One-Step Synthesis of Dihydropyrroloquinazolinone Alkaloid Natural Products: S‑(−)- and R‑(+)-Vasicinone and Their Novel Analogues

Abstract

A single-step synthesis of the biologically active dihydropyrroloquinazolinone alkaloid natural products, S-(−)- and R-(+)-vasicinone (5 and 6) has been developed for the first time. This reaction employs a POCl3-mediated coupling of methyl 2-aminobenzoate with either (S)- or (R)-3-hydroxypyrrolidin-2-one resulting in the synthesis of the two enantiomers in excellent yields. The enantiomeric excess (ee) was found to be >99% for both enantiomers and the specific rotations are consistent with the literature values. The reaction can be successfully extended to obtain diverse quinazolinone scaffolds such as substituted benzenoids, naphthalenes, indoles, thiophenes, phenylthiophenes, piperidines, oxazepines, and isoindolinones. We applied this reaction to the synthesis of our orally active antileishmanial lead peganine, and reduction of S-(−)-vasicinone led to a conformationally more flexible analogue, 3a,4-dihydropeganine (28).