Noninnocent Role of <i>N</i>‑Methyl Pyrrolidinone in Thiazolidinethione-Promoted Asymmetric Aldol Reactions

The origin of stereoselectivity in the reaction between α-azido titanium enolate derived from chiral auxiliary <i>N</i>-acyl thiazolidinethione and benzaldehyde is established using the DFT(B3LYP) method. A nonchelated transition state with <i>N</i>-methyl-2-pyrrolidinone (NMP) bound to a TiCl₃ enolate is found to be energetically the most preferred model responsible for the formation of an Evans <i>syn</i> aldol product. The TS model devoid of NMP, although of higher energy, is found to be successful in predicting the right stereochemical outcome

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 transition-metal catalyst (chiral Ir phosphoramidite, <b>P</b>) on racemic allyl alcohol gives the Ir-π-allyl phosphoramidite complex [IrCl­(<b>P</b>)₂(π-allyl)], which serves as the electrophilic partner. The enantioselectivity is directly controlled by the sense of axial chirality of the Ir-bound phosphoramidite ligand, which affects whether an <i>R</i> or <i>S</i> stereocenter would be generated at the β-carbon of the product. The “recognition/interaction” between the two chiral catalysts in the diastereocontrolling C–C bond formation transition states through a series of weak noncovalent interactions (C–H···π, C–H···O, C–H···Cl, C–H···F, and lone pair···π) is identified as playing a pivotal role in influencing the favorable mode of addition of the <i>si</i> or <i>re</i> face of the chiral enamine to Ir-π-allyl phosphoramidite (<i>si-si</i>/<i>re-re</i>) and hence controls the chirality at the α-carbon atom of the developing product

On the Origin of Regio- and Stereoselectivity in Singlet Oxygen Addition to Enecarbamates

The reactions of excited state singlet molecular oxygen (¹Δ_g,¹O₂) continue to witness interesting new developments. In the most recent manifestation, ¹O₂ is tamed to react with enecarbamates in a stereoselective manner, which is remarkable, in view of its inherently high reactivity (Acc. Chem. Res. 2008, 41, 387). Herein, we employed the CAS-MP2­(8,7)/6-31G* as well as the CAS-MP2­(10,8)/6-31G* computations to unravel the origin of (i) diastereoselectivities in dioxetane or hydroperoxide formation and (ii) regioselectivity leading to a [2 + 2] cycloadduct or an ene product when ¹O₂ reacts with an oxazolidinone tethered 2-phenyl-1-propenyl system. The computed Gibbs free energy profiles for <i>E</i>- and <i>Z</i>-isomers when ¹O₂ approaches through the hindered and nonhindered diastereotopic faces (by virtue of chiral oxazolidinone) of the enecarbamates exhibit distinct differences. In the case of <i>E</i>-isomer, the relative energies of the transition structures responsible for hydroperoxide (ene product) are lower than that for dioxetane formation. On the other hand, the ene pathway is predicted to involve higher barriers as compared to the corresponding dioxetane pathway for <i>Z</i>-isomer. The energy difference between the rate-determining diastereomeric transition structures involved in the most favored ene reaction for <i>E</i>-enecarbamate suggests high diastereoselectivity. In contrast, the corresponding energy difference for <i>Z</i>-enecarbamate in the ene pathway is found to be diminishingly close, implying low diastereoselectivity. However, the dioxetane formation from <i>Z</i>-enecarbamate is predicted to exhibit high diastereoselectivity. The application of <i>activation strain model</i> as well as the differences in stereoelectronic effects in the stereocontrolling transition structures is found to be effective toward rationalizing the origin of selectivities reported herein. These predictions are found to be in excellent agreement with the experimental observations

Mechanistic Insights on Cooperative Asymmetric Multicatalysis Using Chiral Counterions

