16 research outputs found

    Mechanism of Nakamuraā€™s Bisphosphine-Iron-Catalyzed Asymmetric C(sp<sup>2</sup>)ā€“C(sp<sup>3</sup>) Cross-Coupling Reaction: The Role of Spin in Controlling Arylation Pathways

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    Quantum mechanical calculations are employed to investigate the mechanism and origin of stereoinduction in asymmetric iron-catalyzed CĀ­(sp<sup>2</sup>)ā€“CĀ­(sp<sup>3</sup>) cross-coupling reaction between Grignard reagents and Ī±-chloroesters. A coherent mechanistic picture of this transformation is revealed. These results have broad implications for understanding the mechanisms of iron-catalyzed cross-coupling reactions and rational design of novel iron-based catalysts for asymmetric transformations

    Stereocontrol in a Combined Allylic Azide Rearrangement and Intramolecular Schmidt Reaction

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    Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid

    Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

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    The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (<i>s</i>, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the Ī±-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution

    Mechanism of Rh<sub>2</sub>(II)-Catalyzed Indole Formation: The Catalyst Does Not Control Product Selectivity

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    Possible mechanisms for Rh-promoted indole formation from vinyl/azidoarenes were examined computationally, and a mechanism is proposed in which the Rh catalyst promotes generation of a nitrene but is not directly involved in cyclization

    Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via Nā€‘Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

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    The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity

    Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

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    Alkenes have been discovered to be chelating groups to ZnĀ­(II), enforcing highly stereoselective additions of organozincs to Ī²,Ī³-unsaturated ketones. <sup>1</sup>H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation-controlled carbonyl additions from heteroatom Lewis bases to simple Cā€“C double bonds, broadening the 60 year old paradigm

    Mild Aromatic Palladium-Catalyzed Protodecarboxylation: Kinetic Assessment of the Decarboxylative Palladation and the Protodepalladation Steps

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    Mechanism studies of a mild palladium-catalyzed decarboxylation of aromatic carboxylic acids are described. In particular, reaction orders and activation parameters for the two stages of the transformation were determined. These studies guided development of a catalytic system capable of turnover. Further evidence reinforces that the second stage, protonation of the arylpalladium intermediate, is the rate-determining step of the reaction. The first step, decarboxylative palladation, is proposed to occur through an intramolecular electrophilic palladation pathway, which is supported by computational and mechanism studies. In contrast to the reverse reaction (Cā€“H insertion), the data support an electrophilic aromatic substitution mechanism involving a stepwise intramolecular protonation sequence for the protodepalladation portion of the reaction

    Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings

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    The cross-coupling of sp<sup>3</sup>-hybridized organoĀ­boron reagents via photoredox/ā€‹nickel dual catalysis represents a new paradigm of reactivity for engaging alkylĀ­metallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylĀ­nickelĀ­(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioĀ­selective variant of the transformation reveals an unexpected manifold for stereoĀ­induction involving dynamic kinetic resolution (DKR) of a NiĀ­(III) intermediate wherein the stereoĀ­determining step is <i>reductive elimination</i>. Furthermore, calculations suggest that the DKR-based stereoĀ­induction manifold may be responsible for stereoĀ­selectivity observed in numerous other stereoĀ­convergent Ni-catalyzed cross-couplings and reductive couplings

    Stereocontrol in Asymmetric S<sub>E</sub>ā€² Reactions of Ī³ā€‘Substituted Ī±,Ī²-Unsaturated Aldehydes

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    Asymmetric S<sub>E</sub>ā€² reactions of (<i>E</i>)- and (<i>Z</i>)-Ī³-substituted-Ī±,Ī²-unsaturated aldehydes have been studied for the stereocontrolled preparation of nonracemic alcohols. Mild exchange reactions of allylic stannanes provide access to chiral 1,3-bisĀ­(tolylsulfonyl)-4,5-diphenyl-1,3-diaza-2-borolidines. These reagents display reactivity with the Ī³-substituted Ī±,Ī²-unsaturated aldehydes, which is characterized by matched and mismatched elements of stereocontrol. Computational analysis (using density functional theory) provides valuable insights to guide reaction development

    Highly Selective Radical Relay 1,4-Oxyimination of Two Electronically Differentiated Olefins

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    Radical addition reactions of olefins have emerged as an attractive tool for the rapid assembly of complex structures, and have plentiful applications in organic synthesis, however, such reactions are often limited to polymerization or 1,2-difunctionalization. Herein, we disclose an unprecedented radical relay 1,4-oxyimination of two electronically differentiated olefins with a class of bifunctional oxime carbonate reagents via an energy transfer strategy. The protocol is highly chemo- and regioselective, and three different chemical bonds (Cā€“O, Cā€“C, and Cā€“N bonds) were formed in a single operation in an orchestrated manner. Notably, this reaction provides rapid access to a large variety of structurally diverse 1,4-oxyimination products, and the obtained products could be easily converted into valuable biologically relevant Ī“-hydroxyl-Ī±-amino acids. With a combination of experimental and theoretical methods, the mechanism for this 1,4-oxyimination reaction has been investigated. Theoretical calculations reveal that a radical chain mechanism might operate in the reaction
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