Mechanism Of Stereoselectivity Research Articles

N-Heterocyclic Carbene-Catalyzed Asymmetric C-O Bond Construction Between Benzoic Acid and o-Phthalaldehyde: Mechanism and Origin of Stereoselectivity.

A computational study was contributed to explore the origin of stereoselectivity of NHC-mediated cyclization reaction between benzoic acid and o-phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o-phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C-O bonds, and (5) dissociation of catalyst with the product. The C-O bond formation was testified as the stereoselectivity-determining step, the R-configurational pathway is more energetically favorable than the S-configurational one. The non-covalent interaction (NCI) and atom-in-molecule (AIM) analyses were performed to reveal that the O-H ⋅⋅⋅ O and C-H ⋅⋅⋅ O hydrogen-bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C-O bond.

Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides.

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N-alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

Mechanism and Origins of Stereoselectivity of the Aldol-Tishchenko Reaction of Sulfinimines.

Density functional theory computations have elucidated the mechanism and origins of stereoselectivity in McGlacken’s aldol-Tishchenko reaction for the diastereoselective synthesis of 1,3-amino alcohols using Ellman’s t-butylsulfinimines as chiral auxiliaries. Variations of stereochemical outcome are dependent on the nature of the ketone starting materials used, and the aspects leading to these differences have been rationalized. The intramolecular hydride transfer step is the rate- and stereochemistry-determining step, and all prior steps are reversible.

8+2] vs [4+2] Cycloadditions of Cyclohexadienamines to Tropone and Heptafulvenes—Mechanisms and Selectivities

The cinchona-alkaloid-catalyzed cycloaddition reactions of 2-cyclohexenone with tropone and various heptafulvenes give [8+2] or [4+2] cycloadducts, depending on the substituents present on the heptafulvene. We report the results of new experiments with heptafulvenes, containing diester and barbiturate substituents, which in combination with computational studies were performed to elucidate the factors controlling [8+2] vs [4+2] cycloaddition pathways, including chemo-, regio-, and stereoselectivities of these higher-order cycloadditions. The protonated cinchona alkaloid primary amine catalyst reacts with 2-cyclohexenone to form a linear dienamine intermediate that subsequently undergoes a stepwise [8+2] or [4+2] cycloaddition. Both tropone and the different heptafulvenes initially form [8+2] cycloadducts. The final product is ultimately decided by the reversibility of the [8+2] cycloaddition and the relative thermal stability of the [4+2] products. The stereoisomeric transition states are distinguished by the steric interactions between the protonated catalyst and tropone/heptafulvenes. The [8+2] cycloaddition of barbiturate-heptafulvene afforded products with an unprecedented trans-fusion of the five- and six-membered rings, while the [8+2] cycloadducts obtained from cyanoester-heptafulvene and diester-heptafulvene were formed with a cis-relationship. The mechanism, thermodynamics, and origins of stereoselectivity were explained through DFT calculations using the ωB97X-D density functional.

Computational study of silver-catalyzed stereoselective hydroalkylation of alkynes: Pauli repulsion controlled Z/E selectivity.

The mechanism and origin of stereoselectivity of silver-catalyzed hydroalkylation of alkynes were computationally investigated at the B3LYP-D3BJ/6-311+G(d,p)-SDD//B3LYP/6-31G(d)-LANL2DZ level. The complex of alkynyl trialkylboronate with cationic silver is a key intermediate, which triggers the rate- and stereoselectivity-determining 1,2-migration step. Energy decomposition analysis indicates that the difference of Pauli repulsion dominates the stereoselectivity.

Site- and Enantiodifferentiating C(sp3)-H Oxidation Enables Asymmetric Access to Structurally and Stereochemically Diverse Saturated Cyclic Ethers.

