Asymmetric synthesis of highly functionalized lactones and lactams using a chiral Bronsted acid

Petersen, Kimberly

Abstract

The development of new synthetic methods in order to synthesize the vast array of structurally diverse compounds that nature produces only in small quantities or to efficiently prepare libraries of small molecules for drug discovery is a constant need in chemistry. This proposal outlines two novel strategies for the synthesis of enantioenriched ?,?-disubstituted lactones and lactams that take advantage of the different rates of cyclization of prochiral or racemic compounds in the presence of a chiral Brnsted acid catalyst The first goal of the project (Aim 1) is the development of a chiral Brnsted acid catalyzed desymmetrization of amino or hydroxyl diesters. In this aim, ?,?-disubstituted lactones will be prepared through the development of a desymmetrization of prochiral hydroxy esters. This will be followed by the expansion of the desymmetrization process to include protected amino diesters to yield ?,?-disubstituted lactams. The second objective of the proposal (Aim 2) is the establishment of a chiral Brnsted acid mediated dynamic kinetic resolution. Here, the rapid racemization of the two enantiomers of a racemic mixture in combination with the preferred cyclization of an enantiomer of the racemic mixture will funnel the reaction to the formation of a single cyclic product. The DKR explored will utilize an oxocarbenium ion intermediate. The third goal (Aim 3) of the project is the application of asymmetric methodologies to the formation of novel heterocyclic cores. In this section, the synthetic methods developed will be utilized in the formation of libraries of novel heterocyclic scaffolds such as spirocycles and new beta-lactam scaffolds with potentially potent antimicrobial or cytotoxic properties.

Public Health Relevance

In nature many biologically active molecules have a specific 3-dimensional shape associated with them and often this shape possesses a certain handedness, or chirality which is critical for activity. This proposal aims to develop new methodology for the preparation of small molecules with a specific geometry that can be readily incorporated into more complex biologically important compounds.