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Functionalized Resins for the Synthesis of Peptide Alcohols
Author(s) -
FerrerGago Fernando J.,
Koh Li Quan,
Lane David P.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903965
Subject(s) - peptide , trifluoroacetic acid , chemistry , alcohol , peptide synthesis , combinatorial chemistry , dichloromethane , organic chemistry , alamethicin , chloride , biochemistry , solvent , lipid bilayer , membrane
Peptide alcohols are clinically important compounds that are underexplored in structure–activity relationship (SAR) studies in drug discovery. One reason for this underutilization is that current syntheses are laborious and time consuming. Herein, we describe the preparation and utility of Rink, Ramage, and Sieber‐chloride resins, which enables the use of a general, easy and practical method for the attachment of fluorenylmethoxycarbonyl (Fmoc)‐amino alcohols to a solid support, in the synthesis of peptide alcohols. This method is the first straightforward Fmoc/ t Bu synthesis of peptide alcohols starting from a pre‐loaded resin. The synthesized peptide alcohols can be detached from the linkers through conventional methods. Treatment with trifluoroacetic acid (TFA) (95 %) and scavengers such as triisopropylsilane and water for 2 h is sufficient to obtain a fully deprotected peptide alcohol, while treatment with 20 % hexafluoroisopropanol in dichloromethane renders a fully protected peptide alcohol that can be further modified at the C‐terminus. As examples, the new resins were used in straightforward, relatively rapid syntheses of the peptide alcohols octreotide, alamethicin, and a segment of trichogin GA IV, as well as the first synthesis of stapled peptide alcohols.