Stereocontrolling Transition States Research Articles

Theoretical Analysis of a Three-Component Reaction between Two Diazo Compounds and a Hydroxylamine Derivative: Mechanism, Enantioselectivity, and Effect of Cooperative Catalysis.

The mechanism, enantioselectivity, and effect of chiral phosphoric acid (CPA) cocatalyst were investigated by the density functional theory (DFT) for the three-component asymmetric aminohydroxylation between two diazo compounds and a hydroxylamine derivative. This type of cascade process is cooperatively catalyzed by Rh2(OAc)4 and CPA. The obtained results clearly indicate that the first step of the global reaction involves a nucleophilic attack at the nitrogen center of N-hydroxyaniline by rhodium-carbene intermediates producing imines. Subsequently, an enolate intermediate was recognized as the key species generated from the second diazo compound and the leaving benzyl alcohol (BnOH) fragment of the first step and in the presence of the same dirhodium catalyst. Then, the reaction is terminated by the asymmetric Mannich-type addition, delivering the aminohydroxylation products of an S-R conformation with the assistance of chiral phosphoric acid. The distortion/interaction analysis shows that the relative distortions of CPA and the enol play a vital role in the energy ordering of the stereocontrolling transition states (TSs). Furthermore, the influence of different substituents in CPA was fully rationalized by distortion/interaction analysis. This study opens up novel synthetic possibilities and improves the reaction predictability when exploring the related types of cooperatively catalyzed organic transformations.

Insights into Synergistic Effects of Counterion and Ligand on Diastereoselectivity Switch in Gold-Catalyzed Post-Ugi Ipso-Cyclization.

The concept of diastereoselectivity switch in gold catalysis is investigated, which primarily depends on the effects of ligand and counterion. The origins of gold-catalyzed post-Ugi ipso-cyclization for the diastereoselective synthesis of spirocyclic pyrrol-2-one-dienone have been explored with density functional theory calculations. The reported mechanism emphasized the importance of the cooperation of ligand and counterion in diastereoselectivity switch, leading to the stereocontrolling transition states. Furthermore, the nonbonding interactions primarily between the catalyst and the substrate play a significant role in the cooperation of ligand and counterion. This work would be useful to further understand the reaction mechanism of gold-catalyzed cyclization and the effects of ligand and counterion.

Insights on Absolute and Relative Stereocontrol in Stereodivergent Cooperative Catalysis.

An increasing number of examples demonstrate that the use of two mutually compatible chiral catalysts in one-pot conditions can help realize the long-cherished goal of simultaneous control of absolute and relative configurations in asymmetric catalysis. Engaging two transition metal catalysts for this goal presents a considerable degree of mechanistic challenge to control the mode of substrate activation as well as origin of enantio- and diastereoselectivities, both of which are central to the burgeoning domain of stereodivergent catalysis. We have employed density functional theory (B3LYP-D3) computations to investigate an important stereodivergent reaction between azaaryl acetamide and cinnamyl methyl carbonate. These compounds participate in the stereocontrolling C-C bond formation in the form of activated substrates, respectively, when bound to chiral Cu-Walphos and Ir-phosphoramidite catalysts. Herein, we provide the molecular origin of how all four stereoisomers of the product bearing two contiguous stereogenic centers could be accessed by changing the combinations of chiral catalysts (C1(R,Rp) or C2(S,Sp) of Cu-Walphos in conjunction with P1(R,R,R) or P2(S,S,S) of Ir-phosphoramidite catalysts). The origin of stereodivergence is identified to depend on the differences in the number and nature of noncovalent interactions (NCIs) in the stereocontrolling transition states. In particular, NCIs between the chiral catalysts (C-H···π in C1-P1 catalyst dyad and C-H···π, C-H···F, and π···π in C2-P1) in stereocontrolling transition states are found to be the differentiating factors rendering one of the four stereochemically distinct transition states to be the lowest energy one for a given catalyst combination. These molecular insights suggest that subtle modifications to the catalyst framework could be further exploited in stereodivergent catalysis.

Mechanism and Origins of Stereoinduction in an Asymmetric Friedel-Crafts Alkylation Reaction of Chalcone Catalyzed by Chiral N, N'-Dioxide-Sc(III) Complex.

