Kinetic Resolution of N-Allylic Pyrazoles via Photoexcited Chiral Copper Complex-Catalyzed Alkene E → Z Isomerization.

Herein, we present an efficient and practical kinetic resolution (KR) of racemic allylic pyrazoles utilizing photoexcited chiral-copper-complex-mediated alkene E → Z isomerization. This method enables the synthesis of both enantioenriched E- and Z-allylic pyrazoles, achieving enantiomeric excesses (e.e.) of up to 97% and selectivity factors (S factors) as high as 217. Remarkably, the method's ability to furnish allylic pyrazoles with the Z-configuration, which is notably arduous to obtain under thermodynamic control, underscores the transformative potential of this synthetic protocol.

Enantioselective Hydroaminoalkylation of Azaaryl Ketones through Asymmetric Photoredox Catalysis.

An enantioselective hydroaminoalkylation of azaaryl ketones under a transition-metal-free asymmetric photoredox catalysis platform is reported. A series of valuable azaarene-functionalized 1,2-amino alcohols featuring attractive quaternary carbon stereocenters have been synthesized in high yields with good to excellent enantioselectivities. The viability of readily accessible N-aryl glycines as reaction partners facilitates the conjugate modification of these products into important derivatives, thereby enhancing the synthetic utility of the current approach.

Interception of Transient Allyl Radicals with Low-Valent Allylpalladium Chemistry: Tandem Pd(0/II/I)-Pd(0/II/I/II) Cycles in Photoredox/Pd Dual-Catalytic Enantioselective C(sp3)-C(sp3) Homocoupling.

We present comprehensive computational and experimental studies on the mechanism of an asymmetric photoredox/Pd dual-catalytic reductive C(sp3)-C(sp3) homocoupling of allylic electrophiles. In stark contrast to the canonical assumption that photoredox promotes bond formation via facile reductive elimination from high-valent metal-organic species, our computational analysis revealed an intriguing low-valent allylpalladium pathway that features tandem operation of Pd(0/II/I)-Pd(0/II/I/II) cycles. Specifically, we propose that (i) the photoredox/Pd system enables the in situ generation of allyl radicals from low-valent Pd(I)-allyl species, and (ii) effective interception of the fleeting allyl radical by the chiral Pd(I)-allyl species results in the formation of an enantioenriched product. Notably, the cooperation of the two pathways highlights the bifunctional role of Pd(I)-allyl species in the generation and interception of transient allyl radicals. Moreover, the mechanism implies divergent substrate-activation modes in this homocoupling reaction, suggesting a theoretical possibility for cross-coupling. Combined, the current study offers a novel mechanistic hypothesis for photoredox/Pd dual catalysis and highlights the use of low-valent allylpalladium as a means to efficiently intercept radicals for selective asymmetric bond constructions.

Photoredox-Catalyzed Synthesis of C-Benzoselenazolyl/Benzothiazolyl Glycosides from 2-Isocyanoaryl Selenoethers/Thioethers and Glycosyl Bromides.

Molecules containing heteroatoms, such as Se and S, play an indispensable role in the discovery and design of pharmaceuticals, whereas Se has been less studied. Here, we described a photoredox strategy to synthesize C-benzoselenazolyl (Bs) glycosides from 2-isocyanoaryl selenoethers and glycosyl bromides. This reaction was carried out under mild conditions with high efficiency. C-Benzothiazolyl (Bt) glycosides could also be synthesized from 2-isocyanoaryl thioethers using this strategy. This method can access novel seleno/thiosugars, which will benefit Se/S-containing drug discovery.

Photoredox-catalyzed C-heteroaryl glycosylation of biphenyl isocyanides with glycosyl bromides.

8,9-Dimethoxyphenanthridine derivatives, as potential antitumor drugs, need modification to improve their biocompatibility and water solubility. Reported here is a strategy to access C-heteroaryl glycosides by photoredox catalysis. C6-glycosylated phenanthridine derivatives are synthesized from biphenyl isocyanides and glycosyl bromides. The reaction conditions are mild and widely applicable, with anomeric α selectivity and good functional group tolerance.

