Enantioselective synthesis of hindered cyclic dialkyl ethers via catalytic oxa-Michael/Michael desymmetrization

Abstract

An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and α,β-unsaturated aldehydes provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the concomitant formation of four contiguous stereocenters in a single step. The highly functionalized bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection and serve as valuable precursors for further manipulation.

Asymmetric transformations of achiral 2,5-cyclohexadienones

“…More recently, Johnson 35 reported an interesting extension of the desymmetrization reported by Hayashi and Gaunt. In this case, the chiral enamine responsible for the desymmetrization was generated by an initial asymmetric oxa-Michael addition of quinols 101 into α,β-unsaturated aldehydes (Scheme 20).…”

Organocatalytic enantioselective desymmetrisation

“…201 Electron-neutral aromatic R 2 substituents provided the best results, while electron-rich, strongly electron-deficient or heteroaromatic groups caused a decrease in diastereoselectivity to 5 : 1-9 : 1 dr. 201 Electron-neutral aromatic R 2 substituents provided the best results, while electron-rich, strongly electron-deficient or heteroaromatic groups caused a decrease in diastereoselectivity to 5 : 1-9 : 1 dr.…”

Enantioselective Kinetic Resolution/Desymmetrization of Para‐Quinols: A Case Study in Boronic‐Acid‐Directed Phosphoric Acid Catalysis

“…Because the CAPT fluorination chemistry requires the use of heterogeneous conditions, support for this hypothesis derived from the observation of hemiester formation under conditions lacking the insoluble components, with no test for kinetic relevance of the intermediate possible. [6][7][8][9] The homogeneity of the reaction mixtures allowed us to examine the kinetic relevance of alcoholÀ boronic acid condensation. By examining oxa-Michael addition rather than fluorination, the insoluble reagent could be excluded.…”

“…As such, we developed a chiral phosphoric acid-catalyzed kinetic resolution /desymmetrization of quinol derivatives ( Figure 1C). [6][7][8][9] The homogeneity of the reaction mixtures allowed us to examine the kinetic relevance of alcoholÀ boronic acid condensation. These studies have enabled the gathering of some new insights into the nature of reactions involving boronicÀ acid-directed chiral phosphoric acid catalysis.…”