Synthesis and Stereoselective CC Bond‐forming Reactions of Peptide Aldehydes

Abstract

AbstractThe reaction of the activated form of N‐protected amino acids 6 and 10 or peptides 14 and 18 with chiral amino alcohols derived from the corresponding α‐amino acids affords peptide alcohols which can be oxidized under Swern conditions to produce the corresponding peptide aldehydes 9, 12, 16 and 20. The rational synthesis of diastereomeric di‐ and tripeptide aldehydes, e.g., (S,S)‐ or (R,S)‐dipeptides as well as (S,S,S)‐ or (R,S,S)‐tripeptides is possible by proper choice of the respective building blocks [(S)‐ versus (R)‐amino acids]. The compounds can be prepared without any undesired α‐epimerization. However, the long‐term configurational stability depends upon the configuration at the remote stereogenic center, e.g., (R,S)‐dipeptide aldehydes epimerize faster than the (S,S) diastereomers. Di‐ and tripeptide aldehydes 9, 12, 16 and 20 undergo chelation‐controlled Grignard‐type additions with Me2CuLi that involve little or no undesired α‐epimerization. The (S,S)‐ and (R,S)‐dipeptide aldehydes 9 and 12 undergo chelation‐controlled pinacol reactions induced by the low‐valent vanadium reagent [V2Cl3(THF)6]2[Zn2Cl6]. The major products in both cases are the corresponding C2‐symmetric diols 33 and 36, respectively, which are of interest as potential HIV‐protease inhibitors. The degree of stereoselectivity is significantly higher in the case of the (S,S)‐dipeptide aldehydes relative to the (R,S) analogs, an observation which can be explained on the basis of three‐point binding of the peptides to vanadium.