The Development of the Asymmetric Morita—Baylis—Hillman Reaction Catalyzed by Chiral Brønsted Acids

Abstract

This report describes the development of a chiral Brønsted acid-catalyzed asymmetric MoritaBaylis À Hillman (MBH) reaction of cyclohexenone with aldehydes. During the course of our studies on chiral Lewis acid-promoted MBH reactions, we discovered that chiral binaphthol-derived Brønsted acids serve as promoters of the asymmetric MBH reaction. We propose that the phosphonium enolate of cyclohexenone is stabilized via hydrogen-bonding with the binaphthol-derived Brønsted acid, creating a chiral nucleophile. A practical and efficient set of conditions was developed using stoichiometric PEt 3 as the nucleophilic promoter and catalytic amounts of a binaphthol-derived Brønsted acid to effect the reaction of cyclohexenone with various aliphatic and aromatic aldehydes in good yields and enantiomeric excesses (up to 96% ee).

Asymmetric Catalysis by Chiral Hydrogen‐Bond Donors

“…The ability of this species to function as a chiral H-bond donor was discovered by McDougal and Schaus in the context of enantioselective Morita-Baylis-Hillman reactions (Scheme 18). [72] The observation that acidic additives such as phenols accelerate Morita-Baylis-Hillman reactions constitutes important precedent for this work. [73] Optimization of the binaphthol structure revealed that arene-substituted octahydro(BINOL) derivatives such as 16 afforded high enantioselectivity for reactions of a range of aldehyde partners with 2-cyclohexenone in the presence of triethylphosphine.…”

Recent Progress in Chiral Brønsted Acid Catalysis

“…[48,49] Saturation of the BINOL derivative and introduction of bulky substituents on the 3,3'-positions are essential for the excellent enantioselectivity. They proposed that the phosphonium enolate of cyclohexanone is stabilized via a hydrogen bond with the binaphtholderived Brønsted acid, creating a chiral nucleophile.…”

Synthesis of Enantiopure (S)‐Indolylglycine by Organocatalyzed Friedel–Crafts Alkylation of Indole

“…(R)-3,3Ј-Bis(benzhydryl)-octahydro-1,1Ј-binaphthol (11) was prepared by reaction of (R)-octahydro-1,1Ј-binaphthol [22] with benzhydryl chloride. [23] Phosphorylation of 11 (0.120 g, 0.19 mmol) was performed with POCl 3 (37 mL, 0.40 mmol) in pyridine (0.6 mL) over 1 h at 90°C.…”