I. Phosphinate inhibitors of peptidoglycan biosynthesis. II. Development of a new ring system for combinatorial chemistry.

摘要

Part I. A bacteria's peptidoglycan cell wall is necessary for its survival; accordingly, interruption of peptidoglycan biosynthesis is the mechanism of action of many antibiotics. The cell wall precursors, peptidyl-UDP-MurNAc derivatives, are synthesized by a set of amino-acid adding enzymes that are ideal for a strategy of inhibition by transition-state analogs. In an effort to study three of the amino acid adding enzymes, we hoped to synthesize and test transition-state analog inhibitors based on a phosphinate moiety intended to mimic the tetrahedral transition state of the ligases, MurD, MurE and MurF. In order to simplify the synthesis of the proposed inhibitors, we proposed using enzymes upstream of an inhibitor's target to couple phosphinate precursors to UDP-MurNAc in order to complete the proposed inhibitors. Although significant progress was made towards the phosphinate portions of the inhibitors, we were not able to finish the proposed inhibitors of MurD, MurE and MurF due to the fact that we could not effect the proposed enzymatic coupling.; Part II. Creation of novel heterocycles from simple, diverse starting materials is desirable for generating prospecting libraries for combinatorial chemistry. In a novel reaction, a 5,7-fused ring system is formed by cyclization of a cinnamic acid-derived double bond onto an iminium ion. Trapping of the resulting carbocation by a nucleophile linked to the imine nitrogen completes the heterocycle. Connecting the imine and ene partners via an amino acid-derived aldehyde provides the bicyclic structure. Forming a complex ring system from simple starting materials: amino acids, cinnamic acids and amino alcohols, in a few simple steps, makes the cyclization ideal for constructing prospecting libraries. The new reaction was found to proceed in solution with several classes of amine-linked nucleophiles, under Lewis acid catalysis. The diastereoselective cyclization creates products with a trans, anti, trans relationship between the new stereocenters. Transfer of the methodology to solid-phase was begun, with the exploration of several different linker strategies.