Development of New Late-Stage Labeling Methods with Labeled Carbon for Stabilized Carboxylic Acids and α-Amino Acids

Abstract

Isotope labeling of small molecules is a crucial tool for drug discovery and understanding biochemical processes. Expanding the toolbox of a radiochemist with methods that allow late-stage labeling is therefore important. Of the methods that have been developed, the use of isotopically labeled CO2 ( = 14, 13, 11) precursor is among of the most useful platforms for installing isotopically-labeled carbon into the molecule. While this area has undergone a tremendous amount of development in recent years, the preparation of isotopically-labeled molecules with isotopically labeled C ( = 14, 13, 11) remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This thesis describes the development of new methods to label stabilized carboxylic acids and α-amino acids with CO2 ( = 14, 13, 11). It describes reversible decarboxylation/carboxylation reactions by stabilized carboxylic acids and their derivatives that prepare isotopically-labeled carboxylic acids. Through careful pilot studies, reaction optimization, and mechanistic probes, the achiral aryl aldehyde catalyzed isotopic carboxylate exchange of native α-amino acids with CO2 ( = 14, 13, 11) was discovered. This reaction likely proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Subsequent work revealed that a chiral aldehyde receptor can mediate the resolution/carboxylate exchange of native α-amino acids with *CO2.