Approach control. Stereoelectronic origin of geometric constraints on N-to-S and N-to-O acyl shifts in peptides

Intramolecular N-to-S or N-to-O acyl shifts in peptides are of fundamental and practical importance, as they constitute the first step in protein splicing and can be used for the synthesis of thioester-modified peptides required for native chemical ligation. It has been stated that the nucleophile must be positioned anti to the carbonyl oxygen, as in a cis amide. Despite the importance of such reactions, an understanding of this geometric restriction remains obscure. Here we argue that the empirical requirement for positioning the nucleophile is a stereoelectronic effect arising from the ease of approach of the nucleophile to a carbonyl group, not ground-state destabilization. DFT calculations on model amides support our explanation and indicate a significant decrease in both the transition-state energy and the activation energy for a cis amide. However, the approach of the nucleophile must be anti not only to the carbonyl oxygen but also to the nitrogen. The direction of approach is expressed by a new, modified Bürgi–Dunitz angle. Our data shed light on the mechanisms of acyl shifts in peptides, and they explain why a cis peptide might be required for protein splicing. The further implications for acyl shits in homoserine and homocysteine peptides and for aldol condensations are also considered.