created by an act of Parliament, Institute of Technologies Act, 1961
Indian Institute of Technology, Bombay, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a process for preparing g-nitrophosphonates. More particularly, the invention relates to process of preparation of g-nitrophosphonates reacting phosphonate stabilized carbanion to nitroalkenes selectively comprising steps of asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric induction, i.e. without using any chiral source.
BACKGROUND AND PRIOR ART
Last few decades have seen development of chiral catalysis to an extent where it can be thought of biomimicking. However, source of pure enantiomer still beholds in the technique of classic resolution, biochemical and biological methods. This is due to the fact that most of the asymmetric reactions are not absolute in the sense of selectivity. The present invention envisages that the autocatalytic amplification can be critical leading to the utilization of general reactions where enantiomeric excess is anything but absolute. The exclusion of external ligand for catalysis save costs to a great extent and also removes the necessity to separate the product from catalyst which could further prove economical in commercial applications.
The origin of homochirality and the chemical routes mimicking the process leading to high enantiomeric enrichment of organic compounds generated great interest in the past few years. Soai reaction was pivotal which led to utilization of several chiral initiators including product itself in these reactions [Chirality 2006, 18, 469-478]. However, only a rare set of reactions with very limited substrate scope is known to show asymmetric autocatalytic amplification (AAA). A recent report demonstrated

Mannich reaction of acetone with (E)-ethyl 2-(4-methoxyphenylimino)acetate [Angew. Chem., Int. Ed. 2007, 46, 393-396]. Another report shows the phenomenon with moderate amplification in Mannich and aldol reactions [Chirality 2007, 19, 816-825]. The milestone of breaking the symmetry and absolute asymmetric synthesis are even rarer [Mirror symmetry breaking: Chem. Rev. 2003, 103, 3369-3400; Absolute asymmetric synthesis (3 papers, 1 patent): Tetrahedron: Asymmetry 2003, 14, 185-188; Org. Lett. 2003, 5, 4337-4339; J. Am. Chem. Soc. 2002, 124, 10010-10011; Japan Kokai Tokkyo Koho 9,268,179,1997].
The Soai reaction, i.e. addition of organozinc compounds to aldehydes, works with only a few substrates and the report on Mannich reaction is based on only one example of substrates (references; vide supra). These reactions are generally based on weak interactions which are very sensitive to minor change in electronic and steric factors. On practical hand, the best condition [Angew. Chem., Int. Ed. 2003, 42, 315-317] takes at least three steps for amplification upto >99% ee after addition of product of low ee's as the chiral catalyst.
The main disadvantage with the prior art is that the projected speculations for these reactions in the presence of product as the chiral catalyst require three steps to attain such enantioselectivities and in the absence of any catalyst for which the prior art is also limited to a specific reaction, i.e. addition of dialkyl zinc to an aromatic aldehyde, the selectivities are only moderate. The existing process for preparation of aminophosphonates requires addition of other chiral catalysts such as cinchonine [Tetrahedron:Asymmetry,,2001',18, 2719]. Such types of processes are cumbersome and costly.

Thus, there is a need for development in terms of a process for preparation of nitrophosphonates, more particularly, y-nitrophosphonates which would be first and cost effective.
The present inventors have found a process which by adopting selectively asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis in Michael addition produces an amplification of greater than 99% enantiomeric excess (ee) in one step which is about three times superior to that of Soai reaction in literature. The products synthesized and their derivatives are possible drug candidates and their asymmetric synthesis was highly desirable.
OBJECTS OF THE INVENTION
Accordingly, one object of the present invention is to provide a process for preparing y-nitrophosphonates with high stereoselectivity and chemical yields.
Yet another object of the present invention is to develop a methodology which can serve the above purpose by autocatalysis in the presence/absence of any chiral/achiral ligand. This provides a highly commercially viable process for y-nitrophosphonates giving an access to several well known biologically active molecules (e.g. y-aminophosphonic acid, [Bioorganic and Medicinal Chemistry Letters 1991, /, 501]) in enantiopure form.
Further object of the present invention is to take this field a step ahead so that the plethora of asymmetric reactions can also gain practical importance by contributing to pool of pure enantiomers.

SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a process for preparation of y-nitrophosphonate of general formual (4),

said process steps comprising:
(i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities;
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4CI solution and
(v) extracting by ethyl acetate after saturating with brine
Another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4),

said process steps comprising :
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities and
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and
(v) extracting by ethyl acetate after saturating with brine
Yet another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4),

EtCk ^0 EtO"°

N02

said process steps comprising :

(i) mixing of phosphonate at low temperature in freshly prepared LDA
solution in THF for an hour thereby forming phosphonate stabilized
carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute
asymmetric synthesis, i.e. without using any catalyst and
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution
and
(v) extracting by ethyl acetate after saturating with brine
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains to asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis (i.e. achieving enantioselectivity without any catalyst or additive) in the Michael addition of alkyl and benzyl phosphonates to nitroalkenes.
A typical procedure involves the following steps:
(i) mixing of phosphonate at low temperature (-78 °C) in freshly prepared
LDA solution in THF for an hour thereby forming phosphonate stabilized
carbanion;
(ii) addition of nitroalkene (with the same product, non-racemic, in the case of
asymmetric autocatalysis, racemic, in the case of mirror symmetry
breaking and none in the case of absolute asymmetric synthesis) and (iii) further mixing till completion of the reaction
(iv) quenching the reaction mixture by saturated aqueous NH4C1 solution and
(v) extracting by ethyl acetate after saturating with brine.

In case of solid product, the product is washed by isopropanol/hexane (1:10) after trituration and further recrystallization with CH2Cl2/hexane (1:10) to afford chemically pure product. In case of liquid product, the residue is purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution).
The methodology proved to be general after screening various phosphonates (benzyl, naphthyl, p-chlorobenzyl and methyl) and nitroalkenes (p-chloronitrostyrene and p-methoxynitrostyrene).
Non-racemic catalysts with enantiomeric excess (R,R) or (S,S) provides the same enantiomers as products in excellent yields. The substrates undergo >50% conversion within a minute of reaction in high ee's. The rate of reaction is greater in the mirror symmetry breaking experiment by using racemic catalyst as compared to that of absolute asymmetric synthesis.
The stereoselectivity may vary according to the solvent/mixture concentration (e.g. 1/4-1/8 molar), but the preferred concentration is 1/6 molar.
The reaction mixture can be brought to ambient temperature after addition of all the reagents to give the product in good yields without much depletion in stereoselectivity, but a common procedure best suited to all the substrates needs 8 h of low temperature with 10 h of stirring at room temperature.
The reaction is sensitive to additives and solvent, but the best solvent is found to be THF.
The invention is now illustrated with a few but non-limiting examples (See Tables 1-3).

Example 1
Preparation of diethyl 2-(4-chlorophenyl)-3-nitro-l-phenylpropylphosphonate 3a

A solution of LDA (1.5 mmol) was prepared by dropwise addition of w-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2a (114 mg, 0.5 mmol) in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3a (21 mg, 0.05 mmol, non-racemic, racemic or none, see Tables 1, 2 and 3, respectively) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4C1 (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was triturated, washed by isopropanol/hexane (1:10, 3 x 1 ml) and recrystallized from CH2Cl2/hexane (1:10) to afford the pure product. Notably, the product can be prepared with high purity without involvement of column chromatography in case of solid products.

Example 2
Preparation of diethyl 2-(4-chlorophenyl)-3-nitropropylphosphonate 3e
EtCk
3e
A solution of LDA (1.5 mmol) was prepared by dropwise addition of «-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2d (0.075 mg, 0.5 mmol)in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3e (17 mg, 0.05 mmol, non-racemic, racemic or none) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4CI (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution).

