Ni/Photoredox-Catalyzed Enantioselective Acylation of α-Bromobenzoates with Aldehydes: A Formal Approach to Aldehyde-Aldehyde Cross-Coupling.

The catalytic cross-coupling of identical or similar functional groups is a cornerstone strategy for carbon-carbon bond formation, as exemplified by renowned methods, such as olefin cross-metathesis, Kolbe electrolysis, and various cross-electrophile couplings. However, similar methodologies for coupling aldehydes─fundamental building blocks in organic synthesis─remain underdeveloped. While the benzoin-type condensation, first reported in 1832, offers a reliable route for aldehyde dimerization, the chemo- and enantioselective cross-coupling of nonidentical yet similar aldehydes remains an unsolved challenge. Herein, we report a unified platform enabling highly chemo- and enantioselective cross-coupling of aldehydes. By leveraging nickel photoredox catalysis in tandem with discrete activation strategies for each aldehyde, this mechanistically distinct approach facilitates the enantioselective union of an aldehyde-derived α-oxy radical with an acyl radical, photocatalytically generated from a distinct aldehyde. This novel strategy enables modular access to enantioenriched α-oxygenated ketones with two minimally differentiated aliphatic substituents, a feat not achievable with existing chemocatalytic or biocatalytic techniques. The synthetic utility of this method is demonstrated by its application in the streamlined asymmetric synthesis of various medicinally relevant molecules. Additionally, mechanistic investigations rationalize the versatility of nickel photoredox catalysis to exploit new pathways for addressing long-standing synthetic challenges.

Metallaphotoredox-Catalyzed Enantioselective Cross-Electrophile Coupling Using Alcohols as Reducing Agents.

The cross-electrophile coupling (XEC) represents a powerful strategy for C-C bond formation. However, controlling the enantioselectivity in these processes remains a challenge. Here, we report an unprecedented enantioselective XEC of α-amino acid derivatives with aryl bromides, enabled by alcohols as reducing agents via Ni/photoredox catalysis. This mechanistically distinct approach exploits the ability of photocatalytically generated α-hydroxyalkyl radicals to convert alkyl electrophiles to the corresponding alkyl radicals that are then enantioselectively coupled with aryl bromides. The readily scalable protocol allows modular access to valuable enantioenriched benzylic amines from abundant and inexpensive precursors, and is applicable to late-stage diversification with broad functional group tolerance. Mechanistic studies rationalize the versatility of this alcohol-based reactivity for radical generation and subsequent asymmetric cross-coupling. We expect that this alcohol-based cross-coupling will render a general platform for the development of appealing yet challenging enantioselective XECs.

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis.

Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids-two of the most abundant and versatile functionalities-to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C-H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling.

Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general and modular approach for the direct enantioselective α-arylation of saturated azacycles and acyclic N-alkyl benzamides via nickel/photoredox dual catalysis. This process exploits the hydrogen atom transfer ability of photoeliminated chlorine radicals to convert azacycles to the corresponding α-amino alkyl radicals that then are coupled with ubiquitous and inexpensive (hetero)aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, a broad substrate scope, and high enantioselectivities, and are applicable to late-stage diversification of medicinally relevant complex molecules. Mechanistic studies suggest that the nickel catalyst uncommonly plays multiple roles, accomplishing chlorine radical generation, α-amino radical capture, cross-coupling, and asymmetric induction.

Enantioselective ß-C(sp3)-H arylation of amides via synergistic nickel and photoredox catalysis.

An enantioselective benzylic ß-C(sp3)-H arylation of amides via synergistic nickel and photoredox catalysis is reported. The C-H bond is activated by a bromine-radical-mediated C-H cleavage. This mild yet straightforward protocol provides arylation products in up to 96% yield and with up to 95% ee.

Asymmetric benzylic C(sp3)-H acylation via dual nickel and photoredox catalysis.

Asymmetric C(sp3)-H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C-H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C-H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C-H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.

Direct Enantioselective C(sp3)-H Acylation for the Synthesis of α-Amino Ketones.

