Showing papers by "Kendall N. Houk published in 2015"

Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds

Abstract: Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.

Unconventional, chemically stable, and soluble two-dimensional angular polycyclic aromatic hydrocarbons: from molecular design to device applications.

Abstract: ConspectusPolycyclic aromatic hydrocarbons (PAHs), consisting of laterally fused benzene rings, are among the most widely studied small-molecule organic semiconductors, with potential applications in organic field-effect transistors (OFETs) and organic photovoltaics (OPVs). Linear acenes, including tetracene, pentacene, and their derivatives, have received particular attention due to the synthetic flexibility in tuning their chemical structure and properties and to their high device performance. Unfortunately, longer acenes, which could exhibit even better performance, are susceptible to oxidation, photodegradation, and, in solar cells which contain fullerenes, Diels–Alder reactions. This Account highlights recent advances in the molecular design of two-dimensional (2-D) PAHs that combine device performance with environmental stability.New synthetic techniques have been developed to create stable PAHs that extend conjugation in two dimensions. The stability of these novel compounds is consistent with Clar...

Theoretical study of the molecular ordering, paracrystallinity, and charge mobilities of oligomers in different crystalline phases.

Abstract: Molecular ordering and charge transport have been studied computationally for 22 conjugated oligomers fabricated as crystal or thin-film semiconductors. Molecular dynamics (MD) simulations are employed to equilibrate crystal morphologies at 300 K. The paracrystalline order parameter, g, is calculated to characterize structural order in the materials. Charge-transport dynamics are predicted using kinetic Monte Carlo methods based on a charge-hopping mechanism described by the Marcus theory of electron transfer to calculate charge-transfer rates using the VOTCA package. We introduce an error function to assess the reliability of our computed values to reproduce experimental hole mobilities in both crystalline and thin-film morphologies of the 22 conjugated oligomers. For each of the oligomers, we compute hole mobility with three different theoretical models incorporating increasing measures of disorder: (1) a perfect crystal, based on the experimentally derived crystal structure, with no disorder, (2) an MD...

Enzymatic hydroxylation of an unactivated methylene C–H bond guided by molecular dynamics simulations

Abstract: The hallmark of enzymes from secondary metabolic pathways is the pairing of powerful reactivity with exquisite site selectivity. The application of these biocatalytic tools in organic synthesis, however, remains under-utilized due to limitations in substrate scope and scalability. Here, we report how the reactivity of a monooxygenase (PikC) from the pikromycin pathway is modified through computationally guided protein and substrate engineering, and applied to the oxidation of unactivated methylene C–H bonds. Molecular dynamics and quantum mechanical calculations were used to develop a predictive model for substrate scope, site selectivity and stereoselectivity of PikC-mediated C–H oxidation. A suite of menthol derivatives was screened computationally and evaluated through in vitro reactions, where each substrate adhered to the predicted models for selectivity and conversion to product. This platform was also expanded beyond menthol-based substrates to the selective hydroxylation of a variety of substrate cores ranging from cyclic to fused bicyclic and bridged bicyclic compounds. The reactivity of a monooxygenase (P450 PikC) has been modified through protein and substrate engineering, and applied to the oxidation of unactivated methylene C–H bonds. The protein engineering was guided by using molecular dynamics and quantum mechanical calculations to develop a predictive model for substrate scope, site selectivity and stereoselectivity of the C–H hydroxylation.

Origins of Initiation Rate Differences in Ruthenium Olefin Metathesis Catalysts Containing Chelating Benzylidenes

Abstract: A series of second-generation ruthenium olefin metathesis catalysts was investigated using a combination of reaction kinetics, X-ray crystallography, NMR spectroscopy, and DFT calculations in order to determine the relationship between the structure of the chelating o-alkoxybenzylidene and the observed initiation rate. Included in this series were previously reported catalysts containing a variety of benzylidene modifications as well as four new catalysts containing cyclopropoxy, neopentyloxy, 1-adamantyloxy, and 2-adamantyloxy groups. The initiation rates of this series of catalysts were determined using a UV/vis assay. All four new catalysts were observed to be faster-initiating than the corresponding isopropoxy control, and the 2-adamantyloxy catalyst was found to be among the fastest-initiating Hoveyda-type catalysts reported to date. Analysis of the X-ray crystal structures and computed energy-minimized structures of these catalysts revealed no correlation between the Ru–O bond length and Ru–O bond s...

Origins of stereoselectivity in evolved ketoreductases.

