Trifluoroacetate release in synthesis and drug discovery
Abstract
The invention of new synthetic reagents and reactions is a highly important chemical endeavor, especially the selective modification of natural products for the identification of biologically active lead compounds. To this end, this work entails the development of a synthetic process which exploits the facile release of trifluoroacetate for chemical transformations. A novel, efficient method for the installation the α-methylenation of carbonyl groups through a unique release of trifluoroacetate is reported. Our detrifluoroacetylative methylenation provides a very mild and highly efficient protocol that is amenable to a series of ketones, lactams, and lactones. Our method is also an improvement for α-methlyenation of sterically hindered carbonyl groups on highly complex natural products such as (+)-sclareolide and (–)-eburnamonine. Mechanistic information was gathered through a time course 19F NMR studies. Additionally, biological evaluation of a library natural product derivatives led to the discovery of an analogue of (–) eburnamonine with significant activity to MDA-MB-231 cells. The release of trifluoroacetate is again demonstrated to be a facile, powerful process to perform synthetic reactions. Expanding from this work, a powerful, new amidinate salt of hexafluoroacetone hydrate is developed to perform trifluoromethylations after a base-induced release of trifluoroacetate. This salt is an air stable, anhydrous, non hygroscopic solid which can be obtained in multi gram scale through a simple one step acid base process. Nucleophilic trifluoromethylations of non-enolizable aldehydes and ketones can be performed at both milligram and gram scales to provide excellent yields of product. The salt is a synthetically viable alternative to generate gaseous fluoroform which we believe can aid in further discoveries using fluoroform..
Degree
Ph.D.
Advisors
Colby, Purdue University.
Subject Area
Chemistry|Organic chemistry|Pharmaceutical sciences
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