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, αchloroamide, 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.
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.
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.
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.
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 Taddolbased 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.
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