Total Syntheses of Scabrolide A and Nominal Scabrolide B

Abstract

The marine natural product scabrolide A was obtained by isomerization of the vinylogous 1,4-diketone entity of nominal scabrolide B as the purported pivot point of the biosynthesis of these polycyclic norcembranoids. Despite the success of this maneuver, the latter compound itself turned out not to be identical with the natural product of that name. The key steps en route to the carbocyclic core of these targets were a [2,3]-sigmatropic rearrangement of an allylic sulfur ylide to forge the overcrowded C12–C13 bond, an RCM reaction to close the congested central six-membered ring, and a hydroxy-directed epoxidation/epoxide opening/isomerization sequence to set the “umpoled” 1,4-dicarbonyl motif and the correct angular configuration at C12.

Total Syntheses of Scabrolide A and Yonarolide

“…These compounds also possess noteworthy structural features, including a unique all- cis stereochemical arrangement surrounding the central cyclohexene core and a rich oxidative decoration of the carbon framework. Both 1 and 2 have resisted synthetic efforts for decades; only recently have the Stoltz and Fürstner laboratories disclosed their approaches leading to the first total syntheses of (−)-scabrolide A ( 2 ) …”

“…Ultimately, TASF/H 2 O afforded (−)-scabrolide A ( 2 ) in 42% yield through concurrent deprotection/isomerization. Spectroscopic analysis of our synthetic sample matched spectral data from the natural isolate, as well as data provided by Fürstner and Stoltz . Our synthetic strategy enabled preparation of (−)-scabrolide A ( 2 ) in batches >20 mg at a time.…”

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.…”

Asymmetric Total Synthesis of Neobraclactone C

“…Oxidation of the hemiacetal with the Fétizon reagent furnished lactone 18 in a 88% yield. Compound 18 was then epoxidated with m -CPBA, followed by an eliminative ring-opening reaction, giving intermediate 20 in good yield . Finally, a Dess–Martin oxidation of the alcohol offered α,β-unsaturated ketone 6 , the right wing of the molecule, in a 90% yield on a gram scale.…”