Enantioselectivity-determining Step Research Articles

Unveiling the Mechanistic Role of Chiral Palladacycles in Pd(II)-Catalyzed Enantioselective C(sp3)-H Functionalization.

Palladium-catalyzed enantioselective C(sp3)-H functionalization reactions has attracted considerable attention due to its ability for the synthesis of enantiomerically enriched molecules and stimulation of novel retrosynthetic disconnections. Understanding the reaction mechanism, especially the stereochemical process of the reaction, is crucial for the rational design of more efficient catalytic systems. Previously, we developed a Pd(II)/sulfoxide-2-hydroxypridine (SOHP) catalytic system for asymmetric C(sp3)-H functionalization reactions. In this study, we focused on unraveling the chemistry of chiral palladacycles involved in the Pd(II)-catalyzed enantioselective C(sp3)-H functionalization. We have isolated key palladacycle intermediates involved in the enantioselective β-C(sp3)-H arylation of carboxylic acids catalyzed by the Pd(II)/SOHP system. These palladacycles, exhibiting ligand-induced chirality, provided a significant opportunity to investigate the stereochemical process and the ligand effect in this asymmetric C-H functionalization. Our investigation provided direct evidence for the C-H palladation step as the enantioselectivity-determining step, which forms diastereomeric palladacycles that exhibited preservation of chirality in the functionalization step. DFT calculations provided insights into the chiral induction in palladacycle formation. This work highlights the value of chiral palladacycle chemistry in offering mechanistic insights into the Pd(II)-catalyzed asymmetric C(sp3)-H functionalization reactions.

Mechanistic study of the Ni-catalyzed hydroalkylation of 1,3-dienes: The origins of regio- and enantioselectivities and a further rational design.

The development of the catalytic regio- and enantioselective hydrofunctionalization of 1,3-dienes remains a challenge and requires deep insight into the reaction mechanisms. We herein thoroughly studied the reaction mechanism of the Ni-catalyzed hydroalkylation of 1,3-dienes with ketones by density functional theory (DFT) calculations. It reveals that the reaction is initiated by stepwise oxidative addition of EtO-H followed by 1,3-diene migratory insertion to generate the alkylnickel(II) intermediate, rather than the experimentally proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism. In addition, we rationalized the role of t BuOK in the subsequent addition of enolate of ketone and transmetalation process. Based on the whole catalysis, the CC reductive elimination step, turns out to be the rate- and enantioselectivity-determining step. Furthermore, we disclosed the origins of the regio- and enantioselectivity of the product, and found that the 1,2-selectivity lies in the combination effects of the ligand-substrate electrostatic interactions, orbital interactions and Pauli repulsions, while the enantioselectivity mainly arises from substrate-ligand steric repulsions. Based on mechanistic study, new biaryl bisphosphine ligands affording higher enantioselectivity were designed, which will help to improve current catalytic systems and develop new transition-metal-catalyzed hydroalkylations.

Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Origin of Enantio- and Chemoselectivity in the Synthesis of Spirocycles via Palladium/Xu-Phos-Catalyzed Cascade Heck/Remote C(sp2)-H Alkylation: A Computational Mechanistic Study.

Density functional theory (DFT) calculations were performed to study the mechanism and factors affecting the enantio-, regio-, and chemoselectivities in the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp2)-H alkylation reaction. The active catalyst is found to be able to sustain coordination with P and S atoms and can adapt its coordination mode to accommodate the significant steric hindrance between the ligand and substrate, unlike previous findings that showed coordination with P and O atoms. The reaction is established to occur in sequence through the oxidative addition of the aryl iodide to Pd(0), intramolecular alkene insertion, C(sp2)-H bond activation, and C(sp2)-C(sp3) bond reductive elimination. The C(sp2)-C(sp3) bond reductive elimination is identified as the rate-determining step, and the intramolecular alkene insertion as the enantioselectivity-determining step. The high enantioselectivity originates from the stronger electronic interaction between the catalyst and substrate; the exclusive 5-exo-regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom, and the chemoselectivity of C-H activation over carboiodination is driven by thermodynamics.

