Enantioselective Construction Research Articles

Carbon-silicon-switch effect in enantioselective construction of silicon-stereogenic center from silacyclohexadienones.

Carbon-silicon-switch strategy, replacing one specific carbon atom in organic molecules with a silicon, has garnered significant interest for developing new functional molecules. However, the influence of a reaction regarding its selectivity and reactivity by carbon-silicon-switch strategy has far less been investigated. Here we discover an unusual carbon-silicon-switch effect in the enantioselective construction of silicon-stereogenic center. It is found that there has been a significant change in the desymmetrization reaction of silacyclohexadienones using asymmetric conjugate addition or oxidative Heck reaction with aryl/alkyl nucleophiles when compared with their carbon analogues cyclohexadienones. Specifically, the carbon-silicon-switch leads to a reversal in enantioselectivity with arylzinc as the nucleophile by the same chiral catalyst, and results in totally different reactivity with arylboronic acid as the nucleophile. Control experiments and density functional theory (DFT) calculations have shown that the unusual carbon-silicon-switch effect comes from the unique stereoelectronic feature of silicon.

Total Syntheses of β‐ and γ‐Naphthocyclinones

AbstractAfter half a century from their isolation in 1974, we report the first total syntheses of β‐ and γ‐naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]‐octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh‐catalyzed enantioselective 1,4‐addition followed by thiolate‐mediated reductive cyclization, and 2) judicious design of a common chiral, non‐racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

AbstractThe first asymmetric condensation of prochiral silacyclohexanones with hydroxylamines by chiral phosphoric acid catalysis has been developed, which provides a facile and straightforward protocol for the enantioselective construction of valuable axially chiral silacyclohexylidene oxime ethers that are otherwise inaccessible. Notably, this constitutes a rare example for accessing silacycles featuring axial chirality.

EnantioselectiveSynthesis ofspiro[indoline-3,4- pyrrolo [3,4-b]pyridines] via Organocatalysed Three-Component Cascade Reaction.

Asymmetric synthesis of spiro[indoline-3,4-pyrrolo [3,4-b]pyridines] derivatives was first developed through organocatalytic cascade Knoevenagel/Michael/cyclization reaction using a quinidine -derived squaramide. Under the optimized conditions, the three-component reaction of isatins, cyanoacetates, and 3-aminomaleimides yield the desired heterocycle-fused spirooxindoles in good yields (78-91%) with 53-99% enantiomer excess (ee). Notably, this reaction enabled a broad substrate scope under mild conditions, and provided a convenient method for enantioselective construction of diverse spirooxindoles combined with dihydropyridine and maleimide skeleton, which brought great potential to build new bioactive chemical entities.

Total Syntheses of β- and γ-Naphthocyclinones.

After half a century from their isolation in 1974, we report the first total syntheses of β- and γ-naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]-octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh-catalyzed enantioselective 1,4-addition followed by thiolate-mediated reductive cyclization, and 2) judicious design of a common chiral, non-racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

Enantioselective Borylative Functionalization of Internal Alkenes: A Platform for Constructing Vicinal Stereocenters†

Comprehensive SummaryVicinal stereogenic centers are ubiquitous structural scaffolds in both natural products and synthetic compounds, yet their enantioselective construction remains a significant challenge in organic synthesis. Organoboron compounds are of paramount importance in synthetic chemistry due to their ability to undergo facile transformations, yielding diverse essential chemical bonds such as carbon‐carbon, carbon‐oxygen, carbon‐nitrogen, and carbon‐halogen bonds. Transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes offer a promising strategy for the enantioselective installation of two adjacent chiral centers across carbon‐carbon bonds. By leveraging the versatile transformations of the newly introduced boryl unit, this approach holds great potential for expanding the structural diversity of vicinal stereogenic scaffolds. In this concise review, we aim to highlight recent advancements in transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes, underscore their utility as a versatile approach for constructing vicinal stereogenic centers, and discuss unsolved challenges and future directions in this field. Key Scientists

Highly Enantioselective Construction of Chiral Eight-Membered Cyclic Ethers through Tandem Cyclization of Ynones and Dicarbonyl Compounds.

The enantioselective synthesis of eight-membered cyclic ether has always been a challenge in organic synthesis. Herein, we reported a highly enantioselective tandem cyclization reaction of alkyne ketone and dioxypyridines mediated by chiral bifunctional catalysts. This reaction generates two adjacent stereocenters using an atomeconomic manner, providing a simple and effective method for the one-step synthesis of highly enantioselective eight-membered cyclic ethers.