Abstract: Mutants of Lactobacillus kefir short-chain alcohol dehydrogenase, used here as ketoreductases (KREDs), enantioselectively reduce the pharmaceutically relevant substrates 3-thiacyclopentanone and 3-oxacyclopentanone. These substrates differ by only the heteroatom (S or O) in the ring, but the KRED mutants reduce them with different enantioselectivities. Kinetic studies show that these enzymes are more efficient with 3-thiacyclopentanone than with 3-oxacyclopentanone. X-ray crystal structures of apo- and NADP+-bound selected mutants show that the substrate-binding loop conformational preferences are modified by these mutations. Quantum mechanical calculations and molecular dynamics (MD) simulations are used to investigate the mechanism of reduction by the enzyme. We have developed an MD-based method for studying the diastereomeric transition state complexes and rationalize different enantiomeric ratios. This method, which probes the stability of the catalytic arrangement within the theozyme, shows a correlation between the relative fractions of catalytically competent poses for the enantiomeric reductions and the experimental enantiomeric ratio. Some mutations, such as A94F and Y190F, induce conformational changes in the active site that enlarge the small binding pocket, facilitating accommodation of the larger S atom in this region and enhancing S-selectivity with 3-thiacyclopentanone. In contrast, in the E145S mutant and the final variant evolved for large-scale production of the intermediate for the antibiotic sulopenem, R-selectivity is promoted by shrinking the small binding pocket, thereby destabilizing the pro-S orientation.

1,3-Dipolar Cycloaddition Reactivities of Perfluorinated Aryl Azides with Enamines and Strained Dipolarophiles

Abstract: The reactivities of enamines and predistorted (strained) dipolarophiles toward perfluoroaryl azides (PFAAs) were explored experimentally and computationally. Kinetic analyses indicate that PFAAs undergo (3 + 2) cycloadditions with enamines up to 4 orders of magnitude faster than phenyl azide reacts with these dipolarophiles. DFT calculations were used to identify the origin of this rate acceleration. Orbital interactions between the cycloaddends are larger due to the relatively low-lying LUMO of PFAAs. The triazolines resulting from PFAA–enamine cycloadditions rearrange to amidines at room temperature, while (3 + 2) cycloadditions of enamines and phenyl azide yield stable, isolable triazolines. The 1,3-dipolar cycloadditions of norbornene and DIBAC also show increased reactivity toward PFAAs over phenyl azide but are slower than enamine–azide cycloadditions.

Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization.

Abstract: The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)–H vs the C(4)–H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For N-oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C–H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C–H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consist...

Molecular Dynamics Explorations of Active Site Structure in Designed and Evolved Enzymes

Abstract: ConspectusThis Account describes the use of molecular dynamics (MD) simulations to reveal how mutations alter the structure and organization of enzyme active sites. As proposed by Pauling about 70 years ago and elaborated by many others since then, biocatalysis is efficient when functional groups in the active site of an enzyme are in optimal positions for transition state stabilization. Changes in mechanism and covalent interactions are often critical parts of enzyme catalysis. We describe our explorations of the dynamical preorganization of active sites using MD, studying the fluctuations between active and inactive conformations normally concealed to static crystallography. MD shows how the various arrangements of active site residues influence the free energy of the transition state and relates the populations of the catalytic conformational ensemble to the enzyme activity. This Account is organized around three case studies from our laboratory. We first describe the importance of dynamics in evaluati...

Involvement of Lipocalin-like CghA in Decalin-Forming Stereoselective Intramolecular [4+2] Cycloaddition

Abstract: Understanding enzymatic Diels-Alder (DA) reactions that can form complex natural product scaffolds is of considerable interest. Sch 210972 1, a potential anti-HIV fungal natural product, contains a decalin core that is proposed to form through a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo (1) and a diastereomeric exo adduct of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin-like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1.

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Abstract: The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol–1 due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings.

