Evolution of an oxidative dearomatization enabled total synthesis of vinigrol

Abstract

The evolution of the synthetic strategy resulting in a total synthesis of vinigrol is presented. Oxidative dearomatization/intramolecular Diels-Alder cycloaddition has served as the successful cornerstone for all of the approaches. Extensive radical cyclization efforts to form the tetracyclic core resulted in interesting and surprising reaction outcomes, none of which could be advanced to vinigrol. These cyclization obstacles were successfully overcome by using Heck instead of radical cyclizations. The total synthesis features a trifluoroethyl ether protecting group being used for the first time in organic synthesis. The logic of its selection and the group’s importance beyond protecting the C8a hydroxyl group is presented along with a discussion of strategies for its removal. Because of the compact tetracyclic cage the route is built around many unusual reaction observations and solutions have emerged. For example, a first of its kind Grob fragmentation reaction featuring a trifluoroethyl leaving group has been uncovered, interesting interrupted selenium dioxide allylic oxidations have been observed as well as intriguing catalyst and counterion dependent directed hydrogenations.

Copper‐Catalyzed Chemoselective O‐Aroylation of Phenolic Oxime Ethers with Aryl Aldehydes

“…3, Scheme 2). The selective protection of hydroxy functional group in the acetophenone O ‐methyl oxime is an important transformation in the organic synthesis of biologically active natural products [20] . Further, we explored the application of developed approach on gram‐scale under optimized reaction conditions which furnished the desired compounds 3 aa , 3 ae and 3 bg in quantitative yields (table 4).…”

Oxidative Dearomatization of Phenols and Polycyclic Aromatics with Hydrogen Peroxide Triggered by Heterogeneous Sulfonic Acids

“…The quinone motif is found in a myriad of functional molecules, both of synthetic, technological and societal interest. [1][2][3][4][5][6] For this reason, several methods for the preparation of these derivatives have been developed. Among these, the oxidative dearomatization of bare aromatics represents the most appalling route, [1,[7][8] and that of phenols and naphthols an easier yet sensible target.…”

Structural Basis for Selectivity in Flavin-Dependent Monooxygenase-Catalyzed Oxidative Dearomatization

“…3 A suite of I(III), I(V), Cu(I) and Pb(IV) reagents have been developed for oxidative dearomatization. [4][5][6][7][8] In these reactions, a phenolic substrate is activated as an electrophile, which is intercepted by an oxygen nucleophile in either an intra-or intermolecular fashion. 9 Achieving high levels of selectivity in this reaction is desirable as site-selectivity is often substrate rather than catalyst-controlled.…”