Advancements in the diastereoselective synthesis of acyl pyrrolidines via the tandem aza-Cope—Mannich cyclization pathway

We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization to form acyl pyrrolidines from conformationally mobile substrates. In earlier studies from our lab, Brønsted acid-catalyzed reactions to form the same acyl pyrrolidines resulted in diastereoselectivities of 8:1 trans to cis at elevated temperatures (60 °C) over the course of 150 minutes. We have demonstrated an improvement in our method yielding exclusively the trans isomers at ambient temperature with substoichiometric amounts of BF3•OEt2 within 3 minutes. Catalyst loadings as low as 0.05 equivalents of BF3•OEt2 initiate this transformation. Our synthetic method employs the oxazolidine starting material as a mixture of diastereomers to produce one pyrrolidine diastereomer. Both ethyland substituted phenyl-oxazolidines were successfully rearranged. This work is the first example of a truly catalytic aza-Cope—Mannich reaction and provides the first examples of diastereoselective syntheses of 2-phenyl-4-acylpyrrolidines via this reaction