Persistent organonickel complexes as general platforms for Csp-Csp coupling reactions.

The importance of constructing Csp-Csp bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown.

Accessing three-dimensional molecular diversity through benzylic C-H cross-coupling.

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C()-hybridized carbon atoms (e.g.

Broad Survey of Selectivity in the Heterogeneous Hydrogenation of Heterocycles.

A broad survey of heterogeneous hydrogenation catalysts has been conducted for the reduction of heterocycles commonly found in pharmaceuticals. The comparative reactivity of these substrates is reported as a function of catalyst, temperature, and hydrogen pressure. This analysis provided several catalysts with complementary reactivity between substrates.

Analysis of Laboratory-Evolved Flavin-Dependent Halogenases Affords a Computational Model for Predicting Halogenase Site Selectivity.

Flavin-dependent halogenases (FDHs) catalyze selective halogenation of electron-rich aromatic compounds without the need for harsh oxidants required by conventional oxidative halogenation reactions. Predictive models for halogenase site selectivity could greatly improve their utility for chemical synthesis. Toward this end, we analyzed the structures and selectivity of three halogenase variants evolved to halogenate tryptamine with orthogonal selectivity.

Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C-H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design.

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates.

Driving to a Better Understanding of Acyl Glucuronide Transformations Using NMR and Molecular Modeling.

Acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs and products of their transformations have long been implicated in drug-induced liver injury (DILI). To inform on the DILI risk arising from AG reactive intermediates, a comprehensive mechanistic study of enzyme-independent AG rearrangements using nuclear magnetic resonance (NMR) and density functional theory (DFT) was undertaken. NMR spectroscopy was utilized for structure elucidation and kinetics measurements of nine rearrangement and hydrolysis products of 1β-O-acyl glucuronide of ibufenac.

Lewis acid mediated, mild C-H aminoalkylation of azoles three component coupling.

This manuscript reports the development of a mild, highly functional group tolerant and metal-free C-H aminoalkylation of azoles a three-component coupling approach. This method enables the C-H functionalization of diverse azole substrates, such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, imidazoles, and benzimidazoles. DFT calculations identify a key deprotonation equilibrium in the mechanism of the reaction.

Thermodynamic consequences of Tyr to Trp mutations in the cation-π-mediated binding of trimethyllysine by the HP1 chromodomain.

Evolution has converged on cation-π interactions for recognition of quaternary alkyl ammonium groups such as trimethyllysine (Kme3). While computational modelling indicates that Trp provides the strongest cation-π interaction of the native aromatic amino acids, there is limited corroborative data from measurements within proteins. Herein we investigate a Tyr to Trp mutation in the binding pocket of the HP1 chromodomain, a reader protein that recognizes Kme3.

Catalytic Effects of Ammonium and Sulfonium Salts and External Electric Fields on Aza-Diels-Alder Reactions.

The mechanism of the aza-Diels-Alder reaction catalyzed by tetraalkylammonium or trialkylsulfonium salts is explored with density functional theory. Favorable electrostatic interactions between the dienophile and the charged catalyst stabilize the highly polar transition state, leading to lower free energy barriers and higher dipole moments. Endo selectivity is predicted for both uncatalyzed and catalyzed systems.

Mechanism and Regioselectivity of an Unsymmetrical Hexadehydro-Diels-Alder (HDDA) Reaction.

Hoye reported intramolecular hexadehydro-Diels-Alder (HDDA) reactions to generate arynes that functionalize natural product phenols and amines. In their studies, Hoye found that unsymmetrical tetraynes selectively form a single aryne. We report density functional theory (DFT) calculations that reveal the factors controlling the regioselectivity.

Organocatalytic [6+4] Cycloadditions via Zwitterionic Intermediates: Chemo-, Regio-, and Stereoselectivities.

The mechanisms and origins of chemo- and stereoselectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2-cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate-determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition.

Origins of Selectivities in the Stork Diels-Alder Cycloaddition for the Synthesis of (±)-4-Methylenegermine.

The remarkably high  stereoselectivity of  a Diels-Alder cycloaddition  designed by  Stork for the synthesis of germine has been examined with theory. We conceived a collaboration with Gilbert Stork, the great synthetic chemist and collaborator. We wished to complement Stork's insights with computations to explain the extraordinary selectivity he designed to introduce four new stereocenters in one step.