The mechanism and selectivity of the asymmetric Friedel-Crafts (F-C) alkylation reaction between indole and chalcone catalyzed by chiral N, N'-dioxide-Sc(III) complexes were investigated at the M06/6-311+G(d,p)//M06/[LANL2DZ,6-31G(d)](SMD,CH2Cl2) level. The reaction occurred via a three-step mechanism: (i) the C3-Cβ bond formation by interacting the most mucleophilic C3 center of indole with the most electrophilic Cβ center of chalcone; (ii) the abstraction of the proton at the C3 atom of indole by counterion OTf-; (iii) proton transfer from HOTf to the Cα atom of chalcone, generating the F-C alkylation product. The reaction preferred to occur along the favorable re-face attack pathway, producing the dominant R-product. The turnover frequency (TOF) of catalysis was predicted to be 1.59 × 10-7 s-1, with a rate constant of K( T) = 1.58 × 10-7 exp(-29057/ RT) dm6·mol-2·s-1 over the temperature range of 248-368 K. Activation strain model (ASM) and energy decomposition analysis (EDA), as well as noncovalent interaction (NCI) analysis, for the stereocontrolling transition state revealed that the substituent attached to the N atom of the amide subunits as well as the amino acid backbone of ligand played important roles in chiral inductivity. The benzyl group with structural flexibility tended to form strong π-π stacking with substrate as well as the terminal phenyl group of chalcone, stabilizing re-face attack transition state.

Unveiling Mechanism of a Quinine-Squaramide Catalyzed Enantioselective Aza-Friedel-Crafts Reaction between Cyclic Trifluoromethyl Ketimine and Naphthol: A DFT Study.

A mechanism study of quinine-squaramide catalyzed enantioselective aza-Friedel-Crafts (aza-F-C) reaction is described using density functional theory (DFT). The most favorable pathway is obtained through the discussions of four possible modes of hydrogen bond interactions, in which the nucleophile is activated by the squaramide N-H groups (N-Ha and N-Hb) and the electrophile binds to the protonated amine by hydrogen bonding. Meanwhile, we have also studied the energy barrier of the stereocontrolling transition states that might play a role of stereoselectivity. In addition, noncovalent interaction (NCI) analyses show a series of favorable cooperative noncovalent interactions, including N-H···O and C-H···F hydrogen-bonding, and π···π interactions. The strong interactions and lower barrier were found for TS3R, indicating the preference for the R-configuration adduct, which is in good agreement with the experimental observations.

Asymmetric Dual Chiral Catalysis using Iridium Phosphoramidites and Diarylprolinol Silyl Ethers: Insights into Stereodivergence

Recent examples of asymmetric dual chiral catalysis (ADCC), where two chiral catalysts are employed under one-pot reaction conditions, have demonstrated how all stereoisomers of a product could be effectively accomplished through changes in the catalyst chirality. Insufficient mechanistic details on the action of two chiral catalysts and molecular insights into the origin of stereodivergence prompted us to undertake a comprehensive density functional theory (B3LYP-D3) investigation on an α-allylation reaction of an aldehyde by using an allyl alcohol, resulting in two new chiral centers in the product. The structural and energetic features of the stereocontrolling transition states helped us delineate how all four product stereoisomers could be accessed by using suitable combinations of chiral iridium phosphoramide and diarylprolinol silyl ether in this ADCC reaction. The covalent activation of the pronucleophile (aldehyde) by the organocatalyst furnishes a chiral enamine, whereas the action of the transit...

Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium‐Catalyzed Asymmetric Hydrogenation

AbstractA computational toolkit (AARON: An automated reaction optimizer for new catalysts) is described that automates the density functional theory (DFT) based screening of chiral ligands for transition‐metal‐catalyzed reactions with well‐defined reaction mechanisms but multiple stereocontrolling transition states. This is demonstrated for the Rh‐catalyzed asymmetric hydrogenation of (E)‐β‐aryl‐N‐acetyl enamides, for which a new C2‐symmetric phosphorus ligand is designed.

Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium-Catalyzed Asymmetric Hydrogenation.

A computational toolkit (AARON: An automated reaction optimizer for new catalysts) is described that automates the density functional theory (DFT) based screening of chiral ligands for transition-metal-catalyzed reactions with well-defined reaction mechanisms but multiple stereocontrolling transition states. This is demonstrated for the Rh-catalyzed asymmetric hydrogenation of (E)-β-aryl-N-acetyl enamides, for which a new C2 -symmetric phosphorus ligand is designed.

