Origin Of Regio Research Articles

Theoretical study on the copper-catalyzed asymmetric alkene trifluoromethyl–arylation cross-coupling reaction: origin of regio- and stereo-selectivity

Theoretical studies reported that this reaction proceeds via single electron transfer, radical addition, transmetallation, one-electron oxidation, and reductive elimination.

Mechanism of palladium-catalyzed allylic substitution of tertiary allylic carbonates with sodium sulfinates: unusual bifunctional nucleophile-enabled inner-sphere pathway and origin of regio- and enantioselectivities

DFT calculations were performed to investigate Pd-catalyzed allylic sulfonylation of tertiary allylic carbonates. The bifunctional role of the sulfonate nucleophile enables the C–S bond formation via a unique inner-sphere pathway.

Elucidating the mechanism and origin of diastereoselectivity in scandium-catalyzed β-C(sp3)–H activation and transformation of an aliphatic aldimine

The mechanism and origin of regio- and diastereoselectivity in the reaction of divergent [3 + 2] annulation of aliphatic aldimines with alkenes by scandium-catalyzed β-C(sp3)–H activation have been revealed in detail using DFT calculations.

NHC-catalyzed enantioselective radical reactions of enal and pyridinium salt: mechanism and origin of regio- and stereoselectivities

The origin of regio- and stereoselectivities of NHC-catalyzed enantioselective radical reactions of an enal and a pyridinium salt has been explored via theory for the first time.

Anti-Selective Borylstannylation of Alkynes with (o-Phenylenediaminato)borylstannanes by a Radical Mechanism.

We have achieved the first anti-borylstannylation of alkynes by using (o-phenylenediaminato)borylstannanes. This reaction afforded 1-boryl-2-stannylalkenes with excellent regio- and stereoselectivity by a radical mechanism. This anti-addition manner is in sharp contrast to the syn-selectivity obtained during transition metal-catalyzed borylstannylation. The mild radical conditions enabled a broad substrate scope, and various types of aromatic and aliphatic alkynes were applicable. The origin of regio- and stereoselectivity was elucidated by DFT calculation of the reaction mechanism. The application of the borylstannylation products to cross- or homocoupling reactions provided ready access to either triarylethenes or bisborylbutadienes.

Anti‐Selective Borylstannylation of Alkynes with (o‐Phenylenediaminato)borylstannanes by a Radical Mechanism

AbstractWe have achieved the first anti‐borylstannylation of alkynes by using (o‐phenylenediaminato)borylstannanes. This reaction afforded 1‐boryl‐2‐stannylalkenes with excellent regio‐ and stereoselectivity by a radical mechanism. This anti‐addition manner is in sharp contrast to the syn‐selectivity obtained during transition metal‐catalyzed borylstannylation. The mild radical conditions enabled a broad substrate scope, and various types of aromatic and aliphatic alkynes were applicable. The origin of regio‐ and stereoselectivity was elucidated by DFT calculation of the reaction mechanism. The application of the borylstannylation products to cross‐ or homocoupling reactions provided ready access to either triarylethenes or bisborylbutadienes.

Enantioselective Rh-Catalyzed Azide-Internal-Alkyne Cycloaddition for the Construction of Axially Chiral 1,2,3-Triazoles.

Significant advances have been achieved for the construction of chiral skeletons containing 1,2,3-triazoles via transition-metal-catalyzed asymmetric azide-alkyne cycloaddition; however, most of them have been limited to terminal alkynes in the synthesis of central chirality via desymmetrization and dynamic/dynamic kinetic resolution. Enantioselective transition-metal-catalyzed azide-internal-alkyne cycloaddition is extremely limited. Moreover, the construction of a challenging five-membered (hetero)biaryl axially chiral molecule via transition-metal-catalyzed asymmetric azide-internal-alkyne cycloaddition is still underexplored. Herein, we first report an atroposelective and atom-economical synthesis of axially chiral 1,4,5-trisubstituted 1,2,3-triazoles, directly acting as core chiral units of challenging five-membered atropisomers, via the enantioselective Rh-catalyzed azide-alkyne cycloaddition (E-RhAAC) of internal alkynes and azides. The reaction demonstrates excellent functional group tolerance, forging a variety of C-C axially chiral 1,2,3-triazoles under mild conditions with moderate to excellent yields (up to 99% yield) and generally high to excellent enantioselectivities (up to 99% ee) along with specific regiocontrol. The origin of regio- and enantioselectivity control is disclosed by density functional theory (DFT) calculations, providing new guidance for the facile construction of axially chiral compounds.

Mechanistic Studies of Copper(I)-Catalyzed Stereoselective [2,3]-Sigmatropic Rearrangements of Diazoesters with Allylic Iodides/Sulfides

Density functional theory calculations have revealed the mechanism and origin of regio- and stereoselectivity in [2,3]-sigmatropic rearrangements of diazoesters with allylic iodides/sulfides via ch...

