Extended Solution-phase Peptide Synthesis Strategy Using Isostearyl-Mixed Anhydride Coupling and a New C‑Terminal Silyl Ester-Protecting Group for N‑Methylated Cyclic Peptide Production

• Published in: Organic process research & development 2021-09, Vol.25 (9), p.2029-2038
• Main Authors: Nagaya, Akihiro, Murase, Shota, Mimori, Yuji, Wakui, Kazuya, Yoshino, Madoka, Matsuda, Ayumu, Kobayashi, Yutaka, Kurasaki, Haruaki, Cary, Douglas R, Masuya, Keiichi, Handa, Michiharu, Nishizawa, Naoki
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.1c00078

Herein, we present a new and efficient convergent solution-phase synthetic strategy for producing peptides containing N-methyl amino acids. Specifically, we have synthesized a model cyclic octapeptide with two N-methyl amino acids, utilizing an isostearyl-mixed anhydride coupling methodology and a novel silyl ester-protecting group, cyclohexyl di-tert-butyl silyl (cHBS). This newly developed method uses an isostearic acid chloride (ISTA-Cl) and silylation reagent that allows coupling between N- and C-terminally unprotected amino acids with sterically hindered N-methyl amino acids. High yields of four dipeptide fragments are efficiently synthesized by omitting the traditional C-terminal deprotection step. The silyl ester-protecting group at the C-terminus is stable during general peptide synthesis, and is selectively cleaved by fluoride ions. This group further suppresses diketopiperazine formation during the deprotection of the N α-amino-protecting group. The linear octapeptide precursor is convergently synthesized utilizing protection and selective deprotection of the silyl ester-protecting group, and the cyclic octapeptide can be obtained with high purity using this novel methodology, via a route shorter than conventional solution-phase peptide synthesis strategies.