Enantioselective reductive allylic alkylation enabled by dual photoredox/palladium catalysis.

A dual photoredox/palladium catalyzed regio- and enantioselective reductive cross-coupling of allylic acetates with tertiary/secondary alkyl bromides has been achieved, and Hantzsch ester is used as a homogeneous organic reductant. This straightforward protocol enables the stereoselective construction of C(sp3)-C(sp3) bonds under mild reaction conditions. Mechanistic studies suggest that this reaction involves radical pathways and a chiral Pd complex enables the control of the regio- and enantioselectivities.

Photoexcited Palladium-Initiated Remote Desaturation of N-Alkoxypyridinium Salts.

1,5-Hydrogen atom transfer (HAT) is an effective strategy to achieve remote desaturation of nonfunctionalized alkanes. Herein, we report a photoinduced remote desaturation reaction of N-alkoxypyridinium salts, which serve as alkoxyl radical precursors. Mechanistic studies show that a single electron transfer between the excited palladium complex and a N-alkoxypyridinium salt initiates a radical chain process leading to desaturation of N-alkoxypyridinium salts. This chain mechanism is supported by the measurement of the quantum yield of this reaction (Φ = 82). This reaction is applicable to a range of N-alkoxypyridinium salts, including some complex molecule-derived ones.

Photoexcited Chiral Copper Complex-Mediated Alkene E → Z Isomerization Enables Kinetic Resolution.

While asymmetric synthesis has been established as a powerful synthetic tool for the construction of versatile enantioenriched molecules in the most efficient and practical manner, the resolution of racemates is still the most universal industrial approach to the synthesis of chiral compounds. However, the direct formation of enantiopure Z-isomers through the catalytic nonenzymatic kinetic resolution of racemic E-alkenes remains challenging. Herein, we disclose an unprecedented enantioselective E → Z isomerization mediated by a photoexcited chiral copper complex. This catalytic system enables kinetic resolution of 2-styrylpyrrolidines. This process is difficult to realize under thermal conditions. Mechanistic experiments and density functional theory (DFT) calculations revealed that different overall sensitization rates of the substrate-catalyst complex of the two enantiomers led to the observed excellent kinetic resolution efficiency. This photochemical transformation expands the potential of kinetic resolution beyond their established ground-state reactivity, furnishing a novel reaction mode for enantioselective catalysis at its excited state.

In Vitro Reconstitution of Cinnamoyl Moiety Reveals Two Distinct Cyclases for Benzene Ring Formation.

Cinnamoyl-containing natural products (CCNPs) are a small class of bacterial metabolites with notable bioactivities. The biosynthesis of cinnamoyl moiety has been proposed to be assembled by an unusual highly reducing (HR) type II polyketide synthases (PKS). However, the biosynthetic route, especially the cyclization step for the benzene ring formation, remains unclear. In this work, we successfully reconstituted the pathway of cinnamoyl moiety in kitacinnamycin biosynthesis through a step-wise approach in vitro and demonstrated that a three-protein complex, Kcn17-Kcn18-Kcn19, can catalyze 6π-electrocyclization followed by dehydrogenation to form the benzene ring. We found that the three-protein homologues were widely distributed among 207 HR type II PKS biosynthetic gene clusters including five known CCNPs. In contrast, in the biosynthesis of youssoufene, a cinnamoyl-containing polyene, we identified that the benzene ring formation was accomplished by a distinct orphan protein. Thus, our work resolved the long-standing mystery in cinnamoyl biosynthesis and revealed two distinct enzymes that can synthesize benzene rings via polyene precursors.

Synthesis of C-Alkynyl Glycosides by Photoredox-Catalyzed Reductive Coupling of Alkynyl Bromides with Glycosyl Bromides.