Solvent Effects on Polymer Sorting of Carbon Nanotubes with Applications in Printed Electronics

Abstract: Regioregular poly(3-alkylthiophene) (P3AT) polymers have been previously reported for the selective, high-yield dispersion of semiconducting single-walled carbon nanotubes (SWCNTs) in toluene. Here, five alternative solvents are investigated, namely, tetrahydrofuran, decalin, tetralin, m-xylene, and o-xylene, for the dispersion of SWCNTs by poly(3-dodecylthiophene) P3DDT. The dispersion yield could be increased to over 40% using decalin or o-xylene as the solvents while maintaining high selectivity towards semiconducting SWCNTs. Molecular dynamics (MD) simulations in explicit solvents are used to explain the improved sorting yield. In addition, a general mechanism is proposed to explain the selective dispersion of semiconducting SWCNTs by conjugated polymers. The possibility to perform selective sorting of semiconducting SWCNTs using various solvents provides a greater diversity of semiconducting SWCNT ink properties, such as boiling point, viscosity, and surface tension as well as toxicity. The efficacy of these new semiconducting SWCNT inks is demonstrated by using the high boiling point and high viscosity solvent tetralin for inkjet-printed transistors, where solvent properties are more compatible with the inkjet printing head and improved droplet formation.

Substrate control in stereoselective lanthionine biosynthesis

Abstract: Enzymes are typically highly stereoselective catalysts that enforce a reactive conformation on their native substrates. We report here a rare example in which the substrate controls the stereoselectivity of an enzyme-catalysed Michael-type addition during the biosynthesis of lanthipeptides. These natural products contain thioether crosslinks formed by a cysteine attack on dehydrated Ser and Thr residues. We demonstrate that several lanthionine synthetases catalyse highly selective anti-additions in which the substrate (and not the enzyme) determines whether the addition occurs from the re or si face. A single point mutation in the peptide substrate completely inverted the stereochemical outcome of the enzymatic modification. Quantum mechanical calculations reproduced the experimentally observed selectivity and suggest that conformational restraints imposed by the amino-acid sequence on the transition states determine the face selectivity of the Michael-type cyclization.

Molecular dynamics of the Diels-Alder reactions of tetrazines with alkenes and N2 extrusions from adducts.

Abstract: The cycloadditions of tetrazines with cyclopropenes and other strained alkenes have become among the most valuable bioorthogonal reactions. These reactions lead to bicyclic Diels–Alder adducts that spontaneously lose N2. We report quantum mechanical (QM) and quasiclassical trajectory simulations on a number of these reactions, with special attention to stereoelectronic and dynamic effects on spontaneous N2 loss from these adducts. QM calculations show that the barrier to N2 loss is low, and molecular dynamics calculations show that the intermediate is frequently bypassed dynamically. There is a large preference for N2 loss anti to the cyclopropane moiety rather than syn from adducts formed from reactions with cyclopropenes. This is explained by the interactions of the Walsh orbitals of the cyclopropane group with the breaking C–N bonds in N2 loss. Dynamical effects opposing the QM preferences have also been discovered involving the coupling of vibrations associated with the formation of the new C–C bonds ...

Thermodynamic evaluation of aromatic CH/π interactions and rotational entropy in a molecular rotor.

Abstract: A molecular rotor built with a stator formed by two rigid 9β-mestranol units having a 90° bent angle linked to a central phenylene rotator has an ideal structure to examine aromatic CH/π interactions. Energies and populations of the multiple solution conformations from quantum-mechanical calculations and molecular dynamics simulations were combined with variable-temperature (VT) 1H NMR data to establish the enthalpy of this interaction and the entropy associated with rotation about a single bond. Rotational dynamics in the solid state were determined via VT cross-polarization magic-angle spinning 13C NMR spectroscopy.

Computational Exploration of Mechanism and Selectivities of (NHC)Nickel(II)hydride-Catalyzed Hydroalkenylations of Styrene with α-Olefins

Abstract: The [LNiH]+-catalyzed hydroalkenylation between styrene and α-olefins gives distinctive chemo- and regioselectivities with N-heterocyclic carbene (L = NHC) ligands: (a) the reaction with NHC ligands produces the branched tail-to-tail products, whereas the reaction with phosphine ligands (L = PR3) favors the tail-to-head regio-isomers; (b) the reaction stops at heterodimerization with no further oligomerization even with excess α-olefin substrates; (c) typical side reactions with α-olefins, such as isomerization to internal olefins or polymerization, are either significantly diminished or eliminated. To understand the operating mechanism and origins of selectivities, density functional theory (DFT) calculations were performed, and several additional experiments were conducted. The olefin insertion step is found to determine both the regioselectivity and chemoselectivity, leading to the tail-to-tail heterohydroalkenylation product. With a small NHC ligand (1,3-dimethylimidazol-2-ylidene), the intrinsic elec...

