An insight into asymmetric synthesis and bioorganic applications of novel Calpha-methyl-lysine, -proline, -nipecotic acid analogues

Prochiral malonic diesters consisting of a quaternary carbon center have been successfully converted into a different set of tBoc-Fmoc-alpha 2,2-methyllysine-OH analogues through chiral malonic half-ester intermediates achieved via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The selection of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in high optical purity (92% - 97% ee) and in good yields (65% - 72%). The PLE hydrolysis of malonic diesters with a variety of side chain lengths observed to obey the Jones's PLE model as evidenced from the stereochemical configurations of the resulting chiral half-esters. The optimized synthetic strategy allows the construction of both enantiomers of alpha2,2-methyllysine analogues, and a ( S)-beta2,2-methyllysine analogue from a common synthon by straightforward exploitation of protecting groups. Two different straightforward synthetic strategies are illustrated for the synthesis of alpha2,2 -methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-alpha2,2 -methyllysine was constructed. However, the Vapreotide analogue with (S)-alpha-methyl-alpha-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2). In an additional project, a stereoselective and enantiodivergent cyclization strategy for the preparation of gamma/delta-lactams is exhibited. The cyclization strategy exploits chiral malonic esters prepared from enantiomerically enriched (92% ee - 97% ee) mono esters of disubstituted malonic acid. The cyclization takes place with the selective departure of a substituted benzyl alcohol as the leaving group. A Hammett study demonstrates that the cyclization is under electronic control. The resulting gamma/delta-lactam was readily converted into a novel proline/nipecotic acid analogue.