Enantioselective Construction of Planar‐Chiral Molecules by Catalytic Asymmetric Late‐Stage Functionalizations

AbstractPlanar chirality, as one of the most important manifestations of chirality, is frequently employed to constrain three‐dimensional chiral configurations. Recent advancements in the study of planar chirality by chemists have opened up innovative possibilities for designing new catalysts, developing novel drugs, and creating new optical materials. However, the flexible ansa chains present a challenge during the synthesis process of these unique planar‐chiral macrocycles, hindering chemists from achieving high enantioselectivity. In this mini review, we primarily introduce the catalytic asymmetric synthesis methods that have been reported for late‐stage functionalization of planar macrocycles to generate planar chirality. Additionally, we present several recent examples of catalytic enantioselective synthesis of mechanically planar‐chiral rotaxanes through late‐stage functionalization methods. The sources of stereoselectivity are also discussed in this mini review. We aim to inform more researchers about this field and attract chemists to engage in this important and scientifically significant area of research.

Recent advances in catalytic enantioselective construction of monofluoromethyl-substituted stereocenters.

Chiral organofluorine compounds featuring a monofluoromethyl (CH2F)-substituted stereocenter are often encountered in a number of drugs and bioactive molecules. Consequently, the development of catalytic asymmetric methods for the enantioselective construction of CH2F-substituted stereocenters has made great progress over the past two decades, and a variety of enantioselective transformations have been accordingly established. According to the types of fluorinated reagents or substrates employed, these protocols can be divided into the following major categories: (i) enantioselective ring opening of epoxides or azetidinium salts by fluoride anions; (ii) asymmetric monofluoromethylation with 1-fluorobis(phenylsulfonyl)methane; (iii) asymmetric fluorocyclization of functionalized alkenes with Selectfluor; and (iv) asymmetric transformations involving α-CH2F ketones, α-CH2F alkenes, or other CH2F-containing substrates. This feature article aims to summarize these recent advances and discusses the possible reaction mechanisms, advantages and limitations of each protocol and their applications. Synthetic opportunities still open for further development are illustrated as well. This review article will be an inspiration for researchers engaged in asymmetric catalysis, organofluorine chemistry, and medicinal chemistry.

New Synthetic Approaches for the Construction of Enantioenriched Molecules Bearing Quaternary Stereocenters

AbstractOptically active molecule architectures stand as an important class of organic compounds and occupy a key role in academic and industrial communities. Particularly, the molecules bearing quaternary carbon are of vital importance because of its favorable conformation and valuable three‐dimensional molecules, which frequently play a key role in a broad spectrum of functional materials, pharmaceutical relevant natural molecules, and agrochemicals. Over the past few decades, a large number of synthetic strategies for the enantioselective construction of compounds with chiral quaternary carbon centers have been the focus of a number of research initiatives. In this review, the state‐of‐the‐art toward the synthesis of enantioenriched molecules bearing quaternary stereocenters are summarized, which could be segmented into four categories: 1) Construction of optically active quaternary carbon centers by addition to prochiral sp2 carbon; 2) Construction of optically active all‐carbon quaternary stereocenters via substitution at non‐chiral tetra‐substituted carbon; 3) Construction of optically active all‐carbon quaternary stereocenters via kinetic resolution; 4) Construction of optically active all‐carbon quaternary stereocenters via desymmetrization reactions.

Cooperative chemoenzymatic and biocatalytic cascades to access chiral sulfur compounds bearing C(sp3)–S stereocentres

Biocatalysis has been widely employed for the generation of carbon-carbon/heteroatom stereocentres, yet its application in chiral C(sp3)–S bond construction is rare and limited to enzymatic kinetic resolutions. Herein, we describe the enantioselective construction of chiral C(sp3)–S bonds through ene-reductase biocatalyzed conjugate reduction of prochiral vinyl sulfides. A series of cooperative sequential/concurrent chemoenzymatic and biocatalytic cascades have been developed to access a broad range of chiral sulfides, including valuable β-hydroxysulfides bearing two adjacent C(sp3)–S and C(sp3)–O stereocentres, in a stereoconvergent manner with good to excellent yields (up to 96%) and enantioselectivities (up to >99% ee). Notably, this biocatalytic strategy allows to overcome the long-standing shortcomings of catalyst poisoning and C(sp2)/C(sp3)–S bond cleavage faced in transition-metal-catalyzed hydrogenation of vinyl sulfides. Finally, the potential of this methodology is also exemplified by its broader application in the stereoconvergent assembly of chiral C(sp3)–N/O/Se bonds with good to excellent enantioselctivities.

