Resolving Conflicting Mechanisms for Photoredox Allylic sp-CH Arylation Using Deuterium-Labeling and Isotope Effects.

Two conflicting mechanisms have emerged for the direct arylation of allylic C-H bonds enabled by the combined use of thiol and photoredox catalysis. In the original report ( , , 74-77), a radical coupling step-between a radical anion of an arene and an allylic radical-is proposed to be the key C-C bond-forming step. A recent mechanistic study (.

A Lewis Acid-Controlled Enantiodivergent Epoxidation of Aldehydes.

Two epoxidation catalysts, one of which consists of two VANOL ligands and an aluminum and the other that consists of two VANOL ligands and a boron, were compared. Both catalysts are highly effective in the catalytic asymmetric epoxidation of a variety of aromatic and aliphatic aldehydes with diazoacetamides, giving high yields and excellent asymmetric inductions. The aluminum catalyst is effective at 0 °C and the boron catalyst at -40 °C.

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant.

Enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes proceed under weakly acidic conditions utilizing a combination of two catalysts, an indoline HCl salt and a bisthiourea compound. Mechanistic investigations revealed the roles of both catalysts and confirmed the involvement of oxocarbenium ion intermediates, ruling out alternative scenarios. A stereochemical model was derived from density functional theory calculations, which provided the basis for the development of a highly enantioselective stereodivergent variant with racemic tryptophol derivatives.

Isotope Effects Reveal the Catalytic Mechanism of the Archetypical Suzuki-Miyaura Reaction.

Experimental and theoretical C kinetic isotope effects (KIEs) are utilized to obtain atomistic insight into the catalytic mechanism of the Pd(PPh)-catalyzed Suzuki-Miyaura reaction of aryl halides and aryl boronic acids. Under catalytic conditions, we establish that oxidative addition of aryl bromides occurs to a 12-electron monoligated palladium complex (Pd-(PPh)). This is based on the congruence of the experimental KIE for the carbon attached to bromine (KIE = 1.

Rapid Evaluation of the Mechanism of Buchwald-Hartwig Amination and Aldol Reactions Using Intramolecular C Kinetic Isotope Effects.

A practical approach is introduced for the rapid determination of C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of -butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional molecular C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental C KIEs are determined using an molecular KIE approach.

Study of Ground State Interactions of Enantiopure Chiral Quaternary Ammonium Salts and Amides, Nitroalkanes, Nitroalkenes, Esters, Heterocycles, Ketones and Fluoroamides.

Chiral phase-transfer catalysis provides high level of enantiocontrol, however no experimental data showed the interaction of catalysts and substrates. H NMR titration was carried out on Cinchona and Maruoka ammonium bromides vs. nitro, carbonyl, heterocycles, and N-F containing compounds.

Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst.

The mechanism of the enantioselective Michael addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.

Isotope Effects Reveal an Alternative Mechanism for "Iminium-Ion" Catalysis.

A novel mechanism for the epoxidation of enals with hydrogen peroxide catalyzed by diarylprolinol silyl ether supported by experimental C kinetic isotope effects (KIEs) and density functional theory calculations is presented. Normal C KIEs, measured on both the carbonyl- and β-carbon atoms of the enal, suggest participation of both carbon atoms in the rate-determining step. Calculations show that the widely accepted iminium-ion mechanism does not account for this experimental observation.

C Kinetic Isotope Effects as a Quantitative Probe To Distinguish between Enol and Enamine Mechanisms in Aminocatalysis.

A combination of experimental C kinetic isotope effects (KIEs) and high-level density functional theory (DFT) calculations is used to distinguish between "enamine" and "enol" mechanisms in the Michael addition of acetone to trans-β-nitrostyrene catalyzed by Jacobsen's primary amine thiourea catalyst. In light of the recent findings that the widely used O-incorporation probe for these mechanisms is flawed, the results described in this communication demonstrate an alternative probe to distinguish between these pathways. A key advantage of this probe is that quantitative mechanistic information is obtained without modifying experimental conditions.

Asymmetric Induction via a Helically Chiral Anion: Enantioselective Pentacarboxycyclopentadiene Brønsted Acid-Catalyzed Inverse-Electron-Demand Diels-Alder Cycloaddition of Oxocarbenium Ions.

An enantioselective catalytic inverse-electron-demand Diels-Alder reaction of salicylaldehyde acetal-derived oxocarbenium ions and vinyl ethers to generate 2,4-dioxychromanes is described. Chiral pentacarboxycyclopentadiene (PCCP) acids are found to be effective for a variety of substrates. Computational and X-ray crystallographic analyses support the unique hypothesis that an anion with point-chirality-induced helical chirality dictates the absolute sense of stereochemistry in this reaction.

Pyro-Borates, Spiro-Borates, and Boroxinates of BINOL-Assembly, Structures, and Reactivity.

