High Levels Of Enantioselectivity Research Articles

Asymmetric Dearomatization of Indoles through Cobalt‐Catalyzed Enantioselective C−H Functionalization Enabled by Photocatalysis

AbstractPhotocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition‐metal‐catalyzed asymmetric C−H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt‐catalyzed enantioselective C−H activation reaction enabled by visible‐light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Asymmetric Dearomatization of Indoles through Cobalt-Catalyzed Enantioselective C-H Functionalization Enabled by Photocatalysis.

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Recent Advances in the Enantioselective Construction of gem‐Difluorinated Carbonyl Moieties

AbstractThe enantioselective introduction of gem‐difluorinated carbonyl (i. e. α,α‐difluoro carbonyl) moieties into organic structures is a synthetically valuable but highly challenging approach. During the past decades, continuous efforts have been made for the developments of synthetic strategies for constructing C(sp3)−CF2COR chiral centers with high levels of enantioselectivities. This review summarizes and discusses the recent advance in the enantioselective construction of gem‐difluorinated carbonyl moieties, which are organized according to the reaction categories.

Desymmetrization of Cyclic Sulfonimidamides by Asymmetric Allylation.

Herein we report the first transition metal-catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High-throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2-substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity.

Desymmetrization of Cyclic Sulfonimidamides by Asymmetric Allylation

AbstractHerein we report the first transition metal‐catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High‐throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2‐substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity.

D4-Symmetric Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C-H Bonds.

Dirhodium tetrakis(2,2'-binaphthylphosphate) catalysts were successfully developed for asymmetric C-H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2'-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4',6,6' positions. As the BNP ligands are C2-symmetric, the resulting dirhodium tetrakis(2,2'-binaphthylphosphate) complexes were expected to be D4-symmetric, but X-ray crystallographic and computational studies revealed this is not always the case because of internal T-shaped CH-π and aryl-aryl interactions between the ligands. The optimum catalyst is Rh2(S-megaBNP)4, with 3,5-di(tert-butyl)phenyl substituents at the 4,4' positions and chloro substituents at the 6,6' positions. This catalyst adopts a D4-symmetric arrangement and is ideally suited for site-selective C-H functionalization at unactivated tertiary sites with high levels of enantioselectivity, outperforming the best dirhodium tetracarboxylate catalyst developed for this reaction. The standard reactions were conducted with a catalyst loading of 1 mol % but lower catalyst loadings can be used if desired, as illustrated in the C-H functionalization of cyclohexane in 91% ee with 0.0025 mol % catalyst loading (29,400 turnover numbers). These studies further illustrate the effectiveness of donor/acceptor carbenes in site-selective intermolecular C-H functionalization and expand the toolbox of catalysts available for catalyst-controlled C-H functionalization.

Synthesis of 2-tetrazolyl azetidines and their evaluation in organocatalysis

A library of stereodefined 2-tetrazolyl azetidines has been synthesized starting from readily available enantiopure amino alcohols. This library was then screened to assess catalytic activity in a benchmark asymmetric aldol reaction between 4-nitrobenzaldehyde and acetone. The azetidine derived from (1S,2R)-(+)-norephedrine exhibited the best balance between good reactivity and a high level of enantioselectivity in this reaction.

Manganese(I)-Catalyzed Enantioselective C(sp2)-C(sp3) Bond-Forming for the Synthesis of Skipped Dienes with Synergistic Aminocatalysis.

Mn(I)-catalyzed enantioselective C-C bond-forming reactions represent a great challenge in homogeneous catalysis primarily due to a limited understanding of its mechanistic principles. Herein, we have developed an interesting catalytic strategy that leverages a synergistic combination of a dimeric manganese(I) catalyst and a chiral aminocatalyst to address this issue. A range of conjugated dienals and trienals can exclusively proceed 1,4-hydroalkenylation by using readily available aromatic and aliphatic alkenyl boronic acids as coupling partners, producing a rich library of skipped diene aldehydes in synthetically useful yields and high levels of enantioselectivities. Notably, downstream transformations of these products can not only afford a concise approach to construct enantioenriched skipped trienes but also realize enantioselective total synthesis of analogues to (-)-Blepharocalyxin D in four steps. DFT calculations suggest the 1,4-hydroalkenylation is kinetically more favorable than 1,6-hydroalkenylation.

