A new catalyst for asymmetric [2+2] photocycloadditions
Some of the most successful strategies in asymmetric photochemistry employ Lewis acids as chiral catalysts. Here, we show that chiral Brønsted acids can control the stereochemistry of [2+2] photocycloadditions, affording a new class of cyclobutane products.
The Yoon group has a longstanding interest in developing enantioselective photoreactions. When designing asymmetric photochemical methodologies we think about two key criteria which must be satisfied to achieve high levels of enantioselectivity: (1) the substrate must exist in a well-defined chiral environment upon binding to the chiral catalyst, and (2) the catalyst–substrate interaction must confer a kinetic advantage to the photoreaction.1 While the first requirement is a challenge encountered both in photochemical and thermal reactions, the second is especially relevant in photochemistry and concerns managing racemic background photoreactions. Due to the high reactivity and short lifetimes of excited-state organic molecules, it is challenging to confer a kinetic advantage to the chiral catalyst-bound substrate relative to the unbound substrate. When using a sub-stoichiometric loading of the chiral catalyst, both catalyst-bound and catalyst-unbound substrate will be present in the reaction, and both excited-state species will react at similar rates, the latter leading to racemic product. To circumvent this problem, several methods have been developed which enable selective excitation of the chiral catalyst-bound substrate, thus minimizing racemic background photoreactions.
Originally developed by the Bach group, “chromophore activation” has been highly successful in the development of asymmetric photocatalytic reactions.2 Under this regime, a chiral Lewis acid catalyst is employed to bind to a Lewis basic substrate. Upon binding, the absorption of the substrate is red shifted. In this way, the substrate (chromophore) is activated towards excitation and can be selectively excited by the careful selection of a light source which emits light that matches the absorption of the catalyst-bound substrate, but not the unbound substrate.
Our group has developed a mechanistically distinctive strategy that we have termed “triplet activation”.3 In this approach, chiral Lewis acid coordination lowers the triplet energy of organic substrates, allowing for their selective activation by a triplet sensitizer over unbound substrate molecules. While fundamentally distinct, both strategies use chiral Lewis acids to modify the excited-state properties of the substrate and preferentially activate the catalyst-bound complex, thereby minimizing racemic background reactivity.
At its outset, the goal of this project was to use Brønsted acids rather than Lewis acids in triplet activation. We previously published a paper showing that simple achiral acids increase the rate of triplet energy transfer from triplet sensitizers to Brønsted basic substrates, which subsequently undergo [2+2] photocycloadditions.4 We reasoned that if a chiral Brønsted acid was used instead, the [2+2] cycloaddition could be rendered enantioselective.
Of the chiral acids screened, BINOL-derived acids gave the best enantioselectivities when combined with iridium triplet sensitizers. After we found optimized conditions, we conducted control experiments and discovered that the photosensitizer was not necessary in the reaction, implying that the expected triplet activation mechanism was not operative. Instead, UV-Vis absorption experiments revealed that a chromophore activation mechanism was more likely. The emission of the light source overlapped well with the bound substrate, but poorly with the unbound substrate, consistent with minimal contribution from the racemic background reaction.
The unexpected mechanistic results underscore the similarities between the chromophore and triplet activation mechanisms. Both approaches use a catalyst to modify the photophysical properties of a substrate, allowing for its selective excitation in the presence of a chiral catalyst. The approaches also have key differences, including the requirement of one catalyst for chromophore activation (chiral acid catalyst) and two catalysts for triplet activation (chiral acid catalyst and triplet sensitizer). Further, while in chromophore activation, light source screening is often necessary to ensure that only the catalyst-bound substrate can be excited, in triplet activation, the photosensitizer identity is varied to ensure selective sensitization of the catalyst-bound substrate.
Finally, despite the supposed similarities between Lewis and Brønsted acids, we show that the different catalyst systems can produce different selectivities in the resulting products. While our previous studies with chiral Lewis acids afford a trans-trans cyclobutane isomer, the present work yields a previously inaccessible trans-cis isomer, underscoring the synthetic utility of the new catalyst system.
1 Cauble, D. F., Lynch, V. & Krische, M. J. Studies on the Enantioselective Catalysis of Photochemically Promoted Transformations: “Sensitizing Receptors” as Chiral Catalysts. J. Org. Chem. 68, 15–21 (2003).
2 Brenninger, C., Jolliffe, J. D. & Bach, T. Chromophore activation of α,β-unsaturated carbonyl compounds and its application to enantioselective photochemical reactions. Angew. Chem., Int. Ed. 57, 14338−14349 (2018).
3 Blum, T. R., Miller, Z. D., Bates, D. M., Guzei, I. A. & Yoon, T. P. Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer. Science 354, 1391−1395 (2016).
4 Sherbrook, E. M., Jung, H., Cho, D., Baik, M.-H. & Yoon, T. P. Brønsted acid catalysis of photosensitized cycloadditions. Chem. Sci. 11, 856–861 (2020).