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

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.

Natural product total synthesis using rearrangement reactions

“…The group of Dai recently reported a pyrrole strategy for the total synthesis of complanadine A ( 82 ). 26 The transformation of pyrrole into pyridine by a one-carbon insertion process is known as the Ciamician–Dennstedt rearrangement (Scheme 10). The process itself is not a complexity-generating transformation; however, in Dai's work, the identification of pyrrole as a precursor of pyridine enabled two key bond forming reactions that were crucial for the rapid construction of the complex architecture of complanadine A.…”

Total synthesis of huperserratines A and B

“…7–9 Owing to their intricate polycyclic skeletons and diverse bioactivities, Lycopodium alkaloids have attracted broad interest from synthetic and medicinal chemists in the past decade. 10–20…”

“…[7][8][9] Owing to their intricate polycyclic skeletons and diverse bioactivities, Lycopodium alkaloids have attracted broad interest from synthetic and medicinal chemists in the past decade. [10][11][12][13][14][15][16][17][18][19][20] Huperserratines A (1) and B (2), two Lycopodium alkaloids, were previously isolated from Huperzia serrata by our group in 2020 and their absolute configurations were determined by single-crystal X-ray diffraction (Fig. 1).…”

Scaffold hopping by net photochemical carbon deletion of azaarenes

“…An interesting consequence of the switch between electron-poor quinoline and electronrich indole heterocycles is the ability to interface their distinct reactivities and syntheses through carbon deletion. This is exemplified in the first instance by the preparation of indole 2af through Minisci alkylation of the parent quinoline at the 4-position, resulting in the net 3-alkylation of the final, nucleophilic indole product with an nucleophilic radical-a challenging retrosynthetic strategy to realize via known methods (31)(32)(33). Quinoline 4ag demonstrates the latter interplay of the two heterocyclic scaffolds, allowing the Pfitzinger quinoline synthesis to serve additionally as an indole synthesis (34).…”