A general, convenient, and highly α stereoselective approach to access C-alkynyl glycosides via the photoredox-catalyzed reductive coupling of alkynyl bromides and glycoside bromides has been developed. Cheap and small-load eosin Y is used as the photocatalyst, and organic base N,N-diisopropylethylamine serves as the reducing reagent. This strategy features readily available starting materials, diverse substrates, mild conditions, and high α stereoselectivity. Moreover, a glycoconjugated peptide could also be achieved using this strategy.

Enantioselective Radical SN2-Type Alkylation of Morita-Baylis-Hillman Adducts Using Dual Photoredox/Palladium Catalysis.

An enantioselective radical alkylation of 4-alkyl-1,4-dihydropyridines with Morita-Baylis-Hillman (MBH) adducts has been reported. The SN2-type products are predominant. This reaction is enabled by dual photoredox/palladium catalysis. The alkylation products are provided in good yields with good regio- and enantioselectivity. The use of Ding's spiroketal-based bis(phosphine) (SKP) ligand is crucial to achieving satisfactory regio- and enantioselectivity. The resultant α,ß-unsaturated ester can be easily reduced to a synthetically useful chiral allyl alcohol.

Enantioselective Reductive Homocoupling of Allylic Acetates Enabled by Dual Photoredox/Palladium Catalysis: Access to C2-Symmetrical 1,5-Dienes.

Transition-metal-catalyzed reductive coupling reactions have emerged as powerful protocols to construct C-C bonds. However, the development of enantioselective C(sp3)-C(sp3) reductive coupling remains challenging. Herein, we report a highly regio-, diastereo-, and enantioselective reductive homocoupling of allylic acetates through cooperative palladium and photoredox catalysis using diisopropylethylamine or Hantzsch ester as a homogeneous organic reductant. This straightforward protocol enables the stereoselective construction of C(sp3)-C(sp3) bonds under mild reaction conditions. A series of C2-symmetrical chiral 1,5-dienes were easily prepared with excellent enantioselectivities (up to >99% ee), diastereoselectivities (up to >95:5 dr), and regioselectivities (up to >95:5 rr). The resultant chiral 1,5-dienes can be directly used as chiral ligands in asymmetric synthesis, and they can be also transformed into other valuable chiral ligands.

Photoinduced and Palladium-Catalyzed Remote Desaturation of Amide Derivatives.

A photoinduced and palladium-catalyzed remote desaturation of O-acyl hydroxamides to unsaturated amides under mild conditions has been achieved. The formation of the alkyl Pd(II) intermediate by the recombination of alkyl radical and Pd(I) species is critical to achieve this efficient and selective desaturation of alkanes. This reaction features good site-selectivity, is terminal oxidant-free, and produces moderate to excellent yields for a variety of unsaturated amides. Remarkably, this approach enables late-stage desaturation of complex and biologically important molecules.

Diastereoselective and Stereodivergent Synthesis of 2-Cinnamylpyrrolines Enabled by Photoredox-Catalyzed Iminoalkenylation of Alkenes.

A photoredox-catalyzed iminoalkenylation of γ-alkenyl O-acyl oximes has been developed. Readily available alkenylboronic acids serve as alkenylation reagents, leading to densely functionalized pyrrolines. Both (E)- and (Z)-cinnamylpyrrolines are accessible depending on the reaction solvent. In dichloromethane, (E)-cinnamylpyrrolines are produced through a photoredox-mediated single-electron-transfer process. In tetrahydrofuran, (Z)-cinnamylpyrrolines are generated by photocatalytic contra-thermodynamic E-to-Z isomerization of (E)-cinnamylpyrrolines though an energy-transfer pathway. Two stereocenters are established with complete diastereoselectivity and only one diastereomer is isolated.

Access to Cyanoimines Enabled by Dual Photoredox/Copper-Catalyzed Cyanation of O-Acyl Oximes.

An efficient strategy for the synthesis of pharmaceutically important and synthetically useful cyanoimines, as well as cyanamides, has been described. This strategy is enabled by dual photoredox/copper-catalyzed cyanation of O-acyl oximes or O-acyl hydroxamides. This state of the art protocol for cyanoimines and cyanamides features readily available starting materials, mild reaction conditions, good functional group tolerance, and operational simplicity. The resultant cyanoimines can be transformed into structurally diverse and functionally important N-containing heterocycles.

