Asymmetric Total Synthesis of the Rearranged Steroid Phomarol Enabled by a Biomimetic SN2' Cyclization

Xudong Wang; Ganlin Huang; Yun Wang; Jinghan Gui

doi:10.1021/jacs.3c02817

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

J Am Chem Soc. 2023 Apr 26;145(16):9354-9363. doi: 10.1021/jacs.3c02817. Epub 2023 Apr 12.

Authors

Xudong Wang¹, Ganlin Huang¹, Yun Wang¹, Jinghan Gui¹

Affiliation

¹ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

PMID: 37043285
DOI: 10.1021/jacs.3c02817

Abstract

Phomarol is a structurally unusual 1(10 → 19)abeo-steroid 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 fragment-coupling approach. Key transformations include a diastereoselective allylboration, a decarboxylative elimination, a Schönecker-Baran C-H hydroxylation, a biomimetic S_N2' 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_N2' cyclization cascade rather than via an epoxide-opening process.