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

Abstract

Described herein are the first total syntheses of the nor-furanocembranoid natural products (+)-ineleganolide (1) and (−)-sinulochmodin C (2). The synthetic strategy is predicated on a transannular Michael reaction that provides both natural products from a common macrocyclic intermediate and leverages a diastereoselective radical cyclization to furnish a key bicyclic lactone. The latter is further advanced to a macrocyclic precursor via a Nozaki–Hiyama–Kishi cyclization and a one-pot furan oxidation/oxa-Michael cascade. Unexpected stereochemical nuances that guided the evolution and eventual completion of the total synthesis are discussed.

Total synthesis of (−)-scabrolide A and (−)-yonarolide

“…As mentioned in the introduction, the past three years have seen several elegant syntheses of both the Sinularia-derived polycylclic cembranoid and norcembranoid natural products. [9][10][11][12]49 In addition to total syntheses, a number of new members of the polycyclic furanobutenolide-derived norcembranoid family have been isolated 1d,e and characterized (including the structural reassignment of flagship member scabrolide B). Despite the fact that these molecules have been known for decades, the recent explosion in total syntheses and the continuing isolation of new members indicates that this class of natural products remains a relevant and exciting area of research.…”

“…The Fürstner group published an elegant total synthesis of both scabrolide A (1) and the (incorrectly) reported structure of scabrolide B (12). 9 Additionally, the Wood group very recently reported the first successful total syntheses of ineleganolide (8) and sinulochmodin C (3), 10 a ground-breaking achievement within this field. Finally, recent publications by the Romo group as well as our group detailed the successful syntheses of the closely related C 20 cembranoids ramesewaralide 11 and havellockate, 12 respectively.…”

Structure‐Unit‐Based Total Synthesis of (−)‐Sinulochmodin C

“…The ether linkage in sinulochmodin C is fused to two quaternary carbon atoms, posing significant steric hindrance and ring strain. Although the total synthesis of sinulochmodin C has been completed elegantly by Wood in a biomimetic approach, [14] alternative strategies specifically to address the oxo-bridged [7,6,5,5] ring system are still of interest for the challengeable norcembranoid diterpenoids. As part of our program towards the synthesis of polycyclic and cagelike natural products and their analogues, [16] we recently started a research program to construct the [7,6,5,5] skeleton presented in sinulochmodin C related diterpenes.…”

“…[3] Numerous elegant methodologies to synthesize the polycyclic ring system in this sub-type of norcembranoids have been developed, including, chronologically, model studies on anodic oxidative cyclization by Tang and Moeller, [4] an intermolecular Diels-Alder reaction to con-struct the tricyclic lactone (highlighted rings in yonarolide) by Ito and co-workers, [5] biomimetic semisyntheses of 1 and 4 starting from episinuleptolide (5) by Li and Pattenden, [6] radical cyclization to prepare the tetrahydrofuran fused tricyclic lactone by Vanderwal and co-workers, [7] strategies developed by the Stoltz research group, [8] including an intramolecular cyclopropanation-Cope rearrangement cascade, [8a] a tandem translactonization-Cope rearrangement to synthesize the ineleganolide (4, Figure 1) [6,7,5,5] tetracyclic core, [8b] and later a Diels-Alder cyclization to assemble the tricyclic lactone, [8e] an intramolecular 1,3-dipolar cycloaddition to fuse the [6,5,5] tricyclic framework by Liang and co-workers, [9] and most recently, a Diels-Alder lactonization organocascade to build the tricyclic lactone by Romo and co-workers. [10] Synthetic studies towards the scabroliderelated norcembranoids culminated in recent total synthesis of scabrolide A by the research groups of Stoltz, [11] Fürstner [12] and Sarlah, [13] sinulochmodin C by Tuccinardi and Wood, [14] and closely related ineleganolide by the groups of Wood [14] and Stoltz. [15] The diterpenoid sinulochmodin C (1) and its congener ineleganolide (4) are among the most synthetically challenging targets owing to the presence of a transannular ether bridge β-keto tetrahydrofuran moiety.…”

“…The ether linkage in sinulochmodin C is fused to two quaternary carbon atoms, posing significant steric hindrance and ring strain. Although the total synthesis of sinulochmodin C has been completed elegantly by Wood in a biomimetic approach, [14] alternative strategies specifically to address the oxo‐bridged [7,6,5,5] ring system are still of interest for the challengeable norcembranoid diterpenoids.…”