Role of complexation in the photochemical reduction of chromate by acetylacetone.

Organic ligands can alter the redox behavior of metal species through the generation of metal-ligand complexes. Photo-induced complexation between ligands and metals is an important, but under-appreciated, aspect of process. Acetylacetone (AA) is a good chelating agent due to keto-enol tautomerization. In the presence of AA, photoreduction of Cr(VI) is accelerated; however, it is unclear exactly how complexation is involved in UV/AA mediated Cr(VI) reduction. On the basis of spectral and kinetic analyses, this study shows that the formation of {Cr(VI)-AA}* complexes is the main mechanism of Cr(VI) reduction by UV/AA. Evidence for this includes (1) the formation rate constant of Cr(III)-AA complexes in the UV system was 2-3 orders of magnitude greater than that in the thermal system; (2) there was a linear relationship between the photons absorbed by AA and the reduction rate constants of Cr(VI); and (3) the reaction appeared initially zero-order in Cr(VI) and turned to first-order as the pool of available Cr(VI) ran out. The results presented here are not only important for the better understanding of the complexation effects in the reduction of Cr(VI), but also crucial for the possible application of the UV/AA process in many other scenarios.

Enantioselective Remote C(sp3)-H Cyanation via Dual Photoredox and Copper Catalysis.

The remote C(sp3)-H cyanation of carboxamides has been described by merging photoredox and copper catalysis in a site-selective and enantiocontrolled manner. The protocol is the integration of photoinduced and nitrogen-centered radical-mediated intermolecular hydrogen atom transfer with chiral copper-complex-catalyzed radical cyanation. This strategy gives enantio-enriched cyanated amides in high yields.

Remote C-C bond formation via visible light photoredox-catalyzed intramolecular hydrogen atom transfer.

Carbon-carbon bonds comprise the major framework of organic molecules, rendering their formation one of the most fundamental transformations in synthetic organic chemistry. Visible light photoredox catalysis has recently been established as a powerful technique to construct molecular architectures that would otherwise be inaccessible under mild conditions. Photoredox catalysis combined with intramolecular hydrogen atom transfer (HAT) can serve as a unique tool for achieving remote C-C bond formation. In this review, the recent advances in remote C-C bond formation via photoredox-catalyzed intramolecular HAT are summarized.

Site-selective remote C(sp3)-H heteroarylation of amides via organic photoredox catalysis.

Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann-Löffler-Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)-H bonds. Here we report an amidyl radical-triggered site-selective remote C(sp3)-H heteroarylation of amides under organic photoredox conditions. This approach provides a mild and highly regioselective reaction affording remote C(sp3)-H heteroarylated amides at room temperature under transition-metal free, weakly basic, and redox-neutral conditions. Non-prefunctionalized heteroarenes, such as purines, thiazolopyridines, benzoxazole, benzothiazoles, benzothiophene, benzofuran, thiazoles and quinoxalines, can be alkylated directly. Sequential and orthogonal C-H functionalization of different heteroarenes by taking advantage pH value or polarity of radicals has also been achieved. DFT calculations explain and can predict the site-selectivity and reactivity of this reaction. This strategy expands the scope of the Minisci reaction and serves as its alternative and potential complement.

Atroposelective Haloamidation of Indoles with Amino Acid Derivatives and Hypohalides.

An atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypohalides is described. A series of 2-amido-3-haloindoles with a C-N chiral axis are delivered using this strategy. The C3 halogen atoms can facilitate further transformation. Various functionalities, such as carbonyl, phosphine, aryl, and alkenyl groups, can be introduced into the C3 position of indoles. These structurally diverse and axially chiral indole derivatives can find further synthetic utilities. It can be exemplified with an axially chiral phosphine, which serves as a ligand in Pd-catalyzed cross couplings.