Chiral 3-substituted isoindolinones and their derivatives are common structural motifs in a variety of compounds with biological activities. For example, they have been established as precursors to anti–ischemic stroke agents, as well as antimicrobial and antitumor agents. Their activity as MDM2–p53 protein–protein, HIV–1 integrase, and protein–tyrosine phosphatase inhibitors is also well known. In addition, registered and commercially available anxiolytic, anticonvulsant and antihypertensive drugs also contain 3–substituted isoindolinone cores. Hence, the development of facile and effective methods for their asymmetric synthesis is of great interest. As a part of our ongoing research of asymmetric organocatalytic transformations that generate structural cores of natural compounds, we developed chiral Brønsted-acid catalyzed asymmetric additions of nucleophiles to N-Acyl iminium species, generated in situ from 3-substituted 3-hydroxyisoindolinones. The asymmetric addition of thiols provided chiral α-tetrasubstituted N(acyl),S-acetals in high isolated yields and excellent enantioselectivities. The application of the developed protocol was demonstrated in the synthesis of a known HIV-1 reverse transcriptase inhibitor. In a similar fashion, asymmetric Friedel-Crafts reaction resulted in products comprising α-triaryl tetrasubstituted stereocentres isolated in high yields and enantioselectivities.

Chiral Brønsted acid-catalyzed asymmetric transformations of 3-substituted 3-hydroxyisoindolinones

256th National Meeting (2018)

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