The synthesis of γ- and δ-unnatural amino acids are of interest to those studying foldamers, peptidomimetics, and pharmaceuticals. Research has also shown α-methyl substituted unnatural amino acids to have a higher propensity in forming stable secondary structures and a greater resistance to proteolytic degradation. The challenge is to synthesize these Cα,α-disubstituted amino acid analogues in high yields and enantiomeric purity. Our synthetic method meets these demands by utilizing pig liver esterase to desymmetrize prochiral 1a/1b into (R)-selective chiral half esters 2a/2b. Deprotection of the phthalimide group through hydrazine hydrolysis promotes the selective cyclization to lactam esters 3a/3b which are reduced to alcohol intermediates 4a/4b. These lactam alcohols are protected and ring opened via a basic hydrolysis into Cα-methyl-γ- or δ-serine. Alternatively 4a/4b can be converted into azides to prepare Cα-methyl-γ- and δ-azido analogues. The current results of this method show the potential of making this a high yielding enantiodivergent strategy through the selective cyclization and further functionalization of the lactam intermediates into other unnatural amino acid analogues.

Synthesis of enantiomeric enriched disubstituted Cα-methyl-γ- and δ-unnatural amino acids analogs

249th National Meeting (2015)

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