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)
We utilize ab initio quantum mechanics calculations to evaluate a range of plausible mechanistic pathways for the unexpected formation of a [6−4−4] ring system from an enone− olefin photocycloaddition in the synthesis of (−)-scabrolide A, previously reported by our group. We present a mechanistic analysis that is consistent with all current experimental observations, including the photoexcitation, the C−C bond formation, and the associated chemo-and diastereoselectivity.
Strempeliopidine is a member of the monoterpenoid bisindole alkaloid family, a class of natural products that have been shown to elicit an array of biological responses including modulating protein−protein interactions in human cancer cells. Our synthesis of strempeliopidine leverages palladium-catalyzed decarboxylative asymmetric allylic alkylations to install the requisite allcarbon quaternary centers found in each of the two monomeric natural products, aspidospermidine and eburnamine. Initial studies employing Suzuki−Miyaura cross-coupling followed by diastereoselective hydrogenation provided evidence for a structural reassignment of the natural product. Our final synthetic sequence employs a diastereoselective Petasis borono−Mannich reaction to couple eburnamine to a trifluoroborate aspidospermidine derivative. These convergent approaches enabled the synthesis of eight diastereomers of this heterodimer and offer support for the reassignment of the absolute configuration of strempeliopidine.
The complete account of the total syntheses of scabrolide A and yonarolide are disclosed. This article describes an initial approach involiving a bio-inspired macrocyclization/transannular Diels–Alder cascade, which ultimately failed due...
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