High yielding and selective preparation of chiral organic molecules is critical to the availability of therapeutic agents. Development of catalytic, enantioselective synthetic methods is a compelling objective in chemistry and medicine. Among the most useful building blocks in organic synthesis are optically pure amines and alcohols; our program will address issues regarding enantioselective preparation of these important classes of molecules. We will establish new, practical, and efficient and highly enantioselective methods for the synthesis of secondary and tertiary amines and alcohols that are otherwise difficult to obtain in high yield and optical purity. One main goal of our program is the development of new chiral ligands and catalysts, all of which are amino acid-based. A crucial advantage of amino acid-based molecules is that they can be easily prepared and modified, allowing for rapid (mechanism-driven) synthesis and screening of variants so that catalysts that best fit a specific set of transformations can be identified expeditiously. We will develop new amino acid-based chiral ligands and practical methods for efficient enantioselective additions of enolsilanes and nitroalkanes to aldimines (Mannich reactions). Catalyst discovery will be guided by mechanistic principles and will be accomplished by screening protocols developed in this program. The new synthetic methods will offer practical (distilled solvents, air exclusion not required) and unique procedures for the synthesis of various acyclic and cyclic amines that cannot be prepared by alternative catalytic enantioselective methods. We will also develop new amino acid-based chiral ligands and methods for efficient enantioselective additions of carbon nucleophiles to ketoimines. The aforementioned principles will be used in the development of catalytic asymmetric alkylations and Mannich reactions that provide access to optically enriched alpha- and beta-quaternary amino acids. We will also develop new chiral amino acid-based ligands, catalysts and methods for efficient enantioselective synthesis of alcohols. Amino acid-based chiral ligands will be developed that effect Ag-catalyzed asymmetric aldol additions for a range of enolsilanes to various ketones. Finally, a new class of low molecular weight and easily available amino acid-based chiral catalysts will be developed for enantioselective silylations of alcohols. In all studies utility in the preparation of biologically active compounds in high optical purity will be demonstrated.
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