Total Synthesis of (−)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy

Abstract

A unified synthetic strategy leading to the total synthesis of (-)-nodulisporic acids D, C, and B is described. Key synthetic transformations include a nickel-chromium-mediated cyclization, an aromatic ring functionalization employing a novel copper-promoted alkylation, a palladium-catalyzed cross-coupling cascade/indole ring construction, and a palladium-mediated regio- and diastereoselective allylic substitution/cyclization reaction, the latter to construct ring D.

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

“…For example, the flagship congener, nodulisporic acid A ( 1 ), exhibits high efficacy against fleas while lacking overt toxicity in dogs. , The producing organism has proven difficult to culture. , Nevertheless, detailed investigations of nodulisporic acids as a starting point for the development of new antiflea medications for companion animals have been performed, resulting in identification of promising lead compounds . As a part of broader efforts toward the paxilline indoloterpenoids, − multiple inquiries from organic chemists recently culminated in the syntheses of nodulisporic acids B ( 2 ), C ( 3 ), and D. , In addition to the common indoloterpenoid core, these natural products contain an indenopyran motif found in other members of the paxilline family, such as the janthitrems and shearinines. , Here we demonstrate a 12-step asymmetric synthesis of (−)-nodulisporic acid C ( 3 ) enabled by the development and implementation of new polycyclization-based strategies and a highly convergent assembly of a challenging indole moiety.…”

“…In this setting, diastereomer 29 returned the corresponding aminoketone and attempted cyclodehydration under forcing conditions led to elimination of the benzyl ether moiety. The sensitive nature of the indenopyran fragment was previously highlighted in the isolation and synthetic literature. , The facility of conversion of ketone 30 to the desired indole is in stark contrast to the previous reports of cyclodehydrations of relevant aminoketones and can be instructive during synthetic planning toward the other paxilline indoloterpenoids. Final manipulations in our synthesis of (−)-nodulisporic acid C ( 3 ) included deprotection of the silyl ether and saponification of the intermediate diester, which delivered the natural product in 12 steps from commercially available material (longest linear sequence).…”

Synthesis of Pyranocyclopentaindolines Representing the Western Sections of Janthitrem B, JBIR‐137, and Shearinine G

“…Of the indole diterpenes functionalized at the benzene section, penitrem D, [5] and the nodulisporic acids B, [6b] C, [6b,7] and D [6] have been synthesized. Until very recently, there was no total synthesis of the janthitrem‐type indole diterpenoids published.…”

Total Synthesis of Shearinines D and G: A Convergent Approach to Indole Diterpenoids

“…In a complementary approach, conjugate addition to cyclopentenone derivatives followed by alkylation of the resulting enolate set the necessary vicinal anti relationship, which sets the stage for installation of the fused 6‐ring [7, 8] . Another strategy to these relies on a sequence of 1,4‐addition and α‐alkylation reactions to generate 1,6‐dienes that are then subject to ring‐closing metathesis reactions [4c,d, 15] . More recently, cationic cyclization has provided entry to the trans ‐hydrindane, albeit as the minor product [9] …”