The rare cis-configured trisubstituted lactam products obtained by the Castagnoli–Cushman reaction in N,N-dimethylformamide

Abstract

Unlike its trans counterpart, the cis-configured scaffold derived from the Castagnoli–Cushman reaction (CCR) is scarce and has not been explored in bioactive compound design. We found that conducting this reaction in DMF (in contrast to conventional toluene or xylene) led to a significantly higher proportion of cis-configured lactams in the diastereomeric product mixture. This allowed us, for the first time, to obtain and thoroughly characterize both stereoisomers of a significant number of lead-like CCR lactams. Simple rules for ¹H NMR-based stereochemical assignment have been devised and correlated with the single-crystal X-ray structures obtained for pure cis- and trans-configured lactams.