Synthesis of a Halicyclamine-Type Macrocyclic Scaffold via Biomimetic Transannular Cyclization

Previous attempts for biomimetic transannular reactions between two dihydropyrdine (DHP) rings incorporated in macrocycle frameworks relevant to manzamine alkaloids have been unsuccessful. Herein, we report an efficient regiocontrolled transannular cyclization of C2-symmetric macrocyclic precursor with rational modifications of the 3 and 6 positions of the DHP rings to synthesize a halicyclamine-type scaffold. The cis-double bonds installed in the macrocyclic alkyl loops played a crucial role in achieving the biomimetic transannular cyclization.

Automated summary

Previous attempts to perform biomimetic transannular reactions utilizing DHP rings within macrocycles similar to manzamine alkaloids had been unsuccessful. In this study, an efficient regiocontrolled transannular cyclization of a C2-symmetric macrocyclic precursor was achieved through rational modifications of the 3 and 6 positions of the DHP rings, resulting in the synthesis of a halicyclamine-type scaffold. The presence of cis-double bonds in the macrocyclic alkyl loops played a critical role in the success of the biomimetic transannular cyclization.