PEPTIDE ENOLATES - C-ALKYLATION OF GLYCINE RESIDUES IN LINEAR TRIPEPTIDES, TETRAPEPTIDES, AND PENTAPEPTIDES VIA DILITHIUM AZADIENEDIOLATES

The Boc-protected tripeptides Boc-Val-Gly-Leu-OH (1), Boc-Leu-Sar-Leu- OH (2), Boc-Leu-Gly-MeLeu-OH (3), and Boc-Val-BzlGly-Leu-OMe (64), tet rapeptide Boc-Leu-Gly-Pro-Leu-OH (9), and pentapeptides Boc-Val-Leu-Gl y-Abu-Ile-OH (4), Boc-Val-Leu-Sar-MeAbu-Ile-OH (5), Boc-Val-Leu-Gly-Me Abu-Ile-OH (6), Boc-Val-Leu- BzlGly-BzlAbu-Ile-OH (7), and Boc-Val-Leu -Gly-BzlAbu-Ile-OH (8) are prepared by conventional methods (Schemes 4 -7) or by direct benzylation of the corresponding precursors (Scheme 8 ). Polylithiations in THF give up to Li-6 derivatives containing glyci ne, sarcosine, or N-benzylglycine Li enolate moieties (A-H). The polyl ithiated systems with a dilithium azadienediolate unit (C, F-H) are be st generated by treatment with t-BuLi. The yields of alkylation of the glycine or sarcosine residues are up to 90%, with diastereoselectivit ies from nil to 9:1. Normally, the newly formed stereogenic center has (R)-configuration (i.e. a D-amino-acid residue is incorporated in the peptide chain). Electrophiles which can be employed with the highly r eactive azadienediolate moiety are: Mel, EtI, i-PrI, allyl and benzyl bromide, ethyl bromoacetate, CO2, and Me(2)S(2) (Schemes 11-13). No ep imerizations of the starting materials (racemization of the amino-acid residues) are observed under the strongly basic conditions. Selected conformations of the peptide precursors, generated by shock-freezing o r by very slow cooling from room temperature to -75 degrees before lit hiation, give rise to different stereoselectivities (Scheme II), The l atter and the yields can also be influenced by tempering the lithiated species before (Scheme 9) or after addition of the electrophiles (Sch eme 12). Besides the desired products, starting peptides are recovered in the chromatographic purification and isolation procedures (materia l balance 80-95%). The results described are yet another demonstration that peptides may be backbone-modified through Li enolates, and that whole series of analogous peptide derivatives with various side chains may thus be produced from a given precursor.