Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

We report herein the fourth generation of our synthetic strategy to chaetominine-type alkaloids featuring two modifications of the last step of our 4 to 6-step approach. Firstly, by employing EDCI/HOBt as the coupling system for the last step of the one-pot <i>O</i>-debenzylation-lactamization reaction, the overall yield of our previous total synthesis of (-)-isochaetominine A was increased from 25.4% to 30.8% over five steps. Secondly, a new protocol featuring the use of an aged solution of K₂CO₃/MeOH to quench the DMDO epoxidation-triggered cascade reaction was developed, which allowed the in situ selective mono- or double epimerization at C11/C14 as shown by the diastereodivergent synthesis of a pair of diastereomers of versiquinazoline H from its tripeptide precursor. This double epimerization at the last-step allowed the enantiodivergent synthesis of two enantiomers in either racemate form or two pure enantiomers from the same precursor. The former was demonstrated by the synthesis of alkaloid 14-<i>epi</i>-isochaetominine C that was used to determine the enantiomeric excess of the synthesized natural product (98.7% ee), while the latter was illustrated by the synthesis of both enantiomers of the alkaloid isochaetominine. Additionally, the reported structures of alkaloids aspera chaetominines A and B have been synthesized. Moreover, the four-step synthesis of the reported structure of aspera chaetominine B generated another diastereomer that was converted in one-pot to (-)-isochaetominine C, which turned out to be the revised structure of aspera chaetominine B.