Table 1 Asymmetric autocatalysis and amplification in the Michael addition of phosphonate 2a to nitroalkene la

O OEt Jr^p
P-OEt
2a
-78°C(8h) to rt (10 h)

entry catalyst 3a ee (%)m yield (%)[bJ dr® ee (%)LcJ

1 99 (&J?)
2 75 (££)
3 50 (R,R)
4 25 (i?,i?)
5 10 (R,R)
6 10 (5,5)
7 25 (S,S)
8 50 (5,S)

85 100:0 >99 (R,R)
82 99:01 >99 (R,R)
82 95:05 >99 (&£)
77 93:07 >99 (£*)
79 92:08 >99 (R,R)
75 98:02 98 (5.S)
76 99:01 >99 (S,S)
78 >99:01 >99 (5,S)

[a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane).

Table 2 Mirror symmetry breaking in the Michael addition of phosphonate 2a to nitroalkene la.

EtCk ^.0 i-P
ci

la

NO,

(3 OEt P-OEt
O^
2a

LDA(3 equiv),THF -78°C(8h) to rt(10h)

Entry conditions

W

yield
(%)[b]

w*

ee (%)

W

1 3 equiv LDA, rac 3a, 10 mol %
2 3 equiv LDA, rac 3a, 5 mol %
3 3 equiv LDA, rac 3a, 1 mol %
4 2 equiv LDA, rac 3a, 1 mol %
5 1 equiv LDA, rac 3a, 1 mol %
6 3 equiv LDA, no catalyst
7 3 equiv LDA, rac 3a, 1 mol %[d]

72 98:02 99
68 99:01 >99
64 98:02 98
12 98:02 84
2 70:30 40
54 99:01 99
64 98:02 98

[a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane); [d] Ambient temperature after addition.

Table 3 Absolute asymmetric induction in the Michael addition of phosphonates 2 to nitroalkenes l.[a]

NO,

R'-

o OEt
P-OEt

LDA (3 equiv), THF -78°C(8h) tort (10 h)

NO,
EtOs. ^.O ^r\ ^R EtO"P

Entry 1,R 2,R' 3,yield (%)[b] dr[ci ee (%)[cJ
1 la, CI 2a, Ph 3a,55 99:01 99 (S,S)
2 lb, OMe 2a, Ph 3b,63 89:11 89 (R,R)
3 la, CI 2b, Naphthyl 3c,73 75:25 60 (R,R)
4 la, CI 2c, 4-Cl-Ph 3d,54 54:46 91e
5 la, CI 2d,H 3e,64 - 88f
[a] Conditions were kept constant though ideal conditions for each case may differ;
[b] Isolated yield after purification by silica gel column chromatography and/or recrystallization; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane); [d] One in four cases (16 experiments) gave (R,R) enantiomer; [e] (S,R) or (R,S); [f] Absolute configuration not determined.

WE CLAIM:
1. A process for preparation of g-nitrophosphonate of general formula (4),

said process steps comprising :
(i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities and
(iii) further mixing till completion of the reaction
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine

2. A process for preparation of g-nitrophosphonate having general formula,

said process steps comprising :
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities;
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine.
3. A process for preparation of y-nitrophosphonate having general formula (4),

said process steps comprising:
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst;
(iii) further mixing till completion of the reaction.
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine
4. Process as claimed in any one of claims 1,2 or 3 wherein the low temperature for mixing the phosphonate is -78°C.
5. Process as claimed in any one of claims 1, 2 or 3 wherein said saturated aqueous solution is NH4CI.
6. Process as claimed in any preceding claims comprising optionally adding additives in the reaction of a phosphonate stabilized carbanion to nitroalkenes.

7. Process as claimed in claim 6, wherein the additives are selected from chiral, achiral and mixture thereof.
8. Process as claimed in any preceding claims comprising controlling of reaction of phosphonate stabilized carbanion to nitroalkenes by control factors selectively concentration of reaction mixture, reaction time and reaction temperature or combination thereof.
9. Process as claimed in claim 8 wherein the concentration of the mixture ranges from 1/4 to 1/8 molar.
10. Process as claimed in claims 8 and 9 wherein the concentration of the mixture is preferably 1/6 molar.
11. Process as claimed in claim 8 wherein the reaction temperature ranges from -100°Cto+50°C.
12. Process as claimed in claim 11 wherein the reaction temperature is preferably -78°C to 25 °C.
Dated this the 30th day of November 2007

