Chiral Brønsted acid-controlled intermolecular asymmetric [2 + 2] photocycloadditions

Abstract

Control over the stereochemistry of excited-state photoreactions remains a significant challenge in organic synthesis. Recently, it has become recognized that the photophysical properties of simple organic substrates can be altered upon coordination to Lewis acid catalysts, and that these changes can be exploited in the design of highly enantioselective catalytic photoreactions. Chromophore activation strategies, wherein simple organic substrates are activated towards photoexcitation upon binding to a Lewis acid catalyst, rank among the most successful asymmetric photoreactions. Herein, we show that chiral Brønsted acids can also catalyze asymmetric excited-state photoreactions by chromophore activation. This principle is demonstrated in the context of a highly enantio- and diastereoselective [2+2] photocycloaddition catalyzed by a chiral phosphoramide organocatalyst. Notably, the cyclobutane products arising from this method feature a trans-cis stereochemistry that is complementary to other enantioselective catalytic [2+2] photocycloadditions reported to date.

Fig. 1. Asymmetric acid-catalyzed photoreactions.

a Intramolecular [2 + 2] photocycloadditions via Lewis acid-catalyzed chromophore activation; LA = Lewis acid. b Intermolecular [2 + 2] photocycloadditions via Lewis acid-catalyzed triplet activation. c Intermolecular [2 + 2] photocycloadditions via Bronsted acid-catalyzed chromophore activation. HA = Brønsted acid.

Fig. 2. Optimization studies.

^aYields and diastereomer ratios determined by ¹H NMR spectroscopy. ^bEnantiomeric excess of the major diastereomer determined by chiral HPLC. ^cRatio of trans–cis isomer to trans–trans isomer. ^dConducted at room temperature. ^eConducted in the dark.

Fig. 3. Scope studies.

Reactions conducted using 1 equiv 2-acyl imidazole, 10 equiv alkene, 20 mol% AC-3 in toluene, irradiating for 14 h with a Kessil H150 LED unless otherwise noted. Yields represent the isolated yield of both diastereomers. Enantiomeric excess of the major diastereomer determined by chiral HPLC. ^aConducted for 24 h. ^bConducted with 40 mol% acid catalyst AC-3. ^cConducted in CH₂Cl₂.

Fig. 4. Auxiliary cleavage.

The imidazolyl group of the cycloadduct is readily cleaved in good yield with retention of enantioselectivity.

Fig. 5. Mechanistic studies.

a Ultraviolet-visible spectra of 1 and AC-3 in CH₂Cl₂. b X-ray crystal structure of acid-bound substrate. c Binding depiction of acid-bound substrate. d HOMO(π) and LUMO(π*) of 1 and 1–H⁺–AC-4.

Fig. 6. Effect of structurally diverse Brønsted acids on the cycloaddition.

Yields and diastereomer ratios determined by ¹H NMR spectroscopy.