A sequential cycloaddition strategy for the synthesis of Alsmaphorazine B traces a path through a family of Alstonia alkaloids

Abstract

Driven by a new biogenetic hypothesis, the first total synthesis of alsmaphorazine B and several related indole alkaloids has been achieved. Numerous early approaches proved unsuccessful owing to unproductive side reactivity; nevertheless, they provided important clues that guided the evolution of our strategy. Critical to our success was a major improvement in our Zincke aldehyde cycloaddition strategy, which permitted the efficient gram-scale synthesis of akuammicine. The sequential chemoselective oxidations of akuammicine leading up to the key oxidative rearrangement also yielded several biogenetically related indole alkaloids en route to alsmaphorazine B.

Total Synthesis of (–)-Voacinol and (–)-Voacandimine C

“…29 We envisioned accessing the pentacyclic N-oxide 9 via chemoselective oxidation of vinylogous urethane (-)-10, an advanced intermediate used in our synthesis of kopsifolines A and E. Our synthesis of the key hexacyclic enamine 8 commenced with derivatization of vinylogous urethane (-)-10 (Scheme 2), a C21-oxygenated variant of tabersonine 37 that we have previously prepared in enantiomerically enriched form in ten steps from a readily available indole derivative. 29,36,38 We found that treatment of vinylogous urethane (-)-10 (90% ee) with peracetic acid (1.3 equiv) 29,39 provided the desired N9-oxidation (70%) while minimizing a competitive C3-oxidation. 40 Subsequent unveiling of the primary alcohol afforded the N-oxide alcohol 9 in 96% yield (Scheme 2).…”

Total Synthesis of (−)-Voacinol and (−)-Voacandimine C

“…Our synthesis of the key hexacyclic enamine 8 commenced with the derivatization of vinylogous urethane (−)- 10 (Scheme ), a C21-oxygenated variant of tabersonine that we have previously prepared in enantiomerically enriched form in 10 steps from a readily available indole derivative. ,, We found that the treatment of vinylogous urethane (−)- 10 (90% ee) with peracetic acid (1.3 equiv) , provided the desired N9-oxidation (70%) while minimizing a competitive C3-oxidation . Subsequent unveiling of the primary alcohol afforded the N-oxide alcohol 9 in 96% yield (Scheme ).…”

Synthetic Approaches to Tetracyclic Indolines as Versatile Building Blocks of Diverse Indole Alkaloids

“…This convenient route to tetracyclic skeleton 103 opened the way to the synthesis of naturally occurring and biologically important indole monoterpene alkaloids, such as (±)‐norfluorocurarine, (±)‐dehydrodesacetylretuline, (±)‐valparicine, and (±)‐strychnine. In 2017, the first total synthesis of (±)‐alsmaphorazine B and several related indole alkaloids were accomplished through this strategy as well …”

“…In 2017, the first total synthesis of (AE)-alsmaphorazine Ba nd severalr elatedi ndole alkaloids were accomplished through this strategy as well. [36] Scheme9.An intramolecular Diels-Alder cycloaddition strategy to tetracyclic indoline 81 (Szµntay et al [32] ).…”