Chiral 1,3,2-Oxazaborolidine Catalysts for Enantioselective Photochemical Reactions

Abstract

Asymmetric synthesis has posed a significant challenge to organic chemists for over a century. Several strategies have been developed to synthesize enantiomerically enriched compounds, which are ubiquitous in the pharmaceutical and agrochemical industries. While many organometallic and organic catalysts have been found to mediate thermal enantioselective reactions, the field of photochemistry lacks similar depth. Recently, chiral 1,3,2-oxazaborolidines have made the transition from Lewis acids that were exclusively applied to thermal reactions to catalysts for enantioselective photochemical reactions. Due to their modular structure, various 1,3,2-oxazaborolidines are readily available and can be easily fitted to a given chemical transformation. Their use holds great promise for future developments in photochemistry. This Account gives an overview of the substrate classes that are known to undergo enantioselective photochemical transformations in the presence of chiral 1,3,2-oxazaborolidines and touches on the catalytic mode of action, on the proposed enantiodifferentiation mechanism, as well as on recent computational studies.Based on the discovery that the presence of Lewis acids enhances the efficiency of coumarin [2 + 2] photocycloadditions, chiral 1,3,2-oxazaborolidines were applied in 2010 for the first time to prepare enantiomerically enriched photoproducts. These Lewis acids were then successfully used in intramolecular [2 + 2] photocycloaddition reactions of 1-alkenoyl-5,6-dihydro-4-pyridones and 3-alkenyloxy-2-cycloalkenones. In the course of this work, it became evident that the chiral 1,3,2-oxazaborolidine must be tailored to the specific reaction; it was shown that both inter- and intramolecular [2 + 2] photocycloadditions of cyclic enones can be conducted enantioselectively, but the aryl rings of the chiral Lewis acids require different substitution patterns. In all [2 + 2] photocycloaddition reactions in which chiral 1,3,2-oxazaborolidines were used as catalysts, the catalyst loading could not be decreased below 50 mol % without sacrificing enantioselectivity due to competitive racemic background reactions. To overcome this constraint, substrates that reacted exclusively when bound to an oxazaborolidine were tested, notably phenanthrene-9-carboxaldehydes and cyclohexa-2,4-dienones. The former substrate class underwent an ortho photocycloaddition, the latter an oxadi-π-methane rearrangement. Several new 1,3,2-oxazaborolidines were designed, and the products were obtained in high enantioselectivity with only 10 mol % of catalyst. Recently, an iridium-based triplet sensitizer was employed to facilitate enantioselective [2 + 2] photocycloadditions of cinnamates with 25 mol % of chiral 1,3,2-oxazaborolidine. In this case, the relatively low catalyst loading was possible because the oxazaborolidine-substrate complex exhibits a lower triplet energy and an improved electronic coupling compared to the uncomplexed substrate, allowing for a selective energy transfer.By synthetic and theoretical studies, it has become evident that chiral 1,3,2-oxazaborolidines are multifaceted catalysts: they change absorption behavior, alter energetic states, and induce chirality. While a diverse set of substrates has been shown to undergo enantioselective photochemical transformations in the presence of chiral 1,3,2-oxazaborolidines either through direct excitation or through triplet sensitization, these catalysts took on different roles for different substrates. Based on the studies presented in this Account, it can be assumed that there are still more photochemical reactions and substrate classes that could profit from chiral 1,3,2-oxazaborolidines.

Figure 1

Structures of some historically relevant 1,3,2-oxazaborolidines 1–4.

Scheme 1. Activation of Oxazaborolidines by Brønsted or Lewis Acids and the Use of Catalysts 6–8 in an Enantioselective Diels–Alder Reaction

Scheme 2. Lewis-Acid-Catalyzed [2 + 2] Photocycloaddition of 2,3-Dimethyl-2-butene and Coumarin 9, Furnishing rac-10

Scheme 3. Generation of Oxazaborolidine-Based Lewis Acid 8a by Condensation of l-Prolinol Derivative 12 and Boronic Acid 13 and Subsequent Activation of 14 by AlBr₃ to Prepare Lewis Acid 8b

Scheme 4. First Example of an Enantioselective [2 + 2] Photocycloaddition with a Chiral 1,3,2-Oxazaborolidine as Catalyst

Figure 2

(a) Proposed conformation of the oxazaborolidine–substrate complex 11a·8a. (b) Intermediate 16b of the [2 + 2] photocycloaddition of 11b.

Figure 3

Representative products 15 obtained by enantioselective [2 + 2] photocycloaddition of 4-substituted coumarins.

Scheme 5. Intramolecular [2 + 2] Photocycloaddition of 5,6-Dihydro-4-pyridones 17 in the Presence of Lewis Acid 8a

Figure 4

UV/vis spectra of 17a in the absence and presence of EtAlCl₂ as the Lewis acid and corresponding species with selected ¹³C NMR signals. Reproduced with permission from ref (1). Copyright 2015 American Chemical Society.

Scheme 6. Intramolecular [2 + 2] Photocycloaddition of 3-Alkenyloxy-2-cycloalkenones 19 in the Presence of Lewis Acid 8b

Figure 5

Structures of 1,3,2-oxazaborolidine Lewis acid catalysts 8c–8e.

Scheme 7. Enantioselective Intermolecular [2 + 2] Photocycloadditions of Cyclic Enones with Simple Olefins, Catalyzed by Oxazaborolidine 8c

Scheme 8. Enantioselective Intramolecular [2 + 2] Photocycloadditions of Cyclic 3-Substituted 2-Alkenones, Catalyzed by Oxazaborolidine 8c

Figure 6

UV/vis spectra of phenanthrene-9-carboxaldehyde (25a, Scheme 9) in the absence and presence of EtAlCl₂ as Lewis acid. Adapted with permission from ref (3). Copyright 2018 John Wiley and Sons.

Scheme 9. Enantioselective ortho Photocycloaddition of Phenanthrene-9-carboxaldehyde (25a) with 2,3-Dimethylbut-2-ene, Catalyzed by Oxazaborolidine 8d

Figure 7

Exemplary products of the studied enantioselective ortho photocycloaddition.

Scheme 10. Combining Oxazaborolidine Catalyst 8b′ (Activation with Tf₂NH instead of AlBr₃) and an Iridium Sensitizer to Accomplish an Enantioselective [2 + 2] Photocycloaddition of Cinnamate 27a and Styrene

Figure 8

Exemplary products 28b–e of the iridium-sensitized [2 + 2] photocycloaddition of cinnamates.

Scheme 11. Photoinduced Oxadi-π-methane Rearrangement of Cyclohexa-2,4-dienone 29a to Bicyclo[3.1.0]hexenone 30a Catalyzed by Novel Oxazaborolidine Catalyst 8e

Figure 9

(a) Two-point coordination of a generic 1,3,2-oxazaborolidine Lewis acid (8) to 2-methylacrolein (32) and ethyl acrylate (33). (b) Structure of isolated benzylidenacetone–BF₃ complex 34.

Figure 10

Qualitative, simplified energy diagrams highlighting calculated photophysical processes^, of (a) 5,6-dihydro-4-pyridones and (b) coumarins in the absence and presence of Lewis acid (energy levels not to scale).