Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 40, Pages 16383-16387Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c08626
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Funding
- NIH [GM128570, P30 CA023168]
- NSF through the MRI Program [CHE 1625543]
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In this study, a novel pyrrole strategy was used to synthesize Complanadine A and Lycodine, demonstrating their catalytic mechanism and potential applications.
Complanadine A and lycodine are representative members of the Lycopodium alkaloids with a characteristic pyridinecontaining tetracyclic skeleton. Complanadine A has demonstrated promising neurotrophic activity and potential for persistent pain management. Herein we report a pyrrole strategy enabled by one-carbon insertion and polarity inversion for concise total syntheses of complanadine A and lycodine. The use of a pyrrole as the pyridine precursor allowed the rapid construction of their tetracyclic skeleton via a one-pot Staudinger reduction, amine-ketone condensation, and Mannich-type cyclization. The pyrrole group was then converted to the desired pyridine by the Ciamician-Dennstedt rearrangement via a one-carbon insertion process, which also simultaneously introduced a chloride at C3 for the next C-H arylation. Other key steps include a direct anti-Markovnikov hydroazidation, a Mukaiyama-Michael addition, and a Paal-Knorr pyrrole synthesis. Lycodine and complanadine A were prepared in 8 and 11 steps, respectively, from a readily available known compound.
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