Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins.

Intermolecular C-C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent 'ene'-reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, α-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.

Divergent Synthesis of Pyrone Diterpenes via Radical Cross Coupling.

A divergent strategy for assembling pyrone diterpenes is presented. Capitalizing on the unique stereo- and chemoselectivity features of radical-based chemistry, the core decalin of these structures is efficiently forged using an electrochemically assisted oxidative radical polycyclization while key peripheral substituents are appended using decarboxylative radical cross couplings. In this way, access to four natural products (subglutinols A/B, higginsianin A, and sesquicillin A) is achieved in a concise and stereocontrolled fashion that is modular and amenable to future medicinal chemistry explorations.

Phase-transfer-catalysed asymmetric synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.

1,4-Benzoxazin-3-one is a scaffold which is found in a variety of biologically active molecules. Because of its unique structure and drug-like activities, 1,4-benzoxazin-3-ones have been widely used in drug discovery. However, just a few methods have been developed to access these molecules by catalytic asymmetric synthesis. We report herein the phase-transfer-catalysed asymmetric alkylation of 2-aryl-1,4-benzoxazin-3-ones as a new way for the highly enantioselective synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.

Enantioselective rhodium-catalyzed isomerization of 4-iminocrotonates: asymmetric synthesis of a unique chiral synthon.

An enantioselective isomerization of 4-iminocrotonates catalyzed by a rhodium(I)/phosphoramidite complex is described. This reaction uses widely available amines to couple with 4-oxocrotonate to provide a convenient access to a central chiral building block in good yield and high enantioselectivity. Although the mechanism of this new transformation remains unclear, both Rh and the phosphoramidite play a central role.

Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Pentenyl Isocyanate and 4-Ethynylanisole: Preparation and Use of Taddolpyrrolidine Phosphoramidite.

Caution, alkyl acyl azides can rapidly decompose with heat to release large amounts of nitrogen. Care should be taken during handling: do not attempt to convert neat and avoid handling neat.

SNAr-Derived Decomposition By-products Involving Pentafluorophenyl Triazolium Carbenes.

Pentafluorophenyl triazolium carbenes, widely used in NHC-catalysis, can decompose by several mechanisms. Under high concentration conditions, the azolium may undergo a pentafluorophenyl exchange by a proposed SNAr mechanism to give an inactive salt. In the presence of appropriate substrates, cyclization on the ortho-position of the arene can occur, also by SNAr. These adducts provide a potential pathway for catalyst decomposition and serve as a caveat to the development of new reactions and catalysts.

Isolable analogues of the Breslow intermediate derived from chiral triazolylidene carbenes.

Since Breslow's initial report on the thiamine mode of action, the study of catalytic acyl carbanion processes has been an area of immense interest. With the advent of azolylidene catalysis, a plethora of reactivtiy has been harnessed, but the crucial nucleophilic intermediate proposed by Breslow had never been isolated or fully characterized. Herein, we report the isolation and full characterization of nitrogen analogues of the Breslow intermediate. Both stable and catalytically relevant, these species provide a model system for the study of acyl carbanion and homoenolate processes catalyzed by triazolylidene carbenes.

Enantioselective rhodium-catalyzed [4+2] cycloaddition of α,ß-unsaturated imines and isocyanates.

A [4+2] cycloaddition of α,ß-unsaturated imines and isocyanates catalyzed by a phosphoramidite-rhodium complex provides pyrimidinones in good yields and high enantioselectivities.

Enantioselective rhodium-catalyzed [2 + 2 + 2] cycloadditions of terminal alkynes and alkenyl isocyanates: mechanistic insights lead to a unified model that rationalizes product selectivity.

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Catalytic asymmetric intermolecular stetter reaction of heterocyclic aldehydes with nitroalkenes: backbone fluorination improves selectivity.

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.

Regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of alkynes and isocyanates to form pyridones.

A highly regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of terminal alkynes with a variety of isocyanates to provide 2- and 4-pyridones has been developed. This reaction proceeds in good to excellent yields and overcomes the problem of dimerization and trimerization through the use of phosphoramidite ligands. A CO migration in the metallacycle is proposed to account for the formation of 4-pyridone.

Phosphoramidite-Rhodium Complexes as Catalysts for the Asymmetric [2+2+2] Cycloaddition of Alkenyl Isocyanates and Alkynes.

The discovery and development of the asymmetric rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and exogenous alkynes to form indolizinone and quinolizinone scaffolds is described. This methodology has been expanded to include substituted alkenes and dienes, a variety of sterically and electronically diverse alkynes, and carbodiimides in place of the isocyanate. Through X-ray analysis of Rh(cod)/phosphoramidite complexes, additives that modify the enantio-determining step, and other experimental data, a mechanism has been proposed that explains lactam, vinylogous amide, and pyridone products and the factors governing their formation. Finally, we have applied this methodology to the synthesis of (+)-lasubine-II and (-)-209D.