Catalytic Asymmetric Conjugate Reduction.

Enantioselective reduction reactions are privileged transformations for the construction of trisubstituted stereogenic centers. While these include established synthetic strategies, such as asymmetric hydrogenation, methods based on the enantioselective addition of hydridic reagents to electrophilic prochiral substrates have also gained importance. In this context, the asymmetric conjugate reduction (ACR) of α,ß-unsaturated compounds has become a convenient approach for the synthesis of chiral compounds with trisubstituted stereocenters in α-, ß-, or γ-position to electron-withdrawing functional groups. Because such activating groups are diverse and amenable of further derivatizations, ACRs provide a general and powerful synthetic entry towards a variety of valuable chiral building blocks. This Review provides a comprehensive collection of catalytic ACR methods involving transition-metal, organic, and enzymatic catalysis since its first versions dating back to the late 1970s.

Metal-Free Deoxygenation of Chiral Nitroalkanes: An Easy Entry to α-Substituted Enantiomerically Enriched Nitriles.

A metal-free, mild and chemodivergent transformation involving nitroalkanes has been developed. Under optimized reaction conditions, in the presence of trichlorosilane and a tertiary amine, aliphatic nitroalkanes were selectively converted into amines or nitriles. Furthermore, when chiral ß-substituted nitro compounds were reacted, the stereochemical integrity of the stereocenter was maintained and α-functionalized nitriles were obtained with no loss of enantiomeric excess. The methodology was successfully applied to the synthesis of chiral ß-cyano esters, α-aryl alkylnitriles, and TBS-protected cyanohydrins, including direct precursors of four active pharmaceutical ingredients (ibuprofen, tembamide, aegeline and denopamine).

Nucleophilicity Prediction via Multivariate Linear Regression Analysis.

The concept of nucleophilicity is at the basis of most transformations in chemistry. Understanding and predicting the relative reactivity of different nucleophiles is therefore of paramount importance. Mayr's nucleophilicity scale likely represents the most complete collection of reactivity data, which currently includes over 1200 nucleophiles. Several attempts have been made to theoretically predict Mayr's nucleophilicity parameters N based on calculation of molecular properties, but a general model accounting for different classes of nucleophiles could not be obtained so far. We herein show that multivariate linear regression analysis is a suitable tool for obtaining a simple model predicting N for virtually any class of nucleophiles in different solvents for a set of 341 data points. The key descriptors of the model were found to account for the proton affinity, solvation energies, and sterics.

Enantioselective α-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System.

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides.

Computational Analysis of Enantioselective Pd-Catalyzed α-Arylation of Ketones.

The direct α-arylation of carbonyl compounds emerged over the last two decades as a straightforward method for the formation of C(sp3)-C(sp2) bonds. Mechanistic studies suggested a classical cross-coupling catalytic cycle. This consists of oxidative addition of the aryl halide (ArX) to the Pd(0)-catalyst, transmetallation of the Na- or K-enolate generated in situ, and subsequent reductive elimination. Even though the general reaction mechanism was thoroughly investigated, studies focusing on enantioselective variants of this transformation are rare. Here, the computational study of the [Pd(BINAP)]-catalyzed α-arylation of 2-methyltetralone with bromobenzene is reported. The whole reaction energy profile was computed and several mechanistic scenarios were investigated for the key steps of the reaction, which are the enolate transmetallation and the C-C bond-forming reductive elimination. Among the computed mechanisms, the reductive elimination from the C-bound enolate Pd complex was found to be the most favorable one, providing a good match with the stereoselectivity observed experimentally with different ligands and substrates. Detailed analysis of the stereodetermining transition structures allowed us to establish the origin of the reaction enantioselectivity.

Enantioselective fluorination of homoallylic alcohols enabled by the tuning of non-covalent interactions.

The study of the enantioselective fluorination of homoallylic alcohols via chiral anion phase transfer (CAPT) catalysis using an in situ generated directing group is described. Multivariate correlation analysis, including designer π-interaction derived parameters, revealed key structural features affecting the selectivity at the transition state (TS). Interpretation of the parameters found in the model equation highlights the key differences as well as similarities for the reaction of homoallylic and allylic substrates. A similar T-shaped π-interaction was found to occur between the substrate and the catalyst. The tuning of this crucial interaction by identification of the best combination of phosphoric acid catalyst and boronic acid directing group allowed for the development of a methodology to access γ-fluoroalkenols in typically high enantioselectivities (up to 96% ee).

