Synthesis of chiral lactams by asymmetric nitrogen insertion
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Abstract
Asymmetric nitrogen insertion into prochiral and meso cycloalkanones is achieved using diphenylphosphinyl hydroxylamine (DPPH) as the nitrogen source. A combination of Brønsted acid catalyst and Lewis acid promoter enables high yields and selectivity in the syntheses of a range of 5- to 7-membered lactams (19 examples, up to 97 : 3 er). Mechanistically, the sequence follows a Beckmann pathway involving an asymmetric condensation followed by a stereospecific rearrangement. The utility of the method is showcased by the syntheses of the drugs phenotropil, rolipram, pregabalin, and baclofen.