Phosphine-Catalyzed Doubly Stereoconvergent γ-Additions of Racemic Heterocycles to Racemic Allenoates: The Catalytic Enantioselective Synthesis of Protected α,α-Disubstituted α-Amino Acid Derivatives

Methods have recently been developed for the phosphine-catalyzed asymmetric γ-addition of nucleophiles to readily available allenoates and alkynoates to generate useful α,β-unsaturated carbonyl compounds that bear a stereogenic center in either the γ or the δ position (but not both) with high stereoselectivity. The utility of this approach would be enhanced considerably if the stereochemistry at both termini of the new bond could be controlled effectively. In this report, we describe the achievement of this objective, specifically, that a chiral phosphepine can catalyze the stereoconvergent γ-addition of a racemic nucleophile to a racemic electrophile; through the choice of an appropriate heterocycle as the nucleophilic partner, this new method enables the synthesis of protected α,α-disubstituted α-amino acid derivatives in good yield, diastereoselectivity, and enantioselectivity

Caution in the Use of Nonlinear Effects as a Mechanistic Tool for Catalytic Enantioconvergent Reactions: Intrinsic Negative Nonlinear Effects in the Absence of Higher-Order Species

Investigation of the dependence of product enantiometric excess (ee) on catalyst ee is a widely used tool to probe the mechanism of an enantioselective reaction; in particular, the observation of a nonlinear relationship is usually interpreted as an indication of the presence of one or more species that contain at least two units of the chiral entity. In this report, we demonstrate that catalytic enantioconvergent reactions can display an intrinsic negative nonlinear effect that originates purely from the kinetic characteristics of certain enantioconvergent processes and is independent of possible aggregation of the chiral entity. Specifically, this intrinsic negative nonlinear effect can arise when there is a kinetic resolution of the racemic starting material, and its magnitude is correlated with the selectivity factor and the conversion; the dependence on conversion provides a ready means to distinguish it from a more conventional nonlinear effect. We support our analysis with experimental data for two distinct enantioconvergent processes, one catalyzed by a chiral phosphine and the other by a chiral Pd/phosphine complex

Phosphine-Catalyzed Enantioselective Intramolecular [3+2] Annulations To Generate Fused Ring Systems

Substantial progress has been described in the development of asymmetric variants of the phosphine-catalyzed intermolecular [3+2] annulation of allenes with alkenes; however, there have not been corresponding advances for the intramolecular process, which can generate a higher level of complexity (an additional ring and stereocenter(s)). In this study, we describe the application of chiral phosphepine catalysts to address this challenge, thereby providing access to useful scaffolds that are found in bioactive compounds, including diquinane and quinolin-2-one derivatives, with very good stereoselectivity. The products of the [3+2] annulation can be readily transformed into structures that are even more stereochemically rich. Mechanistic studies are consistent with β addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle, followed by a concerted [3+2] cycloaddition to the pendant olefin

Mg2+-Dependent Methyl Transfer by a Knotted Protein: A Molecular Dynamics Simulation and Quantum Mechanics Study

Mg2+ is required for the catalytic activity of TrmD, a bacteria-specific methyltransferase that is made up of a protein topological knot-fold, to synthesize methylated m1G37-tRNA to support life. However, neither the location of Mg2+ in the structure of TrmD nor its role in the catalytic mechanism is known. Using molecular dynamics (MD) simulations, we identify a plausible Mg2+ binding pocket within the active site of the enzyme, wherein the ion is coordinated by two aspartates and a glutamate. In this position, Mg2+ additionally interacts with the carboxylate of a methyl donor cofactor S-adenosylmethionine (SAM). The computational results are validated by experimental mutation studies, which demonstrate the importance of the Mg2+-binding residues for the catalytic activity. The presence of Mg2+ in the binding pocket induces SAM to adopt a unique bent shape required for the methyl transfer activity and causes a structural reorganization of the active site. Quantum mechanical calculations show that the methyl transfer is energetically feasible only when Mg2+ is bound in the position revealed by the MD simulations, demonstrating that its function is to align the active site residues within the topological knot-fold in a geometry optimal for catalysis. The obtained insights provide the opportunity for developing a strategy of antibacterial drug discovery based on targeting of Mg2+-binding to TrmD

Synthesis of C(sp2)-P bonds by palladium-catalyzed reactions : Mechanistic investigations and synthetic studies