A manganese-catalyzed site- and enantiodifferentiating oxidation of C(sp3)-H bonds in saturated cyclic ethers has been described. The mild and practical method is applicable to a range of tetrahydrofurans, tetrahydropyrans, and medium-sized cyclic ethers with multiple stereocenters and diverse substituent patterns in high efficiency with extremely efficient site- and enantiodiscrimination. Late-stage application in complex biological active molecules was further demonstrated. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity. The ability to employ ether substrates as the limiting reagent, together with a broad substrate scope, and a high level of chiral recognition, represent a valuable demonstration of the utility of asymmetric C(sp3)-H oxidation in complex molecule synthesis.

Evidence for a Stereoselective Mechanism for Bitopic Activity by Extended-Length Antagonists of the D3 Dopamine Receptor.

The D3 dopamine receptor (D3R) has been suggested as a drug target for the treatment of a number of neuropsychiatric disorders, including substance use disorders (SUD). Many D3R-selective antagonists are bivalent in nature in that they engage two distinct sites on the receptor-a primary pharmacophore binds to the orthosteric site, where dopamine binds, whereas a secondary pharmacophore interacts with a unique secondary binding pocket (SBP). When engagement of the secondary pocket exerts allosteric activity, the compound is said to be bitopic. We recently reported the synthesis and characterization of two bitopic antagonists of the D3R, (±)-VK04-87 and (±)-VK05-95, which incorporated a racemic trans-cyclopropylmethyl linking chain. To gain a better understanding of the role of chirality in determining the pharmacology of such compounds, we resolved the enantiomers of (±)-VK04-87. We found that the (+)-isomer displays higher affinity for the D3R and exhibits greater selectivity versus the D2R than the (-)-isomer. Strikingly, using functional assays, we found that (+)-VK04-87 inhibits the D3R in a noncompetitive manner, while (-)-VK04-87 behaves as a purely competitive antagonist, indicating that the apparent allosteric activity of the racemate is due to the (+)-isomer. Molecular dynamic simulations of (+)-VK04-87 and (-)-VK04-87 binding to the D3R suggest that the (+)-isomer is able to interact with the SBP of the receptor whereas the (-)-isomer bends away from this pocket, thus potentially explaining their differing pharmacology. These results emphasize the importance of the linker, and its isomeric conformations, within extended-length molecules for their positioning and engagement within GPCR binding pockets.

Reacting at the most substituted center

Organic Synthesis Nucleophilic substitution is one of the key fundamental mechanisms in organic synthesis that is generally used, except for a few isolated instances, to functionalize sterically unhindered primary and secondary carbon centers. Lanke and Marek report an efficient regio- and stereoselective mechanism of intermolecular nucleophilic displacement at the quaternary carbon center of cyclopropyl carbinol derivatives. It proceeds with a complete inversion of configuration at the quaternary stereocenter and demonstrates high diastereo- and enantioselectivities. Because cyclopropyl carbinols can be easily formed from commercially available alkynes, the proposed mechanism could be used as a general synthetic method to produce various acyclic structures with stereodefined tertiary alkyl groups. J. Am. Chem. Soc. 142 , 5543 (2020).

Strong and Confined Acids Control Five Stereogenic Centers in Catalytic Asymmetric Diels-Alder Reactions of Cyclohexadienones with Cyclopentadiene.

We describe a highly enantioselective Diels–Alder reaction of cross‐conjugated cyclohexadienones with cyclopentadiene, in which five stereocenters are effectively controlled by a strongly acidic and confined imidodiphosphorimidate catalyst. Our approach provides tricyclic products in excellent stereoselectivity. We also report methods to convert the obtained products into useful intermediates and a computational study that aids in gaining deeper insight into the reaction mechanism and origin of stereoselectivity.

Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers.

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

(2Sp,4R,8Sp)-4-Methyl-1-phenyl-diferroceno-5-Z-ethylene-1-phosphinoxide

We present a synthesis of the title compound, a homochiral diferroceno cycle intended for use in asymmetric catalysis. We present a hydrovinylation protocol, which allows the production of the title compound in two steps from a known diferrocenyl precursor. We obtained one of two possible diastereomers selectively and propose a plausible regio- and stereoselective reaction mechanism.