ABSTRACT

Title: ASYMMETRIC SYNTHESIS OF y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST
The present invention relates to a process for preparation of y-nitrophosphonate of general formula (4),

The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction mixture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking)and in the absence of any catalyst (absolute asymmetric synthesis).
FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: ASYMMETRIC SYNTHESIS OF g-NITROPHOSPHONATES
IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

INDIAN INSTITUTE OF TECHNOLOGY
Created by an act of Parliament, Institute of Technologies Act, 1961
Indian Institute of Technology, Bombay, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a process for preparing g-nitrophosphonates. More particularly, the invention relates to process of preparation of g-nitrophosphonates reacting phosphonate stabilized carbanion to nitroalkenes selectively comprising steps of asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric induction, i.e. without using any chiral source.
BACKGROUND AND PRIOR ART
Last few decades have seen development of chiral catalysis to an extent where it can be thought of biomimicking. However, source of pure enantiomer still beholds in the technique of classic resolution, biochemical and biological methods. This is due to the fact that most of the asymmetric reactions are not absolute in the sense of selectivity. The present invention envisages that the autocatalytic amplification can be critical leading to the utilization of general reactions where enantiomeric excess is anything but absolute. The exclusion of external ligand for catalysis save costs to a great extent and also removes the necessity to separate the product from catalyst which could further prove economical in commercial applications.
The origin of homochirality and the chemical routes mimicking the process leading to high enantiomeric enrichment of organic compounds generated great interest in the past few years. Soai reaction was pivotal which led to utilization of several chiral initiators including product itself in these reactions [Chirality 2006, 18, 469-478]. However, only a rare set of reactions with very limited substrate scope is known to show asymmetric autocatalytic amplification (AAA). A recent report demonstrated

Mannich reaction of acetone with (E)-ethyl 2-(4-methoxyphenylimino)acetate [Angew. Chem., Int. Ed. 2007, 46, 393-396]. Another report shows the phenomenon with moderate amplification in Mannich and aldol reactions [Chirality 2007, 19, 816-825]. The milestone of breaking the symmetry and absolute asymmetric synthesis are even rarer [Mirror symmetry breaking: Chem. Rev. 2003, 103, 3369-3400; Absolute asymmetric synthesis (3 papers, 1 patent): Tetrahedron: Asymmetry 2003, 14, 185-188; Org. Lett. 2003, 5, 4337-4339; J. Am. Chem. Soc. 2002, 124, 10010-10011; Japan Kokai Tokkyo Koho 9,268,179,1997].
The Soai reaction, i.e. addition of organozinc compounds to aldehydes, works with only a few substrates and the report on Mannich reaction is based on only one example of substrates (references; vide supra). These reactions are generally based on weak interactions which are very sensitive to minor change in electronic and steric factors. On practical hand, the best condition [Angew. Chem., Int. Ed. 2003, 42, 315-317] takes at least three steps for amplification upto >99% ee after addition of product of low ee's as the chiral catalyst.
The main disadvantage with the prior art is that the projected speculations for these reactions in the presence of product as the chiral catalyst require three steps to attain such enantioselectivities and in the absence of any catalyst for which the prior art is also limited to a specific reaction, i.e. addition of dialkyl zinc to an aromatic aldehyde, the selectivities are only moderate. The existing process for preparation of aminophosphonates requires addition of other chiral catalysts such as cinchonine [Tetrahedron:Asymmetry,,2001',18, 2719]. Such types of processes are cumbersome and costly.

Thus, there is a need for development in terms of a process for preparation of nitrophosphonates, more particularly, y-nitrophosphonates which would be first and cost effective.
The present inventors have found a process which by adopting selectively asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis in Michael addition produces an amplification of greater than 99% enantiomeric excess (ee) in one step which is about three times superior to that of Soai reaction in literature. The products synthesized and their derivatives are possible drug candidates and their asymmetric synthesis was highly desirable.
OBJECTS OF THE INVENTION
Accordingly, one object of the present invention is to provide a process for preparing y-nitrophosphonates with high stereoselectivity and chemical yields.
Yet another object of the present invention is to develop a methodology which can serve the above purpose by autocatalysis in the presence/absence of any chiral/achiral ligand. This provides a highly commercially viable process for y-nitrophosphonates giving an access to several well known biologically active molecules (e.g. y-aminophosphonic acid, [Bioorganic and Medicinal Chemistry Letters 1991, /, 501]) in enantiopure form.
Further object of the present invention is to take this field a step ahead so that the plethora of asymmetric reactions can also gain practical importance by contributing to pool of pure enantiomers.

SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a process for preparation of y-nitrophosphonate of general formual (4),

said process steps comprising:
(i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities;
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4CI solution and
(v) extracting by ethyl acetate after saturating with brine
Another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4),

said process steps comprising :
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities and
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution and
(v) extracting by ethyl acetate after saturating with brine
Yet another aspect of the present invention is to provide a process for preparation of y-nitrophosphonate of general formula (4),

EtCk ^0 EtO"°

N02

said process steps comprising :

(i) mixing of phosphonate at low temperature in freshly prepared LDA
solution in THF for an hour thereby forming phosphonate stabilized
carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute
asymmetric synthesis, i.e. without using any catalyst and
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous NH4C1 solution
and
(v) extracting by ethyl acetate after saturating with brine
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains to asymmetric autocatalysis, mirror symmetry breaking and absolute asymmetric synthesis (i.e. achieving enantioselectivity without any catalyst or additive) in the Michael addition of alkyl and benzyl phosphonates to nitroalkenes.
A typical procedure involves the following steps:
(i) mixing of phosphonate at low temperature (-78 °C) in freshly prepared
LDA solution in THF for an hour thereby forming phosphonate stabilized
carbanion;
(ii) addition of nitroalkene (with the same product, non-racemic, in the case of
asymmetric autocatalysis, racemic, in the case of mirror symmetry
breaking and none in the case of absolute asymmetric synthesis) and (iii) further mixing till completion of the reaction
(iv) quenching the reaction mixture by saturated aqueous NH4C1 solution and
(v) extracting by ethyl acetate after saturating with brine.

In case of solid product, the product is washed by isopropanol/hexane (1:10) after trituration and further recrystallization with CH2Cl2/hexane (1:10) to afford chemically pure product. In case of liquid product, the residue is purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution).
The methodology proved to be general after screening various phosphonates (benzyl, naphthyl, p-chlorobenzyl and methyl) and nitroalkenes (p-chloronitrostyrene and p-methoxynitrostyrene).
Non-racemic catalysts with enantiomeric excess (R,R) or (S,S) provides the same enantiomers as products in excellent yields. The substrates undergo >50% conversion within a minute of reaction in high ee's. The rate of reaction is greater in the mirror symmetry breaking experiment by using racemic catalyst as compared to that of absolute asymmetric synthesis.
The stereoselectivity may vary according to the solvent/mixture concentration (e.g. 1/4-1/8 molar), but the preferred concentration is 1/6 molar.
The reaction mixture can be brought to ambient temperature after addition of all the reagents to give the product in good yields without much depletion in stereoselectivity, but a common procedure best suited to all the substrates needs 8 h of low temperature with 10 h of stirring at room temperature.
The reaction is sensitive to additives and solvent, but the best solvent is found to be THF.
The invention is now illustrated with a few but non-limiting examples (See Tables 1-3).

Example 1
Preparation of diethyl 2-(4-chlorophenyl)-3-nitro-l-phenylpropylphosphonate 3a

A solution of LDA (1.5 mmol) was prepared by dropwise addition of w-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2a (114 mg, 0.5 mmol) in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3a (21 mg, 0.05 mmol, non-racemic, racemic or none, see Tables 1, 2 and 3, respectively) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4C1 (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was triturated, washed by isopropanol/hexane (1:10, 3 x 1 ml) and recrystallized from CH2Cl2/hexane (1:10) to afford the pure product. Notably, the product can be prepared with high purity without involvement of column chromatography in case of solid products.

