Twelve-Step Asymmetric Synthesis of (−)-Nodulisporic Acid C

Abstract

A short, enantioselective synthesis of (–)-nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step synthesis of the target indoloterpenoid from commercially available material.

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods

“…While many applications of HAT reactions are focused on introduction of oxygenation via olefin hydration under mild conditions, several recent applications feature the application of HAT reaction for the C‐C bond constructions that result in the formation of challenging motifs present in various steroids. Below we provide a brief overview of the recent applications of such transformations and highlight their use in the synthesis of aplysiasecosterol by the Li group and construction of (–)‐nodulisporic acid C by the Pronin group …”

“…Below we provide a brief overview of the recent applications of such transformations and highlight their use in the synthesis of aplysiasecosterol by the Li group [31] and construction of (-)-nodulisporic acid C by the Pronin group. [32]…”

“…Proposed mechanism for the iron(III)-promoted HAT cyclization. [31] [32] Pronin's group recently applied iron-catalyzed HAT cyclization/ aldol addition sequence to establish the eastern portion of indole diterpenoid, (-)-nodulisporic acid C (Scheme 20). [32,39] The synthesis began with the copper-catalyzed asymmetric conjugate addition to 86 using the JosiPhos derivative SL-J015-1 to prepare the silyl-enol ether 87 in 95 % yield and 73 % ee.…”

“…[31] [32] Pronin's group recently applied iron-catalyzed HAT cyclization/ aldol addition sequence to establish the eastern portion of indole diterpenoid, (-)-nodulisporic acid C (Scheme 20). [32,39] The synthesis began with the copper-catalyzed asymmetric conjugate addition to 86 using the JosiPhos derivative SL-J015-1 to prepare the silyl-enol ether 87 in 95 % yield and 73 % ee. This silyl enol ether underwent an addition catalyzed by indium (III) bromide to the TBS-protected pent-4-yn-1-ol, [40] and the following acid work-up provided access to 88 containing a quaternary stereocenter.…”

Change the channel: CysLoop receptor antagonists from nature

“…Its congener nodulisporic acid C (NAC) possesses the common structure of NA secondary metabolites and exhibits toxicity in the flea feeding assay (LD 50 = 15 μ m ) about 10‐fold lower than NAA, still a useful potency. Pronin and coworkers published a remarkably concise synthesis of NAC, substantially simplifying the functional development of this complex scaffold 127 . A key metal‐hydride atom transfer (MHAT) cyclization promoted formation of the trans ‐decalin fragment in one step followed by chain elongation providing the right‐hand fragment in eight steps.…”