Enantiodetermining Step Research Articles

The Impact of Computational Uncertainties on the Enantioselectivity Predictions: A Microkinetic Modeling of Ketone Transfer Hydrogenation with a Noyori-type Mn-diamine Catalyst.

Selectivity control is one of the most important functions of a catalyst. In asymmetric catalysis the enantiomeric excess (e.e.) is a property of major interest, with a lot of effort dedicated to developing the most enantioselective catalyst, understanding the origin of selectivity, and predicting stereoselectivity. Herein, we investigate the relationship between predicted selectivity and the uncertainties in the computed energetics of the catalytic reaction mechanism obtained by DFT calculations in a case study of catalytic asymmetric transfer hydrogenation (ATH) of ketones with an Mn‐diamine catalyst. Data obtained from our analysis of DFT data by microkinetic modeling is compared to results from experiment. We discuss the limitations of the conventional reductionist approach of e.e. estimation from assessing the enantiodetermining steps only. Our analysis shows that the energetics of other reaction steps in the reaction mechanism have a substantial impact on the predicted reaction selectivity. The uncertainty of DFT calculations within the commonly accepted energy ranges of chemical accuracy may reverse the predicted e.e. with the non‐enantiodetermining steps contributing to e.e. deviations of up to 25 %.

A Combined Computational and Experimental Study of Rh-Catalyzed C-H Silylation with Silacyclobutanes: Insights Leading to a More Efficient Catalyst System.

The study of new C-H silylation reagents and reactions remains an important topic. We reported that under Rh catalysis, silacyclobutanes (SCBs) for the first time were able to react with C(sp2)-H and C(sp3)-H bonds, however the underlying reasons for such a new reactivity were not understood. Through this combined computational and experimental study on C-H silylation with SCBs, we not only depict a reaction pathway that fully accounts for the reactivity and all the experimental findings but also streamline a more efficient catalyst that significantly improves the reaction rates and yields. Our key findings include: (1) the active catalytic species is a [Rh]-H as opposed to the previously proposed [Rh]-Cl; (2) the [Rh]-H is generated via a reductive elimination/β-hydride (β-H) elimination sequence, as opposed to previously proposed endocyclic β-H elimination; (3) the regio- and enantio-determining steps are identified; (4) and of the same importance, the discretely synthesized [Rh]-H is shown to be a more efficient catalyst. This work suggests that the [Rh]-H/diphosphine system should find further applications in C-H silylations involving SCBs.

Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands.

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

Theoretical mechanistic study of 4CzIPN/Ni0-metallaphotoredox catalyzed enantioselective desymmetrization of cyclic meso-anhydrides.

Visible-light-induced inexpensive photocatalyst and transition metal dual catalytic cross-coupling has attracted much attention for efficiently constructing various chemical bonds. The 4CzIPN/Ni0-metallaphotoredox catalyzed enantioselective desymmetrization of cyclic meso-anhydrides with benzyl trifluoroborates has been systematically investigated using density functional theory (DFT) calculations. A radical mechanism merging reductive quenching (PC-*PC-PC--PC) and nickel catalytic cycles (Ni0-NiII-NiIII-NiI-Ni0) is favourable. It consists of seven major processes: single-electron reduction of *PC by benzyl trifluoroborates to generate benzyl radical, ligand exchange, oxidative addition, radical addition, reductive elimination, reduction of NiI by PC- complex via single-electron transfer (SET) process to obtain ground-state PC, and the ion exchange to afford the desired product enantio-enriched keto-acids and regenerate Ni0 catalyst. The oxidative addition is not only the enantio-determining step but also the rate-determining step of the catalytic cycle. In addition, we tried to disclose the origin of high enantioselectivity from both the steric and electronic effects and explain the origin of diastereoselectivity based on the proposed mechanism. Meanwhile, the difference of catalytic activity between Ni0 and NiII as the initial catalysts is caused by the different activation energy barriers based on their respective favourable reaction pathways. This study will hopefully benefit the future understanding of such photoredox-mediated dual catalyzed asymmetric synthesis.

N-Triflylphosphoramides: highly acidic catalysts for asymmetric transformations.

N-Triflylphosphoramides (NTPA), have become increasingly popular catalysts in the development of enantioselective transformations as they are stronger Brønsted acids than the corresponding phosphoric acids (PA). Their highly acidic, asymmetric active site can activate difficult, unreactive substrates. In this review, we present an account of asymmetric transformations using this type of catalyst that have been reported in the past ten years and we classify these reactions using the enantio-determining step as the key criterion. This compendium of NTPA-catalysed reactions is organised into the following categories: (1) cycloadditions, (2) electrocyclisations, polyene and related cyclisations, (3) addition reactions to imines, (4) electrophilic aromatic substitutions, (5) addition reactions to carbocations, (6) aldol and related reactions, (7) addition reactions to double bonds, and (8) rearrangements and desymmetrisations. We highlight the use of NTPA in total synthesis and suggest mnemonics which account for their enantioselectivity.

