Tale of Twisted Molecules. Atropselective Photoreactions: Taming Light Induced Asymmetric Transformations through Non-biaryl Atropisomers

Abstract

Photochemical transformations are a powerful tool in organic synthesis to access structurally complex and diverse synthetic building blocks. However, this great potential remains untapped in the mainstream synthetic community due to the challenges associated with stereocontrol originating from excited state(s). The finite lifetime of an excited state and nearly barrierless subsequent processes present significant challenges in manipulating the stereochemical outcome of a photochemical reaction. Several methodologies were developed to address this bottleneck including photoreactions in confined media and preorganization through noncovalent interactions resulting in stereoenhancement. Yet, stereocontrol in photochemical reactions that happen in solution in the absence of organized assemblies remained largely unaddressed. In an effort to develop a general and reliable methodology, our lab has been exploring non-biaryl atropisomers as an avenue to perform asymmetric phototransformations. Atropisomers are chiral molecules that arise due to the restricted rotation around a single bond (chiral axis) whose energy barrier to rotation is determined by nonbonding interactions (most often by steric hindrance) with appropriate substituents. Thus, atropisomeric substrates are chirally preorganized during the photochemical transformation and translate their chiral information to the expected photoproducts. This strategy, where "axial to point chirality transfer" occurs during the photochemical reaction, is a hybrid of the successful Curran's prochiral auxiliary approach involving atropisomers in thermal reactions and the Havinga's NEER principle (nonequilibrating excited-state rotamers) for photochemical transformations. We have investigated this strategy in order to probe various aspects such as regio-, enantio-, diastereo-, and chemoselectivity in several synthetically useful phototransformations including 6π-photocyclization, 4π-ring closure, Norrish-Yang photoreactions, Paternò-Büchi reaction, and [2 + 2]- and [5 + 2]-photocycloaddition. The investigations detailed in this Account clearly signify the scope of our strategy in accessing chirally enriched products during phototransformations. Simple design modifications such as tailoring the steric handle in atropisomers to hold reactive units resulted in permanently locked/traceless axial chirality in addition to incorporating multiple stereocenters in already complex scaffolds obtained from phototransformation. Further improvements allowed us to employ low energy visible light rather than high energy UV light without compromising the stereoenrichment in the photoproducts. Continued investigations on atropisomeric scaffolds have unraveled new design features, with outcomes that are unique and unprecedented for excited state reactivity. For example, we have established that reactive spin states (singlet or triplet excited state) profoundly influence the stereochemical outcome of an atropselective phototransformation. In general, the photochemistry and photophysics of atropisom...

Enantioselective, Visible Light Mediated Aza Paternò–Büchi Reactions of Quinoxalinones

“…The only notable way to access enantioenriched compounds is based on the use of axially chiral enamides which allow for a chirality transfer in the course of the aza Paternò–Büchi reaction [8] . Despite the beauty of atropselective photochemical reactions, [11] they rely on the stoichiometric use of the chiral substrate and do not offer the option of a catalytic enantioselective process. We have now found a way to prepare chiral azetidines in enantiomerically pure form by employing a chiral triplet sensitizer that invites the precoordination of imine substrates by hydrogen bonding and operates with visible light ( λ =420 nm).…”

Entropy‐Driven Diastereoselectivity Improvement in the Paternò–Büchi Reaction of 1‐Naphthyl Aryl Ethenes with a Chiral Cyanobenzoate through Remote Alkylation

“…These selectivities have also been manipulated by introducing steric hindrance, allylic strain, or hydrogen‐bonding interactions . As an alternative approach to enhance the selectivity during photocycloaddition, axially chiral substrates have been employed …”

Realizing an Aza Paternò–Büchi Reaction

“…As a solution, several methodologies were introduced which mainly focused on organizing the reactants either through non‐covalent interactions or conformational/steric bias . In an effort to improve the selectivity, we have explored the asymmetric photochemistry of non‐biaryl atropisomers and were successful in achieving high stereoselectivity in a variety of synthetically useful phototransformations . In our continuing efforts, we disclose our results on the first atropselective intramolecular [2+2]‐photocycloaddition between acyclic imines and enamides.…”