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Catalytic asymmetric desymmetrization of prochiral and meso compounds

a technology of prochiral and meso compounds, applied in the preparation of carboxylic acid esters, chemistry apparatus and processes, organic chemistry, etc., can solve the problems of wasting half of the material, reducing efficiency, and wasting tim

Inactive Publication Date: 2006-12-21
BRANDEIS UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral or meso substituted cyclic anhydride and a nucleophile in the presence of a chiral, non-racemic tertiary amine catalyst. The method produces a high yield of the desired compound with high purity. The use of a specific catalyst can improve the efficiency of the reaction. The invention also provides a method for preparing specific types of chiral compounds, such as alcohols, thiols, or amines, from prochiral or meso substituted cyclic anhydrides.

Problems solved by technology

Each of these methods has serious drawbacks, however.
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 decreasing efficiency and wasting half of the material.

Method used

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  • Catalytic asymmetric desymmetrization of prochiral and meso compounds
  • Catalytic asymmetric desymmetrization of prochiral and meso compounds
  • Catalytic asymmetric desymmetrization of prochiral and meso compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

REFERENCES AND NOTES FOR EXAMPLE 1

[0132] 1. Toyota, M.; Yokota, M.; Ihara, M. Organic Lett. 1999, 1, 1627-1629. [0133] 2. Couche, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi, M.; Mandvile, G.; Bloch, R. Synlett. 1999, 87-88. [0134] 03. Paterson, I.; Cowden, C. J.; Woodrow, M. D. Tetrahedron Lett. 1998, 39, 6037-6040. [0135] 4. a) Borzilleri, R. B.; Weinreb, S. M. J. Am. Chem. Soc. 1994, 116, 9789-9790. [0136] b) Borzilleri, R. B.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc. 1995, 117, 10905-10913. [0137] 5. Marie, F. B. C.; Mackiewicz, P.; Roul, J. M.; Buendia, J. Tetrahedron Lett. 1992, 33, 4889-4892. [0138] 6. a) Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. J Org. Chem. 1991, 56, 4120-4123. b) Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. J Org. Chem. 1991, 56, 2122-2127. [0139] 7. Wender, P. A.; Singh, S. K. Tetrahedron Lett. 1990, 31, 2517-1520. [0140] 8. Suzuki, T.; Tomino, A.; Matsuda, Y.; Unno, K.; Kametani, T. Heterocycles, 1980, 14, 1735-1738. [0141] 9....

example 2

General Method for Synthesizing Tertiary Amine Catalysts

[0150]

[0151] To a solution of diamine 1 (1.40 g, 4.67 mmol) in dry tetrahydrofuran (93 mL) under nitrogen at room temperature was added sodium hydride (60% suspension in mineral oil, 1.87 g, 46.7 mmol). The mixture was stirred for 10 minutes, and then glycidol nosylate 2 was added. After being stirred for 88 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [basic aluminum oxide, CH3OH:CH2Cl2 (1:100 to 1:20)] to give the chiral tertiary amine 3 (667 mg, 35%) as a white solid.

example 3

Catalytic Desymmetrization of a Meso Bicyclic Succinic Anhydride Comprising a Urea

[0152]

[0153] To a mixture of anhydride (16.8 mg, 0.05 mmol) and DHQD-PHN (20 mol %, 5 mg) in Et2O (2.5 mL) at —40° C., anhydrous MeOH (0.5 mmol, 20.2 ul) cooled at —20° C. was added in one portion. The resulting mixture was stirred until the reaction was complete (˜30 hrs) as monitored by TLC (20% MeOH in CH2Cl2). The reaction was quenched with aqueous HCl (1 N, 3 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (100% CH2Cl2 to 10% MeOH in CH2Cl2) to afford the hemiester (16.7 mg, 91% yield). The ee of the hemiester was determined to be 93% by converting the hemiester into the corresponding ester amide (J. Chem. Soc. Perkin. Trans l 1987, 1053) via a reaction of the hemiester with (R)- 1-(1-napthyl) ethyl amine. The ester amide was analyzed by chiral HPLC (Chiralpak, OD, 280 nm,...

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Abstract

The present invention relates to methods for the synthesis of chiral non-racemic products, e.g., enantiomerically-enriched hemiesters, from prochiral and meso starting materials, e.g., prochiral and meso cyclic anhydrides. The present invention also relates to catalysts for the aforementioned methods, and methods for synthesizing these catalysts.

Description

RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10 / 366,581, filed Feb. 13, 2003; which is a continuation of U.S. patent application Ser. No. 09 / 825,167, filed Apr. 3, 2001; which claims the benefit of the filing date of U.S. Provisional Patent Application Ser. No. 60 / 194,520, filed Apr. 4, 2000.GOVERNMENT SUPPORT [0002] The invention was made with support provided by the National Institutes of Health (grant number GM-61591); therefore, the government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] 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, 1...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C69/76C07C69/52C07C69/34C07B53/00C07D493/08
CPCC07B53/00C07B2200/07C07D493/08C07D471/08C07D307/89C07C2102/42C07C2101/16C07C67/08C07C2101/08C07C2101/14C07C69/75C07C69/34C07C69/753C07C2601/08C07C2601/14C07C2601/16C07C2602/42
Inventor DENG, LICHEN, YONGGANGTIAN, SHIKAI
Owner BRANDEIS UNIV
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