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“On‐Resin” Disulfide Peptide Synthesis with Methyl 3‐Nitro‐2‐pyridinesulfenate
Author(s) -
Kobayashi Kiyotaka,
Taguchi Akihiro,
Cui Yan,
Shida Hayate,
Muguruma Kyohei,
Takayama Kentaro,
Taniguchi Atsuhiko,
Hayashi Yoshio
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202001517
Subject(s) - chemistry , reagent , disulfide bond , peptide , intramolecular force , oxidizing agent , bicyclic molecule , peptide synthesis , combinatorial chemistry , solvent , nitro , organic chemistry , biochemistry , alkyl
New methodologies for the construction of full peptide structures with all disulfide bonds on the resin are attractive for the development of solid phase peptide synthesis. Detailed reaction conditions for the on‐resin disulfide bond formation have been investigated using a mild and chemically stable oxidizing reagent, methyl 3‐nitro‐2‐pyridinesulfenate (Npys‐OMe). Monocyclic oxytocin, MCH and bicyclic α‐conotoxin ImI were synthesized in both semi‐automated and full‐automated protocols. It was found that on‐resin intramolecular disulfide bond formation with Npys‐OMe proceeds with the minimal formation of peptide oligomers by adopting a solvent system with 0.4 M LiCl/DMF. Crude peptides with complete disulfide bond patterns can be obtained in high purity using both protocols. This minimized the RP‐HPLC purification step and the desired peptides were obtained with better yields. To our knowledge, this is the first fully automated construction of a bicyclic disulfide peptide on resin with more than 50 % purity in Fmoc‐based SPPS. These results suggest that Npys‐OMe is a useful reagent for the disulfide bond formation in automated protocols.