Stereoretention in styrene heterodimerisation promoted by one-electron oxidants.

Radical cations generated from the oxidation of C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C π-bonds are synthetically useful reactive intermediates for C–C and C–X bond formation. Radical cation formation, induced by sub-stoichiometric amounts of external oxidant, are important intermediates in the Woodward–Hoffmann thermally disallowed [2 + 2] cycloaddition of electron-rich alkenes. Using density functional theory (DFT), we report the detailed mechanisms underlying the intermolecular heterodimerisation of anethole and β-methylstyrene to give unsymmetrical, tetra-substituted cyclobutanes. Reactions between trans-alkenes favour the all-trans adduct, resulting from a kinetic preference for anti-addition reinforced by reversibility at ambient temperatures since this is also the thermodynamic product; on the other hand, reactions between a trans-alkene and a cis-alkene favour syn-addition, while exocyclic rotation in the acyclic radical cation intermediate is also possible since C–C forming barriers are higher. Computations are consistent with the experimental observation that hexafluoroisopropanol (HFIP) is a better solvent than acetonitrile, in part due to its ability to stabilise the reduced form of the hypervalent iodine initiator by hydrogen bonding, but also through the stabilisation of radical cationic intermediates along the reaction coordinate.

Computational Exploration of Chiral Iron Porphyrin-Catalyzed Asymmetric Hydroxylation of Ethylbenzene Where Stereoselectivity Arises from π-π Stacking Interaction.

The mechanism and origins of stereoselectivity of chiral iron porphyrin-catalyzed asymmetric hydroxylation of ethylbenzene were explored with density functional theory. The hydrogen atom abstraction is the rate- and stereoselectivity-determining step. In good agreement with experimental results, the formation of the (R)-1-phenylethanol product is found to be the most favorable pathway. The transition state of hydrogen atom abstraction which leads to the (S)-1-phenylethanol product is unfavorable by 1.7 kcal/mol compared to the corresponding transition state which leads to the (R)-1-phenylethanol product. Enantioselectivity arises from an attractive π-π stacking interaction between the phenyl group of ethylbenzene substrate and the naphthyl group of the porphyrin ligand.

Size is Important: Artificial Catalyst Mimics Behavior of Natural Enzymes

Heavily substituted (R)-DTBM-SegPHOS is active in the asymmetric Pd(II)-catalyzed hydrogenation or C−O bond cleavage of α-pivaloyloxy-1-(2-furyl)ethanone, whereas (R)-SegPHOS fails to catalyze either of these transfornations. An extensive network of C−H … H−C interactions provided by the heavily substituted phenyl rings of (R)-DTBM-SegPHOS results in increased stability of all intermediates and transition states in the corresponding catalytic cycles comkpared to the unsubstituted analogue. Moreover, formation of the encounter complex and its rearrangement into the reactive species proceeds in a fashion similar to that seen in natural enzymatic reactions. Computations demonstrate that this ability is the origin of enantioselection in asymmetric hydrogenation, since the stable precursor is formed only when the catalyst is approached by one prochiral plane of the substrate. Catalysis, Enzymatic catalysis, asymmetric hydrogenation, enantioselectivity, catalytic activity, mechanism of stereoselection

Structure‐Guided Evolution of Aryl Alcohol Oxidase from Pleurotus eryngii for the Selective Oxidation of Secondary Benzyl Alcohols

