Xiaoqiang Huang

Asymmetric Catalysis with Organic Azides and Diazo Compounds Initiated by Photoinduced Electron Transfer

Electron-acceptor-substituted aryl azides and α-diazo carboxylic esters are used as substrates for visible-light-activated asymmetric α-amination and α-alkylation, respectively, of 2-acyl imidazoles catalyzed by a chiral-at-metal rhodium-based Lewis acid in combination with a photoredox sensitizer. This novel proton- and redox-neutral method provides yields of up to 99% and excellent enantioselectivities of up to >99% ee with broad functional group compatibility. Mechanistic investigations suggest that an intermediate rhodium enolate complex acts as a reductive quencher to initiate a radical process with the aryl azides and α-diazo carboxylic esters serving as precursors for nitrogen and carbon-centered radicals, respectively. This is the first report on using aryl azides and α-diazo carboxylic esters as substrates for asymmetric catalysis under photoredox conditions. These reagents have the advantage that molecular nitrogen is the leaving group and sole byproduct in this reaction.

Direct Visible-Light-Excited Asymmetric Lewis Acid Catalysis of Intermolecular [2+2] Photocycloadditions

A reaction design is reported in which a substrate-bound chiral Lewis acid complex absorbs visible light and generates an excited state that directly reacts with a cosubstrate in a highly stereocontrolled fashion. Specifically, a chiral rhodium complex catalyzes visible-light-activated intermolecular [2+2] cycloadditions, providing a wide range of cyclobutanes with up to >99% ee and up to >20:1 d.r. Noteworthy is the ability to create vicinal all-carbon-quaternary stereocenters including spiro centers in an intermolecular fashion.

Catalytic asymmetric synthesis of a nitrogen heterocycle through stereocontrolled direct photoreaction from electronically excited state

The reactivity of photoexcited molecules has been extensively studied for decades but until today direct bond-forming reactions of such excited states in a catalytic and asymmetric fashion are restricted to the synthesis of cyclobutanes via [2 + 2] photocycloadditions. Herein, we demonstrate a previously elusive visible-light-induced catalytic asymmetric [2 + 3] photocycloaddition of alkenes with vinyl azides. A wide range of complex 1-pyrrolines are obtained as single diastereoisomers and with up to >99% enantiomeric excess using a simple reaction setup and mild reaction conditions. The reaction is proposed to proceed through the photoexcitation of a complex out of chiral rhodium catalyst coordinated to α,β-unsaturated N-acylpyrazole substrates. All reactive intermediates remain bound to the catalysts thereby providing a robust catalytic scheme (no exclusion of air necessary) with excellent stereocontrol. This work expands the scope of stereocontrolled bond-forming reactions of photoexcited intermediates by providing catalytic asymmetric access to a key nitrogen heterocycle in organic chemistry.Despite intensive research on photoexcited molecules, stereocontrol of direct bond formation upon photoexcitation remains limited. Here the authors expand the research on stereocontrolled bond forming photochemistry and introduce the catalytic asymmetric synthesis of chiral nitrogen heterocycles.

Visible-Light-Activated Asymmetric β-C–H Functionalization of Acceptor-Substituted Ketones with 1,2-Dicarbonyl Compounds

We report a visible-light-activated asymmetric β-C(sp3)-H functionalization of 2-acyl imidazoles and 2-acylpyridines with 1,2-dicarbonyl compounds (typically α-ketoesters) catalyzed by a tailored stereogenic-at-rhodium Lewis acid catalyst. The C-C bond formation products are obtained in high yields (up to 99%) and with excellent stereoselectivities (up to >20:1 dr and up to >99% ee). Experimental and computational studies support a mechanism in which a photoactivated Rh-enolate transfers a single electron to the 1,2-dicarbonyl compound followed by proton transfer and a subsequent stereocontrolled radical-radical recombination.

