Origin Of Stereoselectivity Research Articles

Demystifying Ziegler–Natta Catalysts: The Origin of Stereoselectivity

Industrial Ziegler–Natta catalysts for polypropylene production are complex formulations with a reputation for being “black boxes”. In this paper, we report the results of an extensive investigation of the three latest commercial generations, performed with advanced high-throughput experimentation tools and methods. The thus obtained database of structure–property relationships, of extraordinary width and depth, provided a high-definition picture of the screened systems, allowing us to highlight important details of their inner workings. In particular, the delicate relationship between surface coverage and lateral steric pressure on the stereoselectivity of the catalytic species, as well as the role of chemisorbed donor and Al-alkyl species on said parameters for different formulations, was revealed.

Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity

The need for metal-free environmentally benign catalysts has provided a strong impetus toward the emergence of hypercoordinate iodine reagents. At this stage of development, molecular insights on the mechanism and origin of stereoselectivity are quite timely. In this study, the origin of stereoinduction in a class of iodoresorcinol-based chiral hypercoordinate iodine-catalyzed synthesis of biologically important spirocyclic bisoxindoles from aryl dianilides has been established by using density functional computations. Formation of an interesting helical fold by the 2,6-chiral amide arms on the resorcinol framework is found to be facilitated by a network of noncovalent interactions. In the chiral environment provided by the helical fold, enantioselectivity is surprisingly controlled in a mechanistic event prior to the ring closure to the final spirocyclic product, unlike that commonly found in spirocyclic ring formation. A vital 1,3-migration of the chiral aryl iodonium (Ar*-I(CF3COO)) in an O-iodonium en...

Insights into the Diels-Alder Reaction between 3-Vinylindoles and Methyleneindolinone without and with the Assistance of Hydrogen-Bonding Catalyst Bisthiourea: Mechanism, Origin of Stereoselectivity, and Role of Catalyst.

The Diels-Alder reaction between 3-vinylindoles and methyleneindolinone can proceed both under catalyst-free conditions and with bisthiourea as the catalyst. The reaction with bisthiourea is much faster and results in higher stereoselectivity of the product. The reaction mechanism, origin of stereoselectivity, and role of the catalyst were elaborated based on quantum mechanical calculations and theoretical methods of reactivity indices, NCI, QTAIM, and distortion/interaction models. In the uncatalyzed reaction, the two C-C bonds that are formed undergo conversion from noncovalent to covalent bonding via a concerted asynchronous mechanism. The weak intermolecular interactions formed in the transition state play important roles. The difference between the interaction and distortion energies is responsible for the stereoselectivity. In the catalyzed reaction, bisthiourea induces both the diene and dienophile to approach it via weak intermolecular interactions, which greatly lowers the energy barrier of the reaction and leads to the product with excellent stereoselectivity. The possible pathways of this reaction were explored, which suggested that the formation of the two C-C bonds goes through either a stepwise or concerted asynchronous mechanism. These results detail the reaction mechanism and shed light on both the significant role of the bisthiourea catalyst and the origin of stereoselectivity for this type of Diels-Alder reaction and related ones.

Theoretical investigation toward organophosphine‐catalyzed [3 + 3] annulation of Morita–Baylis–Hillman carbonates with azomethine imines: Mechanism, origin of stereoselectivity, and role of catalyst

AbstractA computational study on the detailed mechanism and stereoselectivity of the chiral phosphine‐catalyzed C(sp2)H activation/[3 + 3] annulation between Morita–Baylis–Hillman (MBH) carbonates and C,N‐cyclic azomethine imines has been performed. Generally, the catalytic cycle consists of two stages, that is, C(sp2)H activation companied by the dissociation of the t‐BuO group forming phosphonium enolate, and [3 + 3] cycloaddition process followed by regeneration of the catalyst. The calculated results indicate that C(sp2)H activation is rate‐determining while [3 + 3] cycloaddition is stereoselectivity‐determining. Furthermore, the advantageous hydrogen bond interactions and less steric hindrance in the RR configurational CC bond forming transition states should be responsible for the favorability of RR‐configured product among the four possible products. The special role of the organocatalyst was also identified by natural bond orbital (NBO) and global reactivity index (GRI) analyses. The mechanistic insights obtained in the present study should be useful for understanding the novel organocatalytic C(sp2)H activation and cycloaddition cascade reaction of MBH carbonates, and thus provide valuable clues on rational design of efficient organocatalysts for the C(sp2)H activation/functionalizations.