Reversing Enantioselectivity Using Noncovalent Interactions in Asymmetric Dearomatization of β-Naphthols: The Power of 3,3' Substituents in Chiral Phosphoric Acid Catalysts.

The sense of enantioselectivity in asymmetric dearomative amination of β-naphthols is reported to pivotally depend on the 3,3' substituents on the chiral BINOL-phosphoric acid (CPA) catalysts. The origin of reversal in the sense of stereoinduction from R to S, when the aryl substituent is changed from 3,5-(CF3)2-C6H3 (CPA-1) to 9-anthryl (CPA-2), has been identified as arising due to the change in the pattern of noncovalent interactions (from predominantly C-H···F to C-H···π interactions) in the stereocontrolling transition states.

Cinchona Alkaloid-Squaramide Catalyzed Sulfa-Michael Addition Reaction: Mode of Bifunctional Activation and Origin of Stereoinduction.

The mechanism of the enantioselective sulfa-Michael addition reaction catalyzed by a cinchona alkaloid-squaramide bifunctional organocatalyst was studied using density functional theory (DFT). Four possible modes of dual activation mechanism via hydrogen bonds were considered. Our study showed that Houk's bifunctional Brønsted acid-hydrogen bonding model, which works for cinchonidine or cinchona alkaloid-urea catalyzed sulfa-Michael addition reactions, also applies to the catalytic system under investigation. In addition, we examined the origin of the stereoselectivity by identifying stereocontrolling transition states. Distortion-interaction analysis revealed that attractive interaction between the substrates and catalyst in the C-S bond forming transition state is the key reason for stereoinduction in this catalytic reaction. Noncovalent interaction (NCI) analysis showed that a series of more favorable cooperative noncovalent interactions, namely, hydrogen bond, π-stacking, and C-H···π interaction and C-H···F interactions, in the major R-inducing transition state. The predicted enantiometric excess is in good accord with the observed value.

Mechanism and Stereoselectivity in an Asymmetric N-Heterocyclic Carbene-Catalyzed Carbon–Carbon Bond Activation Reaction

The mechanism and origin of stereoinduction in a chiral N-heterocyclic carbene (NHC) catalyzed C-C bond activation of cyclobutenone has been established using B3LYP-D3 density functional theory computations. The activation of cyclobutenone as an NHC-bound vinyl enolate and subsequent reaction with the electrophilic sulfonyl imine leads to the lactam product. The most preferred stereocontrolling transition state exhibits a number of noncovalent interactions rendering additional stabilization. The computed enantio- and diastereoselectivities are in good agreement with the previous experimental observations.

Origin of Kinetic Resolution of Hydroxy Esters through Catalytic Enantioselective Lactonization by Chiral Phosphoric Acids.

Kinetic resolution is a widely used strategy for separation and enrichment of enantiomers. Using density functional theory computations, the origin of how a chiral BINOL-phosphoric acid catalyzes the selective lactonization of one of the enantiomers of α-methyl γ-hydroxy ester is identified. In a stepwise mechanism, the stereocontrolling transition state for the addition of the hydroxyl group to the si face of the ester carbonyl in the case of the S isomer exhibits a network of more effective noncovalent interactions between the substrate and the chiral catalyst.

ChemInform Abstract: Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design

AbstractReview: 49 refs.

Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design.

