Control Of Stereoselectivity Research Articles

“Boron Ylide” Enables Stereoselective Construction of gem‐Diborylcyclopropanes

AbstractThe stereoselective cyclopropanation of olefins with “boron ylide” is disclosed for the first time, providing a modular strategy for the synthesis of stereospecific diboryl‐functionalized cyclopropanes. The chiral gem‐diborylcyclopropanes are synthesized with excellent enantioselectivity with the aid of a chiral auxiliary. Based on the powerful transformable ability of boryl group, those challenging multi‐quaternary carbon centers in cyclopropane units have been facilely constructed with excellent stereoselectivity. Control experiments indicate that the boryl groups are necessary for both chemoselectivity and stereoselectivity control.

"Boron Ylide" Enables Stereoselective Construction of gem-Diborylcyclopropanes.

The stereoselective cyclopropanation of olefins with "boron ylide" is disclosed for the first time, providing a modular strategy for the synthesis of stereospecific diboryl-functionalized cyclopropanes. The chiral gem-diborylcyclopropanes are synthesized with excellent enantioselectivity with the aid of a chiral auxiliary. Based on the powerful transformable ability of boryl group, those challenging multi-quaternary carbon centers in cyclopropane units have been facilely constructed with excellent stereoselectivity. Control experiments indicate that the boryl groups are necessary for both chemoselectivity and stereoselectivity control.

Stereoselectivity Control Interplay in Racemic Lactide Polymerization by Achiral Al-Salen Complexes.

The origin of stereocontrol in ring opening polymerization (ROP) of racemic lactide (rac-LA) promoted by achiral aluminium-based catalysts has been explained through DFT calculations combined with a molecular descriptor (%VBur) and the activation strain model (ASM-NEDA) analysis. The proposed chain end control (CEC) model suggests that the ligand framework adopts a chiral configuration mimicking the enantiomorphic site control (ESC) while also incorporating control of the last inserted monomer unit. It is found that the ligand wrapping mode around the aluminium centre is dictated by the monomer configuration (R,R-LA and S,S-LA). A good correlation with experimental data is achieved only when accounting for the ligand dynamic features and its steric influences, as highlighted by %VBur steric maps and ASM-NEDA analysis. Understanding the ESC and CEC interplay is an important target for obtaining stereoselective ROP polymerization for the synthesis of biodegradable materials with tailored properties.

Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-β-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-β-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions. The reaction proceeds in a sequential fashion involving synergistic Cu/Ir-catalyzed stereodivergent allylation and the Brønsted acid-promoted stereospecific Pictet-Spengler reaction, affording a wide range of chiral tetrahydro-β-carbolines bearing up to four stereogenic centers in good yields with excellent stereoselectivity control. When N-aryl-substituted tryptophan-derived aldimine esters were utilized, notably, a unique C-N heterobiaryl axis could be simultaneously constructed with the formation of the third point stereogenic center in the last cyclization step through dynamic kinetic resolution (DKR). Computational mechanistic studies established a plausible synergistic mechanism for dual Cu/Ir-catalyzed asymmetric allylation and the succeeding protonation-assisted Pictet-Spengler cyclization to complete the annulation. Structure-activity relationship analyses unveil the origins of stereochemistry for the building of one axis and three point stereogenic centers.

Bifunctional Chiral Electrocatalysts Enable Enantioselective α-Alkylation of Aldehydes.

Herein, we describe an innovative approach to the asymmetric electrochemical α-alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α-alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C-H/C-H oxidative α-alkylation of aldehydes in a highly chemo- and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio-induction.

Bifunctional Chiral Electrocatalysts Enable Enantioselective α‐Alkylation of Aldehydes

AbstractHerein, we describe an innovative approach to the asymmetric electrochemical α‐alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α‐alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C−H/C−H oxidative α‐alkylation of aldehydes in a highly chemo‐ and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio‐induction.

Palladium-Catalyzed Asymmetric Allylic Alkylation of Azlactones: An Efficient Access to Unsaturated Trifluoromethylated α-Amino Acid Derivatives Possessing α-Quaternary Stereogenic Centers

AbstractA new strategy for the asymmetric allylic alkylation of azlactones with α-(trifluoromethyl)allyl acetates catalyzed by Pd(OAc)2/(R)-BINAP is designed and developed, providing access to unsaturated α-quaternary α-amino acid derivatives bearing a trifluoromethyl group and contiguous quaternary and tertiary stereogenic centers. The products are obtained in good yields with exclusive regioselectivity and excellent stereoselective control under relatively mild reaction conditions. A scale-up experiment shows no loss of reactivity or stereoselectivity. The synthetic utility of the current strategy is demonstrated through transformations of a representative product to afford several potentially bioactive species.

Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides

The enantioselective synthesis of S-stereogenic sulfinamides has garnered considerable attention due to their structural and physicochemical properties. However, catalytic asymmetric synthesis of sulfinamides still remains daunting challenges, impeding their broad application in drug discovery and development. Here, we present an approach for the synthesis of S-stereogenic sulfinamides through peptide-mimic phosphonium salt-catalyzed asymmetric skeletal reorganization of simple prochiral and/or racemic sulfoximines. This methodology allows for the facile access to a diverse array of substituted sulfinamides with excellent enantioselectivities, accommodating various substituent patterns through desymmetrization or parallel kinetic resolution process. Mechanistic experiments, coupled with density functional theory calculations, clarify a stepwise pathway involving ring-opening and ring-closing processes, with the ring-opening step identified as crucial for achieving stereoselective control. Given the prevalence of S-stereogenic centers in pharmaceuticals, we anticipate that this protocol will enhance the efficient and precise synthesis of relevant chiral molecules and their analogs, thereby contributing to advancements in drug discovery.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

Asymmetric Pd/Organoboron‐Catalyzed Site‐Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol

AbstractHerein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site‐, regio‐, enantio‐ and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH‐π interactions between the resting states of the Pd‐π‐allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ‐Hydroxy α‐Amino Acids and Small Peptides

AbstractAn atom‐ and step‐economical and redox‐neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium‐catalyzed asymmetric borrowing‐hydrogen reaction with copper‐catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2‐amino‐5‐hydroxyvaleric acid esters or peptides bearing 1,4‐non‐adjacent stereogenic centers have been prepared in high yields with excellent enantio‐ and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α‐epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Nanoscale and chiral metal-organic frameworks for asymmetric reactions in water: bridging Lewis acid catalysis and biological systems.

Nowadays, stereoselective control over the sheer variety of chemical transformations benefits from the multipotency of chiral Lewis acids. Their use under biocompatible conditions has long posed a challenge because profuse amounts of biogenic nucleophiles readily deactivate them. To bridge the gap between chiral Lewis acid catalysis and biocompatible chemistry, the conversion of UiO(BPY)-type nanosized metal-organic frameworks (NMOFs) into chiral variants was herein exemplified. The combination of an elongated 2,2'-bipyridyl linker and scandium salt with a hydrophobic anion proved essential to implement traits such as robustness, biocompatibility, and catalytic activity. The catalyst could construct sufficiently hydrophobic environments sequestered within the framework, catalyzing asymmetric ring-opening reactions of meso-epoxide with low catalyst loading to afford β-amino acid alcohols in high yield (up to >99%) with high enantioselectivity (up to 88%). Most impressively, it exhibited a tolerance to the ex vivo poisoning of chiral Lewis acid catalysis by biogenic nucleophiles in sharp contrast to conventional water-compatible Lewis acids.

Using BpyAla to generate copper artificial metalloenzymes: a catalytic and structural study.

Artificial metalloenzymes (ArMs) have emerged as a promising avenue in the field of biocatalysis, offering new reactivity. However, their design remains challenging due to the limited understanding of their protein dynamics and how the introduced cofactors alter the protein scaffold structure. Here we present the structures and catalytic activity of novel copper ArMs capable of (R)- or (S)-stereoselective control, utilizing a steroid carrier protein (SCP) scaffold. To incorporate 2,2'-bipyridine (Bpy) into SCP, two distinct strategies were employed: either Bpy was introduced as an unnatural amino acid (2,2'-bipyridin-5-yl)alanine (BpyAla) using amber stop codon expression or via bioconjugation of bromomethyl-Bpy to cysteine residues. The resulting ArMs proved to be effective at catalysing an enantioselective Friedel-Crafts reaction with SCP_Q111BpyAla achieving the best selectivity with an enantioselectivity of 72% ee (S). Interestingly, despite using the same protein scaffold, different attachment strategies for Bpy at the same residue (Q111) led to a switch in the enantiopreference of the ArM. X-ray crystal structures of SCP_Q111CBpy and SCP_Q111BpyAla ArMs with bound Cu(ii) ions unveiled crucial differences in the orientation of the catalytic centre. Combining structural information, alanine scanning studies, and computational analysis shed light on the distinct active sites of the ArMs, clarifying that these active sites stabilise the nucleophilic substrate on different sides of the electrophile leading to the observed switch in enantioselectivity. This work underscores the importance of integrating structural studies with catalytic screening to unravel the intricacies of ArM behaviour and facilitate their development for targeted applications in biocatalysis.

Dirhodium(II) complex catalyzed dehydrosilylation of styrenes: theoretical investigations on the mechanism, selectivity, and ligand effects.

