Asymmetric 1,4-reductions of and 1,4-additions to enoates...

Details Asymmetric 1,4-reductions of and 1,4-additions to enoates... Asymmetric 1,4-reductions of and 1,4-additions to enoates...

2000-09-13

2002-10-15

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S295000, C549S323000, C560S008000, C568S343000, C568S347000, C568S376000, C568S379000, C568S392000

Reexamination Certificate

active

06465664

ABSTRACT:

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. The advantages of enantiomerically pure compounds (reviewed in, e.g., Stinson, S. C.,
Chem Eng News,
Sep. 28, 1992, pp. 46-79) include fewer side effects and greater potency in many cases.
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: the use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); or the 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 absolute configurations are readily available. Resolution of racemates often requires the use of resolving agents; this process may be inconvenient and is certain to be time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thereby wasting half of the material.
Currently, few catalysts are available that can reduce carbon-carbon double bonds to generate asymmetric products wherein the products comprise a stereocenter &bgr; to a carbonyl group and are produced in high enantiomeric excess (ee). In this area, asymmetric conjugate additions of nucleophiles to &agr;,&bgr;-unsaturated ketones have been investigated; however, the best catalysts for these reactions work well for only a limited number of substrates and nucleophiles. In certain limited cases, asymmetric hydrogenation catalysts can provide access to products with stereocenters &bgr; to carbonyls. Asymmetric conjugate reduction of an &agr;,&bgr;-unsaturated carbonyl portion of a molecule is also capable of generating a stereocenter &bgr; to a carbonyl. Despite the availability of catalysts for conjugate reductions, only Pfaltz's chiral semicorrin cobalt system is an effective catalyst for asymmetric conjugate reductions. In this system, sodium borohydride is used as the stoichiometric reducing agent.
The ability to effect asymmetric 1,4-reduction of and asymmetric 1,4-addition to enoates and the like, in good yield, with good enantiomeric excess, and under mild reaction conditions, would constitute a highly desirable addition to the palette of synthetic transformations available to research and process chemists in both academic and industrial settings. The ability to realize these goals utilizing asymmetric catalysis, e.g., asymmetric transition metal catalysts, is particularly appealing. Furthermore, the ability to achieve these transformations without the need to resort to the use of metal hydrides is also highly desirable.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to the transition metal catalyzed asymmetric. 1,4-reduction of enoates and related systems, e.g., enones and acrylonitriles. Another aspect of the present invention relates to the transition metal catalyzed asymmetric 1,4-addition of nucleophiles to enoates and related systems, e.g., enones and acrylonitriles. In certain embodiments of the present invention, the asymmetric 1,4-reductions and 1,4-additions rely upon a transition metal catalyst consisting essentially of copper and an asymmetric bidentate ligand.
For example, highly enantioselective conjugate reductions of &agr;,&bgr;-unsaturated esters were achieved by combining catalytic amounts of CuCl, NaOt-Bu, and (S)-p-Tol-BINAP with 4 equivalents of PMHS relative to the substrate. These reductions proceeded at room temperature to give products in high yields and with enantiomeric excesses of 80-92%.


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