A direct enantioselective acylation of α-amino C(sp3)-H bonds with carboxylic acids has been achieved via the merger of transition metal and photoredox catalysis. This straightforward protocol enables cross-coupling of a wide range of carboxylic acids, one class of feedstock chemicals, with readily available N-alkyl benzamides to produce highly valuable α-amino ketones in high enantioselectivities under mild conditions. The synthetic utility of this method is further demonstrated by gram scale synthesis and application to late-stage functionalization. This method provides an unprecedented solution to address the challenging stereocontrol in metallaphotoredox catalysis and C(sp3)-H functionalization. Mechanistic studies suggest the α-C(sp3)-H bond of the benzamide coupling partner is cleavage by photocatalytically generated bromine radicals to form α-amino alkyl radicals, which subsequently engages in nickel-catalyzed asymmetric acylation.

Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles.

Stereochemical control in the construction of carbon-carbon bonds between an alkyl electrophile and an alkyl nucleophile is a persistent challenge in organic synthesis. Classical substitution reactions via SN1 and SN2 pathways are limited in their ability to generate carbon-carbon bonds (inadequate scope, due to side reactions such as rearrangements and eliminations) and to control stereochemistry when beginning with readily available racemic starting materials (racemic products). Here, we report a chiral nickel catalyst that couples racemic electrophiles (propargylic halides) with racemic nucleophiles (ß-zincated amides) to form carbon-carbon bonds in doubly stereoconvergent processes, affording a single stereoisomer of the product from two stereochemical mixtures of reactants.

Catalytic, Enantioselective Addition of Alkyl Radicals to Alkenes via Visible-Light-Activated Photoredox Catalysis with a Chiral Rhodium Complex.

An efficient enantioselective addition of alkyl radicals, oxidatively generated from organotrifluoroborates, to acceptor-substituted alkenes is catalyzed by a bis-cyclometalated rhodium catalyst (4 mol %) under photoredox conditions. The practical method provides yields up to 97% with excellent enantioselectivities up to 99% ee and can be classified as a redox neutral, electron-transfer-catalyzed reaction.

Cooperative Photoredox and Asymmetric Catalysis.

Chemical processes combining visible-light-activated redox catalysis with asymmetric catalysis are reviewed, including enamine catalysis in the presence or absence of an additional photoredox sensitizer, phase transfer catalysis exploiting an in situ -generated electron donor-acceptor complex, photosensitized chiral Lewis acid catalysis, and photoactivated nickel-catalyzed asymmetric cross-couplings. The transfer of a single electron leads to intermediate radical ions, whose strongly modulated reactivities can be exploited for asymmetric catalysis in a novel fashion. All processes discussed here are redox neutral so that the electron serves as a real catalyst which cooperates with an asymmetric catalyst for the overall asymmetric transformation.

Enantioselective, Catalytic Trichloromethylation through Visible-Light-Activated Photoredox Catalysis with a Chiral Iridium Complex.

An enantioselective, catalytic trichloromethylation of 2-acyl imidazoles and 2-acylpyridines is reported. Several products are formed with enantiomeric excess of ≥99%. In this system, a chiral iridium complex serves a dual function, as a catalytically active chiral Lewis acid and simultaneously as a precursor for an in situ assembled visible-light-triggered photoredox catalyst.

Octahedral Chiral-at-Metal Iridium Catalysts: Versatile Chiral Lewis Acids for Asymmetric Conjugate Additions.

Octahedral iridium(III) complexes containing two bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole (IrO) or 5-tert-butyl-2-phenylbenzothiazole (IrS) ligands in addition to two labile acetonitrile ligands are demonstrated to constitute a highly versatile class of asymmetric Lewis acid catalysts. These complexes feature the metal center as the exclusive source of chirality and serve as effective asymmetric catalysts (0.5-5.0 mol % catalyst loading) for a variety of reactions with α,ß-unsaturated carbonyl compounds, namely Friedel-Crafts alkylations (94-99% ee), Michael additions with CH-acidic compounds (81-97% ee), and a variety of cycloadditions (92-99% ee with high d.r.). Mechanistic investigations and crystal structures of an iridium-coordinated substrates and iridium-coordinated products are consistent with a mechanistic picture in which the α,ß-unsaturated carbonyl compounds are activated by two-point binding (bidentate coordination) to the chiral Lewis acid.

Merger of visible light induced oxidation and enantioselective alkylation with a chiral iridium catalyst.

A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2-acyl-1-phenylimidazoles with N,N-diaryl-N-(trimethylsilyl)methylamines provides aminoalkylated products in 61-93 % yields with high enantiomeric excess (90-98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non-racemic chiral molecules.