Example 2
Preparation of diethyl 2-(4-chlorophenyl)-3-nitropropylphosphonate 3e
EtCk
3e
A solution of LDA (1.5 mmol) was prepared by dropwise addition of «-BuLi (2.4 ml, 1.5 mmol, 1.6 M solution in hexanes) to diisopropylamine (0.21 ml, 152 mg, 1.5 mmol) in THF (2 ml) at 0 °C followed by stirring for 30 min at the same temperature. To this freshly prepared LDA, cooled to -78 °C, was added dropwise phosphonate 2d (0.075 mg, 0.5 mmol)in THF (1 ml). After stirring the reaction mixture for 1 h, catalyst 3e (17 mg, 0.05 mmol, non-racemic, racemic or none) and nitroalkene la (138 mg, 0.75 mmol) in THF (1 ml) were added to the reaction mixture and the temperature was maintained at -78 °C for an additional 8 h. The reaction mixture was warmed to ambient temperature and stirring continued for 10 h. The time at -78 °C can be varied with minor (~1%) depletion in stereoselectivity. The reaction mixture was quenched with saturated aqueous NH4CI (2 ml), further saturated with NaCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (anhyd Na2S04) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/pet ether, 0-50%, gradient elution).

Table 1 Asymmetric autocatalysis and amplification in the Michael addition of phosphonate 2a to nitroalkene la

O OEt Jr^p
P-OEt
2a
-78°C(8h) to rt (10 h)

entry catalyst 3a ee (%)m yield (%)[bJ dr® ee (%)LcJ

1 99 (&J?)
2 75 (££)
3 50 (R,R)
4 25 (i?,i?)
5 10 (R,R)
6 10 (5,5)
7 25 (S,S)
8 50 (5,S)

85 100:0 >99 (R,R)
82 99:01 >99 (R,R)
82 95:05 >99 (&£)
77 93:07 >99 (£*)
79 92:08 >99 (R,R)
75 98:02 98 (5.S)
76 99:01 >99 (S,S)
78 >99:01 >99 (5,S)

[a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane).

Table 2 Mirror symmetry breaking in the Michael addition of phosphonate 2a to nitroalkene la.

EtCk ^.0 i-P
ci

la

NO,

(3 OEt P-OEt
O^
2a

LDA(3 equiv),THF -78°C(8h) to rt(10h)

Entry conditions

W

yield
(%)[b]

w*

ee (%)

W

1 3 equiv LDA, rac 3a, 10 mol %
2 3 equiv LDA, rac 3a, 5 mol %
3 3 equiv LDA, rac 3a, 1 mol %
4 2 equiv LDA, rac 3a, 1 mol %
5 1 equiv LDA, rac 3a, 1 mol %
6 3 equiv LDA, no catalyst
7 3 equiv LDA, rac 3a, 1 mol %[d]

72 98:02 99
68 99:01 >99
64 98:02 98
12 98:02 84
2 70:30 40
54 99:01 99
64 98:02 98

[a] Catalyst 3a was diastereomerically pure in all the cases; [b] Isolated yield after purification by silica gel column chromatography; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in «-hexane); [d] Ambient temperature after addition.

Table 3 Absolute asymmetric induction in the Michael addition of phosphonates 2 to nitroalkenes l.[a]

NO,

R'-

o OEt
P-OEt

LDA (3 equiv), THF -78°C(8h) tort (10 h)

NO,
EtOs. ^.O ^r\ ^R EtO"P

Entry 1,R 2,R' 3,yield (%)[b] dr[ci ee (%)[cJ
1 la, CI 2a, Ph 3a,55 99:01 99 (S,S)
2 lb, OMe 2a, Ph 3b,63 89:11 89 (R,R)
3 la, CI 2b, Naphthyl 3c,73 75:25 60 (R,R)
4 la, CI 2c, 4-Cl-Ph 3d,54 54:46 91e
5 la, CI 2d,H 3e,64 - 88f
[a] Conditions were kept constant though ideal conditions for each case may differ;
[b] Isolated yield after purification by silica gel column chromatography and/or recrystallization; [c] Determined by HPLC (Chiralcel OD-H column, 5% IPA in n-hexane); [d] One in four cases (16 experiments) gave (R,R) enantiomer; [e] (S,R) or (R,S); [f] Absolute configuration not determined.

