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Homologs of 1,2,5‐hexahydro‐3‐one‐1 H ‐1,4‐diazepine (DAP) as novel dipeptidomimetics and molecular scaffolds: Efficient preparation of synthons
Author(s) -
Han Yinglin,
Mierke Dale F.,
Chorev Michael
Publication year - 2002
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10079
Subject(s) - synthon , chemistry , stereochemistry , alkylation , catalysis , organic chemistry
Structurally constraint dipeptidomimetics represent an important class of conformationally rigid dipeptide surrogates and molecular scaffolds, which are frequently employed in peptide‐based structure–activity relationships (SAR) and construction of combinatorial libraries. We report on the design of an improved and general synthetic procedure to prepare synthons related to the trisubstituted 1,2,5‐hexahydro‐3‐one‐1 H ‐1,4‐diazepines [DAP(Xxx) α7 ] (DAP: 1,2,5‐hexahydro‐3‐one‐1 H ‐1,4‐diazepine; DAP(Xxx) α7 : the homologous series of DAP in which α refers to the location of the chiral carbon in the i th amino acid, Xxx represents the three letter notation for the i −1 amino acids, and 7 denotes the number of atoms in the ring) and their higher homologs [DAP(Xxx) α N ] [Xxx = Phe, Asp(β‐OcHex) (cHex: cyclohexyl), and Arg(N G ‐Tos] (Tos: p‐toluenesulfonyl); N = 8–10]. These dipetidomimetic structures are generated by reductive alkylation‐mediated Cα i ‐to‐N i −1 bridging between a Cα i ‐(CH 2 ) i−1 n ‐COSEt ( n = 1–4) and H 2 N‐C i −1 HR‐CO 2 Fm (Fm: 9‐fluorenylmethyl) followed by H 2 N i ‐to‐C i −1 ‐CO 2 H lactam formation. We also describe the preparation of blocked N ‐Ac‐[DAP(Phe) α N ]‐CONMe 2 ( N = 8–10), which serve as model systems for detailed conformational analysis reported in the accompanying article. © 2002 Wiley Periodicals, Inc. Biopolymers 64: 1–15, 2002