Asymmetric Lewis acid catalysis directed by octahedral rhodium centrochirality.

A rhodium-based asymmetric catalyst is introduced which derives its optical activity from octahedral centrochirality. Besides providing the exclusive source of chirality, the rhodium center serves as a Lewis acid by activating 2-acyl imidazoles through two point binding and enabling a very effective asymmetric induction mediated by the propeller-like C2-symmetrical ligand sphere. Applications to asymmetric Michael additions (electrophile activation) as well as asymmetric α-aminations (nucleophile activation) are disclosed, for which the rhodium catalyst is found to be overall superior to its iridium congener. Due to its straightforward proline-mediated synthesis, high catalytic activity (catalyst loadings down to 0.1 mol%), and tolerance towards moisture and air, this novel class of chiral-at-rhodium catalysts will likely to become of widespread use as chiral Lewis acid catalysts for a large variety of asymmetric transformations.

Asymmetric photoredox transition-metal catalysis activated by visible light.

Asymmetric catalysis is seen as one of the most economical strategies to satisfy the growing demand for enantiomerically pure small molecules in the fine chemical and pharmaceutical industries. And visible light has been recognized as an environmentally friendly and sustainable form of energy for triggering chemical transformations and catalytic chemical processes. For these reasons, visible-light-driven catalytic asymmetric chemistry is a subject of enormous current interest. Photoredox catalysis provides the opportunity to generate highly reactive radical ion intermediates with often unusual or unconventional reactivities under surprisingly mild reaction conditions. In such systems, photoactivated sensitizers initiate a single electron transfer from (or to) a closed-shell organic molecule to produce radical cations or radical anions whose reactivities are then exploited for interesting or unusual chemical transformations. However, the high reactivity of photoexcited substrates, intermediate radical ions or radicals, and the low activation barriers for follow-up reactions provide significant hurdles for the development of efficient catalytic photochemical processes that work under stereochemical control and provide chiral molecules in an asymmetric fashion. Here we report a highly efficient asymmetric catalyst that uses visible light for the necessary molecular activation, thereby combining asymmetric catalysis and photocatalysis. We show that a chiral iridium complex can serve as a sensitizer for photoredox catalysis and at the same time provide very effective asymmetric induction for the enantioselective alkylation of 2-acyl imidazoles. This new asymmetric photoredox catalyst, in which the metal centre simultaneously serves as the exclusive source of chirality, the catalytically active Lewis acid centre, and the photoredox centre, offers new opportunities for the 'green' synthesis of non-racemic chiral molecules.

Metal-templated enantioselective enamine/H-bonding dual activation catalysis.

An octahedral bis-cyclometalated iridium(III) complex catalyzes the enantioselective α-amination of aldehydes with catalyst loadings down to 0.1 mol%. In this metal-templated design, the metal serves as a structural center and provides the exclusive source of chirality, whereas the catalysis is mediated through the organic ligand sphere.

Asymmetric catalysis with substitutionally labile yet stereochemically stable chiral-at-metal iridium(III) complex.

A metal-coordination-based high performance asymmetric catalyst utilizing metal centrochirality as the sole element of chirality is reported. The introduced substitutionally labile chiral-at-metal octahedral iridium(III) complex exclusively bears achiral ligands and effectively catalyzes the enantioselective Friedel-Crafts addition of indoles to α,ß-unsaturated 2-acyl imidazoles (19 examples) with high yields (75%-99%) and high enantioselectivities (90-98% ee) at low catalyst loadings (0.25-2 mol %). Counterintuitively, despite its substitutional lability, which is mechanistically required for coordination to the 2-acyl imidazole substrate, the metal-centered chirality is maintained throughout the catalysis. This novel class of reactive chiral-at-metal complexes will likely be of high value for a large variety of asymmetric transformations.

Enantioselective total syntheses of (-)-FR901483 and (+)-8-epi-FR901483.

The enantioselective total syntheses of the potent immunosuppressant FR901483 (1) and its 8-epimer (47) have been accomplished. Our approach features the use of building block 6 as the chiron, the application of the one-pot amide reductive bis-alkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and RCM to form the 3-pyrrolin-2-one ring.

A formal enantioselective total synthesis of FR901483.

A formal enantioselective total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. Our approach features the use of chiron 6 as the starting material, the application of the one-pot amide reductive bisalkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and ring closing metathesis to form the 3-pyrrolin-2-one ring.