Preparation of chiral-at-metal catalysts and their use in asymmetric photoredox chemistry

Asymmetric catalysis is a powerful approach for the synthesis of optically active compounds, and visible light constitutes an abundant source of energy to enable chemical transformations, which are often triggered by photoinduced electron transfer (photoredox chemistry). Recently, bis-cyclometalated iridium(III) and rhodium(III) complexes were introduced as a novel class of catalysts for combining asymmetric catalysis with visible-light-induced photoredox chemistry. These catalysts are attractive because of their unusual feature of chirality originating exclusively from a stereogenic metal center, which offers the prospect of an especially effective asymmetric induction upon direct coordination of the substrate to the metal center. As these chiral catalysts contain only achiral ligands, special strategies are required for their synthesis. In this protocol, we describe strategies for preparing two types of chiral-at-metal catalysts, namely the Λ- and Δ-enantiomers (left- and right-handed propellers, respectively) of the iridium complex IrS and the rhodium complex RhS. Both contain two cyclometalating 5-tert-butyl-2-phenylbenzothiazoles in addition to two acetonitrile ligands and a hexafluorophosphate counterion. The two cyclometalated ligands set the propeller-shaped chiral geometry, but the acetonitriles are labile and can be replaced by substrate molecules. The synthesis protocol consists of three stages: first, preparation of the ligand 5-tert-butyl-2-phenylbenzothiazole; second, preparation of salicylthiazoline (used for iridium) and salicyloxazoline (used for rhodium) chiral auxiliaries; and third, the auxiliary-mediated synthesis of the individual enantiopure Λ- and Δ-configured catalysts. This class of stereogenic-only-at-metal complexes is of substantial value in the field of asymmetric catalysis, offering stereocontrolled radical reactions based on visible-light-activated photoredox chemistry. Representative examples of visible-light-induced asymmetric catalysis are provided.

Asymmetric [3+2] Photocycloadditions of Cyclopropanes with Alkenes or Alkynes through Visible‐Light Excitation of Catalyst‐Bound Substrates

The herein reported visible-light-activated catalytic asymmetric [3+2] photocycloadditions between cyclopropanes and alkenes or alkynes provide access to chiral cyclopentanes and cyclopentenes, respectively, in 63-99 % yields and with excellent enantioselectivities of up to >99 % ee. The reactions are catalyzed by a single bis-cyclometalated chiral-at-metal rhodium complex (2-8 mol %) which after coordination to the cyclopropane generates the visible-light-absorbing complex, lowers the reduction potential of the cyclopropane, and provides the asymmetric induction and overall stereocontrol. Enabled by a mild single-electron-transfer reduction of directly photoexcited catalyst/substrate complexes, the presented transformations expand the scope of catalytic asymmetric photocycloadditions to simple mono-acceptor-substituted cyclopropanes affording previously inaccessible chiral cyclopentane and cyclopentene derivatives.

Sequential asymmetric hydrogenation and photoredox chemistry with a single catalyst

An important objective in organic synthesis is the generation of structural complexity in a straightforward and economical fashion. Herein, we address this challenge by reporting a process in which a single chiral iridium catalyst promotes two mechanistically distinct reaction types in a sequential fashion, namely asymmetric hydrogenation (two-electron mechanism) and photoredox chemistry (one-electron mechanism). A variety of chiral alcohols are generated with enantioselectivities of 91–99% ee using a single batch of catalyst added at the beginning of the reaction sequence without any requirement for isolating the reaction intermediates.

Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study

The origin of asymmetric induction in the additions of carbon- and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion-interaction analysis indicates that for both carbon- and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Λ-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that compared to N-Me, N-iPr and N-Ph variants, the N-o-tolyl variant of the rhodium enolate results in the most substantial improvement in stereodiscrimination, a finding that is in agreement with experimental ee values.

Visible-Light-Activated Catalytic Enantioselective β-Alkylation of α,β-Unsaturated 2-Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs

An efficient and practical method for the enantioselective β-functionalization of α,β-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Λ-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent enantioselectivities up to 98% ee and can be classified as a redox-neutral, electron-transfer-catalyzed reaction.