AbstractAryl alcohol oxidase (AAO) is a fungal flavoenzyme capable of oxidizing aromatic primary alcohols into their correspondent aldehydes through a stereoselective hydride abstraction. Unfortunately, this enzyme does not act on secondary benzyl alcohols in racemic mixtures due to the strict control of substrate diffusion and positioning at the active site restricted to primary benzyl alcohols. Here we describe the engineering of AAO from Pleurotus eryngii to oxidize chiral benzyl alcohols with high enantioselectivity. The secondary benzyl alcohol oxidase was remodeled at the active site through four cycles of structure‐guided evolution, including a final step of in vivo site‐directed recombination to address the positive epistatic interactions between mutations. The final variant, with five substitutions and a renovated active site, was characterized at biochemical and computational level. The mutational sculpting helped position the bulkier (S)‐1‐(p‐methoxyphenyl)‐ethanol, improving the mutant's catalytic efficiency by three orders of magnitude relative to the native enzyme while showing a high enantioselectivity (ee >99%). As a promising candidate for racemic resolution, this evolved secondary benzyl alcohol oxidase maintained its natural stereoselective mechanism while displaying activity on several secondary benzyl alcohols.magnified image

Mechanism and Origin of Stereoselectivity of Pd-Catalyzed Cascade Annulation of Aryl Halide, Alkene, and Carbon Monoxide via C–H Activation

The combination of carbon monoxide with palladium chemistry has been demonstrated to be a promising tool for the synthesis of carbonyl compounds, and relative mechanistic studies are desirable to take this field one step further. In this manuscript, density functional theory calculations were performed to investigate the mechanism and origin of stereoselectivity of Pd-catalyzed cascade annulation of aryl iodide, alkene, and carbon monoxide to access the core of cephanolides B and C. It was found that the favorable mechanism proceeds via oxidative addition of Ar-I bond, migratory insertion of the C═C bond, CO insertion into the Pd-(sp3) bond, Ar-H activation, and C(sp2)-C(sp2) reductive elimination. The Ar-H activation is the rate-determining step and goes through an I-assisted outer-sphere concerted metalation-deprotonation mechanism. The C═C bond insertion is irreversible and controls the stereoselectivity. In contrast, other two pathways involving the direct Ar-H activation after the C═C bond insertion is less favored because of the following difficult CO insertion on the palladacycle intermediate. Further calculations well reproduced the experimental results, which supports the rationality of our computation. Meanwhile, the influence of the steric effect of three substitution sites on the stereoselectivity was disclosed, which should be helpful to the further experimental design in the synthesis of analogues.

Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations.

The aminotransferase from Bacillus circulans (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.

Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness

To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.

Mechanistic studies on the N-heterocyclic carbene-catalyzed reaction of isatin-derived enals with hydrazones.

The possible reaction mechanism and origin of stereoselectivity of the NHC-catalyzed annulation reaction between isatin-derived enals and hydrazones were theoretically studied by using density functional theory (DFT). According to the computational results, the Michael addition process was identified to be the stereoselectivity determining step and led to the experimentally observed S-configured product predominantly. The distortion-interaction analysis showed that the electrostatic interaction between two interactive fragments controls the stereoselectivity. Moreover, the types of interactions were further verified by non-covalent interaction analysis, in which the ππ, C-HF and LPπ interactions involved in the favorable transition state are the key for determining the stereoselectivity.

Stereoselective catalysis controlled by a native leucine or variant isoleucine wing-gatekeeper in 2-haloacid dehalogenase.

Comprehensively understanding enzymatic stereoselectivity will assist in the creation of new enzymes for producing optically pure compounds for chemical applications. The essential features for selecting enantiomers are controlled by particular residues or regions of the enzymes. We report a stereoselective mechanism in the D-2-haloacid dehalogenase HadD AJ1, in which L288 is identified as a gatekeeper in the access channel that strictly recognizes D-enantiomers. Mutagenesis of L288 to isoleucine (I) enlarges the size of the channel and allows the enzyme to accommodate L-enantiomers. Furthermore, the wing flip of I288 induces hydrophobic interactions with the L-enantiomer and directly affects the catalytic efficiency. The results illustrate the dynamic catalytic mechanisms of Leu-Ile gatekeepers and provide knowledge for unveiling the basis of stereospecificity in biocatalysts.