New catalytic methods for the rapid synthesis of N-unprotected chiral aziridines and amines

Rice University, Houston TX

Investigators

Linked publications & trials

Abstract

Project Summary Amines and their derivatives are ubiquitous substances since they are present in the overwhelming majority of drug molecules, agrochemicals, functional materials as well as many compounds that are produced by living organisms (i.e., natural products). Notably, there are, on average, 2.8 nitrogen atoms in each of the 200 best- selling small molecule drugs and, of these drugs, 80% contain at least one N-heterocyclic fragment. It is also estimated that 45% of drug candidates contain a chiral amine moiety. Not surprisingly, organic chemists invest a considerable amount of effort devising better strategies for synthesis of amines that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. These strategies may be used for both the early-stage functionalization of simple feedstock chemicals and the late- stage functionalization of complex molecules. Together these approaches enable the exploration of new chemical space for biological studies. Consequently, new and powerful synthetic strategies and methods for the rapid and direct introduction of nitrogen into readily available and inexpensive precursors such as alkanes, alkenes, arenes, heteroarenes are expected to have a far-reaching impact upon how organic synthesis, medicinal chemistry, biochemistry and chemical biology are practiced. In particular, the introduction of unprotected and/or functionalized nitrogen atoms under mild conditions will result in processes that are more efficient and “greener” than currently used multi-step routes and ultimately will lead to the faster development of new medicines. During the course of the proposed project we will focus on the development of novel direct (i.e., non-catalytic) olefin difunctionalization methods. In particular, we are evaluating the native reactivity of N-acyl-N-halo-O- sulfonyl as well as N-acyl-N-halo-O-alkyl/silyl hydroxylamines with feedstock olefins to obtain structurally diverse and multifunctional hydroxylamine derivatives in a single pot (i.e., halo-aminohydroxylation of alkenes). The resulting compounds can serve as structurally complex and versatile electrophilic aminating agents that readily form C-N bonds with a variety of substrates. For example, non-catalytic as well as metal-catalyzed intra- and intermolecular processes will be explored that take advantage of both stoichiometrically and catalytically generated electrophilic aminating agents (i.e., complexity-building transformations, such as in intramolecular and/or intermolecular aliphatic and aromatic C-H amination reactions, olefin aziridinations as well 1,3-dipolar cycloadditions). Thus, the direct synthesis of chiral secondary and tertiary amines from structurally simple precursors will be achieved. The proposed regio- and stereoselective amination processes will be thoroughly investigated to uncover and understand their mechanistic underpinnings. Emphasis will be given to the development of reactions that can utilize abundant and inexpensive starting materials and convert these to structurally complex/value added products under operationally simple and mild reaction conditions.