Versatile Construction of 6-Substituted cis-2,8-Dioxabicyclo[3.3.0]octan-3-ones: Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C

Abstract

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids: cheloviolenes A and B and dendrillolide C.

Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C via Convergent Fragment Coupling Using a Tertiary Carbon Radical

“…The reaction was allowed to cool to rt and transferred to a separatory funnel and extracted with Et 2 O (3 × 5 mL). The combined organic layers were dried over 31 Preparation of Methyl Oxalate S7. A round-bottom flask was charged with 54 (560 mg, 2.7 mmol, 1.0 equiv), DMAP (33 mg, 0.27 mmol, 0.1 equiv), dichloromethane (13 mL, 0.20 M), and a stir bar under ambient atmosphere.…”

Light‐Mediated Formal Radical Deoxyfluorination of Tertiary Alcohols through Selective Single‐Electron Oxidation with TEDA2+.

“…Light-mediated methodologies have become popular strategies to initiate radical reactions, becauset hey allow for am ild and controlled generation of open-shell species. [12] Therefore, we wondered if it could be possible to access TEDA 2+ + C using visible light, and then have it selectively reactw ith as uitable radicalprecursor,for example, oxalate salts, which can be readily accessed from the corresponding alcohols, [13] to achievet he formal deoxyfluorination of tertiary alcohols under very mild conditions ( Figure 1B). Cesium oxalate 1 presents three possible reactive sites towards TEDA 2+ + C:a )ano xalate anion,b )ana ctivated benzylic CÀ Hb ond, and c) an aryl moiety.T EDA 2+ + C has been shown to engage in HATr eactions with benzylic CÀHb onds, [9a, b, d-g] as well as to undergo radical addition to aryl groups to form CÀN bonds.…”

“…Furthermore, mestanolone-derivedp roduct 11 [15] showcases the improved functional-group tolerance of our protocol, because if DAST would be used in this reaction, the carbonyl group would be converted to the corresponding gem-difluoride species. Substrates derived from b-aminoa lcohols also werer eadily fluorinated using our methodology (13)(14). Substrate 14,derived from enantiomerically pure l-phenylalanine, was obtained with complete stereoretention.…”

Radicals in natural product synthesis

“…The syntheses of (−)-aplyviolene ( 112 ), (+)-cheloviolene A ( 114 ) & B ( 113 ), and (+)-dendrillolide C ( 111 ) were produced by the Overman group. 37,38 These natural products are marine sponge-derived diterpenes with biological activities that remain unexplored. The conserved 7/5-fused bicyclic core in addition to the vicinal stereocenters between the 5-membered rings provide an challenging target for the development of synthetic methods.…”