Asymmetric Total Synthesis of the Rearranged Steroid Phomarol Enabled by a Biomimetic S_N2′ Cyclization

Abstract

Phomarol is a structurally unusual 1(10 → 19)abeosteroid with a pseudo-symmetrical cycloheptene-1,3-diol motif, an aromatic B ring, and a densely functionalized tetrahydropyran ring. Herein, we report a 13-step synthesis of this natural product from inexpensive sitolactone by means of a convergent fragmentcoupling approach. Key transformations include a diastereoselective allylboration, a decarboxylative elimination, a Schonecker− Baran C−H hydroxylation, a biomimetic S N 2′ cyclization, and a late-stage 6π electrocyclization. Mechanistic studies indicate that the pivotal formation of the tetrahydropyran ring occurs via a silyl migration/intramolecular S N 2′ cyclization cascade rather than via an epoxide-opening process.

Strategic convergent synthesis en route to Veratrum steroidal alkaloids

“…Inspired by semi-synthesis which often begins from the NPs possessing the skeleton of the target product, we envision that the preparation of the necessary fragments using commercially available feedstocks 71 ( e.g. santonin, 72 sclareolide, 73 cedrol, 74 sitolactone, 75 etc .) may reduce the step count and eventually improve the synthetic efficiency of convergent synthesis (Scheme 5B).…”

Total Synthesis of abeo-Steroids via Cycloaddition Strategy

“…In 2021, our group reported the first asymmetric total synthesis of phomarol . Very recently, Gui’s group achieved the second total synthesis of this novel target molecule . Our synthetic approach to phomarol was based on a very mild acid-promoted type I [5 + 2] cycloaddition for assembling the rearranged A/B ring system and a subsequent regio- and chemoselective C–O bond cleavage and spontaneous aromatization cascade to generate the aromatic B ring.…”

Exploring the synthetic potential of epoxide ring opening reactions toward the synthesis of alkaloids and terpenoids: a review

“… 17 Vinyl epoxides are important synthetic precursors in organic synthesis 18 as they lead towards the synthesis of (−)-(4 R ,5 R )-Muricatacin (a natural acetogenin) via regio or stereoselective ring opening reaction of epoxide. 19 Syntheses of numerous biological active compounds such as Sphingofungin, 20 Zoanthenol, 21 marine ladder polyethers, 22 Zampanolide, 23 epi -Muscarine, 24 Molestin E, 25 (−)-Epicoccin G and (−)-Rostratin A, 26 homoisoflavonoids, 27 Chlorotonils, 28 Lingzhiol, 29 Phomarol, 30 Isoandrographolide, 31 Citrinadins, 32 Isosilybin, 33 polyester, 34 Mupirocin 35 and Bisfuranoxide 36 etc. have been accomplished by involving epoxide chemistry.…”