Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin

• DOI: 10.1021/jacs.1c03336
• Publication Date: 2021-05-04T22:23:33Z
• Authors: Paul D. Scesa; Lyndon M. West; Stéphane P. Roche
• Keywords: Conformational isomerism; Moiety; Furan; Alkene; Atropisomer

Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (e.g. plumarellide, verrillin, bielschowskysin). These architecturally complex metabolites thought originate from site-selective oxidation macrocycle backbone series intricate transannular reactions. Yet development common biomimetic route has been hampered by lack synthetic methods for pivotal furan dearomatization in regio- stereoselective manner. To address these shortcomings, concise strategy epoxidation followed kinetically controlled is reported. The surprising switch facial α:β-discrimination observed most strained E-acerosolide versus E-deoxypukalide E-bipinnatin J derived macrocycles rationalized variation 3D conformational landscape between macrocyclic scaffolds. A careful analysis VT-NMR NOESY experiments at low temperature was supported DFT calculations characterize equilibrating conformers. shift topology associated with swing butenolide ring general agreement reversal β-selectivity epoxidation. We also describe downstream functionalization FBC-macrocycles how C-7 epoxide configuration retentively translated C-3 stereogenicity dearomatized products under kinetic control secure requisite 3S,7S,8S configurations bielschowskysin synthesis. Unlike previously speculated, our results suggest that bearing E-(Δ7,8)-alkene moiety may stand as true several other natural this class.