Further C-Alkylations of Cyclotetrapeptides via Lithium and Phosphazenium (P4) Enolates: Discovery of a New Conformation

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-MeD Ala-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 C_i 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.