The Total Synthesis of (−)-Scabrolide A

Abstract

The first total synthesis of the norcembranoid diterpenoid scabrolide A is disclosed. The route begins with the synthesis of two chiral pool-derived fragments, which undergo a convergent coupling to expediently introduce all 19 carbon atoms of the natural product. An intramolecular Diels-Alder reaction and an enone-olefin cycloaddition/fragmentation sequence are then employed to construct the fused [5-6-7] linear carbocyclic core of the molecule and to complete the total synthesis. File list (3) download file view on ChemRxiv ScabrolideAManuscriptFinalDraft.pdf (479.10 KiB) download file view on ChemRxiv TOCGraphic.pdf (129.56 KiB) download file view on ChemRxiv ScabrolideSIFinal.pdf (13.10 MiB)

Bridging the gap between natural product synthesis and drug discovery

“…The bioactivity and complexity of these molecules has stimulated interest for several synthetic studies including those toward rameswaralide (56), 42 ineleganolide (55), 43 scabrolides A & B (52), 44 and yonarolide (51). 45 In addition, biomimetic strategies toward ineleganolide (55) and sinulochmodin C (54) 46 were reported.…”

“…45 In addition, biomimetic strategies toward ineleganolide (55) and sinulochmodin C (54) 46 were reported. However, despite these extensive synthetic efforts, only the biomimetic synthesis of ineleganolide ( 55) and sinulochmodin C ( 54) by Pattenden 46 and the recent de novo synthesis of scabrolide A (52) by the Stoltz group 44 were successful. A desire to gain further SAR information for this bioactive Sinularia family of natural products while also gaining access to further quantities of these rare natural products made them an ideal opportunity to further explore and apply our PDR strategy as described below.…”

Total Syntheses of Scabrolide A and Nominal Scabrolide B

“… 4 We can hence confirm that scabrolide A ( 2 ) is the thermodynamic product and the assigned structure is correct, as had already been shown by the Stoltz group. 12 Moreover, the ease of isomerization of compound 1 into 2 lends credence to the proposed biosynthesis; 2 , 3 at the same time, however, it reduces the chance to extract compound 1 from a Sinularia species in a future isolation campaign as a proper natural product, even though this possibility does exist. 41 The question as to the correct structure of scabrolide B, however, which differs from synthetic 1 as well as from the C12-epimer 12- epi - 1 , has to remain open at this point; all chiral centers and even the constitution of the compound isolated from the natural source need to be carefully reassessed.…”

“…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 …”

Chemoselective Cleavage of Si–C(sp3) Bonds in Unactivated Tetraalkylsilanes Using Iodine Tris(trifluoroacetate)

“…A notable exception is the Tamao–Fleming oxidation, which transforms alkylsilanes into the corresponding alcohols, typically using peroxides and fluoride activators. These protocols have often been employed in the total synthesis of complex natural products . Nevertheless, to facilitate oxidation of the silyl groups, the silicon atom must carry at least one heteroatomic functional group or aryl/allyl substituent, which can be selectively converted into a heteroatomic functional group through electrophilic transformations .…”