Strategic use of amino acid N-substituents to limit α-carbon-centered radical formation and consequent loss of stereochemical integrity

Ab initio calculations have been used to investigate the effect of N-substituents on the stability of alpha-carbon-centered amino acid radicals. Optimized structures of glycine derivatives and related substituted methanes, and the corresponding radicals, were determined with B3-LYP/6-31G(d). Single-point RMP2/6-31G(d) calculations on these structures were then used to obtain radical stabilization energies, which were compared with the relative rates of formation of the same or closely similar radicals in reactions with N-bromosuccinimde. These studies show that N-acylation and sulfonation decrease both the stability and the ease of formation of the alpha-carbon-centered radicals. Greater effects are seen with fluoroacyl, fluoroalkylsulfonyl and imido groups. The extent of the effect of the imido and fluoroalkylsulfonyl groups is such that N-plthaloyl- and trifluoromethanesttlfonyl-protected amino acids react by hydrogen-atom abstraction from the side chain, thereby avoiding reaction at the chiral alpha-center and preserving its stereochemical integrity. The origins of these substituent effects are examined. (C) 2003 Elsevier Ltd. All rights reserved.