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.

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.

Acryloyl and vinyl monomers functionalized with a chiral oxazolidinone auxiliary have been successfully polymerized in a stereospecific fashion to highly isotactic, optically active polymers, through either the previously established isospecific coordination polymerization (for acryloyl monomers) or a novel isospecific cationic polymerization (for vinyl monomers). Specifically, conjugated chiral acryloyloxazolidinones, N-acryloyl-(R or S)-4-phenyl-2-oxazolidinone [(R or S)-AOZ], are readily polymerized by chiral ansa-zirconocenium coordination catalysts, (R,R-, S,S-, or R,R/S,S)-, in an isospecific manner through a catalyst-site-controlled mechanism, producing the corresponding optically active chiral polymers, (R or S)-PAOZ. Owing to the nature of stereocontrol dictated by the chiral catalyst site, even the coordination polymerization of the parent AOZ, without the chiral side group, also affords PAOZ with nearly quantitative isotacticity. A series of experiments have shown that the chiral polymers (R or S)-PAOZ exhibit no chiral amplifications, despite having stereoregularly placed stereogenic centers in the main chain, and the optical activity of the polymers arises solely from their chiral auxiliary, a consequence of adopting a random-coil secondary structure and thus having a cryptochiral chain. In sharp contrast, the chiral isotactic polymers derived from nonconjugated chiral vinyl oxazolidinones, N-vinyl-(R)-4-phenyl-2-oxazolidinone [(R)-VOZ] and its p-hexyloxyphenyl derivative (R)-HVOZ (designed to solve the solubility issue of the resulting polymer), exhibit substantial chiral amplifications by virtue of adopting a solution-stable, one-handed helical conformation. The synthesis of such helical vinyl polymers has been accomplished by the development of a novel isospecific cationic polymerization using Lewis and Brønsted acids, such asthrough a chiral auxiliary-controlled mechanism. Noteworthy is the combination of the near-quantitative isotactic placement of the stereogenic centers of the polymer main chain with the chiral side groups located near those stereocenters that renders one-handed helicity of (R)-PVOZ and (R)-PHVOZ. Significantly, this novel cationic polymerization process, operating at ambient temperature, effectively assembles two elements of polymer local chirality-side-chain chirality and main-chain chirality-into global chirality in the form of excess one-handed helicity. Furthermore, the resulting chiral helical vinyl polymers exhibit considerably higher thermal decomposition temperatures and polymer crystallinity, in comparison to the random-coil chiral acryloyl polymers, having a similarly high degree of main-chain stereoregularity.

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