Z-to-E isomerization processes in reactions catalyzed by cyclometalated ruthenium alkylidenes

The Z-content of products generated in reactions catalyzed by adamantyl-activated Z-selective metathesis catalysts is at first very high but degrades at higher conversions. The degree to which this undesirable process occurs is dependent on both the substrate and catalyst structure. Studies of Z-to-E isomerization processes and methods of preventing them are explored. Furthermore, an interesting Fischer carbene species was found to affect these isomerization processes

Metathesis and Decomposition of Fischer Carbenes of Cyclometalated Z-Selective Ruthenium Metathesis Catalysts

The addition of vinyl ethers to Z-selective, cyclometalated ruthenium metathesis catalysts generates Fischer carbene complexes. Although Fischer carbenes are usually thought to be metathesis inactive, we show that Fischer carbenes are metathesis active under certain circumstances. These species were found to decompose facilely to Ru hydride complexes, as identified by both experiment and computation. Since vinyl ethers are often used to quench metathesis reactions implementing Ru-based metathesis catalysts, their decomposition to hydrides can have a deleterious effect on the desired stereochemistry of the olefin product

Metathesis and Decomposition of Fischer Carbenes of Cyclometalated Z-Selective Ruthenium Metathesis Catalysts

The addition of vinyl ethers to Z-selective, cyclometalated ruthenium metathesis catalysts generates Fischer carbene complexes. Although Fischer carbenes are usually thought to be metathesis inactive, we show that Fischer carbenes are metathesis active under certain circumstances. These species were found to decompose facilely to Ru hydride complexes, as identified by both experiment and computation. Since vinyl ethers are often used to quench metathesis reactions implementing Ru-based metathesis catalysts, their decomposition to hydrides can have a deleterious effect on the desired stereochemistry of the olefin product

Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Griseofulvin is an antifungal agent that has recently been determined to have potential antiviral and anticancer applications. The role of specific enzymes involved in the biosynthesis of this natural product has previously been determined, but the mechanism by which a p450 (GsfF), catalyzes the key oxidative cyclization of griseophenone B remains unknown. Using density functional theory (DFT), we have determined the mechanism of this oxidation that forms the oxa-spiro core of griseofulvin. Computations show GsfF preferentially performs phenolic O–H abstraction over epoxidation to catalyze the oxidation

Synthesis and Evaluation of Sterically Demanding Ruthenium Dithiolate Catalysts for Stereoretentive Olefin Metathesis

Dithiolate ligands have recently been used in ruthenium-catalyzed olefin metathesis and have provided access to a kinetically <i>E</i> selective pathway through stereoretentive olefin metathesis. The typical dithiolate used is relatively simple with low steric demands imparted on the catalyst. We have developed a synthetic route that allows access to sterically demanding dithiolate ligands. The catalysts generated provided a pathway to study the intricate structure–activity relationships in olefin metathesis. It was found that DFT calculations can predict the ligand arrangement around the ruthenium center with remarkable accuracy. These dithiolate catalysts proved resistant to ligand isomerization and were stable even under forcing conditions. Additionally, catalyst initiation and olefin metathesis studies delivered a better understanding to the interplay between dithiolate ligand structure and catalyst activity and selectivity

Computational-Based Mechanistic Study and Engineering of Cytochrome P450 MycG for Selective Oxidation of 16-Membered Macrolide Antibiotics

MycG is a cytochrome P450 that performs two sequential oxidation reactions on the 16-membered ring macrolide M-IV. The enzyme evolved to oxidize M-IV preferentially over M-III and M-VI, which differ only by the presence of methoxy vs free hydroxyl groups on one of the macrolide sugar moieties. We utilized a two-pronged computational approach to study both the chemoselective reactivity and substrate specificity of MycG. Density functional theory computations determined that epoxidation of the substrate hampers its ability to undergo C-H abstraction, primarily due to a loss of hyperconjugation in the transition state. Metadynamics and molecular dynamics simulations revealed a hydrophobic sugar-binding pocket that is responsible for substrate recognition/specificity and was not apparent in crystal structures of the enzyme/substrate complex. Computational results also led to the identification of other interactions between the enzyme and its substrates that had not previously been observed in the cocrystal structures. Site-directed mutagenesis was then employed to test the effects of mutations hypothesized to broaden the substrate scope and alter the product profile of MycG. The results of these experiments validated this complementary effort to engineer MycG variants with improved catalytic activity toward earlier stage mycinamicin substrates

Mechanism of Permanganate-Promoted Dihydroxylation of Complex Diketopiperazines: Critical Roles of Counter-cation and Ion-Pairing

The mechanism of permanganate-mediated dual C-H oxidation of complex diketopiperazines has been examined with density functional theory computations. The products of these oxidations are enabling intermediates in the synthesis of structurally diverse ETP natural products. We evaluated, for the first time, the impact of ion-pairing and aggregation states of the permanganate ion and counter-cations, such as bis(pyridine)-silver(I) (Ag[superscript +]) and tetra-n-butylammonium (TBA[superscript +]), on the C-H oxidation mechanism. The C-H abstraction occurs through an open shell singlet species, as noted previously, followed by O-rebound and a competing OH-rebound pathway. The second C-H oxidation proceeds with a second equivalent of oxidant with lower free energy barriers than the first C-H oxidation due to directing effects and the generation of a more reactive oxidant species after the first C-H oxidation. The success and efficiency of the second C-H oxidation are found to be critically dependent on the presence of an ion-paired oxidant. We used the developed mechanistic knowledge to rationalize an experimentally observed oxidation pattern for C[superscript 3]-indole-substituted diketopiperazine (+)-5 under optimal oxidation conditions: namely, the formation of diol (-)-6 as a single diastereomer and lack of the ketone products. We proposed two factors that may impede the ketone formation: (i) the conformational flexibility of the diketopiperazine ring, and (ii) hindrance of this site, making it less accessible to the ion-paired oxidant species. Keywords: oxidation reactions; free energy; oxidation; quantum mechanics; transition metalsNational Institute of General Medical Sciences (U.S.) (Award GM089732

Origins of the Stereoretentive Mechanism of Olefin Metathesis with Ru-Dithiolate Catalysts

A comprehensive computational study of stereoretentive olefin metathesis with Ru-dithiolate catalysts has been performed. We have determined how the dithiolate ligand enforces a side-bound mechanism and how the side-bound mechanism allows for stereochemical control over the forming olefin. We have used density functional theory (DFT) and ligand steric contour maps to elucidate the origins of stereoretentive metathesis with the goal of understanding how to design a new class of <i>E</i>-selective metathesis catalysts