An Efficient Strategy to Orthogonally Protected (R)- and (S)-α-Methyl(alkyl)serine-Containing Peptides via a Novel Azlactone/Oxazoline Interconversion Reaction

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Abstract
A novel strategy for the synthesis of (R)- and (S)-α-methyl(alkyl)serine-containing peptides is presented. Using (S)-phenylalanine cyclohexylamide 6 as chiral auxiliary, the optically pure azlactones (R)- and (S)-2 were synthesized via a novel azlactone/oxazoline interconversion reaction (Figures 3 and 6). These azlactones constitute fully protected and activated synthetic equivalents of (R)- and (S)-α-methylserine and can be directly incorporated into peptides without further protective group manipulations. Like other α,α-dialkylated glycines, optically pure α-alkylserines can be used to stabilize β-turn and α-helical conformations in short peptides.