Origin of Regio‐ and Stereoselectivity in the NHC‐catalyzed Reaction of Alkyl Pyridinium with Aliphatic Enal

AbstractThe mechanisms of N‐heterocyclic carbene (NHC)‐catalyzed dearomatization reaction of alkyl pyridinium have been intensively studied using the density functional theory (DFT) method. The chemoselectivity and stereoselectivity were both analyzed based on the established mechanisms. The computational results showed that the chemoselective C4‐addition occurred before the C2‐addition, which is mainly because the C4 atom was more reactive according to the local reactivity analysis. The stereoselectivity was also investigated, and the C−C bond formation step was identified as the stereoselectivity‐determining step. The C−H⋅⋅⋅F and O−H⋅⋅⋅N interactions are identified as the main factors that govern the stereoselectivity by NCI analysis, and the preferred product was the RS‐configuration. This theoretical investigation would provide a case for understanding and predicting the selectivity of the organocatalytic dearomatization reactions of alkyl pyridinium.

Origin of Regio- and Stereospecific Catalysis by 8-Lipoxygenase.

Lipoxygenases (lox's) are a group of non-heme iron containing enzymes that catalyze oxygenation of polyunsaturated fatty acids with precise regio- and stereoselectivities. The origin of regio- and stereospecific catalysis by 8-lox is explored in its wild-type (wt) form and in three mutants (Arg185Ala, Ala592Met, and Ala623His). The catalytic action of this enzyme progresses in two steps, namely, hydrogen abstraction from one double allylic carbon atom of substrate followed by oxygen insertion at the resulting prochiral carbon radical of the substrate. It is shown that the positional specificity of the hydrogen abstraction is a result of conformational dynamics of the bound substrate. While the C10 atom of the substrate is found to be the most probable site of hydrogen abstraction in the wt-lox, hydrogen abstraction from C13 is more favorable in the mutants. The present study discovers the presence of an interconnected network of a three-channel migration pathway operating in the protein matrix for efficient oxygen transport. Each migration channel is bestowed with a pocket at the peripheral region of protein as an oxygen access site, which transfers the oxygen to the active site through a well-connected migration path on a time scale of a few hundred picoseconds. By a careful geometric analysis of the oxygen pockets near the substrate binding cleft, the present study identifies the launching sites for oxygenation at the prochiral carbon centers C8, C11, C12, and C15 and the stereochemistry (R/S) of the corresponding products. It is found that the dominating 8R product in the wt-lox is due to the presence of the aromatic ring pair of Tyr181 and Phe173 acting as a gatekeeper for efficient delivery of oxygen at the pro-R face of C8. The change in the stereochemistry of the products in mutants is explained in terms of dynamic interactions between substrate and the surrounding residues.

A Mechanistic Insight into the Ligand-Controlled Asymmetric Arylation of Aliphatic α-Amino Anion Equivalents: Origin of Regio- and Enantioselectivities.

The reaction mechanism and the origins of regio- and enantioselectivities for Pd-catalyzed asymmetric arylation of aliphatic α-amino anion equivalents were investigated computationally. The results indicate that the reaction proceeds via mainly six sequential steps: deprotonation at α'-site of imine, coordination of α-amino anion to Pd-catalyst, oxidative addition, transmetalation, reductive elimination, as well as the final dissociation to release the product and regenerate the catalyst. The transmetalation is a key step on which both enantioselectivity and regioselectivity depend. The charge inversions of α- and α'-C atoms and the orbital interaction between Pd center and α-C in transmetalation step are responsible for the regioselectivity. Additionally, the intermediates before the dissociation step are critical in controlling the enantioselectivity. Noncovalent interactions analyses indicate that the enantioselectivity primarily arises from the CH···π interactions of isopropyl (iPr) groups with the fluorene and the benzene rings for PdL1-catalyzed reaction.

The origin of regio- and stereoselectivity in the 1,3-dipolar cycloaddition of nitrile oxides with C1-substituted 7-oxabenzonorbornadienes, a DFT study

The origin ofexo/antiselectivity in the 1,3-dipolar cycloaddition of nitrile oxides with C1-substituted 7-oxabenzonorbornadienes has been investigated theoretically.

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

The reactions of excited state singlet molecular oxygen ((1)Δ(g),(1)O(2)) continue to witness interesting new developments. In the most recent manifestation, (1)O(2) 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 (1)O(2) reacts with an oxazolidinone tethered 2-phenyl-1-propenyl system. The computed Gibbs free energy profiles for E- and Z-isomers when (1)O(2) approaches through the hindered and nonhindered diastereotopic faces (by virtue of chiral oxazolidinone) of the enecarbamates exhibit distinct differences. In the case of E-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 Z-isomer. The energy difference between the rate-determining diastereomeric transition structures involved in the most favored ene reaction for E-enecarbamate suggests high diastereoselectivity. In contrast, the corresponding energy difference for Z-enecarbamate in the ene pathway is found to be diminishingly close, implying low diastereoselectivity. However, the dioxetane formation from Z-enecarbamate is predicted to exhibit high diastereoselectivity. The application of activation strain model 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.

