By every measure the demand for enantiomerically pure intermediates for the synthesis of chiral pharmaceutical substances is increasing. Discovery of new catalytic reactions, especially those which would yield practical levels of asymmetric induction with high catalyst turnover frequencies (i.e., substrate/catalyst/unit time), will have significant impact on medicinal as well as process chemistry. Invention of new methods for chirality transfer between catalysts and substrates is at the heart of discovery in practical asymmetric synthesis. Through an approach that relies primarily on mechanistic insights and systematic examination of ligand effects, a number of protocols for the enantioselective heterodimerization reactions of ethylene with various alkenes have been discovered. An important class of substrates that did not work well in our earlier attempts is 1,3-dienes, which are among the most accessible and potentially useful starting materials. The primary products of their asymmetric reactions can be further elaborated into more complex molecules. Yet, outside Diels-Alder reactions, few broadly applicable asymmetric catalyzed, intermolecular carbon-carbon bond-forming reactions of 1,3-dienes are known, partly because of the conformational mobility of these compounds. We recently discovered innovative methods to effect highly regio- and enantio-selective asymmetric hydrovinylation (addition of ethylene) of different classes of 1,3-dienes, including highly functionalized ones, using Ni(II)-, Co(II)- and Ru(II)-catalysts. This chemistry, when fully implemented, will provide access to wide variety of enantio-pure, ubiquitous chemical intermediates. The goal of this proposal is to explore the applications of these reactions and the resulting intermediates for the synthesis of compounds with proven biological efficacy. Examples illustrated include powerful anti-microbial and anti-tumor agents, GABA analogs, metalloproteinase inhibitors. Applications of the newly discovered reactions for the efficient syntheses of several broad classes of medicinally relevant compounds are proposed. In summary, the proposed research will provide powerful tools for the synthesis of biologically relevant targets and their congeners, by revealing new ways of accessing reactive enantio-pure intermediates such as skipped-1,4-dienes, enol-ethers, enol-acetates, vinylstannes and vinylsilanes. These intermediates could be useful for making new structures or advanced structural analogs of well-known compounds for testing. We hope that the discoveries made will shorten the considerable distance between the conceptualization of a molecule as a drug candidate and its large-scale synthesis.
The proposed research will provide powerful tools for the synthesis of pharmaceutically relevant compounds and their congeners, in addition to providing broadly applicable, novel enantioselective routes to versatile reactive intermediates like silyl enol ethers and vinyl organometallics from 1,3- dienes. Since highly catalytic reactions and readily available precursors are involved in the proposed new processes, successful conclusion of this project will also add to our repertoire of synthetic methods useful for large scale manufacture of useful pharmaceutical intermediates. This effort will result in tangible economic and environmental benefits. We hope that the discoveries made will shorten the considerable distance between the conceptualization of a molecule as a drug candidate and its large-scale synthesis.