Manganese(I)‐Catalyzed Enantioselective C(sp2)−C(sp3) Bond‐Forming for the Synthesis of Skipped Dienes with Synergistic Aminocatalysis

AbstractMn(I)‐catalyzed enantioselective C−C bond‐forming reactions represent a great challenge in homogeneous catalysis primarily due to a limited understanding of its mechanistic principles. Herein, we have developed an interesting catalytic strategy that leverages a synergistic combination of a dimeric manganese(I) catalyst and a chiral aminocatalyst to address this issue. A range of conjugated dienals and trienals can exclusively proceed 1,4‐hydroalkenylation by using readily available aromatic and aliphatic alkenyl boronic acids as coupling partners, producing a rich library of skipped diene aldehydes in synthetically useful yields and high levels of enantioselectivities. Notably, downstream transformations of these products can not only afford a concise approach to construct enantioenriched skipped trienes but also realize enantioselective total synthesis of analogues to (−)‐Blepharocalyxin D in four steps. DFT calculations suggest the 1,4‐hydroalkenylation is kinetically more favorable than 1,6‐hydroalkenylation.

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)2, as the catalytically active intermediate, which can decay to a dimeric species (κ3-PCNOx)IrH(μ-H)2IrH(κ2-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

Iridium-catalyzed asymmetric hydrogenation of 5-hydroxypicolinate pyridinium salts under batch and flow: stereodefined access to cis-configurated hydroxypiperidine esters

An iridium-catalyzed asymmetric hydrogenation of 2-esteryl-5-hydroxypyridinium salts is reported, providing chiral cis-5-hydroxypiperidine-2-carboxylates in excellent yields with high levels of enantioselectivities and diastereoselectivities.

Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

Highly Enantioselective 6π Photoelectrocyclizations Engineered by Hydrogen Bonding.

Photochemical electrocyclization reactions are valued for both their ability to produce structurally complex molecules and their central role in elucidating fundamental mechanistic principles of photochemistry. We present herein a highly enantioselective 6π photoelectrocyclization catalyzed by a chiral Ir(III) photosensitizer. This transformation was successfully realized by engineering a strong hydrogen-bonding interaction between a pyrazole moiety on the catalyst and a basic imidazolyl ketone on the substrate. To shed light on the origin of stereoinduction, we conducted a comprehensive investigation combining experimental and computational mechanistic studies. Results from density functional theory calculations underscore the crucial role played by the prochirality and the torquoselectivity in the electrocyclization process as well as the steric demand in the subsequent [1,4]-H shift step. Our findings not only offer valuable guidance for developing chiral photocatalysts but also serve as a significant reference for achieving high levels of enantioselectivity in the 6π photoelectrocyclization reaction.

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Cooperative Chiral Lewis Base/Palladium-Catalyzed Asymmetric Syntheses of Methylene-Containing δ-Lactams.

We herein report a two-step approach for the enantioselective synthesis of novel chiral δ-lactams. By using a cooperative chiral ITU/achiral Pd-catalyst system, this protocol proceeds via an asymmetric α-allylation of activated aryl esters first, followed by an acid-mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well.

Is Enol Always the Culprit? The Curious Case of High Enantioselectivity in a Chiral Rh(II) Complex Catalyzed Carbene Insertion Reaction.