Cooperative multicatalytic methods are steadily gaining popularity in asymmetric catalysis. The use of chiral Brønsted acids such as phosphoric acids in conjunction with a range of transition metals has been proven to be effective in asymmetric synthesis. However, the lack of molecular-level understanding and the accompanying ambiguity on the role of the chiral species in stereoinduction continues to remain an unresolved puzzle. Herein, we intend to disclose some novel transition state models obtained through DFT­(B3LYP and M06) computations for a quintessential reaction in this family, namely, palladium-catalyzed asymmetric Tsuji–Trost allylation of aldehydes. The aldehyde is activated as an enamine by the action of a secondary amine (organocatalysis), which then adds to an activated Pd-allylic species (transition metal catalysis) generated through the protonation of allyic alcohol by chiral BINOL-phosphoric acid (Brønsted acid catalysis). We aim to decipher the nature of chiral BINOL-phosphates and their role in creating a quaternary chiral carbon atom in this triple catalytic system. The study reports the first transition state model capable of rationalizing chiral counterion-induced enantioselectivity. It is found that the chiral phosphate acts as a counterion in the stereocontrolling event rather than the conventional ligand mode

Deciphering the Origin of Stereoinduction in Cooperative Asymmetric Catalysis Involving Pd(II) and a Chiral Brønsted Acid

The density functional (M06) computations on a cooperative multicatalytic reaction involving palladium acetate and a chiral Brønsted acid in the conversion of an indenyl cyclobutanol to spirocyclic indene bearing a quaternary carbon ring junction are reported. A chiral Pd-<i>bis</i>-phosphate is identified as the active catalyst in the enantioselective ring expansion as compared to alternative possibilities wherein the chiral phosphate/phosphoric acid is in the outer sphere of palladium. The enantiocontrolling transition state exhibited more effective C–H···π interactions, lower distortion of the catalyst, and an orthogonal orientation of the bulky phosphate ligands

Mechanistic Insights on Organocatalytic Enantioselective Decarboxylative Protonation by Epicinchona-Thiourea Hybrid Derivatives

Mechanism and the origin of enantioselectivity in the decarboxylative protonation of α-amino malonate hemiester promoted by epicinchona–thiourea hybrid organocatalyst is established by using the DFT­(M06-2X/6-311+G**//ONIOM2) computational methods. The origin of stereoselectivity rendered by this hybrid bifunctional catalyst in asymmetric protonation is investigated for the first time using suitable transition-state models. A detailed conformational analysis of <i>N</i>-[3,5-bis­(trifluoromethyl)]­phenylthiourea-based epicinchonidine reveals the potential for a bifunctional mode of activation of the substrate α-amino malonate hemiester through hydrogen bonding. Six different conformer families differing in characteristic dihedral angles are identified within a range of 16 kcal/mol with respect to the lowest energy conformer. Different likely mechanistic pathways obtained through detailed analysis of the transition states and intermediates are compared. It is identified that in the preferred pathway, the decarboxylation is followed by a direct proton transfer from the chiral quinuclidinium moiety to the enolate carbon as opposed to a conventional protonation at the enolate oxygen followed by a keto–enol tautomerization. The factors responsible for high levels of observed stereoselectivity are traced to interesting hydrogen-bonding interactions offered by the thiourea–cinchona bifunctional framework. The predicted stereoselectivities using computed Gibbs free energies of diastereomeric transition states are in fair agreement with the experimental stereoselectivities

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 Brønsted 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 <i>trans</i>-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 Brønsted acid and NHC lowers the energetic barrier both in the Breslow intermediate formation and in the stereocontrolling step through a number of C–H···π, N–H···O, and π···π noncovalent interactions. The enantio- and diastereoselectivities computed using the transition state models with an explicit benzoic acid are in good agreement with the earlier experimental reports

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 <b>P</b>_{<i>R</i>/<i>S</i>}–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 <b>P</b>_{<i>R</i>/<i>S</i>}–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 <b>P</b>_<i>R</i> with the (8<i>R</i>,9<i>R</i>)-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 <b>P</b>_<i>R</i> is used with (8<i>S</i>,9<i>S</i>)-cinchona

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

Mechanism of Cooperative Catalysis in a Lewis Acid Promoted Nickel-Catalyzed Dual C–H Activation Reaction

The mechanism of cooperativity offered by AlMe₃ in a Ni-catalyzed dehydrogenative cycloaddition between substituted formamides and an alkyne is investigated by using DFT(SMD_toluene/M06/6-31G**) methods. The preferred pathway is identified to involve dual C–H activation, with first a higher barrier formyl C(<i>sp</i>²)–H oxidative insertion followed by benzylic methyl C(<i>sp</i>³)–H activation. The cooperativity is traced to be of kinetic origin as evidenced by stabilized transition states when AlMe₃ is bound to the formyl group, particularly in the oxidative insertion step