Enantioselective Synthesis of N,S-Acetals by an Oxidative Pummerer-Type Transformation using Phase-Transfer Catalysis.

Reported is the first enantioselective oxidative Pummerer-type transformation using phase-transfer catalysis to deliver enantioenriched sulfur-bearing heterocycles. This reaction includes the direct oxidation of sulfides to a thionium intermediate, followed by an asymmetric intramolecular nucleophilic addition to form chiral cyclic N,S-acetals with moderate to high enantioselectivites. Deuterium-labelling experiments were performed to identify the stereodiscrimination step of this process. Further analysis of the reaction transition states, by means of multidimensional correlations and DFT calculations, highlight the existence of a set of weak noncovalent interactions between the catalyst and substrate that govern the enantioselectivity of the reaction.

Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States.

The study of the oxidative amination of tetrahydroisoquinolines under chiral-anion phase-transfer (CAPT) catalysis by multidimensional correlation analysis (MCA) is revisited. The parameterization of the transition states (TSs) for the uncatalyzed reaction, the introduction of conformational descriptors, and the use of computed interaction energies and distances as parameters allowed access to a considerably simplified mathematical correlation of substrate and catalyst structure to enantioselectivity. The equation obtained is suggestive of key interactions occurring at the TS. Specifically, the CAPT catalyst is proposed to coordinate the intermediate iminium cation by P=O⋅⋅⋅H-O hydrogen-bonding and N⋅⋅⋅H-C electrostatic interactions. The conformational freedom of the benzyl substituent of the substrate was also found to be important in providing an efficient mode of molecular recognition.

Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates.

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

Parametrization of Non-covalent Interactions for Transition State Interrogation Applied to Asymmetric Catalysis.

The use of computed interaction energies and distances as parameters in multivariate correlations is introduced for postulating non-covalent interactions. This new class of descriptors affords multivariate correlations for two diverse catalytic systems with unique non-covalent interactions at the heart of each process. The presented methodology is validated by directly connecting the non-covalent interactions defined through empirical data set analyses to the computationally derived transition states.

Nickel-Catalyzed Enantioselective Reductive Cross-Coupling of Styrenyl Aziridines.

A Ni-catalyzed reductive cross-coupling of styrenyl aziridines with aryl iodides is reported. This reaction proceeds by a stereoconvergent mechanism and is thus amenable to asymmetric catalysis using a chiral bioxazoline ligand for Ni. The process allows facile access to highly enantioenriched 2-arylphenethylamines from racemic aziridines. Multivariate analysis revealed that ligand polarizability, among other features, influences the observed enantioselectivity, shedding light on the success of this emerging ligand class for enantioselective Ni catalysis.

Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer.

Enantioselective 1,1-diarylation of terminal alkenes enabled by the combination of Pd catalysis with a chiral anion phase transfer (CAPT) strategy is reported herein. The reaction of substituted benzyl acrylates with aryldiazonium salts and arylboronic acids gave the corresponding 3,3-diarylpropanoates in moderate to good yields with high enantioselectivies (up to 98:2 er). Substituents on the benzyl acrylate and CAPT catalyst significantly affect the enantioselectivity, and multidimensional parametrization identified correlations suggesting structural origins for the high stereocontrol.

HSiCl3-Mediated Reduction of Nitro-Derivatives to Amines: Is Tertiary Amine-Stabilized SiCl2 the Actual Reducing Species?

The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro-derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, and spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.

Enantioselective organocatalytic reduction of ß-trifluoromethyl nitroalkenes: an efficient strategy for the synthesis of chiral ß-trifluoromethyl amines.

An efficient organocatalytic stereoselective reduction of ß-trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic ester-dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea-based (S)-valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97% ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched ß-trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal-free catalytic species were computationally investigated; on the basis of DFT transition-state (TS) analysis, a model of stereoselection was also proposed.

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives.

The behavior of readily synthesized and even commercially available (S)-proline derivatives, was studied in the trichlorosilane-mediated reduction of ketoimines. A small library of structurally and electronically modified chiral Lewis bases was considered; such compounds were shown to promote the enantioselective reduction of different substrates in good chemical yields. In the HSiCl3 addition to the model substrate N-phenylacetophenone imine, the organocatalyst of choice led to the formation of the corresponding amine with good stereoselectivity, up to 75% ee. Theoretical studies were also performed in order to elucidate the origin of the stereoselection.