Unsymmetrically 2,5-disubstituted pyrrolidines are found in many natural products. Our group discovered that pyrrolidine could react with o-quinone to form a N,O-acetal in fluorinated alcohol 2,2,2-trifluoroethanol (TFE). The N,O-acetal was then attacked by a Grignard reagent to give an o-pyrrolidine substituted phenol which could either be deprotected to give a 2-substitued pyrrolidine or be reoxidized to N,O-acetal selectively at the C5 position of pyrrolidine. The N,O-acetal formed was further attacked by another Grignard reagent to install another alkyl group at the C5 position. Through the late-stage C-H bond functionalization strategy, we can install different alkyl groups at the C2, C5 positions of pyrrolidine. Also, pyrrolidine alkaloid (+)-preussin which is a potent antifungal agent was synthesized from Boc-protected pyrrolidin-3-ol by two rounds of C-H bond functionalization.

Two-round functionalization of pyrrolidine to synthesize unsymmetrically 2,5-disubstituted pyrrolidines

255th National Meeting (2018)

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