QM/MM Protocol for Direct Molecular Dynamics of Chemical Reactions in Solution: The Water-Accelerated Diels–Alder Reaction

Abstract: We describe a solvent-perturbed transition state (SPTS) sampling scheme for simulating chemical reaction dynamics in condensed phase. The method, adapted from Truhlar and Gao’s ensemble-averaged variational transition state theory, includes the effect of instantaneous solvent configuration on the potential energy surface of the reacting system (RS) and allows initial conditions for the RS to be sampled quasiclassically by TS normal mode sampling. We use a QM/MM model with direct dynamics, in which QM forces of the RS are computed at each trajectory point. The SPTS scheme is applied to the acceleration of the Diels–Alder reaction of cyclopentadiene (CP) + methyl vinyl ketone (MVK) in water. We explored the effect of the number of SPTS and of solvent box size on the distribution of bond lengths in the TS. Statistical sampling of the sampling was achieved when distribution of forming bond lengths converged. We describe the region enclosing the partial bond lengths as the transition zone. Transition zones in ...

Origins of the Stereoselectivity in a Thiourea–Primary Amine-Catalyzed Nazarov Cyclization

Abstract: The origins of stereoselectivity of the Nazarov reactions of α-hydroxydivinylketones catalyzed by a vicinal thiourea–primary amine first reported by Tius have been explored with density functional theory. The electrocyclization transition structures in which the thiourea group of the catalyst donates two hydrogen bonds to the keto carbonyl group of the Nazarov reactant and the primary amine accepts a hydrogen bond from the hydroxyl group of the reactant have been modeled. The enantiomeric Nazarov transition structures, which are conventionally described by the absolute sense of conrotation of the dienone termini (“clockwise” or “counterclockwise”) in the literature, are nonplanar and adopt helically chiral conformations. The interactions of these helical electrocyclization transition structures with the chiral catalyst are studied in detail. The organocatalyst is found to employ a combination of hydrogen bonding and steric effects to achieve helical recognition of the Nazarov transition state.

N-Type Conjugated Polymer-Enabled Selective Dispersion of Semiconducting Carbon Nanotubes for Flexible CMOS-Like Circuits

Abstract: Sorting of semiconducting single-walled carbon nanotubes (SWNTs) by conjugated polymers has attracted considerable attention recently because of its simplicity, high selectivity, and high yield. However, up to now, all the conjugated polymers used for SWNT sorting are electron-donating (p-type). Here, a high-mobility electron-accepting (n-type) polymer poly([N,N-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5-(2,2-bithiophene)) (P(NDI2OD-T2)) is utilized for the sorting of high-purity semiconducting SWNTs, as characterized by Raman spectroscopy, dielectric force spectroscopy and transistor measurements. In addition, the SWNTs sorted by P(NDI2OD-T2) have larger diameters than poly(3-dodecylthiophene) (P3DDT)-sorted SWNTs. Molecular dynamics simulations in explicit toluene demonstrate distinct linear or helical wrapping geometry between P(NDI2OD-T2) and different types of SWNTs, likely as a result of the strong interactions between the large aromatic core of the P(NDI2OD-T2) backbone and the hexagon path of SWNTs. By using high-mobility n-type P(NDI2OD-T2) as the sorting polymer, ambipolar SWNT transistors with better electron transport than that attained by P3DDT-sorted SWNTs are achieved. As a result, flexible negated AND and negated OR logic circuits from the same set of ambipolar transistors are fabricated, without the need for doping. The use of n-type polymers for sorting semiconducting SWNTs and achieving ambipolar SWNT transistor characteristics greatly simplifies the fabrication of flexible complementary metal-oxide-semiconductor-like SWNT logic circuits.

Computational and Experimental Studies of Phthaloyl Peroxide-Mediated Hydroxylation of Arenes Yield a More Reactive Derivative, 4,5-Dichlorophthaloyl Peroxide.

Abstract: The oxidation of arenes by the reagent phthaloyl peroxide provides a new method for the synthesis of phenols. A new, more reactive arene oxidizing reagent, 4,5-dichlorophthaloyl peroxide, computationally predicted and experimentally determined to possess enhanced reactivity, has expanded the scope of the reaction while maintaining a high level of tolerance for diverse functional groups. The reaction proceeds through a novel “reverse-rebound” mechanism with diradical intermediates. Mechanistic insight was achieved through isolation and characterization of minor byproducts, determination of linear free energy correlations, and computational analysis of substituent effects of arenes, each of which provided additional support for the reaction proceeding through the diradical pathway.

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade.

Abstract: The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A RhI-catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel–Crafts alkylation.

Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (-)-Nitidasin.

