Concise Unified Access to (−)-8-Deoxy-13-dehydroserratinine, (+)-Fawcettimine, (+)-Fawcettidine, and (−)-8-Deoxyserratinine Using a Direct Intramolecular Reductive Coupling

Abstract

A short, scalable, and collective total synthesis of four fawcettimine-type Lycopodium alkaloids in eight or nine steps is disclosed. A dense multi-small-ring spiro-α-aminocyclopentanone successfully served as the key intermediate, which was directly accessed by a LiDBB-mediated intramolecular reductive coupling of the aliphatic imine and an ester-carbonyl. Compared to those that employ classical Heathcock intermediate(s) containing a nine-membered ring, the new strategy shows the significant improvement of the synthetic step and redox economies as well as excellent stereochemical control.

Synthetic Studies on Tetracyclic Diquinane Lycopodium Alkaloids Magellanine, Magellaninone and Paniculatine

“…The piperidine ring of 88 could be derived from the reductive amination of aldehyde 89 , which itself could be obtained from an intramolecular Michael addition of 90 , a common procedure for 1,5-dicarbonyl systems. The enone moiety of 90 could come from the dehydration of tertiary alcohol 91 , for which the latter could come from an intramolecular reductive C-C bond formation between the two carbonyls in 92 [ 99 , 100 , 101 ]. Methyl ester 92 can result from a functionally decorated intermediate 93 , which, in turn, can be derived from a four-step sequence of the Morita–Baylis–Hillman reaction, alcohol oxidation, and two Michael additions.…”

“…With a sufficient quantity of 93 in hand, the intramolecular reductive C-C bond was formed. In their 2012 and 2021 reports for the total synthesis of the fawcettimine-type alkaloids [ 99 , 100 ], Yao and coworkers had discovered that lithium-arenides were capable of forming this type of bond through single-electron reduction. This was applied in the currently discussed route with the use of Li-naphthalide, leading to the production of the resulting tertiary alcohol with high stereoselectivity, which was likely due to the coordinating effects between the lithium ion and the neighboring methoxyl group, which forces the alcohol onto the “top” face.…”

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).…”