WE CLAIM:
1. A process for preparation of g-nitrophosphonate of general formula (4),

said process steps comprising :
(i) mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities and
(iii) further mixing till completion of the reaction
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine

2. A process for preparation of g-nitrophosphonate having general formula,

said process steps comprising :
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by mirror symmetry breaking using racemic product as catalyst in varying amounts to obtain the product in excellent yields and stereoselectivities;
(iii) further mixing till completion of the reaction;
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine.
3. A process for preparation of y-nitrophosphonate having general formula (4),

said process steps comprising:
(i) mixing of phosphonate at low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion;
(ii) reaction of a phosphonate stabilized carbanion to nitroalkenes by absolute asymmetric synthesis, i.e. without using any catalyst;
(iii) further mixing till completion of the reaction.
(iv) quenching the reaction mixture by a saturated aqueous solution and
(v) extracting by ethyl acetate after saturating with brine
4. Process as claimed in any one of claims 1,2 or 3 wherein the low temperature for mixing the phosphonate is -78°C.
5. Process as claimed in any one of claims 1, 2 or 3 wherein said saturated aqueous solution is NH4CI.
6. Process as claimed in any preceding claims comprising optionally adding additives in the reaction of a phosphonate stabilized carbanion to nitroalkenes.

7. Process as claimed in claim 6, wherein the additives are selected from chiral, achiral and mixture thereof.
8. Process as claimed in any preceding claims comprising controlling of reaction of phosphonate stabilized carbanion to nitroalkenes by control factors selectively concentration of reaction mixture, reaction time and reaction temperature or combination thereof.
9. Process as claimed in claim 8 wherein the concentration of the mixture ranges from 1/4 to 1/8 molar.
10. Process as claimed in claims 8 and 9 wherein the concentration of the mixture is preferably 1/6 molar.
11. Process as claimed in claim 8 wherein the reaction temperature ranges from -100°Cto+50°C.
12. Process as claimed in claim 11 wherein the reaction temperature is preferably -78°C to 25 °C.
Dated this the 30th day of November 2007

ABSTRACT

Title: ASYMMETRIC SYNTHESIS OF y-NITROPHOSPHONATES IN THE ABSENCE OF ANY OTHER CHIRAL CATALYST
The present invention relates to a process for preparation of y-nitrophosphonate of general formula (4),

The process steps comprise mixing of phosphonate at a low temperature in freshly prepared LDA solution in THF for an hour thereby forming phosphonate stabilized carbanion; addition of said phosphonate stabilized carbanion to nitroalkenes by asymmetric autocatalysis with complete stereochemical control by using a particular enantiomer of the product as catalyst in varying amounts and enantioselectivities; further mixing till completion of the reaction; quenching the reaction mixture by a saturated aqueous ammonium chloride solution and extracting by ethyl acetate after saturating with brine. The addition of the phosphonate to nitroalkenes is also carried out using racemic product as the catalyst (mirror symmetry breaking)and in the absence of any catalyst (absolute asymmetric synthesis).

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Patent Number

269284

Indian Patent Application Number

2359/MUM/2007

PG Journal Number

42/2015

Publication Date

16-Oct-2015

Grant Date

14-Oct-2015

Date of Filing

30-Nov-2007

Name of Patentee

INDIAN INSTITUTE OF TECHNOLOGY

Applicant Address

INDIAN INSTITUTE OF TECHNOLOGY, BOMBAY, POWAI

Inventors:

#	Inventor's Name	Inventor's Address
1	NAMBOOTHIRI IRISHI N.N.	DEPARTMENT OF CHEMISRTY, INDIAN INSTITUTE OF TECHNOLOGY, BOMBAY, POWAI 400076
2	RAI VISHAL	DEPARTMENT OF CHEMISRTY, INDIAN INSTITUTE OF TECHNOLOGY, BOMBAY, POWAI 400076

PCT International Classification Number

A01N57/20; B01J23/00; C02F1/50

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA