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| LICENSOR | Patent Assignee |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 17, 2001 |
| PATENT TITLE |
Stereoselective ring opening reactions |
| PATENT ABSTRACT | The present invention relates to a process for stereoselective or regioselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic, chiral catalyst to produce a stereoisomerically- and/or regioisomerically-enriched product. The present invention also relates to hydrolytic kinetic resolutions of racemic and diastereomeric mixtures of epoxides |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 14, 1998 |
| PATENT REFERENCES CITED |
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Chang, S. et al., "Effect of Chiral Quaternary Ammonium Salts On (Salen) Mn-Catalyzed Epoxidation Of Cis-Olefins. A Highly Enantioselective, Catalytic Route to Trans-Epoxides" J. Am. Chem. Soc. 116 (15):6937-6938 (1994). Chen, X. et al., "Microbiological Transformations 27. The First Examples for Preparative- Scale Enantioselective or Diastereoselective Epoxide Hydrolyses Using Microorganisms. An Unequivocal Access to All Four Bisabolol Stereoisomers", J. of Am. Chem. Soc. 58(20):5528-5532 (1993). Collman, J. et al., "Regioselective and Enantioselective Epoxidation Catalyzed by Metalloporphyrins", Science, 261:1404-1411 (1993). Collman, J. et al., "Enantioselective Epoxidation Of unfunctionalized Olefins Catalyzed By Threitol-Strapped Manganese Porphyrins", J. of Am. Chem. Soc. 115:3834-3835 (1993). Corey, E. and F. Hannon, "Chiral Catalysts For The Enantioselective Addition Of Organometallic Reagents to Aldehydes", Tetrahedron Letters 28(44):5233-5236 (1987). Desimoni, G. et al., Copper(II) In Organic Synthesis X(*). The Importance of Steric Hindrance In The Design of Chiral Tridentate Ligand Copper (II) Catalysts For Enantioselective Michael Reactions(**) Gazzetta Chimica Italiana 122: 268-273 (1992). Emziane, M. et al., "Asymmetric Ring-Opening of Cyclohexene Oxide With Trimethylsilyl Azide In The Presence of Titanium Isopropoxide/Chiral Ligand", J. of Organometallic Chemistry 346: C7-C10(1988). Groves, J. and R. Neumann, "Regioselective Oxidation Catalysis In Synthetic Phospholipid Vesicles. Membrane-Spanning Steroidal Metalloporphyrins" J. Am. Chem. Soc. 111: 2900-2909 (1989). Groves, G. and R. Neumann, "Membrane-Spanning Steroidal Metalloporphyrins as Site-Selective Catalysts in Synthetic Vesicles" J. Am. Chem. Soc. 109:5045-5047 (1987). Hayashi, M. et al., "Novel Asymmetric Ring-Opening Reactions of Symmetrical N-Acylaziridines with Arenethiols Catalysed by Chiral Dialkyl Tartrate-Diathylzinc Complexes", J. of Chem. Soc. Chem. Commun. No. 23: 2699-2700 (1994). Hayashi, M. et al., "Asymmetric Ring-Opening of Symmetrical Epoxides With Trimethylsilyl Azide Using Chiral Titanium Complexes", Synlett. No. 11: 774-776 (1991). Jameson, D. "2,6 Bis (N-pyrazolyl) Pyridines: The Convenient Synthesis of a Family of Planar Tridentate N3 Ligands that are Terpyridine Analogues", J. of Organ. Chem. 55: 4992-4994 (1990). Jacobsen, E. et al., "Highly Enantioselective Epoxidation Catalysts Derived from 1,2-Aminocyclohexane", J. Am. Chem. Soc. 113:7063-7064 (1991). Knebel, W. and R. Angelici, "Kinetic and Equilibrium Studies of Bi- and Tridentate Chelate Ring -Opening Reactions of Metal Carbonyl Complexes", Inorganic Chemistry 13(3):632-637 (1974). Kruper, W. and Dellar, D. "Catalytic Formation of Cyclic Carbonates From Epoxides and Co2 With Chromium Metalloporphirinates", J. Org. Chem. 60:725-727 (1995). Larrow, J. and E. Jacobsen, "Kinetic Resolution of 1,2-Dihydronaphthalene Oxide and Related Epoxides Via Asymmetric C-H Hydroxylation", J. Am .Chem. Soc. 116: 12129-12130 (1994). Larrow, J. and E. Jacobsen, "A Practical Method for the Large-Scale Preparation of [N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-Cyclohexanediaminato (2-)]Manganese(III) Chloride, A Highly Enantiocelective Epoxidation Catalyst", J. Org. Chem. 59: 1939-1942 (1994). Leighton, J. et al., "Efficient Synthesis of (R)-4-((Trimethylsily)oxy)-2-Cyclopentenone by Enantioselective Catalytic Epoxide Ring-Opening", Journal of Organic Chemistry vol. 61: No. 1, pp 389-390 (1996). Li, Z. et al., "Asymmetric Alkene Aziridination With Readily Available Chiral Diimine-Based Catalysts", J. Am. Chem. Soc. 115(12):5326-5327 (1993). Marangoni, G. and B. Pitteri "Crystal Structure of Cationic Square Planar Platinum (II) Complexes Containing The Tridentate Chelate Ligand 2,6-Bis(methylthiomethyl)Pyridine", Polyhdron 12(13):1669-1673 (1993). Martinez, L. et al., "Highly Enantioselective Ring Opening of Epoxides Catalyzed by (Salen) Cr(III) Complexes", J. Am. Chem. Soc. 117:5897-5898 (1995). Maruoka, K. et al., "An Efficient, Catalytic Procedure For Epoxide Rearrangement", Tetrahedron Letters 30(41):5607-5610 (1989). Maruyama, K. et al., "Cobalt Schiff Base Complex Catalysed Solvolytic Ring Opening of Epoxy Compounds", React. Kinet. Catal. Lett. 45(2):165-171 (1991). Narasaka, K. "Chiral Lewis Acids In Catalytic Asymmetric Reactions", Synthesis, pp 1-11 (Jan. 1991). Nugent, W. et al., "Beyond Nature's Chiral Pool: Enantioselective Catalysis in Industry", Science 259:479-483 (1993). Nugent, W. "Chiral Lewis Acid Catalysis. Enantioselective Addition of Azide to Meso Epoxides", J. Am. Chem. Soc. 114: 2768-2769 (1992). Oppolzer, W. and R. Radinov, "Enantioselective Synthesis of Sec-Allylalcohols by Catalytic Asymmetric Addition of Divinlyzinc To Aldehydes", Tetrahedron Letters, 29(44):5645-5648 (1988). Ozaki, S. et al., "Synthesis of Chiral Square Planar Cobalt (III) Complexes and Catalytic Asymmetric Epoxidation With There Complxes", J. of Chem. Soc. Perkin Trans. 2, Issue 1: 353-359 (1990). Palucki, M. et al., "Highly Enantioselective, Low-Temperature Epoxidation of Styrene", J. Am. Chem. Soc. 116: 9333-9334 (1994). Palucki, A. et al., "Asymmetric Oxidation of Sulfides With H202 Catalyzed By (Salen) Mn (III) Complexes", Tetrahedron Letters, 33 (47):7111-7114 (1992). Sasaki, H. et al., "Rational Design of Mn- Salen Catalyst 2: Highly Enantioselective Epoxidation of Conjugated cis Olefins", Tetrahedron 50(41): 11827-11838 (1994). Schurig, V. and F. Betschinger, "Metal-Mediated Enantioselective Access to Unfunctionalized Allphatic Oxiranes: Prochiral and Chiral Recognition", Chem. Rev. 92:873-888 (1992). Srinivasan, K. et al., "Epoxidation of Olefins With Cationic (Salen) Mn III Complexes. The Modulation of Catalytic Activity By Substituents", J. Am. Chem. Soc. 108:2309-2320 (1986). Stinson, S. "Chiral Drugs ", Chemical and Chemical Engineering News, pp 46-79 (Sep. 28, 1992). Ward, R. "Non-Enzymatic Asymmetric Transformations Involving Symmetrical Bifunctional Compounds", Chem. Soc. Rev., 19:1-19 (1990). Woolley, P. "Models For Metal Iron Function In Carbonic Anhydrase", Nature, 258-677-682 (1975). Yamashita, H. "Metal(II) d-Tartrates Catalyzed Asymmetric Ring Opening Of Oxiranes With Various Nucleophiles", The Chemical Society of Japan 61: 1213-1220 (1988). Zhang, W. et al., "Enantioselective Epoxidation Of Unfunctionalized Olefins Catalyzed By (Selen)manganese Complexes", J. Am. Chem. Soc. 112: 2801-2803 (1990). Zhang, W. and E. Jacobsen, "asymmetric Olefin Epoxidation With Sodium Hypochlorite Catalyzed by Easily Preparted Chiral Mn (III) Salen Complexes ", J. of Org. Chem. 56:2296-2298 (1991). Ready and Jacobsen., "Asymmetric Catalytic Synthesis of .alpha.-Aryloxy Alcohols: Kinetic Resolution of Terminal Epoxides via Highly Enantioselective Ring-Opening with Phenols", J. Am. Chem. Soc. 121: 6086-6087 (1999). Tokunaga et al., "Asymmetric Catalytis With Water: Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis", Science, 277:936-938 (1997). |
| PATENT GOVERNMENT INTERESTS |
GOVERNMENT FUNDING Work described herein was supported in part with funding from the National Institutes of Health. The United States Government has certain rights in this invention |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A kinetic resolution process, comprising the step of reacting water and a mixture of stereoisomers of a chiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce by kinetic resolution a stereoisomerically enriched cyclic substrate or a stereoisomerically enriched hydrolysis product or both, wherein said cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by said water, and said chiral catalyst comprises an asymmetric tetradentate ligand complexed with a metal atom, which complex has a rectangular planar or rectangular pyramidal geometry. 2. The process of claim 1, wherein the metal atom is a transition metal from Groups 3-12 or from the lanthinide series. 3. The process of claim 1, wherein the metal atom is selected from the group consisting of Co, Rh, and Ir. 4. The process of claim 1, wherein the metal atom is Co. 5. The process of claim 1, wherein the non-racemic chiral catalyst is selected from the group consisting of chiral crown ethers complexed with a transition metal atom; the chiral catalyst represented by 102, ##STR109## in which the substituents R.sub.1, R.sub.2, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7, or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 8 atoms in the ring structure, which ring structure may be a fused ring, as in the case of, for example, X.sub.1 and X.sub.2 forming a ring, or which ring may be a bridging ring, as in the case of R.sub.1 and R.sub.2, X.sub.2 and X.sub.4, or Y.sub.1 and X.sub.2 representing different ends of a single substituent, with the proviso that at least one of R.sub.1, Y.sub.1, X.sub.1 and X.sub.2 is covalently bonded to at least one of R.sub.2, Y.sub.2, X.sub.3 and X.sub.4 to provide the .beta.-iminocarbonyls as a tetradentate ligand; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; m is zero or an integer in the range of 1 to 8; M represents a transition metal; A represents a counterion or a nucleophile; and the catalyst is asymmetric; the chiral catalyst represented by 108, ##STR110## in which D.sub.1, D.sub.2, D.sub.3 and D.sub.4 each represent heterocycles, such as pyrrole, pyrrolidine, pyridine, piperidine, imidazole, pyrazine, or the like; each R.sub.18 occurring in the structure represents a bridging substituent which links adjacent heterocycles, and preferably contains at least one stereogenic center of the ligand. For example, each R.sub.18, represents an alkyl, an alkenyl, an alkynyl, or --R.sub.15 --R.sub.16 --R.sub.17 --, wherein R.sub.15 and R.sub.17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R.sub.16 is absent or represents an amine, an imine, an amide, a phosphonate, a phosphine, a carbonyl, a carboxyl, a silyl, an oxygen, a sulfonyl, a sulfer, a selenium, or an ester; each R.sub.19, independently, is absent or represents one or more substituents of the heterocycle to which it is attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, and --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the R.sub.18 and R.sub.19 substituents are covalently linked to form a bridge substitution; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; m is zero or an integer in the range of 1 to 8; M represents a transition metal; and the catalyst is asymmetric; the chiral catalyst represented by 112, ##STR111## in which each of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.11, R.sub.12, R.sub.13 and R.sub.14, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents taken together form a carbocycle or heterocycle having at least 4 atoms in the ring structure; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; m is zero or an integer in the range of 1 to 8; and M represents a transition metal; if R.sub.5 is absent, at least one of R.sub.1 and R.sub.2 is covalently bonded to at least one of R.sub.3 and R.sub.4 ; and the catalyst is asymmetric; the chiral catalyst represented by 114 and a complexed transition metal atom, ##STR112## wherein R.sub.21 and R.sub.22 each represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; R.sub.20 is absent or represents one or more substituents of the pyridine to which it is attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; R.sub.23 and R.sub.24 each independently are absent or represent one or more substituents of the 1,3-diiminopropyl to which they are attached, each substituent independently selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the R.sub.20, R.sub.21, R.sub.22, R.sub.23 and R.sub.24 substituents are covalently linked to form a bridging substituent; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8; and the ligand is asymmetric; and the chiral catalyst represented by 116 and a complexed transition metal atom, ##STR113## in which each of the substituents Q.sub.8 indpendently, are absent or represent hydrogen or a lower alkyl; each of R.sub.25, R.sub.26, R.sub.27 and R.sub.28, independently, represent one or more substituents on the ethyl or propyl diimine to which they are attached, which substituents are selected from the group of hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, and --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents taken together form a bridging substituent; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; m is zero or an integer in the range of 1 to 8; and the ligand is asymmetric. 6. The process of claim 1, wherein the non-racemic chiral catalyst is represented by structure A or its enantiomer: ##STR114## wherein M represents Co or Co(O.sub.2 CR); and R represents alkyl or aryl. 7. The process of claim 1, wherein the tetradentate ligand has at least one Schiff base that complexes with the metal atom. 8. The process of claim 1, wherein the chiral catalyst has a molecular weight of less than 10,000 a.m.u. 9. The process of claim 1, wherein the substrate is represented by the general formula 118: ##STR115## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A-B-C; wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group; A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50); and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl; and R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y. 10. The process of claim 9, wherein the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 taken together form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. 11. The process of claim 1, wherein the cyclic substrate is selected from the group consisting of epoxides, aziridines, episulfides, cyclopropanes, cyclic carbonates, cyclic thiocarbonates, cyclic sulfates, cyclic anhydrides, cyclic phosphates, cyclic ureas, cyclic thioureas, lactams, thiolactams, lactones, thiolactones and sultones. 12. The process of claim 1, wherein the cyclic substrate is an epoxide. 13. The process of claim 1, wherein the cyclic substrate is a terminal epoxide. 14. The process of claim 1, wherein the catalyst is immobilized on an insoluble matrix. 15. The process of claim 1, wherein the cyclic substrate is immobilized on an insoluble matrix. 16. A kinetic resolution process, comprising the step of reacting water and a mixture of stereoisomers of a chiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce by kinetic resolution a stereoisomerically enriched cyclic substrate or a stereoisomerically enriched hydrolysis product or both, wherein said cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by said water, and said chiral catalyst comprises an asymmetric tridentate ligand complexed with a metal atom, which complex has a trigonal planar or trigonal pyramidal geometry. 17. The process of claim 16, wherein the metal atom is a transition metal from Groups 3-12 or from the lanthanide series. 18. The process of claim 16, wherein the metal is selected from the group consisting of Co, Rh, and Ir. 19. The process of claim 16, wherein the metal atom is Co. 20. The process of claim 16, wherein the tridentate ligand has at least one Schiff base that complexes with the metal atom. 21. The process of claim 16, wherein the catalyst has a molecular weight of less than 10,000 a.m.u. 22. The process of claim 16, wherein the substrate is represented by the general formula: ##STR116## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A-B-C; wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group; A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50); and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl; and R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y. 23. The process of claim 22, wherein the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 taken together form a carbocyclic or heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. 24. The process of claim 16, wherein the cyclic substrate is selected from the group consisting of epoxides, aziridines, episulfides, cyclopropanes, cyclic carbonates, cyclic thiocarbonates, cyclic sulfates, cyclic anhydrides, cyclic phosphates, cyclic ureas, cyclic thioureas, lactams, thiolactams, lactones, thiolactones, and sultones. 25. The process of claim 16, wherein the cyclic substrate is an epoxide. 26. The process of claim 16, wherein the cyclic substrate is a terminal epoxide. 27. The process of claim 16, wherein the catalyst is immobilized on an insoluble matrix. 28. The process of claim 16, wherein the cyclic substrate is immobilized on an insoluble matrix. 29. The process of any of claims 1-28, wherein said cyclic substrate is racemic. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages (reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp. 46-79) include fewer side effects and greater potency of enantiomerically pure compounds. Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called "chiral pool"), or resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thus wasting half of the material. Epoxides are valuable intermediates for the stereocontrolled synthesis of complex organic compounds due to the variety of compounds which can be obtained by epoxide-opening reactions. For example, .alpha.-amino alcohols can be obtained simply by opening of an epoxide with azide ion, and reduction of the resulting .alpha.-azido alcohol (for example, by hydrogenation). The reaction of can be converted to useful materials. A Lewis acid may be added to act as an epoxide-activating reagent. The utility of epoxides has expanded dramatically with the advent of practical asymmetric catalytic methods for their synthesis (Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis. Ojima, I., Ed.: VCH: New York, 1993; Chapter 4.1. Jacobsen, E. N. Ibid. Chapter 4.2). In addition to epoxidation of prochiral and chiral olefins, approaches to the use of epoxides in the synthesis of enantiomerically enriched compounds include kinetic resolutions of racemic epoxides (Maruoka, K.; Nagahara, S.; Ooi, T.; Yamamoto, H. Tetrahedron Lett 1989, 30, 5607. Chen, X. -J.; Archelas, A.; Rurstoss, R. J Org Chem 1993, 58, 5528. Barili, P. L.; Berti, G.; Mastrorilli, E. Tetrahedron 1993, 49, 6263.) A particularly desirable reaction is the asymmetric ring-opening of symmetrical epoxides, a technique which utilizes easily made achiral starting materials and can simultaneously set two stereogenic centers in the functionalized product. Although the asymmetric ring-opening of epoxides with a chiral reagent has been reported, in most previously known cases the enantiomeric purity of the products has been poor. Furthermore, many previously reported methods have required stoichiometric amounts of the chiral reagent, which is likely to be expensive on a large scale. A catalytic asymmetric ring-opening of epoxides has been reported (Nugent, W. A., J Am Chem Soc 1992, 114, 2768); however, the catalyst is expensive to make. Furthermore, good asymmetric induction (>90% e.e.) was observed only for a few substrates and required the use of a Lewis acid additive. Moreover, the catalytic species is not well characterized, making rational mechanism-based modifications to the catalyst difficult. SUMMARY OF THE INVENTION In one aspect of the present invention, there is provided a process for stereoselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product. The cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a metal atom. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyramidal geometry. The tridentate ligand-metal complex assumes a planar or trigonal pyramidal geometry. In a preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal. In general, the metal atom is a transition metal from Groups 3-12 or from the lanthanide series. and is preferably not in its highest state of oxidation. For example, the metal can be a late transition metal, such as selected from Group 5-12 transition metals. In preferred embodiments, the metal atom is selected from the group consisting of Cr, Mn, V, Fe, Co, Mo, W, Ru and Ni. In preferred embodiments, the substrate which is acted on by the nucleophile and catalyst is represented by the general formula 118: ##STR1## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A-B-C; wherein R.sub.50 is selected from the set comprising hydrogen, alkyls, acyls, carbonyl-substituted alkyls, carbonyl-substituted aryls, and sulfonyls; R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group; A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50); and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl; and R.sub.30, R.sub.31, R.sub.32, and R.sub.33 independently represent an organic or inorganic substituent which forms a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y. For instance, the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents R.sub.30, R.sub.31, R.sub.32, and R.sub.33 taken together form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure. In this formula, R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is an integer in the range of 0 to 8 inclusive. In certain embodiments, R.sub.30, R.sub.31, R.sub.32, and R.sub.33 are chosen such that the substrate has a plane of symmetry. Exemplary cyclic substrates for the subject reactions include epoxides, aziridines, episulfides, cyclopropanes, lactones, thiolactones, lactams, thiolactams, cyclic carbonates, cyclic thiocarbonates, cyclic sulfates, cyclic anhydrides, cyclic phosphates, cyclic ureas, cyclic thioureas, and sultones. In a preferred embodiment, the method includes combining a nucleophilic reactant, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze stereoselective opening of the cyclic substrate at the electrophilic atom by reaction with the nucleophilic reactant. In preferred embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula: ##STR2## in which Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 each represent a Lewis base; the C.sub.1 moiety, taken with Z.sub.1, Z.sub.3 and M, and the C.sub.2 moiety, taken with Z.sub.2, Z.sub.4 and M, each, independently, form a heterocycle; R.sub.1, R.sub.2, R'.sub.1 and R'.sub.2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached, R.sub.40 and R.sub.41 each independently are absent, or represent one or more covalent substitutions of C.sub.1 and C.sub.2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached. or any two or more of the R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 taken together form a bridging substituent; with the proviso that C.sub.1 is substituted at at least one site by R.sub.1, R'.sub.1 or R.sub.41, and C.sub.2 is substituted at at least one site by R.sub.2, R'.sub.2 or R.sub.40, and at least one of R.sub.1, R'.sub.1 and R.sub.41 is taken together with at least one of R.sub.2, R'.sub.2 and R.sub.40 to form a bridging substituent so as to provide Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 as a tetradentate; M represents the transition metal; and A represents a counterion or a nucleophile, wherein each R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 are selected to provide at least one stereogenic center in the tetradentate ligand. In exemplary embodiments, R.sub.1, R.sub.2, R'.sub.1 and R'.sub.2, independently , represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; each R.sub.40 and R.sub.41 occurring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur; and m is an integer in the range of 0 to 8 inclusive. For example, the catalyst can be represented by the general formula: ##STR3## in which the substituents R.sub.1,R.sub.2, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 each, independently, represent hydrogen halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls , phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7, or any two or more of the substituents taken together form a carbocycle or heterocycle ring having from 4 to 8 atoms in the ring structure, with the proviso that at least one of R.sub.1, Y.sub.1, X.sub.1 and X.sub.2 is covalently bonded to at least one of R.sub.2, Y.sub.2, X.sub.3 and X.sub.4 to provide the .beta.-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y.sub.1 and Y.sub.2 is a hydrogen; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; m is an integer in the range of 0 to 8 inclusive; M represents the transition metal; and A represents a counterion or a nucleophile, wherein each of the substituents R.sub.1, R.sub.2, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4, are selected such that the catalyst is asymmetric. For example, a preferred class of catalysts are represented by the general formula: ##STR4## in which the B.sub.1 moiety represents a diimine bridging substituent represented by --R.sub.15 --R.sub.16 --R.sub.17 --, wherein R.sub.15 and R.sub.17 each independently are absent or represent an alkyl, an alkenyl, or an alkynyl, and R.sub.16 is absent or represents an amine, an imine, an amide, a phosphoryl, a carbonyl, a silyl, an oxygen, a sulfur, a sufonyl, a selenium, a carbonyl, or an ester; each of B.sub.2 and B.sub.3 independently represent rings selected from a group consisting of cycloalkyls, cycloakenyls, aryls, and heterocyclic rings, which rings comprising from 4 to 8 atoms in a ring structure; Y.sub.1 and Y.sub.2 each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; R.sub.12, R.sub.13, and R.sub.14 each independently are absent, or represent one or more covalent substitutions of B.sub.1, B.sub.2 and B.sub.3 with halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7, wherein R.sub.12 can occur on one or more positions of --R.sub.15 --R.sub.16 --R.sub.17 --, or any two or more of the R.sub.12, R.sub.13, R.sub.14, Y.sub.1 and Y.sub.2 taken together form a bridging substituent; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle; m is an integer in the range of 0 to 8 inclusive; M represents a transition metal; and A represents a counterion or a nucleophile, wherein R.sub.12, R.sub.13, R.sub.14, Y.sub.1 and Y.sub.2 are selected such that the catalyst is asymmetric. In yet further preferred embodiments, the catalyst is a metallosalenate catalyst represented by the general formula: ##STR5## in which each of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, and X.sub.8, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ; or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 10 atoms in the ring structure; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; m is an integer in the range of 0 to 8 inclusive; M represents a transition metal; and A represents a counterion or a nucleophile; wherein if R.sub.5 is absent, at least one of R.sub.1 and R.sub.2 is taken together with at least one of R.sub.3 and R.sub.4 to form a bridging substituent, and each of the substituents of 106 are selected such that the salenate is asymmetric. Alternatively, the catalyst may comprise a tridentate ligand, such as the catalysts represented by general formula 140: ##STR6## in which Z.sub.1, Z.sub.2, and Z.sub.3 each represent a Lewis base; the E.sub.1 moiety, taken with Z.sub.1, Z.sub.2 and M, and the E.sub.2 moiety, taken with Z.sub.2, Z.sub.3 and M, each, independently, form a heterocycle; R.sub.80 and R.sub.81 each, independently, are absent, or represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7, or any two or more of the R.sub.80 and R.sub.81 substituents taken together form a bridging, substituent; R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; m is an integer in the range of 0 to 8 inclusive; M represents a transition metal; and A represents a counteranion or a nucleophile; wherein the tridentate ligand is asymmetric. As described herein, the subject method can be used for carrying out enantioselective ring openings, diastereoselective ring openings (including kinetic resolutions), and stereoselective ring expansions of cyclic compounds. |
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