Regio- and stereoselectivity of P450-catalysed hydroxylation of steroids controlled by laboratory evolution

A current challenge in synthetic organic chemistry is the development of methods that allow the regio- and stereoselective oxidative C-H activation of natural or synthetic compounds with formation of the corresponding alcohols. Cytochrome P450 enzymes enable C-H activation at non-activated positions, but the simultaneous control of both regio- and stereoselectivity is problematic. Here, we demonstrate that directed evolution using iterative saturation mutagenesis provides a means to solve synthetic problems of this kind. Using P450 BM3(F87A) as the starting enzyme and testosterone as the substrate, which results in a 1:1 mixture of the 2β- and 15β-alcohols, mutants were obtained that are 96-97% selective for either of the two regioisomers, each with complete diastereoselectivity. The mutants can be used for selective oxidative hydroxylation of other steroids without performing additional mutagenesis experiments. Molecular dynamics simulations and docking experiments shed light on the origin of regio- and stereoselectivity.

The origin of regio- and enantioselectivity in the Rh/chiral 1,4-diene-catalyzed addition of phenylboronic acid to enones: insights from DFT

A density functional theory study of the addition of phenylboronic acid to cyclohexenone catalyzed by chiral 1,4-diene-Rh(I) catalyst reveals that 1,4-addition is thermodynamically preferred. The enthalpy-driven enantioselection occurs during the carborhodation step and not the enone binding step, as previously proposed. The chiral ligand selectively destabilizes the disfavored transition state by making it "more early".

Ortho C−H Activation of Haloarenes and Anisole by an Electron-Rich Iridium(I) Complex: Mechanism and Origin of Regio- and Chemoselectivity. An Experimental and Theoretical Study

Reaction of (PNP)Ir(COE)+PF6- (1) (PNP = 2,6-bis(di-tert-butylphosphinomethyl)pyridine; COE = cyclooctene) with benzene yields a stable unsaturated square pyramidal Ir(III) hydrido-aryl complex, 2, which undergoes arene exchange upon reaction with other arenes at 50 °C. Upon reaction of 1 with haloarenes (chlorobenzene and bromobenzene) and anisole at 50 °C, selective ortho C−H activation takes place. No C−halogen bond activation was observed, even in the case of the normally reactive bromobenzene and despite the steric hindrance imposed by the halo substituent. The ortho-activated complexes (8a, 9a, and 10a) exhibited a higher barrier to arene exchange; that is, no exchange took place when heating at a temperature as high as 60 °C. These complexes were more stable, both thermodynamically and kinetically, than the corresponding meta- and para-isomers (8b,c, 9b,c, and 10b,c). The observed selectivity is a result of coordination of the heteroatom to the metal center, which kinetically directs the metal to the ortho C−H bond and stabilizes the resulting complex thermodynamically. Upon reaction of complex 1 with fluorobenzene under the same conditions, no such selectivity was observed, due to low coordination ability of the fluorine substituent. Competition experiments showed that the ortho-activated complexes 8a, 9a, and 10a have similar kinetic stability, while thermodynamically the chloro and methoxy complexes 8a and 10a are more stable than the bromo complex 9a. Computational studies, using the mPW1K exchange−correlation functional and a variety of basis sets for PNP-based systems, provide mechanistic insight. The rate-determining step for the overall C−H activation process of benzene is COE dissociation to form a reactive 14e complex. This is followed by formation of a η2C-C intermediate, which is converted into an η2C-H complex, both being important intermediates in the C−H activation process. In the case of chlorobenzene, bromobenzene, and anisole, η1-coordination via the heteroatom to the 14e species followed by formation of the ortho η2C-H complex leads to selective activation. The unobserved C−halide activation process was shown computationally in the case of chlorobenzene to involve the same Cl-coordinated intermediate as in the C−H activation process, but it experiences a higher activation barrier. The ortho C−H activation product is also thermodynamically more stable than the C−Cl oxidative addition complex.

The Origin of Regio- and Stereoselectivities in 1,3-Cycloadditions of Azomethine Ylides Generated from N-(Benzylidene)trimethylsilylmethylamine and the Related Compounds

Abstract The frontier molecular orbital theory (ab initio procedures) was found to clearly explain the regio- and stereoselectivities in 1,3-dipolar cycloadditions of the azomethine ylides to conjugated olefins yielding the pyrrolidines.