Enantioselective Alkylamination of Unactivated Alkenes under Copper Catalysis.

An enantioselective addition reaction of various alkyl groups to unactivated internal alkenes under Cu catalysis has been developed. The reaction uses amide-linked aminoquinoline as the directing group, 4-alkyl Hantzsch esters as the donor of alkyl radicals, and rarely used biaryl diphosphine oxide as a chiral ligand. β-lactams featuring two contiguous stereocenters at Cβ and the β substituent can be obtained in good yield with excellent enantioselectivity. Mechanistic studies indicate that a nucleophilic addition of the alkyl radical to CuII-coordinated alkene is the enantio-determining step.

Chiral Electron-Rich PNP Ligand with a Phospholane Motif: Structural Features and Application in Asymmetric Hydrogenation.

Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand, the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging diaryl ketones: up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining step.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling.

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C-O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Nickel-catalyzed enantioselective reductive carbo-acylation of alkenes

Recently, transition-metal-catalyzed asymmetric dicarbofunctionalization of tethered alkenes has emerged as a powerful method for construction of chiral cyclic carbo- and heterocycles. However, all these reactions rely on facially selective arylmetalation of the pendant olefinic unit. Here, we successfully apply acylnickelation as the enantiodetermining step in the asymmetric nickel-catalyzed reductive carbo-acylation of aryl carbamic chloride-tethered alkenes with primary and secondary alkyl iodides as well as benzyl chlorides as the coupling partners, using manganese as a reducing agent. By circumventing the use of pre-generated organometallics, this reductive strategy enables the synthesis of diverse enantioenriched oxindoles bearing a quaternary stereogenic center under mild reaction conditions with high tolerance of a broad range of functional moieties.

Ni-Catalyzed Enantioconvergent Coupling of Epoxides with Alkenylboronic Acids: Construction of Oxindoles Bearing Quaternary Carbons

We have developed a nickel- nickel/bisphosphine-catalyzed stereoconvergent cross-coupling reaction of epoxides with alkenylboronic acids. Racemic spiroepoxyoxindoles were converted to chiral homoal...

Catalytic Enantioselective Benzilic Ester Rearrangement.

We report the first examples of catalytic enantioselective benzilic ester rearrangement reaction. In the presence of a catalytic amount of Cu(OTf)2 and a chiral box ligand under mild conditions, reaction of 2,3-diketoesters with alcohols afforded structurally diverse α-aryl(alkyl) substituted-α-hydroxy malonates (tartronic esters) in good to excellent yields with high enantioselectivities. Preliminary mechanistic studies indicated that hemiketalization, rather than the dynamic kinetic resolution of hemiketal, was the enantiodetermining step under our reaction conditions.

Catalytic Enantioselective Benzilic Ester Rearrangement

AbstractWe report the first examples of catalytic enantioselective benzilic ester rearrangement reaction. In the presence of a catalytic amount of Cu(OTf)2 and a chiral box ligand under mild conditions, reaction of 2,3‐diketoesters with alcohols afforded structurally diverse α‐aryl(alkyl) substituted‐α‐hydroxy malonates (tartronic esters) in good to excellent yields with high enantioselectivities. Preliminary mechanistic studies indicated that hemiketalization, rather than the dynamic kinetic resolution of hemiketal, was the enantiodetermining step under our reaction conditions.

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters.

β-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,β-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst. As elucidated by DFT calculations and 13C kinetic isotope effect studies, the rate-limiting and enantiodetermining step of the reaction is the protonation of a zwitterionic intermediate by the catalyst. This represents a rare case in which a thiourea compound functions as an asymmetric Brønsted acid catalyst.

Copper(i)/Ganphos catalysis: enantioselective synthesis of diverse spirooxindoles using iminoesters and alkyl substituted methyleneindolinones.