The mechanism of Rh2 (S-NTTL)4 catalyzed carbene insertion into C(3)-H of indole is investigated using DFT methods. Since the commonly accepted enol mechanism cannot account for enantioinduction, a concerted oxocarbenium pathway was proposed in an earlier work using a model catalyst. However, after considering the full catalytic system, this study finds that akin to other reactions, here, too, the enol pathway is of lower energy, which now naturally raises a conundrum regarding the mode of chiral induction. Herein, a new water promoted mechanistic pathway involving a metal-associated enol intermediate hydrogen bonding and stereochemical model are proposed to solve this puzzle. It is shown how the catalyst bowl-shaped structure along with substrate-catalyst binding is crucial for achieving high levels of enantioselectivity. A stereodetermining water-assisted proton transfer is proposed and confirmed through deuterium-labeling experiments. The water molecules are held together by H-bonding interactions with the carboxylate ligands that is reminiscent of enzyme catalysis. Although several previous studies have aimed at understanding the mechanism of metal catalyzed carbene insertion reactions, the origin of high stereoinduction especially with chiral metal complexes remains unclear, and till date there is no transition state model that can explain the high enantioselectivity with such chiral Rh complexes. The metal-associated enol pathway is currently underrepresented in catalytic cycles and may play a crucial role in catalyst design. Since the enol pathway is commonly adopted in other metal-catalyzed X-H insertion reactions involving a diazoester, the presented results are not specific to the current reaction. Therefore, this study could provide the direction for achieving high levels of enantioselectivity which is otherwise difficult to achieve with a single metal catalyst.

An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization.

A first-of-its-kind enantioselective aromatic Finkelstein reaction is disclosed for the remote desymmetrization of diarylmethanes. The reaction operates through a copper-catalyzed C-I bond-forming event, and high levels of enantioselectivity are achieved through the deployment of a tailored guanidinylated peptide ligand. Strategic use of transition-metal-mediated reactions enables the chemoselective modification of the aryl iodide products; thus, the synthesis of a diverse set of otherwise difficult-to-access diarylmethanes with excellent levels of selectivity is realized from a common intermediate. A mixed experimental/computational analysis of steric parameters and substrate conformations identifies the importance of remote conformational effects as a key to achieving high enantioselectivity in this desymmetrization reaction.

Chiral Lewis Base-Catalysed Asymmetric Syntheses of Benzo-fused ϵ-Lactones.

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.

Enantio- and Diastereoenriched Enzymatic Synthesis of 1,2,3-Polysubstituted Cyclopropanes from (Z/E)-Trisubstituted Enol Acetates.

In nature and synthetic chemistry, stereoselective [2 + 1] cyclopropanation is the most prevalent strategy for the synthesis of chiral cyclopropanes, a class of key pharmacophores in pharmaceuticals and bioactive natural products. One of the most extensively studied reactions in the organic chemist's arsenal, stereoselective [2 + 1] cyclopropanation, largely relies on the use of stereodefined olefins, which can require elaborate laboratory synthesis or tedious separation to ensure high stereoselectivity. Here, we report engineered hemoproteins derived from a bacterial cytochrome P450 that catalyze the synthesis of chiral 1,2,3-polysubstituted cyclopropanes, regardless of the stereopurity of the olefin substrates used. Cytochrome P450BM3 variant P411-INC-5185 exclusively converts (Z)-enol acetates to enantio- and diastereoenriched cyclopropanes and in the model reaction delivers a leftover (E)-enol acetate with 98% stereopurity, using whole Escherichia coli cells. P411-INC-5185 was further engineered with a single mutation to enable the biotransformation of (E)-enol acetates to α-branched ketones with high levels of enantioselectivity while simultaneously catalyzing the cyclopropanation of (Z)-enol acetates with excellent activities and selectivities. We conducted docking studies and molecular dynamics simulations to understand how active-site residues distinguish between the substrate isomers and enable the enzyme to perform these distinct transformations with such high selectivities. Computational studies suggest the observed enantio- and diastereoselectivities are achieved through a stepwise pathway. These biotransformations streamline the synthesis of chiral 1,2,3-polysubstituted cyclopropanes from readily available mixtures of (Z/E)-olefins, adding a new dimension to classical cyclopropanation methods.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification.

The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ-position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.