A Combined DFT/IM-MS Study on the Reaction Mechanism of Cationic Ru(II)-Catalyzed Hydroboration of Alkynes

Recently, the Furstner group reported the first general trans-hydroboration of internal alkynes by using a cationic ruthenium(II) complex, [Cp*Ru(MeCN)3]PF6, as the catalyst. Density functional theory (DFT) calculations have been carried out to elucidate the reaction mechanism and the origin of stereoselectivity. The reaction mechanism was suggested to initiate with the rate-determining oxidative hydrogen migration to stereoselectively form a metallacyclopropene intermediate (that determines the trans selectivity), followed by a reductive boryl migration to form the unusual trans-addition alkenyl-borane product. A combined ion-mobility mass spectrometry (IM-MS) and DFT study has also been employed to investigate the unsuccessful reaction with terminal alkynes. Key oxidative-coupling intermediates have been identified. Our results suggest that [2 + 2 + 2] cycloaddition of terminal alkynes to form a very stable arene compound could be the reason for the unsuccessful hydroboration of the terminal alkynes. Mo...

Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone

An increasing number of examples are now being reported that use chiral N-heterocyclic carbenes (NHCs) in conjunction with Lewis acids to enhance catalytic potential. Herein, we provide molecular insights into an NHC-catalyzed stereoselective annulation reaction between N-methylisatin and an enal leading to spirooxindole lactone in the presence of LiCl as the Lewis acid. Mechanistic features as well as the origin of enantio- and diastereoselectivities of the catalytic reaction have been unraveled using the density functional theory (B3LYP-D3) method. The key mechanistic steps of the reaction are identified to proceed through the formation of a Breslow intermediate between the chiral NHC catalyst and the enal, an enantioselective addition of the re face of this intermediate to the re face of the carbonyl group of N-methylisatin, and an intramolecular proton transfer and lactonization that eventually provide access to (2S,3R)-spirooxindole lactone as the final product. In the most preferred pathway, the Lew...

Guanidine-catalyzed asymmetric Strecker reaction: modes of activation and origin of stereoselectivity

Density functional theory calculations were employed to study the catalytic mechanism, modes of activation, and origin of enantioselectivity of guanidine-catalyzed asymmetric Strecker reaction of N-benzhydryl imine with hydrogen cyanide. Two types of bifunctional activation mode were identified, namely conventional bifunctional Brønsted acid activation and unconventional bifunctional Brønsted–Lewis acid activation. The lowest-energy transition states correspond to the conventional bifunctional mode of activation. The calculated enantiomeric excess, based on eight lowest-energy C–C bond forming transition states, is in good accord with observed enantioselectivity. NCI (noncovalent interaction) analysis of the key transition states reveals extensive noncovalent interactions, including aromatic interactions and hydrogen bonds, between the guanidinium catalyst and substrates. Multiple aryl–aryl interactions between the phenyl groups of guanidine catalyst and the phenyl rings of N-benzhydryl imine are the key stabilizations in the most stable (R)-inducing transition state. Differential attractive aryl–aryl stabilization is the major factor for stereoinduction.

ChemInform Abstract: Cobalt‐Catalyzed Enantioselective Hydrogenation of Minimally Functionalized Alkenes: Isotopic Labeling Provides Insight into the Origin of Stereoselectivity and Alkene Insertion Preferences.

AbstractA highly enantioselective hydrogenation of cyclic and 1,1‐disubstituted alkenes, including substructures of natural products and biologically active compounds, is examined.

Insights into Stereoselective Aminomethylation Reaction of α,β-Unsaturated Aldehyde with N,O-Acetal via N-Heterocyclic Carbene and Brønsted Acid/Base Cooperative Organocatalysis.

