A dual-catalysis approach to enantioselective [2 + 2] photocycloadditions using visible light

Abstract

In contrast to the wealth of catalytic systems that are available to control the stereochemistry of thermally promoted cycloadditions, few similarly effective methods exist for the stereocontrol of photochemical cycloadditions. A major unsolved challenge in the design of enantioselective catalytic photocycloaddition reactions has been the difficulty of controlling racemic background reactions that occur by direct photoexcitation of substrates while unbound to catalyst. Here, we describe a strategy for eliminating the racemic background reaction in asymmetric [2 + 2] photocycloadditions of α,β-unsaturated ketones to the corresponding cyclobutanes by using a dual-catalyst system consisting of a visible light-absorbing transition-metal photocatalyst and a stereocontrolling Lewis acid cocatalyst. The independence of these two catalysts enables broader scope, greater stereochemical flexibility, and better efficiency than previously reported methods for enantioselective photochemical cycloadditions.

Fig. 1. Design plan for enantioselective catalytic [2+2] cycloaddition reactions

(A) Competing enantioselective and racemic pathways in asymmetric photocycloadditions. (B) Ru(bpy)₃²⁺-catalyzed [2+2] cycloaddition reaction using visible light. bpy = 2,2’-bipyridine, MLCT = metal-to-ligand charge transfer. (C) Survey of chiral Lewis acid co-catalysts. OTf = trifluoromethanesulfonate. ^*Yields determined by ¹H NMR analysis using an internal standard. ^†Optimized conditions: 5 equiv. methyl vinyl ketone, 5 mol% Ru(bpy)₃Cl₂, 10 mol% Lewis acid, 20 mol% ligand, 0.2 M MeCN, 2 h. ^‡Reaction conducted at −20 °C for 15 h.

Fig. 2. Control experiments for the asymmetric visible light photocatalyzed [2+2] cycloaddition

(A) Omission of any reaction component results in no [2+2] cycloaddition. (B) Enantioselectivity of the photocatalyzed [2+2] cycloaddition is not affected by the concentration of chiral Lewis acid catalyst.

Fig. 3. Substrate scope of the enantioselective [2+2] cycloaddition reaction

Diastereomer ratios measured by ¹H NMR analysis of the unpurified reaction mixtures. Reported yields represent total isolated yields of the 1,2-cis and 1,2-trans isomers. For each entry, yields represent the average of two reproducible experiments. ^*Reaction conducted for 24 h.

Fig. 4. Diastereocontrol through independent modification of chiral Lewis acid structure

(A) Stereoselective access to 1,2-cis cycloadducts 3 through reduction of chiral Schiff base ligand 8 to amine 9. (B) Substrate scope of 1,2-cis cyclobutanes via enantioselective [2+2] photocycloaddition. Diastereomer ratios measured by ¹H NMR analysis of the unpurified reaction mixtures. Reported yields represent total isolated yields of the 1,2-cis and 1,2-trans isomers. For each entry, yields represent the average of two reproducible experiments. ^*Reaction conducted for 14 h. ^†Reaction conducted for 36 h. ^‡Reaction conducted at 37 °C. ^§Isolated yield of only cis isomer. rt, room temperature.