Unified Total Synthesis of Stemoamide-Type Alkaloids by Chemoselective Assembly of Five-Membered Building Blocks

Abstract

A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactone-selective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.

Total Syntheses of Bisdehydroneostemoninine and Bisdehydrostemoninine by Catalytic Carbonylative Spirolactonization

“…While there are over 20 total syntheses of the simplest member stemoamide ( 1 l , Figure B), total syntheses of the more complex ones are very rare. Notably, Williams and co‐workers reported the first total synthesis of stemonine ( 1 m ) in 2003 and Chida, Sato and co‐workers developed a unified approach to synthesize both 1 m and saxorumamide ( 1 n ) from 1 l in 2017 . So far, there have been no reported total syntheses of these oxaspirolactone‐containing stemona alkaloids ( 1 a – k ).…”

“…While there are over 20 total syntheses of the simplest member stemoamide (1l, Figure 1B), [11] total syntheses of the more complex ones are very rare.N otably,W illiams and coworkers reported the first total synthesis of stemonine (1m)in 2003 [12] and Chida, Sato and co-workers developed au nified approach to synthesize both 1mand saxorumamide (1n)from 1l in 2017. [13] So far, there have been no reported total syntheses of these oxaspirolactone-containing stemona alkaloids (1a-k). Thee xistence of an acid-sensitive oxaspirolactone moiety generates as ignificant synthetic challenge in its installation as well as the control of the stereochemistry at the spirocenter (C11).…”

Reductive Functionalization of Carboxamides: A Recent Update

“…On the other hand, various external nucleophiles were engaged in combination with the Ir-catalyzed hydrosilylation for reductive functionalization of tertiary carboxamides. As for the use of neutral carbon nucleophiles, Sato/Chida employed ketene silyl acetals, 2-siloxyfuran, and allyl tributylstannane in the presence of Brønsted or Lewis acid for reductive functionalization of N-methoxy-N-benzylamides 42 carboxamides. 43 Figure 18 illustrated the reductive vinylogous functionalization of stemonamide (29) for the synthesis of stemonine.…”

Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides

“…The amide functional group can be tuned electronically and conformationally to gain desired structural, physical, and biological properties. The chemistry of amide group is vast, and by its virtue amides can be transformed into many other functional groups [14][15][16][17][18][19][20]. Due to the omnipresence and profound importance of the amide functionality, the development of principally new synthetic routes aiming at installation of the amide structural moiety is of current importance in both modern organic and medicinal chemistry.…”