A theoretical investigation has been performed to interrogate the mechanism and stereoselectivities of aminomethylation reaction of α,β-unsaturated aldehyde with N,O-acetal, which is initiated by N-heterocyclic carbene and Brønsted acid (BA). The calculated results disclose that the reaction contains several steps, i.e., formation of the actual catalysts NHC and Brønsted acid Et3N·H(+) coupled with activation of C-O bond of N,O-acetal, nucleophilic attack of NHC on α,β-unsaturated aldehyde, formation of Breslow intermediate, β-protonation for the formation of enolate intermediate, nucleophilic addition on the Re/Si face to enolate by the activated iminium cation, esterification coupled with regeneration of Et3N·H(+), and dissociation of NHC from product. Addition on the prochiral face of enolate should be the stereocontrolling step, in which the chiral α-carbon is formed. Furthermore, NBO, GRI, and FMO analyses have been performed to explore the roles of catalysts and origin of stereoselectivity. Surprisingly, the added Brønsted base (BB) Et3N plays an indispensable role in the esterification process, indicating the reaction proceeds under NHC-BA/BB multicatalysis rather than NHC-BA dual catalysis proposed in the experiment. This theoretical work provides a case on the exploration of the special roles of the multicatalysts in NHC chemistry, which is valuable for rational design on new cooperative organocatalysis.

Mechanism and origin of stereoselectivity in Robinson annulations leading to bicyclo[3.3.1]nonanes: a rare Curtin–Hammet scenario

Computational studies on the mechanism and diastereoselectivity of base catalyzed synthesis of bicyclo[3.3.1]nonanes by Robinson annulation are reported. Three possible mechanisms were considered, and only the methanol assisted H‐shift process could be the favorable pathway. We have discovered a rare Curtin–Hammet scenario: rate determining steps for the two diastereomeric products formed are completely different reactions, and a correction factor should be considered when gauging the ratio of products from competing pathways. The pathway leading to the anti product is kinetically preferred, which is consistent with experimental results. Finally, the ratio of the two products was rationalized. Copyright © 2016 John Wiley & Sons, Ltd.

Computation and Experiment: A Powerful Combination to Understand and Predict Reactivities.

Computational chemistry has become an established tool for the study of the origins of chemical phenomena and examination of molecular properties. Because of major advances in theory, hardware and software, calculations of molecular processes can nowadays be done with reasonable accuracy on a time-scale that is competitive or even faster than experiments. This overview will highlight broad applications of computational chemistry in the study of organic and organometallic reactivities, including catalytic (NHC-, Cu-, Pd-, Ni-catalyzed) and noncatalytic examples of relevance to organic synthesis. The selected examples showcase the ability of computational chemistry to rationalize and also predict reactivities of broad significance. A particular emphasis is placed on the synergistic interplay of computations and experiments. It is discussed how this approach allows one to (i) gain greater insight than the isolated techniques, (ii) inspire novel chemistry avenues, and (iii) assist in reaction development. Examples of successful rationalizations of reactivities are discussed, including the elucidation of mechanistic features (radical versus polar) and origins of stereoselectivity in NHC-catalyzed reactions as well as the rationalization of ligand effects on ligation states and selectivity in Pd- and Ni-catalyzed transformations. Beyond explaining, the synergistic interplay of computation and experiments is then discussed, showcasing the identification of the likely catalytically active species as a function of ligand, additive, and solvent in Pd-catalyzed cross-coupling reactions. These may vary between mono- or bisphosphine-bound or even anionic Pd complexes in polar media in the presence of coordinating additives. These fundamental studies also inspired avenues in catalysis via dinuclear Pd(I) cycles. Detailed mechanistic studies supporting the direct reactivity of Pd(I)-Pd(I) with aryl halides as well as applications of air-stable dinuclear Pd(I) catalysts are discussed. Additional combined experimental and computational studies are described for alternative metals, these include the discussion of the factors that control C-H versus C-C activation in the aerobic Cu-catalyzed oxidation of ketones, and ligand and additive effects on the nature and favored oxidation state of the active catalyst in Ni-catalyzed trifluoromethylthiolations of aryl chlorides. Examples of successful computational reactivity predictions along with experimental verifications are then presented. This includes the design of a fluorinated ligand [(CF3)2P(CH2)2P(CF3)2] for the challenging reductive elimination of ArCF3 from Pd(II) as well as the guidance of substrate scope (functional group tolerance and suitable leaving group) in the Ni-catalyzed trifluoromethylthiolation of C(sp(2))-O bonds. In summary, this account aims to convey the benefits of integrating computational studies in experimental research to increase understanding of observed phenomena and guide future experiments.