A Lewis Acid-Controlled Enantiodivergent Epoxidation of Aldehydes.

Two epoxidation catalysts, one of which consists of two VANOL ligands and an aluminum and the other that consists of two VANOL ligands and a boron, were compared. Both catalysts are highly effective in the catalytic asymmetric epoxidation of a variety of aromatic and aliphatic aldehydes with diazoacetamides, giving high yields and excellent asymmetric inductions. The aluminum catalyst is effective at 0 °C and the boron catalyst at -40 °C. Although both the aluminum and boron catalysts of (R)-VANOL give very high asymmetric inductions (up to 99% ee), they give opposite enantiomers of the epoxide. The mechanism, rate- and enantioselectivity-determining step, and origin of enantiodivergence are evaluated using density functional theory calculations.

Nickel/SKP-Catalyzed Markovnikov Regio- and Enantioselective Hydroamination of Vinylarenes with Hydroxylamines.

A Ni-catalyzed enantioselective hydroamination of vinylarenes has been developed, affording a wide variety of α-branched chiral alkylamines in good yields with exclusive Markovnikov regioselectivity and excellent enantioselectivity. The SKP ligand was found to be crucial to both the reactivity enhancement and enantiocontrol of the reaction. The synthetic utility of the protocol was exemplified in a gram-scale reaction and late-stage modification of medicinally relevant molecules. The deuterium-labeling experiment revealed that the irreversible hydronickelation of vinylarenes is most likely the enantioselectivity-determining step.

Three-component enantioselective alkenylation of organophosphonates via nickel metallaphotoredox catalysis

•Highly enantioselective synthesis of structurally complex chiral phosphonates •Modular and stereodivergent access to chiral trans- and cis-alkenyl moieties •Asymmetric radical multicomponent reaction via metallaphotoredox catalysis •Enantioselective control of alkyl radicals by guiding the trajectory of radical metalation The development of efficient catalytic multicomponent reactions (MCRs) is highly sought-after in chemical synthesis. However, catalytic asymmetric MCRs, particularly involving radical species, remain largely underdeveloped due to the exceptionally high reactivity of open-shell radical species. Herein, we report a metallaphotoredox-catalyzed asymmetric three-component method to access a diverse array of enantio-enriched α-alkenyl phosphonates from readily available vinyl phosphonates, alkenyl halides, and alkyl trifluoroborates under mild conditions. This operationally simple and redox-neutral protocol exhibits broad substrate scope and excellent chemo-, regio-, stereo-, and enantioselectivity. Furthermore, by simple modification of the triplet energy of the photocatalyst employed, both enantio-enriched trans and cis α-alkenyl phosphonates can be divergently accessed. Detailed computational and experimental studies were undertaken to elucidate the mechanism and origin of the observed reactivity and selectivity, which support a radical cascade sequence with α-phosphonate controlling the trajectory of radical capture by a chiral tetrahedral alkenyl nickel(II) species in the enantioselectivity-determining step. The development of efficient catalytic multicomponent reactions (MCRs) is highly sought-after in chemical synthesis. However, catalytic asymmetric MCRs, particularly involving radical species, remain largely underdeveloped due to the exceptionally high reactivity of open-shell radical species. Herein, we report a metallaphotoredox-catalyzed asymmetric three-component method to access a diverse array of enantio-enriched α-alkenyl phosphonates from readily available vinyl phosphonates, alkenyl halides, and alkyl trifluoroborates under mild conditions. This operationally simple and redox-neutral protocol exhibits broad substrate scope and excellent chemo-, regio-, stereo-, and enantioselectivity. Furthermore, by simple modification of the triplet energy of the photocatalyst employed, both enantio-enriched trans and cis α-alkenyl phosphonates can be divergently accessed. Detailed computational and experimental studies were undertaken to elucidate the mechanism and origin of the observed reactivity and selectivity, which support a radical cascade sequence with α-phosphonate controlling the trajectory of radical capture by a chiral tetrahedral alkenyl nickel(II) species in the enantioselectivity-determining step.