VANOL and VAPOL ligands are known to react with three equivalents of B(OPh) to form a catalytic species that contains a boroxinate core with three boron atoms, and these have proven to be effective catalysts for a number of reactions. However, it was not known whether the closely related BINOL ligand will likewise form a boroxinate species. It had simply been observed that mixtures of BINOL and B(OPh) were very poor catalysts compared to the same mixtures with VANOL or VAPOL.

A Designed Approach to Enantiodivergent Enamine Catalysis.

The rational design and implementation of enantiodivergent enamine catalysis is reported. A simple secondary amine catalyst, 2-methyl-l-proline, and its tetrabutylammonium salt function as an enantiodivergent catalyst pair delivering the enantiomers of α-functionalized aldehyde products in excellent enantioselectivities. This novel concept of designed enantiodivergence is applied to the enantioselective α-amination, aldol, and α-aminoxylation/α-hydroxyamination reactions of aldehydes.

Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride.

An amide-thiourea compound, operating through a novel ion pairing mechanism, is an efficient organocatalyst for the asymmetric reaction of homophthalic anhydride with imines. N-aryl and N-alkyl imines readily undergo formal [4+2] cycloaddition to provide lactams with high levels of enantio- and diastereoselectivity. The nature of the key chiral ion pair intermediate was elucidated by DFT calculations.

Bifunctional Ammonium Salt Catalyzed Asymmetric α-Hydroxylation of β-Ketoesters by Simultaneous Resolution of Oxaziridines.

Chiral bifunctional urea-containing ammonium salts were found to be very efficient catalysts for asymmetric α-hydroxylation reactions of β-ketoesters with oxaziridines under base-free conditions. The reaction is accompanied by a simultaneous kinetic resolution of the oxaziridine and a plausible and so far unprecedented bifunctional transition-state model has been obtained by means of DFT calculations.

Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent.

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step.

Isotope Effects Reveal the Mechanism of Enamine Formation in l-Proline-Catalyzed α-Amination of Aldehydes.

The mechanism of l-proline-catalyzed α-amination of 3-phenylpropionaldehyde was studied using a combination of experimental kinetic isotope effects (KIEs) and theoretical calculations. Observation of a significant carbonyl (13)C KIE and a large primary α-deuterium KIE support rate-determining enamine formation. Theoretical predictions of KIEs exclude the widely accepted mechanism of enamine formation via intramolecular deprotonation of an iminium carboxylate intermediate.

Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines.

Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies.

Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR.

Transition state analogs mimic the geometry and electronics of the transition state of enzymatic reactions. These molecules bind to the active site of the enzyme much tighter than substrate and are powerful noncovalent inhibitors. Immucillin-H (ImmH) and 4'-deaza-1'-aza-2'-deoxy-9-methylene Immucillin-H (DADMe-ImmH) are picomolar inhibitors of human purine nucleoside phosphorylase (hPNP).

Isotope effects and mechanism of the asymmetric BOROX Brønsted acid catalyzed aziridination reaction.

The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring-closing transition structures.

Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase.

Human nicotinamide phosphoribosyltransferase (NAMPT) replenishes the NAD pool and controls the activities of sirtuins, mono- and poly-(ADP-ribose) polymerases, and NAD nucleosidase. The nature of the enzymatic transition-state (TS) is central to understanding the function of NAMPT. We determined the TS structure for pyrophosphorolysis of nicotinamide mononucleotide (NMN) from kinetic isotope effects (KIEs).

Isotope effects and heavy-atom tunneling in the Roush allylboration of aldehydes.

Intermolecular (13)C kinetic isotope effects (KIEs) for the Roush allylboration of p-anisaldehyde were determined using a novel approach. The experimental (13)C KIEs fit qualitatively with the expected rate-limiting cyclic transition state, but they are far higher than theoretical predictions based on conventional transition state theory. This discrepancy is attributed to a substantial contribution of heavy-atom tunneling to the reaction, and this is supported by multidimensional tunneling calculations that reproduce the observed KIEs.

Transition-state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine.

Uridine phosphorylase catalyzes the reversible phosphorolysis of uridine and 2'-deoxyuridine to generate uracil and (2-deoxy)ribose 1-phosphate, an important step in the pyrimidine salvage pathway. The coding sequence annotated as a putative nucleoside phosphorylase in the Trypanosoma cruzi genome was overexpressed in Escherichia coli , purified to homogeneity, and shown to be a homodimeric uridine phosphorylase, with similar specificity for uridine and 2'-deoxyuridine and undetectable activity toward thymidine and purine nucleosides. Competitive kinetic isotope effects (KIEs) were measured and corrected for a forward commitment factor using arsenate as the nucleophile.

Transition state analysis of the arsenolytic depyrimidination of thymidine by human thymidine phosphorylase.

Human thymidine phosphorylase (hTP) is responsible for thymidine (dT) homeostasis, promotes angiogenesis, and is involved in metabolic inactivation of antiproliferative agents that inhibit thymidylate synthase. Understanding its transition state structure is on the path to design transition state analogues. Arsenolysis of dT by hTP permits kinetic isotope effect (KIE) analysis of the reaction by forming thymine and the chemically unstable 2-deoxyribose 1-arsenate.