ChemInform Abstract: Theory and Modeling of Asymmetric Catalytic Reactions

AbstractReview: 70 refs.

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.

Cobalt-Catalyzed Enantioselective Hydrogenation of Minimally Functionalized Alkenes: Isotopic Labeling Provides Insight into the Origin of Stereoselectivity and Alkene Insertion Preferences.

The asymmetric hydrogenation of cyclic alkenes lacking coordinating functionality with a C1-symmetric bis(imino)pyridine cobalt catalyst is described and has been applied to the synthesis of important substructures found in natural products and biologically active compounds. High activities and enantioselectivities were observed with substituted benzo-fused five-, six-, and seven-membered alkenes. The stereochemical outcome was dependent on both the ring size and exo/endo disposition. Deuterium labeling experiments support rapid and reversible 2,1-insertion that is unproductive for generating alkane product but accounts for the unusual isotopic distribution in deuterated alkanes. Analysis of the stereochemical outcome of the hydrogenated products coupled with isotopic labeling, stoichiometric, and kinetic studies established 1,2-alkene insertion as both turnover limiting and enantiodetermining with no evidence for erosion of cobalt alkyl stereochemistry by competing β-hydrogen elimination processes. A stereochemical model accounting for the preferred antipodes of the alkanes is proposed and relies on the subtle influence of the achiral aryl imine substituent on the cobalt catalyst.

Importance of Intermolecular Hydrogen Bonding for the Stereochemical Control of Allene-Enone (3+2) Annulations Catalyzed by a Bifunctional, Amino Acid Derived Phosphine Catalyst.

The origin of stereoselectivity in the (3+2) annulation of allenes and enones catalyzed by an amino acid derived phosphine catalyst has been investigated by the use of dispersion-corrected density functional theory. An intermolecular hydrogen bond between the intermediate zwitterion and the enone was found to be the key interaction in the two enantiomeric transition states. Additional stabilization is provided by intermolecular hydrogen-bonding interactions between acidic positions on the catalyst backbone and the substrate. Enantioselectivity occurs because the intermolecular hydrogen bond in the transition state leading to the minor enantiomer is only possible at the expense of reactant distortion.

Importance of Intermolecular Hydrogen Bonding for the Stereochemical Control of Allene–Enone (3+2) Annulations Catalyzed by a Bifunctional, Amino Acid Derived Phosphine Catalyst

AbstractThe origin of stereoselectivity in the (3+2) annulation of allenes and enones catalyzed by an amino acid derived phosphine catalyst has been investigated by the use of dispersion‐corrected density functional theory. An intermolecular hydrogen bond between the intermediate zwitterion and the enone was found to be the key interaction in the two enantiomeric transition states. Additional stabilization is provided by intermolecular hydrogen‐bonding interactions between acidic positions on the catalyst backbone and the substrate. Enantioselectivity occurs because the intermolecular hydrogen bond in the transition state leading to the minor enantiomer is only possible at the expense of reactant distortion.

