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 ami no acids have been C-alkylated or C-hydroxyalkylated through Li+ or ph osphazenium (P4.H+) enolates. The reactions are completely diastereo-s elective (by NMR or HPLC analysis) with respect to the newly formed ba ckbone stereogenic centres (Tables 2 and 3). The reactivity of the pol ylithiated species responsible for these alkylations is such that only highly reactive electrophiles (Mel. BnBr, primary allylic halides, al dehydes, CO2) can be employed. It is shown that the position, and thus the chirality sense, of the newly formed stereogenic centre in a give n cyclotetrapeptide backbone is controlled by the positioning or N-met hyl 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-benzy lation 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 debanzylated under dissolv ing-metal conditions (Na/NH3). Conformational analysis (NMR spectrosco py and X-ray diffraction) shows that the prevailing species have cis/t ans/cis/trans (ctct) peptide bonds (zigzag conformation of C-i backbon e symmetry, Figs. 2-4). However, a hitherto unknown conformation of cy clotetrapeptides has been found in CDCl3 solutions of the hydroxyalkyl ated products 18-21 (obtained with EtCHO and PhCHO as electrophiles; F ig. 4). The new conformation has four trans peptide bonds and is belie ved to result mainly from intramolecular H-bond formation, involving t he newly generated alkyl- or arylserine residue. This assumption has a lso been supported by modelling (TRIPOS force field, SYBYL, see Fig. 5 and Table 6). The structure may be considered as a beta-turn mimic.