A Catalytic Asymmetric Synthesis of N-Boc-β-Methylphenylalanines

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Abstract
An efficient, stereodivergent, and enantioselective synthesis of the syn and anti diastereomers of N-Boc-β-methylphenylalanine has been developed. Starting from enantiomerically pure (2S,3S)-2,3-epoxy-3-phenyl-1-propanol, a three-step sequence, consisting of the oxidation of the primary alcohol up to the carboxyl stage, ring opening of the epoxy acid with Me2CuCNLi2, and esterification of the resulting hydroxy acid with methyl iodide, leads to the hydroxy ester anti-10, which has been converted in a stereodivergent manner into both the (2S,3R) and the (2R,3R) diastereomers of N-Boc-β-methylphenylalanine, syn-1 and anti-1, respectively. Activation of the secondary hydroxy group in anti-10 as a mesylate, followed by nucleophilic displacement with sodium azide, hydrogenolysis with simultaneous protection of the amino group, and saponification with LiOH, affords syn-1. The same reaction sequence applied to syn-10, obtained in turn by Mitsunobu reaction of anti-10 with p-nitrobenzoic acid followed by the hydrolysis of the resulting p-nitrobenzoate, leads to anti-1. Both products have been obtained with ⩾99% enantiomeric excess.