The dirhodium(II) complexes with bridging phosphine and OAc ligands showed high reactivity and selectivities in olefin dehydrosilylation. In order to determine the structure of the actual catalyst which cannot be determined experimentally, the geometries of the dirhodium catalyst, the detailed catalytic mechanism, and the stereo- and chemo-selectivities of the title reaction were studied using DFT calculations. The results showed that one OAc group is monodentate and the other is bidentate in the dirhodium catalyst C'. The determined catalytic cycle consists of four processes: Rh-H bond activation in C', Si-H bond activation in alkoxysilane, alkylene insertion into the Rh-Si bond, followed by β-H elimination or σ-metathesis reaction. Among them, the alkylene insertion process is the rate-determining step. The stereoselectivity of the title reaction is controlled by the steric effect and orbital interactions between the alkyene and dirhodium catalysts in the β-H elimination process. The chemoselectivity is regulated by the presence of the axial ligand in the dirhodium catalyst, when there is an axial ligand coordinated to the Rh atom, E-alkene is the main product, whereas alkane would be obtained in the absence of an axial ligand. Our work determines the structure of the actual catalyst, and provides explanations and predictions for the activity, and chemo- and stereo-selectivity control of olefin dehydrosilylation.

Stereoselective Control of the Cu Activation of β,β-Diboryl Acrylates for Allylic Coupling Protocols with Concomitant Lactonization.

The key to a successful C-B activation is to discriminate between two geminal boryl moieties that are exposed to the same reaction conditions. Here we describe a stereoselective C-B activation of β,β-diboryl acrylates forming exclusively the (Z)-α-borylalkenyl copper(I) key intermediate, for subsequent allylic alkylation reactions. The new borylated (Z)-skipped dienoates followed a feasible iodo-lactonization sequence for the preparation of borylated lactone cores, which can be used in drug discovery.

Mechanism and Stereoselectivity Control of Terminal Alkyne Dimerization Activated by a Zr/Co Heterobimetallic Complex: A DFT Study.

Heterobimetallic complexes have recently garnered considerable attention in organic synthesis owing to their high activity and selectivity, which surpass those of monometallic complexes. In this study, the detailed mechanisms of terminal alkyne dimerization activated by the heterobimetallic Zr/Co complex, as well as the different stereoselectivities of Me3SiC≡CH and PhC≡CH dimerization, were investigated and elucidated by using density functional theory calculations. After excluding the three-molecule reaction and outer-sphere mechanisms, the inner-sphere mechanism was determined as the most optimal process. The inner-sphere mechanism involves four processes: THF dissociation and coordination of the first alkyne; ligand migration and C-H activation; N2 dissociation and insertion of the second alkyne; and reductive elimination. The stereoselectivity between the E-/Z- and gem-isomers is determined by the C-C coupling mode of the two alkynes and that of the E- and Z-isomers is determined by the sequence of the C-C coupling and hydrogen migration in the reductive elimination process. Me3SiC≡CH dimerization yields only an E-isomer owing to the large differences in the distortion and interaction energies, whereas PhC≡CH dimerization produces an E-, Z-, and gem-isomers owing to the reduced interaction energy differences.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

Stereoselectivity control in Rh-catalyzed β-OH elimination for chiral allene formation

Stereoselectivity control and understanding in the metal-catalyzed reactions are fundamental issues in catalysis. Here we report sterically controlled rhodium-catalyzed SN2’-type substitution reactions of optically active tertiary propargylic alcohols with arylmetallic species affording the non-readily available enantioenriched tetrasubstituted allenes via either exclusive syn- or anti-β-OH elimination, respectively, under two sets of different reaction parameters. Detailed mechanistic experiments and density functional theory (DFT) studies reveal that the exclusive anti-Rh(I)-OH elimination is dictated by the simultaneous aid of in situ generated boric acid and ambient water, which act as the shuttle in the hydroxy relay to facilitate the Rh(I)-OH elimination process via a unique ten-membered cyclic transition state (anti-TS2_u). By contrast, the syn-Rh(III)-OH elimination in C–H bond activation-based allenylation reaction is controlled by a four-membered cyclic transition state (syn-TS3) due to the steric surroundings around the Rh(III) center preventing the approach of the other assisting molecules. Under the guidance of these mechanistic understandings, a stereodivergent protocol to construct the enantiomer of optically active tetrasubstituted allenes from the same starting materials is successfully developed.

Recent Advances in Photochemical Asymmetric Three-Component Reactions.

Over the past decades, asymmetric photochemical synthesis has garnered significant attention for its sustainability and unique ability to generate enantio-enriched molecules through distinct reaction pathways. Photochemical asymmetric three-component reactions have demonstrated significant potential for the rapid construction of chiral compounds with molecular diversity and complexity. However, noteworthy challenges persist, including the participation of high-energy intermediates such as radical species, difficulties in precise control of stereoselectivity, and the presence of competing background and side reactions. Recent breakthroughs have led to the development of sophisticated strategies in this field. This review explores the intricate mechanisms, synthetic applications, and limitations of these methods. We anticipate that it will contribute towards advancing asymmetric catalysis, photochemical synthesis, and green chemistry.