Doubly stereoconvergent crystallization enabled by asymmetric catalysis.

CRYSTALLIZATION; CATALYSIS; DOSAGE forms of drugs; NITROALKANES; ORGANOCATALYSIS

Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization-induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent crystallization. The synthesis of useful g-nitro b-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers. [ABSTRACT FROM AUTHOR]

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