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. 2021 Oct 13;143(40):16383-16387.
doi: 10.1021/jacs.1c08626. Epub 2021 Sep 27.

One-Carbon Insertion and Polarity Inversion Enabled a Pyrrole Strategy to the Total Syntheses of Pyridine-Containing Lycopodium Alkaloids: Complanadine A and Lycodine

Donghui Ma  1 , Brandon S Martin  1 , Katelyn S Gallagher  1 , Takeru Saito  1 , Mingji Dai  1
Affiliations

One-Carbon Insertion and Polarity Inversion Enabled a Pyrrole Strategy to the Total Syntheses of Pyridine-Containing Lycopodium Alkaloids: Complanadine A and Lycodine

Donghui Ma et al. J Am Chem Soc. .

Abstract

Complanadine A and lycodine are representative members of the Lycopodium alkaloids with a characteristic pyridine-containing 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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Figures

Figure 1.
Figure 1.
Lycodine and complanadine natural products, proposed biosynthesis, prior total syntheses, and our synthetic plan.
Scheme 1.
Scheme 1.
Total synthesis of complanadine A and lycodine.
See this image and copyright information in PMC

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