Unified Enantioselective, Convergent Synthetic Approach toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Synthesis of a Series of Ineleganoloids by Oxidation-State Manipulation of the Carbocyclic Core

Abstract

Late-stage synthetic efforts to advance the enatio-and diastereoselectively constructed [6,7,5,5]-fused tetracyclic scaffold toward the polycyclic norditerpenoid ineleganolide are disclosed. The described investigations focus on oxidation state manipulation around the central cycloheptane ring. Computational evaluation of ground state energies of dihydroineleganolide are used to rationalize empirical observations and provide insight for further synthetic development, enhancing the understanding of the conformational constraints of these compact polycyclic structures. Advanced synthetic manipulations generated a series of natural product-like compounds termed the ineleganoloids. Ineleganolide (1)

Total Syntheses of (+)-Ineleganolide and (−)-Sinulochmodin C

“…Preliminary total synthesis efforts targeting these natural products have been disclosed by the Nicolau, Frontier, Romo, and Gaich groups, with only modest success. Furthermore, despite extensive and elegant work published by the Stoltz, − Vanderwal, and Moeller , groups, neither ineleganolide nor sinulochmodin C had succumbed to total synthesis prior to the efforts we report herein.…”

“…In planning our total synthesis, we were clearly beneficiaries of prior work, which had identified a number of difficulties associated with assembling these challenging ring systems. Notably, the embedded keto-tetrahydrofuran moiety, a structural unit present at the point of departure in Pattenden’s semisynthesis ( 7 ), has been a particular challenge in previous efforts, as it proved recalcitrant to formation via logical annulative methods. − Thus, in our efforts, we focused on developing an approach that would not only address this challenge but also allow divergent enantioselective access to both (+)- 1 and (−)- 2 from a common intermediate. Since 1 and 2 respectively possess the 5,7,6- and 5,6,7-fused carbocyclic cores found in the broader family of natural products, achieving this latter goal would potentially allow for unified access to a variety of biogenetically related nor-furanocembranoids ( e.g.…”

A Convergent Total Synthesis of (+)-Ineleganolide

“…Structurally, ineleganolide contains a highly rigid oxidized framework that bears a key central seven-membered ring, a remote isopropenyl group, and a bridging β-keto tetrahydrofuran moiety. Because of its unique and challenging framework, the synthesis of ineleganolide had remained an unsolved challenge over the past two decades, despite efforts by the groups of Vanderwal, Nicolaou, Gaich, Romo, Moeller, and our group . Only recently, in 2022, did Wood and co-workers showcase the first total synthesis of ineleganolide .…”

Total Syntheses of Scabrolide A and Nominal Scabrolide B

“…Though known for (more than) two decades, it was only recently that a member of this family succumbed to total synthesis. 12 − 23 Specifically, the Stoltz group reported an elegant approach to scabrolide A ( 2 ) based on late-stage formation of the seven-membered ring by a sequence of intramolecular enone/alkenylsilane [2 + 2] cycloaddition, followed by a mercury-mediated Tamao–Fleming type oxidation and a strain-driven oxidative fragmentation. 12 …”

“…For the architectural splendor of the caged tetracyclic backbone, the challenging oxygenation pattern comprising an “umpoled” 1,4-diketone motif, and the dense array of up to seven mostly contiguous chiral centers, these terpenoids represent formidable targets. Though known for (more than) two decades, it was only recently that a member of this family succumbed to total synthesis. − Specifically, the Stoltz group reported an elegant approach to scabrolide A ( 2 ) based on late-stage formation of the seven-membered ring by a sequence of intramolecular enone/alkenylsilane [2 + 2] cycloaddition, followed by a mercury-mediated Tamao–Fleming type oxidation and a strain-driven oxidative fragmentation …”