I. Methodology development for the synthesis of geminally disubstituted beta-amino acids, beta-proline analogs and allylic amines. II. Progress towards the synthesis of an artificial transcription activator.

Abstract

As part of an ongoing program to use organic chemistry as a tool to study protein-protein interactions in transcription, my research has focused on the development of new methods for the synthesis of small chiral building blocks such as beta-amino acids and allylic amines. Both of these methods involve the selective formation of nitrogen-bearing stereocenters. These newly developed methods serve as valuable additions to the current approaches for the selective C-N bond formation. In addition, these new approaches have been applied to the synthesis of biopolymer mimics such as beta-proline analogs and artificial transcription activators. The first research project focused on the stereoselective synthesis of beta-amino acids highly substituted at the C2 (alpha) and C3 (beta positions (beta<super> 3,3</super>- and beta<super>2,3,3</super>-). The synthetic strategy utilized a stereospecific construction of isoxazoline via a 1,3-dipolar cycloaddition of nitrile oxides and allylic alcohols. The C3 stereochemistry was then introduced by a highly diastereoselective nucleophilic addition to the <italic>C</italic>=<italic> N</italic> in the isoxazolines. <italic>N-O</italic> bond cleavage by LiAlH₄, <italic>in situ</italic> protection of the resulting free amine followed by oxidative cleavage provided enantiopure beta-amino acids in good yields. This methodology has successfully been used to prepare seven new beta-amino acids with alkyl, aryl, and heteroaryl groups at the C3 (beta) position. This methodology was also adapted for the synthesis of beta-proline analog monomers. The second research project explored a thermal and catalyzed phosphorimidate to phosphoramidate [3,3]-rearrangement for the facile and selective preparation of allylic amines. The precursor of the rearrangement, a phosphorimidate, can be easily assembled from readily available allylic alcohols, azides and phosphites, rendering this new method an efficient three component, one pot process. Chirality transfer study and crossover experiment were also carried out to probe the mechanism of the rearrangement under thermal conditions. Furthermore, a highly efficient Pd (II)-catalyzed rearrangement has also been developed providing a new avenue for future asymmetric synthesis of allylic amines. The third research project aimed to synthesize <italic>Artificial Transcription Activators</italic> (ATA) designed to regulate gene transcription in yeast. Genome-wide expression analyses have revealed that there are critical differences in gene expression profiles between healthy and diseased tissues. As a consequence, the development of transcription-based therapeutics that would selectively reprogram aberrant gene expression in diseased cells is an increasingly attractive goal. Fueled by this goal, a dendritic scaffold with three peptidic activation domains was successfully constructed.