Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization

Abstract

Tubingensin B is an indole diterpenoid that bears a daunting chemical structure featuring a disubstituted carbazole unit, five stereogenic centres-three of which are quaternary-and a decorated [3.2.2]-bridged bicycle. We describe our synthetic design toward a concise and enantiospecific total synthesis of tubingensin B, which hinges on the strategic use of a transient aryne intermediate. Although initial studies led to unexpected reaction outcomes, we ultimately implemented a sequence of carbazolyne cyclization followed by Rh-catalysed fragmentation to install the seven-membered ring and vicinal quaternary stereocentres of the natural product. Coupled with a late-stage radical cyclization to construct the [3.2.2]-bridged bicycle, these efforts have enabled the total synthesis of tubingensin B. The design and evolution of our succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies

“…Finally, we conclude by examining the strategic use of heterocyclic arynes to enable concise total syntheses of tubingensins A and B, as reported by our laboratory. 11 …”

The Aryne Phosphate Reaction

“…[But] arynes can and should be used strategically to enable the synthesis of complex molecules with motifs that have conventionally been viewed as challenging." [47] In the present paper, we meet this suggestion by introducing the aryne phosphate reaction that accesses highly challenging arylated organophosphorous compounds with Kobayashi-type precursors. We demonstrate that inorganic phosphates, organophosphates and cyclophosphates are efficient arynophiles in O-arylation reactions.…”

Discussion Addendum for: The Direct Acyl-Alkylation of Arynes. Preparation of Methyl 2-(2-acetylphenyl)acetate

“…The Garg lab has incorporated carbazolyne chemistry in the total syntheses of tubingensin A 89 (41, Scheme 12) and tubingensin B. 90 The labeled quaternary stereocenter in 41 is formed in good yield and with exquisite diastereoselectivity due to the rigid conformational constraints on the system. Garg has also synthesized indolactam-containing natural products such as indolactam V (43, Scheme 13).…”