Highly enantioselective amination of η3-(2-fluorocycloheptenyl)palladium complexes bearing chiral P,P- and P,N-ligands

The key enantioselectivity-determining step in Pd-catalyzed asymmetric amination of 2-fluoroallylic substrates was optimized using model reaction of η3-(2-fluorocycloheptenyl)-palladium complexes bearing chiral P,P- and P,N-ligands with various amines. (S)-ButPHOX was found to be the most effective ligand allowing the formation of 2-fluoroallyl amines and anilines with high enantioselectivity.

Enantio- and Regioselective Ni-Catalyzed para-C-H Alkylation of Pyridines with Styrenes via Intermolecular Hydroarylation.

Direct asymmetric functionalization of the pyridyl C-H bond represents a longstanding challenge in organic chemistry. We herein describe the first enantioselective para-C-H activation of pyridines through the use of a Ni-Al bimetallic catalyst system and N-heterocyclic carbene (NHC) ligand for intermolecular hydroarylation of styrenes. The reaction procceds in high to excellent enantioselectivities (up to 98.5:1.5 er) and high site-selectivities for both styrene and pyridine components (up to >98:2). Consequently, a broad range of enantioenriched 1,1-diarylalkanes containing pyridine moieties could be prepared in a single step with 100% atom economy. Computational studies supported a mechanism involving a ligand-to-ligand H-transfer (LLHT) and reductive elimination sequence, with LLHT being the rate- and enantioselectivity-determining step. DFT studies indicate that the π-π stacking interaction between the NHC aryl fragment and trans-styrenes is critical for high reactivity and enantiocontrol.

C-N Bond Forming Radical Rebound Is the Enantioselectivity-Determining Step in P411-Catalyzed Enantioselective C(sp3)-H Amination: A Combined Computational and Experimental Investigation.

Engineered metalloenzymes represent promising catalysts for stereoselective C-H functionalization reactions. Recently, P450 enzymes have been evolved to allow for new-to-nature intramolecular C(sp3)-H amination reactions via a nitrene transfer mechanism, giving rise to diamine derivatives with excellent enantiocontrol. To shed light on the origin of enantioselectivity, a combined computational and experimental study was carried out. Hybrid quantum mechanics/molecular mechanics calculations were performed to investigate the activation energies and enantioselectivities of both the hydrogen atom transfer (HAT) and the subsequent C-N bond forming radical rebound steps. Contrary to previously hypothesized enantioinduction mechanisms, our calculations show that the radical rebound step is enantioselectivity-determining, whereas the preceding HAT step is only moderately stereoselective. Furthermore, the selectivity in the initial HAT is ablated by rapid conformational change of the radical intermediate prior to C-N bond formation. This finding is corroborated by our experimental study using a set of enantiomerically pure, monodeuterated substrates. Furthermore, classical and ab initio molecular dynamics simulations were carried out to investigate the conformational flexibility of the carbon-centered radical intermediate. This key radical species undergoes a facile conformational change in the enzyme active site from the pro-(R) to the pro-(S) configuration, whereas the radical rebound is slower due to the spin-state change and ring strain of the cyclization process, thereby allowing stereoablative C-N bond formation. Together, these studies revealed an underappreciated enantioinduction mechanism in biocatalytic C(sp3)-H functionalizations involving radical intermediates, opening up new avenues for the development of other challenging asymmetric C(sp3)-H functionalizations.

Palladium Catalysis Featuring Attractive Noncovalent Interactions Enabled Highly Enantioselective Access to β-Quaternary δ-Lactams

Described herein is a highly enantioselective route to β-quaternary δ-lactams by palladium/pyridine-dihydroisoquinoline (PyDHIQ)-catalyzed conjugate arylations. Notably, the effect of π-interactions on the high enantioselectivity was elucidated by DFT calculations and noncovalent interaction (NCI) analysis. The skeleton of the PyDHIQ ligand plays a key role in the formation of attractive noncovalent interactions with substrates in an enantioselectivity-determining step. The developed methodology was successfully applied to the asymmetric formal synthesis of (−)-picenadol.

