C‐Alkylation of Sarcosine Residues in Cyclic Tetrapeptides via Lithium Enlates

Abstract

The cyclic tetrapeptides cyclo(‐Leu‐Sar‐Gly‐), cyclo(‐Val‐Sar‐Sar‐Gly‐), and cylco(‐Meleu‐Gly‐D‐Alasar‐) have been synthesized from the component amino acids (BOP‐Cl coupling), using the pentafluorophenyl esters for the cyclization step (42, 13, and 30% yield, respectively). Multiple deprotonation (LDA in THF/LiBr/DMPU) and addition of highly reactive electrophiles (CF₃CO₂D, MeI, CH₂O, CH₂CHCH₂Br, PhCH₂Br) produce cyclic tetrapeptides with additional substituents introduced diastereoselectively (70 to > 98% ds) in yields ranging from 20 to 90%. The C‐alkylatd products are all derived from a sarcosine‐enolate moiety adjacent to another N‐methylamino acid. The structures of the resulting products are determined by NMR spectroscopy (DNOE and ROESY techniques) and by hydrolysis to the parent amino acids, suitable derivatization, and analysis by chromatography on a chiral GC column. It was shown in two cases that the overall yield of cyclization/alkylation to give a disubstitued cyclic tetrapeptide is higher than that of a synthesis of the same product from the corresponding amino‐acid building blocks. Surprising temperature and salt effects on the yields and selectivities of the reactions of the cyclic tetrapeptide enolates are presented, and possible mechanistic interpretations are discussed.