Noncovalent interactions are ubiquitous in organic systems, and can play decisive roles in the outcome of asymmetric organocatalytic reactions. Their prevalence, combined with the often subtle line separating favorable dispersion interactions from unfavorable steric interactions, often complicates the identification of the particular noncovalent interactions responsible for stereoselectivity. Ultimately, the stereoselectivity of most organocatalytic reactions hinges on the balance of both favorable and unfavorable noncovalent interactions in the stereocontrolling transition state (TS). In this Account, we provide an overview of our attempts to understand the role of noncovalent interactions in organocatalyzed reactions and to develop new computational tools for organocatalyst design. Following a brief discussion of noncovalent interactions involving aromatic rings and the associated challenges capturing these effects computationally, we summarize two examples of chiral phosphoric acid catalyzed reactions in which noncovalent interactions play pivotal, although somewhat unexpected, roles. In the first, List's catalytic asymmetric Fischer indole reaction, we show that both π-stacking and CH/π interactions of the substrate with the 3,3'-aryl groups of the catalyst impact the stability of the stereocontrolling TS. However, these noncovalent interactions oppose each other, with π-stacking interactions stabilizing the TS leading to one enantiomer and CH/π interactions preferentially stabilizing the competing TS. Ultimately, the CH/π interactions dominate and, when combined with hydrogen bonding interactions, lead to preferential formation of the observed product. In the second example, a series of phosphoric acid catalyzed asymmetric ring openings of meso-epoxides, we show that noncovalent interactions of the substrates with the 3,3'-aryl groups of the catalyst play only an indirect role in stereoselectivity. Instead, the stereoselectivity of these reactions are driven by the electrostatic stabilization of a fleeting partial positive charge in the SN2-like transition state by the chiral electrostatic environment of the phosphoric acid catalyst. Next, we describe our studies of bipyridine N-oxide and N,N'-dioxide catalyzed alkylation reactions. Based on several examples, we demonstrate that there are many potential arrangements of ligands around a hexacoordinate silicon in the stereocontrolling TS, and one must consider all of these in order to identify the lowest-lying TS structures. We also present a model in which electrostatic interactions between a formyl CH group and a chlorine in these TSs underlie the enantioselectivity of these reactions. Finally, we discuss our efforts to develop computational tools for the screening of potential organocatalyst designs, starting in the context of bipyridine N,N'-dioxide catalyzed alkylation reactions. Our new computational tool kit (AARON) has been used to design highly effective catalysts for the asymmetric propargylation of benzaldehyde, and is currently being used to screen catalysts for other reactions. We conclude with our views on the potential roles of computational chemistry in the future of organocatalyst design.

Transition State Models for Understanding the Origin of Chiral Induction in Asymmetric Catalysis.

In asymmetric catalysis, a chiral catalyst bearing chiral center(s) is employed to impart chirality to developing stereogenic center(s). A rich and diverse set of chiral catalysts is now available in the repertoire of synthetic organic chemistry. The most recent trends point to the emergence of axially chiral catalysts based on binaphthyl motifs, in particular, BINOL-derived phosphoric acids and phosphoramidites. More fascinating ideas took shape in the form of cooperative multicatalysis wherein organo- and transition-metal catalysts are made to work in concert. At the heart of all such manifestations of asymmetric catalysis, classical or contemporary, is the stereodetermining transition state, which holds a perennial control over the stereochemical outcome of the catalytic process. Delving one step deeper, one would find that the origin of the stereoselectivity is delicately dependent on the relative stabilization of one transition state, responsible for the formation of the predominant stereoisomer, over the other transition state for the minor stereoisomer. The most frequently used working hypothesis to rationalize the experimentally observed stereoselectivity places an undue emphasis on steric factors and tends to regard the same as the origin of facial discrimination between the prochiral faces of the reacting partners. In light of the increasing number of asymmetric catalysts that rely on hydrogen bonding as well as other weak non-covalent interactions, it is important to take cognizance of the involvement of such interactions in the sterocontrolling transition states. Modern density functional theories offer a pragmatic and effective way to capture non-covalent interactions in transition states. Aided by the availability of such improved computational tools, it is quite timely that the molecular origin of stereoselectivity is subjected to more intelligible analysis. In this Account, we describe interesting molecular insights into the stereocontrolling transition states of five reaction types, three of which provide access to chiral quaternary carbon atoms. While each reaction has its own utility and interest, the focus of our research has been on the mechanism and the origin of the enantio- and diastereoselectivity. In all of the examples, such as asymmetric diamination, sulfoxidation, allylation, and Wacker-type ring expansion, the role played by non-covalent interactions in the stereocontrolling transition states has been identified as crucial. The transfer of the chiral information from the chiral catalyst to the product is identified as taking place through a series of non-covalent interactions between the catalyst and a given position/orientation of the substrate in the chiral environment offered by the axially chiral catalyst. The molecular insights enunciated herein allude to abundant opportunities for rational modifications of the present generation of catalysts and the choice of substrates in these as well as related families of reactions. It is our intent to propose that the domain of asymmetric catalysis could enjoy additional benefits by having knowledge of the vital stereoelectronic interactions in the stereocontrolling transition states.

Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and Brønsted Acid in γ-Lactam Formation: Insights into Mechanism and Stereoselectivity

Current developments in the burgeoning area of cooperative asymmetric catalysis indicate the use of N-heterocyclic carbenes (NHCs) in conjunction with other catalysts such as a Bronsted acid. Herein, mechanistic insights derived through a comprehensive DFT (M06-2X) computational study on a dual catalytic reaction between an enal and an imine leading to trans-γ-lactams, catalyzed by a chiral NHC and benzoic acid, is presented. In the most preferred pathway, we note that the NHC catalyst activates one of the reactants (enal) in the form of a Breslow intermediate, whereas the electrophilic partner (imine) is activated by the benzoic acid through protonation of the imino nitrogen. In this article, we focus on the origin of cooperative action of both catalysts as well as on the stereoselectivity by identifying the stereocontrolling transition states. The explicit and cooperative participation of the Bronsted acid and NHC lowers the energetic barrier both in the Breslow intermediate formation and in the stereoc...

Theory and Modeling of Asymmetric Catalytic Reactions.

Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman-Traxler) or those catalyzed by the organocatalyst proline (Houk-List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For α-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH(+) or NF(+) at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman-Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische's ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon-carbon bond formation occurs via a chair Zimmerman-Traxler-type transition structure and that a formyl CH···O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity.

Origin of Stereodivergence in Cooperative Asymmetric Catalysis with Simultaneous Involvement of Two Chiral Catalysts.

Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match-mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites PR/S-Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of PR/S-Ir-π-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C-C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona-enamine plays an anchoring role. The quinolone ring is noted as participating in a π-stacking interaction with the phenyl ring of the Ir-π-allyl moiety in the case of PR with the (8R,9R)-cinchona catalyst combination, whereas a series of C-H···π interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when PR is used with (8S,9S)-cinchona.

A revisit to proline-catalyzed amination under basic conditions: Insight into the key intermediates and stereocontrolling transition state models for the reversal of enantioselectivity

Density functional calculations have been performed to revisit the reversal of the product enantioselectivity in proline-catalyzed amination between propanal and diethylazodicarboxylate under basic conditions. The efficiencies of three stereodetermining transition state models, involving the key intermediates with different nucleophilic natures e.g. enamine carboxylic acid, enamine carboxylate, and prolinate–DBUH+ to mimic the base-free and basic conditions, are examined at the SMD/mPW1K/6-31+G∗∗ computational level. The activation strain analysis has been employed to explain the stereoselectivity associated with different models. The TS model involving the experimentally validated ion pair intermediate of prolinate–DBUH+ as the key nucleophile in the CN bond formation step exhibits good performance in reproducing the observed reversal of enantioselectivity when switching the conditions from base-free to base-present. The computations support the idea that the simple acid/base manipulation can change the active intermediates and subsequently alter the asymmetric induction strategy in the stereodetermining step.

Axial coordination dichotomy in dirhodium carbenoid catalysis: a curious case of cooperative asymmetric dual-catalytic approach toward amino esters.

One of the most recent developments in asymmetric catalysis is to employ two or more catalysts under one-pot reaction conditions. This article presents some interesting mechanistic insights on a cooperative dual-catalytic protocol relying on the catalytic ability of dirhodium carbenoid (derived from rhodium(II) tetracarboxylate and a diazo compound) and a chiral spirophosphoric acid ((R)-SPA) in an asymmetric N-H insertion reaction. We have employed DFT(M06 and B3LYP) computational methods to identify the stereocontrolling transition states wherein a chiral (R)-SPA protonates a dirhodium-bound enol intermediate. A true cooperative action elicited by both catalysts has been noted in the enantioselective protonation. More importantly, whether the second axial ligand on the remote rhodium atom could influence the energetic features of the reaction has been probed for the first time. In all steps (such as nitrogen extrusion, addition of amine to the dirhodium carbenoid, and the enol formation), except that in the stereocontrolling event, no major effect of axial ligation has been noticed. However, the presence of the axial ligand helps in stabilizing the protonation transition state and reduces the activation barrier for protonation, suggesting a vital role in stereoselectivity. The predicted sense of stereoselectivities is in good agreement with the experimental results.