Enantioselective Nickel-Catalyzed Si–C(sp2) Bond Activation and Migratory Insertion to Aldehydes: Reaction Scope and Mechanism

Transition-metal-catalyzed silicon–carbon bond activation is one of the most important processes in both organosilicon chemistry and homogeneous catalysis that is still rarely reported in the past decades, and the enantioselective versions based on transition-metal-catalyzed Si–C bond activation remain an ongoing challenge in asymmetric catalysis. Herein, we report a convenient and enantioselective Si–C bond cleavage-initiated [4 + 2] annulation of benzosilacyclobutenes with aldehydes, which provides an access to the direct synthesis of chiral six-membered oxasilacycles and their derivatives with high yields and enantioselectivities (up to 97% ee). The catalytic asymmetric reaction proceeds smoothly with the aid of a chiral TADDOL-derived phosphoramidite ligand and its chiral Ni complex with a suitable cavity. By switching the work-up of the reaction involved, the present strategy may be extended to subsequent downstream transformations of silyl ether-containing oxasilacycles to give chiral o-tolyl arylmethanols with high ees and quantitative conversions. A series of experimental results support that the strategy of silicon-mediated organic synthesis controlled by nickel catalysis demonstrates a powerful potential for the facile synthesis of chiral alcohols and its drug-like derivatives. Finally, mechanistic and computational investigations of the nickel-catalyzed Si–C bond activation offer insights into the origin of the observed stereoselective outcome, and the density functional theory calculation shows that the nickel-controlled Si–C(sp2) bond activation enables the controllable migratory insertion of benzaldehyde into the Ni–Si bond, which is recognized as the enantioselectivity-determining step.

Pyrinap ligands for enantioselective syntheses of amines

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step.

Rapid Evaluation of the Mechanism of Buchwald-Hartwig Amination and Aldol Reactions Using Intramolecular 13C Kinetic Isotope Effects.

A practical approach is introduced for the rapid determination of 13C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of tert-butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional intermolecular 13C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental 13C KIEs are determined using an intramolecular KIE approach. This rapid methodology for KIE determination requires substantially less material and time compared to traditional approaches. Details of the Buchwald-Hartwig amination mechanism are investigated under varying synthetic conditions, namely a variety of halides and bases. The enantioselectivity-determining step of the l-proline catalyzed aldol reaction is also evaluated using this approach. We expect this mechanistic methodology to gain traction among synthetic chemists as a practical technique to rapidly obtain high-resolution information regarding the transition structure of synthetically relevant reactions under catalytic conditions.

Palladium‐Catalyzed Asymmetric Hydrosulfonylation of 1,3‐Dienes with Sulfonyl Hydrazides

A highly enantio- and regioselective hydrosulfonylation of 1,3-dienes with sulfonyl hydrazides has been realized by using a palladium catalyst containing a monodentate chiral spiro phosphoramidite ligand. The reaction provided an efficient approach to synthetically useful chiral allylic sulfones. Mechanistic studies suggest that the reaction proceeds through the formation of an allyl hydrazine intermediate and subsequent rearrangement to the chiral allylic sulfone product. The transformation of the allyl hydrazine intermediate to the product is the enantioselectivity-determining step.

Long-Distance Chirality Transfer from P-Ligand to Prochiral Dihydrosilanes via Pd(II) Aryl Iodide Complex in Pd-Catalyzed Silylation of Aryl Iodide: A DFT Study.

The mechanism of Pd-catalyzed desymmetric monoarylation of dihydrosilanes with aryl iodides in the presence of chiral TADDOL-derived phosphoramidite ligand toward deeper understanding of the stereoselectivity has been investigated using hybrid density functional theory (DFT) methodology. The full catalytic cycle for the favorable reaction pathway, which is initiated by the oxidative addition of aryl iodide to monoligated Pd0 leading to the silylation product, was calculated. The DFT calculation results indicate that the enantio-discriminating transmetalation between Pd-Ar bond of the Pd(II) aryl iodide complex and Si-H bond of the prochiral dihydrosilane was the enantioselectivity-determining step. On the basis of the structure of the transition state, the attractive aryl-aryl interactions between the aryl group of ligand, aryl iodide, and dihydrosilane were found to play an important role for the chiral transference from the chiral ligand to asymmetric cleavage of the Si-H bond of the prochiral dihydrosilane.

Mechanism and Origin of MAD-Induced Ni/N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C-H Cyclization of Pyridines with Alkenes.

This work presents a DFT-based computational study on the regio- and enantioselective C-H functionalization of pyridines with alkenes at the relatively unreactive C4-position, which was successfully achieved by Shi et al. [J. Am. Chem. Soc. 2019, 141, 5628-5634] using Ni0 /N-heterocyclic carbene (NHC) catalysis under the assistance of an aluminum-based Lewis acid additive (2,6-tBu2 -4-Me-C6 H2 O)2 AlMe (MAD). The calculations indicate that the selective functionalization involves a three-step mechanism in which a unique H-migration assisted oxidation metalation (HMAOM) step is identified as the rate- and enantioselectivity-determining step. The newly proposed mechanism can well rationalize the experimental observation that the preferred product is the endo-type (vs. exo-type), R-configuration (vs. S-configuration) product at the C4 (vs. C2) position, and also unveil the reasons that the NHC ligand and the MAD additive can facilitate the reaction.

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C-H Olefination Enabled by an Amino Amide Transient Directing Group.

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through PdII -catalyzed atroposelective C-H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII -catalyzed enantioselective C(sp3 )-H amidation of thioamide. Mechanistic studies suggest that C-H cleavage is the enantioselectivity-determining step.

A Computational Mechanistic Study of Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation: Roles of APAO Ligands.

A computational mechanistic study has been performed on Pd(II)-catalyzed enantioselective reactions involving acetyl-protected aminomethyl oxazolines (APAO) ligands that significantly improved reactivity and selectivity in C(sp3)-H borylation. The results support a mechanism including initiation of C(sp3)-H bond activation generating a five-membered palladacycle and ligand exchange, followed by HPO42--promoted transmetalation. These resulting Pd(II) complexes further undergo sequential reductive elimination by coordination of APAO ligands and protonation to afford the enantiomeric products and deliver Pd(0) complexes, which will then proceed by oxidation and deprotonation to regenerate the catalyst. The C(sp3)-H activation is found to be the rate- and enantioselectivity-determining step, in which the APAO ligand acts as the proton acceptor to form the two enantioselectivity models. The results demonstrate that the diverse APAO ligands control the enantioselectivity by differentiating the distortion and interaction between the major and minor pathways.

Theoretical Study of the Addition of Cu-Carbenes to Acetylenes to Form Chiral Allenes.

Terminal alkynes have become one of the most versatile building blocks for C-C bond construction in the past few decades, and they are usually considered to convert to acetylides before further transformations. In this study, a novel direct nucleophilic addition mode for Cu(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes is proposed, and it was investigated by density functional theory with the M11-L density functional. Three different reaction pathways were considered and investigated. The computational results show that the proposed reaction pathway, which includes direct nucleophilicattack of protonated acetylene, deprotonation of the vinyl cation, and catalyst regeneration, is the most favorable pathway. Another possible deprotonation-carbenation-insertion pathway is shown to be unfavorable. The direct nucleophilic addition step is the rate- and enantioselectivity-determining step in the catalytic cycle. Noncovalent interaction analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. In addition, calculation of a series of chiral bisoxazoline ligands shows that a bulky group on the oxazoline ring is favorable for high enantioselectivity, which agrees with experimental observations. Moreover, copper acetylides are stable, and their generation is a favorable pathway in the absence of chiral bisoxazoline ligands.