A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of glycine iminoesters with alkyl substituted 3-methylene-2-oxindoles is described. By using de novo design of P-stereogenic phosphines as ligands, spiro[pyrrolidin-3,3'-oxindole]s are generated in good to excellent yields with high asymmetric induction. A further reduced catalyst loading of 0.1 mol% is sufficient to achieve a satisfactory enantioselectivity of 90% ee. The DFT calculations suggest the second Michael addition of the 1,3-dipole to be the rate- and enantio-determining step. A key feature of this 1,3-dipolar cycloaddition is the wide substrate applicability, even with alkyl aldehyde-derived azomethine ylide; thus it has streamlined a highly enantioselective access to a new class of antiproliferative agents, MDM2-p53.

Lewis Base/Brønsted Acid Co-Catalyzed Asymmetric Thiolation of Alkenes with Acid-Controlled Divergent Regioselectivity.

A divergent strategy for the facile preparation of various enantioenriched phenylthio-substituted lactones was developed based on Lewis base/Brønsted acid co-catalyzed thiolation of homoallylic acids. The acid-controlled regiodivergent cyclization (6-endo vs. 5-exo) and acid-mediated stereoselective rearrangement of phenylthio-substituted lactones were explored. Experimental and computational studies were performed to clarify the origins of the regioselectivity and enantioselectivity. The calculation results suggest that C-O and C-S bond formation might occur simultaneously, without formation of a commonly supposed catalyst-coordinated thiiranium ion intermediate and the potential π-π stacking between substrate and SPh as an important factor in the enantio-determining step. Finally, this methodology was applied in the rapid syntheses of the bioactive natural products (+)-ricciocarpin A and (R)-dodecan-4-olide.

Catalytic Asymmetric Radical-Polar Crossover Hydroalkoxylation.

Asymmetric intramolecular hydrofunctionalization of tertiary allylic alcohols is described. This metal hydride-mediated catalytic radical-polar crossover reaction delivers corresponding epoxides in good to high enantioselectivity and constitutes the first example of asymmetric hydrogen atom transfer-initiated process. A series of modified cobalt salen complexes has proven optimal for achieving good efficiency and asymmetric induction. Experimental data suggest that cationic cobalt complexes may be involved in the enantiodetermining step, where cation-π interactions in the catalyst contribute to the asymmetric induction.

Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

AbstractA CuII‐catalyzed asymmetric 1,3‐dipolar cycloaddition using β‐fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3‐fluoroalkyl pyrrolidines, as well as Δ2‐pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo‐adducts could be converted into the corresponding exo′‐adducts by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene mediated epimerization at C2 of the pyrrolidine core. The free‐energy profiles from DFT calculations suggest the Michael addition of the 1,3‐dipole to be the rate‐ and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.

Molecular Field Analysis Using Intermediates in Enantio-Determining Steps Can Extract Information for Data-Driven Molecular Design in Asymmetric Catalysis

Abstract We report that a regression technique, molecular field analysis (MFA), is useful to design molecules in asymmetric catalysis. We found that MFA using intermediate structures in an enantio-determining step enabled extraction and visualization of important 3D-structural information for improving enantioselectivity. Based on the visualized structural information, we designed a catalyst and substrate. DFT calculations indicated that enantioselectivities of the reactions using the compounds would improve significantly. We confirmed experimentally that the designed substrate exhibited higher enantioselectivity than those in the training set.

Nickel-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes.

Reported is an asymmetric reductive dicarbofunctionalization of unactivated alkenes. Under the catalysis of a Ni/BOX system, various aryl bromides, incorporating a pendant olefinic unit, were successfully reacted with an array of primary alkyl bromides in the presence of Zn as a reductant, furnishing a series of benzene-fused cyclic compounds bearing a quaternary stereocenter in high enantioselectivities. Notably, this reaction avoids the use of pregenerated organometallics and demonstrates high tolerance of sensitive functionalities. The preliminary mechanistic investigations reveal that this Ni-catalyzed reaction proceeds as a cascade consisting of migratory insertion and cross-coupling with a nickel(I)-mediated intramolecular 5-exo cyclization as the enantiodetermining step.

Nickel‐Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes

AbstractReported is an asymmetric reductive dicarbofunctionalization of unactivated alkenes. Under the catalysis of a Ni/BOX system, various aryl bromides, incorporating a pendant olefinic unit, were successfully reacted with an array of primary alkyl bromides in the presence of Zn as a reductant, furnishing a series of benzene‐fused cyclic compounds bearing a quaternary stereocenter in high enantioselectivities. Notably, this reaction avoids the use of pregenerated organometallics and demonstrates high tolerance of sensitive functionalities. The preliminary mechanistic investigations reveal that this Ni‐catalyzed reaction proceeds as a cascade consisting of migratory insertion and cross‐coupling with a nickel(I)‐mediated intramolecular 5‐exo cyclization as the enantiodetermining step.