Furthefurther C-alkylations of cyclotetrapeptides via lithium and phosphazenium (P4) enolates: Discovery of a new conformationr C-Alkylations of Cyclotetrapeptides via Lithium and Phosphazenium (P4) Enolates: Discovery of a new conformation

Article abstract of DOI:10.1002/hlca.19960790303

Four cyclotetrapeptides containing one (1, 2) or two (3, 4) chiral amino acids have been C-alkylated or C-hydroxyalkylated through Li⁺ or phosphazenium (P4·H⁺) enolates. The reactions are completely diastereoselective (by NMR or HPLC analysis) with respect to the newly formed backbone stereogenic centres (Tables 2 and 3). The reactivity of the polylithiated species responsible for these alkylations is such that only highly reactive electrophiles (MeI, BnBr, primary allylic halides, aldehydes, CO₂) can be employed. It is shown that the position, and thus the chirality sense, of the newly formed stereogenic centre in a given cyclotetrapeptide backbone is controlled by the positioning of N-methyl groups in the starting material (cf. cyclo(-MeLeu-Gly-D-Ala-Sar-) (3) and cyclo(-Leu-Sar-MeDAla-Gly-) (4) in Scheme 1). With Schwesinger's phosphazene P4-base, all NH groups are first benzylated and C-benzylation then takes place at a sarcosine, rather than an N-benzylglycine residue (Table 3). In contrast to open-chain N-benzyl peptides, the N-benzylated cyclotetrapeptides could not be debenzylated under dissolving-metal conditions (Na/NH₃). Conformational analysis (NMR spectroscopy and X-ray diffraction) shows that the prevailing species have cis/trans/cis/trans (ctct) peptide bonds (zigzag conformation of C₁, backbone symmetry, Figs. 2-4). However, a hitherto unknown conformation of cyclotetrapeptides has been found in CDCl₃ solutions of the hydroxyalkylated products 18-21 (obtained with EtCHO and PhCHO as electrophiles, Fig. 4). The new conformation has four trans peptide bonds and is believed to result mainly from intramolecular H-bond formation, involving the newly generated alkyl- or arylserine residue. This assumption has also been supported by modelling (TRIPOS force field, SYBYL, see Fig 5 and Table 6). The structure may be considered as a β-turn mimic.