Pentanidium-Catalyzed Asymmetric Phase-Transfer Conjugate Addition: Prediction of Stereoselectivity via DFT Calculations and Docking Sampling of Transition States, and Origin of Stereoselectivity

Density functional theory (DFT) study, at the M06–2X/6–311+G(d,p)//M06–2X/6–31G(d,p) level, was carried out to examine the catalytic mechanism and origin of stereoselectivity of pentanidium-catalyzed asymmetric phase-transfer conjugate addition. We employed a hybrid approach by combining automated conformation generation through molecular docking followed by subsequent DFT calculation to locate various possible transition states for the enantioselective conjugate addition. The calculated enantioselectivity (enantiomeric excess), based on the key diastereomeric C–C bond-forming transition states, is in good accord with experimental result. Non-covalent interaction analysis of the key transition states reveals extensive non-covalent interactions, including aromatic interactions, hydrogen bonds, and non-classical C–H⋯O interactions between the pentanidium catalyst and substrates. The origin of stereoselectivity was analysed using a strain-interaction model.

N-Heterocyclic Carbene (NHC)-Catalyzed sp3 β-C–H Activation of Saturated Carbonyl Compounds: Mechanism, Role of NHC, and Origin of Stereoselectivity

Activation of inert sp3 β-C–H bonds has attracted widespread attention and been developed with significant progress in recent years, but understanding the mechanism of this kind of reaction continues to be one of the most challenging topics in organic chemistry. In this paper, the possible reaction mechanisms and origin of stereoselectivity in the reaction between saturated carbonyl compounds with enones generating cyclopentenes catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory. The computational results show that the additive DBU plays an important role in NHC-catalyzed C–H activation. Analyses of the natural bond orbital charge and global reaction index indicate that NHC can lower the energy barrier of the entire reaction by activating the α/β-C–H bond rather than by strengthening the nucleophilicity of the reactant as a Lewis base. This is remarkably at variance from previous reports. In addition, the π···π stacking between the phenyl of the enone and the ...

Origins of stereoselectivity in evolved ketoreductases

Mutants of Lactobacillus kefir short-chain alcohol dehydrogenase, used here as ketoreductases (KREDs), enantioselectively reduce the pharmaceutically relevant substrates 3-thiacyclopentanone and 3-oxacyclopentanone. These substrates differ by only the heteroatom (S or O) in the ring, but the KRED mutants reduce them with different enantioselectivities. Kinetic studies show that these enzymes are more efficient with 3-thiacyclopentanone than with 3-oxacyclopentanone. X-ray crystal structures of apo- and NADP(+)-bound selected mutants show that the substrate-binding loop conformational preferences are modified by these mutations. Quantum mechanical calculations and molecular dynamics (MD) simulations are used to investigate the mechanism of reduction by the enzyme. We have developed an MD-based method for studying the diastereomeric transition state complexes and rationalize different enantiomeric ratios. This method, which probes the stability of the catalytic arrangement within the theozyme, shows a correlation between the relative fractions of catalytically competent poses for the enantiomeric reductions and the experimental enantiomeric ratio. Some mutations, such as A94F and Y190F, induce conformational changes in the active site that enlarge the small binding pocket, facilitating accommodation of the larger S atom in this region and enhancing S-selectivity with 3-thiacyclopentanone. In contrast, in the E145S mutant and the final variant evolved for large-scale production of the intermediate for the antibiotic sulopenem, R-selectivity is promoted by shrinking the small binding pocket, thereby destabilizing the pro-S orientation.

ChemInform Abstract: Development of Chiral Bis‐hydrazone Ligands for the Enantioselective Cross‐Coupling Reactions of Aryldimethylsilanolates.

A palladium-catalyzed, enantioselective, aryl–aryl cross-coupling reaction using 1-naphthyldimethylsilanolates and chiral bis-hydrazone ligands has been developed. A family of glyoxal bis-hydrazone ligands containing various 2,5-diarylpyrrolidine groups was prepared to evaluate the influence of ligand structure on the rate and enantioselectivity of the cross-coupling. New synthetic routes to the 1-amino-2,5-diarylpyrrolidines were developed to enable the structure/reactivity–selectivity studies. Role reversal experiments of aryldimethylsilanolates and aryl bromides result in biaryl products with the same configuration and similar enantioselectivities implying that reductive elimination is the stereodetermining step. The origin of stereoselectivity is rationalized through computational modeling of diarylpalldium(II) complex which occurs through a conrotatory motion for the two aryl groups undergoing C–C bond formation.