Abstract: Astellatol and nitidasin belong to a subset of sesterterpenoids that share a sterically encumbered trans-hydrindane motif with an isopropyl substituent. In addition, these natural products feature intriguing polycyclic ring systems, posing significant challenges for chemical synthesis. Herein, the evolution of our stereoselective strategy for isopropyl trans-hydrindane sesterterpenoids is detailed. These endeavors included the synthesis of several building blocks, enabling studies toward all molecules of this terpenoid subclass, and of advanced intermediates of our initial route toward a biomimetic synthesis of astellatol. These findings provided the basis for a second-generation and a third-generation approach toward astellatol that eventually culminated in the enantioselective total synthesis of (-)-nitidasin. In particular, a series of substrate-controlled transformations to install the ten stereogenic centers of the target molecule was orchestrated and the carbocyclic backbone was forged in a convergent fashion. Furthermore, the progress toward the synthesis of astellatol is disclosed and insights into some observed yet unexpected diastereoselectivities by detailed quantum-mechanical calculations are provided.

Computational Analysis of the Stereochemical Outcome in the Imidazolidinone-Catalyzed Enantioselective (4 + 3)-Cycloaddition Reaction

Abstract: Computations show why the catalytic, asymmetric (4 + 3)-cycloaddition reaction developed in the Harmata laboratories proceeds with facial selectivity opposite to that for models proposed for related catalyzed Diels–Alder reactions. Computations with M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) show that iminium ions derived from MacMillan’s chiral 2-tert-butyl-5-benzylimidazolidinone and siloxypentadienals undergo (4 + 3)-cycloadditions with furans preferentially on the more crowded face. Conformational reorganization of the benzyl group, to avoid intramolecular interaction with the silyl group, is responsible for differentiating the activation barriers of top- and bottom-face attack.

AlCl3-Catalyzed Ring Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained Cis,Trans-Cycloheptadienone Intermediates

Abstract: We report the first experimental evidence for the generation of highly strained cis,trans-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl3, the cyclobutenamides rearrange to [2.2.1]-bicyclic ketones; DFT calculations provide evidence for a mechanism involving torquoselective 4π-electrocyclic ring opening to a cis,trans-cycloheptadienone followed by a Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-fused cyclobutenamides undergo AlCl3-catalyzed rearrangements to [3.2.1]-bicyclic ketones through cis,trans-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules.

Mechanism and Dynamics of Intramolecular C-H Insertion Reactions of 1-Aza-2-azoniaallene Salts.

Abstract: The 1-aza-2-azoniaallene salts, generated from α-chloroazo compounds by treatment with halophilic Lewis acids, undergo intramolecular C–H amination reactions to form pyrazolines in good to excellent yields. This intramolecular amination occurs readily at both benzylic and tertiary aliphatic positions and proceeds at an enantioenriched chiral center with retention of stereochemistry. Competition experiments show that insertion occurs more readily at an electron-rich benzylic position than it does at an electron-deficient one. The C–H amination reaction occurs only with certain tethers connecting the heteroallene cation and the pendant aryl groups. With a longer tether or when the reaction is intermolecular, electrophilic aromatic substitution occurs instead of C–H amination. The mechanism and origins of stereospecificity and chemoselectivity were explored with density functional theory (B3LYP and M06-2X). The 1-aza-2-azoniaallene cation undergoes C–H amination through a hydride transfer transition state to...

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations

Abstract: The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

Computational and Experimental Investigations of the Formal Dyotropic Rearrangements of Himbert Arene/Allene Cycloadducts

Abstract: The fascinating intramolecular arene/allene cycloaddition discovered by Himbert affords dearomatized, polycyclic intermediates with sufficient strain energy to drive rearrangement processes of the newly formed ring system. We disclose a detailed examination of a thermally induced stepwise dyotropic skeletal rearrangement of these cycloadducts, a reaction also first described by Himbert. We offer computational evidence for a two-stage mechanism for this formal dyotropic rearrangement and provide rationalizations for the significant substitution-dependent rate differences observed in experiments. These investigations led to the development of a Lewis-acid-catalyzed rearrangement of precursors that were unreactive under simple thermal instigation. The isolation of the product of an "interrupted" rearrangement under Lewis acidic conditions provides further support for the proposed stepwise mechanism. Computational results also matched experiments in terms of regiochemical preferences in unsymmetrical rearrangement precursors and explained why lactam O-, S-, and C-heterologues do not easily undergo this rearrangement.