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A general method for preparation of N ‐Boc‐protected or N ‐Fmoc‐protected α,β‐didehydropeptide building blocks and their use in the solid‐phase peptide synthesis
Author(s) -
Wołczański Grzegorz,
Lisowski Marek
Publication year - 2018
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.3091
Subject(s) - chemistry , trifluoroacetic acid , dipeptide , peptide synthesis , peptide , residue (chemistry) , hydrolysis , amino acid , solid phase synthesis , stereochemistry , stereoselectivity , pyridinium , aqueous solution , combinatorial chemistry , catalysis , organic chemistry , biochemistry
N ‐( tert ‐butyloxycarbonyl) or N ‐(9‐fluorenylmethoxycarbonyl) dipeptides with C‐terminal ( Z )‐α,β‐didehydrophenylalanine (∆ Z Phe), ( Z )‐α,β‐didehydrotyrosine (∆ Z Tyr), ( Z )‐α,β‐didehydrotryptophan (∆ Z Trp), ( Z )‐α,β‐didehydromethionine (∆ Z Met), ( Z )‐α,β‐didehydroleucine (∆ Z Leu), and ( Z/E )‐α,β‐didehydroisoleucine (∆ Z/E Ile) were synthesised from their saturated analogues via oxidation of intermediate 2,5‐disubstituted‐oxazol‐5‐(4 H )‐ones (also known as azlactones) with pyridinium tribromide followed by opening of the produced unsaturated oxazol‐5‐(4 H )‐one derivatives in organic‐aqueous solution with a catalytic amount of trifluoroacetic acid or by a basic hydrolysis. In all cases, a very strong preference for Z isomers of α,β‐didehydro‐α‐amino acid residues was observed except of the ΔIle, which was obtained as the equimolar mixture of Z and E isomers. Reasons for the ( Z )‐stereoselectivity and the increased stability of the aromatic α,β‐didehydro‐α‐amino acid residue oxazol‐5‐(4 H )‐ones over the corresponding aliphatic ones are also discussed. It is the first use of such a procedure to synthesise peptides with the C‐terminal unsaturated residues and a peptide with 2 consecutive ΔPhe residues. This approach is very effective especially in the synthesis of peptides with aliphatic α,β‐didehydro‐α‐amino acid residues that are difficult to obtain by other methods. It allowed the first synthesis of the ∆Met residue. It is also more cost‐effective and less laborious than other synthesis protocols. The dipeptide building blocks obtained were used in the solid‐phase synthesis of model peptides on a polystyrene‐based solid support. Peptides containing aromatic α,β‐didehydro‐α‐amino acid residues were obtained with PyBOP or TBTU as a coupling agent with good yields and purities. In the case of aliphatic α,β‐didehydro‐α‐amino acid residues, a good efficiency was achieved only with DPPA as a coupling agent.