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General Fmoc‐Based Solid‐Phase Synthesis of Complex Depsipeptides Circumventing Problematic Fmoc Removal
Author(s) -
LoboRuiz Ariadna,
TullaPuche Judit
Publication year - 2020
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.201901459
Subject(s) - depsipeptide , chemistry , combinatorial chemistry , solid phase synthesis , residue (chemistry) , peptide synthesis , protecting group , total synthesis , peptide , organic chemistry , stereochemistry , biochemistry , alkyl
Development of an Fmoc‐based solid‐phase depsipeptide methodology has been hampered by base‐promoted fragmentation and diketoperazine formation upon Fmoc group elimination. Such a strategy would be a useful tool given the number of commercially available Fmoc‐protected residues. Herein we report that the addition of small percentages of organic acids to the Fmoc‐removal cocktail proves effective to circumvent these drawbacks and most importantly, allowed the development of an exclusively solid‐phase stepwise methodology to prepare a highly complex depsipeptide with multiple and consecutive esters bonds. Alongside, the optimal protecting group scheme for residue incorporation, which is not as straightforward as it is for traditional peptide synthesis, was explored. The developed stepwise strategy proved effective for the synthesis of a highly complex cyclodepsipeptide, being comparable to the yields obtained when using traditional combined chemistry approaches.