Biosynthesis of thiocarboxylic acid-containing natural products.

Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN.

Investigation of Trimethyllysine Binding by the HP1 Chromodomain via Unnatural Amino Acid Mutagenesis.

Trimethyllysine (Kme3) reader proteins are targets for inhibition due to their role in mediating gene expression. Although all such reader proteins bind Kme3 in an aromatic cage, the driving force for binding may differ; some readers exhibit evidence for cation-π interactions whereas others do not. We report a general unnatural amino acid mutagenesis approach to quantify the contribution of individual tyrosines to cation binding using the HP1 chromodomain as a model system.

Origins of Stereoselectivity in Chiral Aminoalcohol Catalysis of Oxyallyl Cation-Indole Reactions.

The enantioselective coupling of indoles with racemic α-tosyloxy ketones mediated by a chiral amino alcohol catalyst is studied with density functional theory (DFT) calculations. The addition of indole to an oxyallyl cation intrinsically favors the (S,S) and (R,R) stereoisomeric products through electrostatic interactions in the transition state. Our model shows that the enantioselectivity is controlled by the cyclohexane moiety of the catalyst; selectivity diminishes upon removal of the cyclohexane ring.

Chirality Sensing of α-Hydroxyphosphonates by N-tert-Butyl Sulfinyl Squaramide.

N-tert-Butyl sulfinyl squaramides were used for chiral discrimination of α-hydroxyphosphonates using P NMR. A free energy relationship study indicates that both steric and the electronic effects influence the chiral recognition of the donors.

Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by Bis-Quaternized Cinchona Alkaloid-Derived Catalysts.

A model for the stereoselectivity of intramolecular alkylations by N,N'-disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the transition state (TS) and catalyst required to achieve favorable electrostatic interactions in the favored TS.

Mechanisms and Origins of Periselectivity of the Ambimodal [6 + 4] Cycloadditions of Tropone to Dimethylfulvene.

The mechanisms and selectivities of the cycloadditions of tropone to dimethylfulvene have been investigated with M06-2X and B3LYP-D3 density functional theory (DFT) calculations and quasi-classical direct molecular dynamics simulations. The originally proposed reaction mechanism (Houk) involves a highly peri-, regio-, and stereoselective [6 + 4] cycloaddition of tropone [4π] to dimethylfulvene [6π], followed by a [1,5] hydrogen shift, and, finally, a second [6 + 4] cycloaddition of tropone [6π] to the cyclopentadiene moiety [4π]. Paddon-Row and Warrener proposed an alternative mechanism: the initial cycloaddition involves a different [6 + 4] cycloaddition in which fulvene acts as the 4π component, and a subsequent Cope rearrangement produces the formal [6 + 4] adduct.

Design and Applications of N-tert-Butyl Sulfinyl Squaramide Catalysts.

A new chiral HBD system, N-tert-butyl sulfinyl squaramide, was designed and synthesized. The core N-tert-butyl sulfinyl squaramide with an 1-aminoindan-2-ol skeleton was found to be an efficient catalyst in the enantioselective Friedel-Crafts alkylation of indoles and acyl phosphonates.

Origins of regioselectivity in 1,3-dipolar cycloadditions of nitrile oxides with alkynylboronates.

Density functional theory (M06-2X) studies of the regioselectivity of 1,3-dipolar cycloaddition reactions of benzo and mesitonitrile oxides with alkynyl pinacol and MIDA boronates are reported. Calculated relative free energies of activation reproduce the experimentally observed product ratios. The electronic energies of activation are found to be mainly controlled by distortion energies required to achieve the transition states.

Distortion, Tether, and Entropy Effects on Transannular Diels-Alder Cycloaddition Reactions of 10-18-Membered Rings.

Density functional theory calculations were performed on a set of 13 transannular Diels-Alder (TADA) reactions with 10-18-membered rings. The results were compared with those for bimolecular and intramolecular Diels-Alder reactions in order to investigate the controlling factors of the high TADA reactivities. The effects of tether length, heteroatoms, and alkynyl dienophiles on reactivity were analyzed.