This thesis focuses on synthetic and mechanistic aspects of palladium-catalyzed C(sp2)-P bond-forming reactions, with the aim to develop mild and efficient methods for the synthesis of biologically active phosphorus compounds, e.g. DNA analogs. The first part of the thesis is devoted to detailed mechanistic investigations of the palladium-catalyzed C-P cross-coupling reaction, in order to fully understand the underlying chemistry and by rational design of the reaction conditions, improve the overall efficiency of the process and broaden its applicability. In particular influence of palladium coordination by different anions on the rate of ligand substitution and reductive elimination steps of the reaction was studied. It was found that coordination of acetate ion results in unprecedented acceleration of both of the mechanistic steps, what leads to remarkable shortening of the overall reaction times. In-depth kinetic investigations enabled to ascribe the observed effects to ability of the acetate ion to act as a bidentate ligand for palladium. This causes considerable alternation of the reaction mechanism, comparing to the reaction involving halide-containing complexes, and results in significant rate increase. Based on the above mechanistic studies an efficient method for the synthesis of arylphosphonates, using substoichiometric amounts of inorganic acetate additive and reduced amount of catalyst, was developed. In the next part of the thesis, efforts to further enhance the palladium-catalyzed cross-coupling efficiency by using a microwave-assisted synthesis are described. These explorations resulted in a successful development of two protocols, one for a cross-coupling of H-phosphonates and the other for H,H-phosphinates, under the microwave heating conditions. Application of this energy source resulted in extremely short reaction times, measured in minutes. The final chapter of this thesis deals with studies on palladium-catalyzed SN2’ propargylic substitution reaction with phosphorus nucleophiles, which leads to allene products. Efficient procedure for the synthesis of allenylphosphonates and related compounds was developed. The method enables full control of stereochemistry in the allene moiety and at the asymmetric phosphorus center. Some conclusions on the mechanism of the reaction were also drawn.At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 7: In press

Regioselective Morita-Baylis-Hillman Reaction with N-Alkylpyridinium Salts as Electrophiles

Morita-Baylis-Hillman reaction employing N-alkylpyridinium salts as electrophiles has been developed. The reaction is promoted by DBU, which acts both as a catalyst activating the electron-poor olefin as well as a base. The transformation delivers a broad range of α-(hydropyridine)vinyl esters, ketones, and sulfones. The dearomatization of N-alkylquinolinium salts occurs regioselctively at the C-2 position, whereas N-alkylpyridinium salts undergo addition at the C-4 position

Metal-Free S-Arylation of Phosphorothioate Diesters and Re-lated Compounds with Diaryliodonium Salts

We developed a direct metal-free S-arylation of phosphorothioate diesters using diaryliodonium salts. The meth-od allows for the preparation under simple conditions of a broad range of S-aryl phosphorothioates, including complex molecules (e.g., dinucleotide- or TADDOL-derivatives), as well as other related organophosphorus compounds arylated at chalcogen. The reaction proceeds with a full retention of the stereogenic center at phos-phorus atom, opening convenient access to P-chiral products. The mechanism of the reaction was established using DFT calculations

Mechanism and Selectivity of Cooperatively Catalyzed Meyer–Schuster Rearrangement/Tsuji–Trost Allylic Substitution. Evaluation of Synergistic Catalysis by Means of Combined DFT and Kinetics Simulations

The reaction between propargylic alcohols and allylic carbonates, engaging vanadium and palladium catalysts, is an exemplary case of a cooperatively catalyzed process. This combined Meyer–Schuster rearrangement/Tsuji–Trost allylic substitution clearly illustrates the enormous advantages offered by the simultaneous use of two catalysts, but also the inherent challenges regarding selectivity associated with such a reaction design. These challenges originate from the fact that the desired product of the combined process is formed by a bimolecular coupling of the two substrates activated by the respective catalysts. However, these two processes may also occur in a detached way via the reactions of the catalytic intermediates with the starting propargylic alcohol present in the reaction mixture, leading to the formation of two side-products. Herein, we investigate the overall mechanism of this reaction using density functional theory (DFT) methodology. The mechanistic details of the catalytic cycles for all the individual processes are established. In particular, it is shown that the diphosphine ligand, dppm, used in the reaction promotes the formation of dinuclear palladium complexes, wherein only a single metal center is directly involved in the catalysis. Due to the complexity of the combined reaction network, kinetics simulation techniques are employed in order to analyze the overall selectivity. The simulations directly link the results of the DFT calculations with the experimental data and confirm that the computed free energy profiles indeed reproduce the observed selectivities. In addition, a sensitivity analysis is carried out to assess the importance of the individual steps on the product distribution. The observed behavior of the kinetic network is rationalized, and trends in the reaction outcome upon changing the initial conditions, such as the catalysts amounts and ratio, are discussed. The results provide a general framework for understanding the factors governing the selectivity of the cooperatively catalyzed reactions

N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H Alkynylation of Aldehydes with Alkynyliodonium Salts

Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent iodine group-transfer reagent allowed for metal-free C–H functionalization and C–C bond formation. The reaction proceeds under exceptionally mild conditions, at –40 ⁰C and in the presence of an amine base, providing access to an array of heteroaryl-propargyl ketones containing various substituents in good to excellent yields. The mechanism of the reaction was investigated by means of both experiments and density functional theory calculations. 13C-labelling and computations determined that the key alkynyl transfer step occurs via an unusual direct SN2 substitution of iodine-based leaving group by Breslow intermediate nucleophile at an acetylenic carbon. Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the generation of the Breslow intermediate, whereas the subsequent C–C bond-formation is a fast process. These results were fully reproduced and rationalized by the computed full free energy profile of the reaction, showing that the largest energy span is located between protonated NHC and the transition state for the carbene attack on the aldehyde substrate.<br /