Asymmetric Alkyl-Alkyl Cross-Coupling Enabled by Ni-Catalyzed Cross-Hydrodimerization of Enamides with Unactivated Alkenes

AbstractSaturated stereogenic centers containing C(sp3)–C(sp3) bonds comprise a major portion of organic molecules. Over the past decades, transition-metal-catalyzed asymmetric C(sp3)–C(sp3) cross-coupling has evolved into an efficient strategy for constructing such stereogenic centers. However, reaction modes to build asymmetric C(sp3)–C(sp3) bonds remain limited. Herein, a nickel-catalyzed enantioselective cross-hydrodimerization between distinct alkenes to enable the enantioselective construction of alkyl–alkyl bonds has been developed. In this reaction mode, N-acyl enamines (enamides) and unactivated alkenes undergo oxidative enantioselective cross-hydrodimerization with excellent levels of chemo- and head-to-tail regioselectivity to give enantioenriched N-acyl α-branched amines by forging the C(sp3)–C(sp3) bond with control of the enantioselectivity. The presence of both reducing and oxidizing reagents in the reaction allows the use of alkenes as sole precursors to forge enantioselective C(sp3)–C(sp3) bonds, representing a new reaction mode for asymmetric alkyl–alkyl cross-coupling. The asymmetric cross-hydrodimerization between distinct alkenes provides a new strategy for constructing saturated stereogenic centers containing C(sp3)–C(sp3) bonds.

Doubly Stereoconvergent Propargylic Alkylation of α-Cyanocarbonyls: Enantioselective Construction of Vicinal Stereocenters.

An asymmetric propargylic alkylation of α-cyanocarbonyls is developed for the first time under cooperative Cu(I) and organocatalysis. With ethynyl benzoxazinanones as the propargylic electrophile, this decarboxylative doubly stereoconvergent reaction evades alkyne hydroamination to furnish acyclic α-propargylic cyanocarbonyls, bearing vicinal tertiary and quaternary stereocenters, with high diastereo- and enantioselectivity (up to >20:1 dr and 99.5:0.5 er).

Ligand-Controlled Enantioselective and Regiodivergent Construction of 1,2- and 1,3-Disubstituted Alicycles.

Three-dimensional alicyclic skeletons with multiple stereochemically defined chiral centers are highly valuable in modern drug discovery. Here, we reported a diverse approach to access 1,2- and 1,3-disubstituted chiral cycloalkanes by the strategy of NiH-catalyzed, transannular-directed alkene desymmetrization. The ring strain of the bridged bicyclic organonickel intermediate and the coordination effect of the ligand were identified as crucial factors in determining site selectivity by influencing the NiH migration step. This methodology demonstrates a broad substrate scope and displays good tolerance toward various functional groups, resulting in excellent outcomes in terms of the yield, regioselectivity, and enantioselectivity.

Enantioselective Construction of Tetrahydroindole Skeletons by Rh‐Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes

AbstractWe have developed the Rh‐catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide‐tethered 1,6‐enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio‐ and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O2 affords hexahydroindole‐diols bearing three stereogenic centers and variable substituents on the nitrogen. Mechanistic studies have revealed that the substituents of the enynes change the ratio of intramolecular and intermolecular rhodacycle formation when using terminal alkynes, varying the ee values of the cycloadducts.

Enantioselective Construction of Tetrahydroindole Skeletons by Rh-Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes.

We have developed the Rh-catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide-tethered 1,6-enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio- and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O2 affords hexahydroindole-diols bearing three stereogenic centers and variable substituents on the nitrogen. Mechanistic studies have revealed that the substituents of the enynes change the ratio of intramolecular and intermolecular rhodacycle formation when using terminal alkynes, varying the ee values of the cycloadducts.

Development of Organocatalytic Reactions for the Synthesis of Natural Products and Pharmaceuticals

This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

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.

Enantioselective Construction of Anthracenylidene-Based Axial Chirality by Asymmetric Heck Reaction.

Anthracenylidene is an intriguing structural unit with potential in various fields. The study presents a novel approach to introducing axial chirality into this all-carbon core skeleton through a remotely controlled desymmetrization strategy. A palladium-catalyzed enantioselective Heck arylation of exocyclic double bond of anthracene with two distinct substituents at the C10 position is harnessed to realize such a transformation. The judicious identification of the P-centrally chiral ligand is pivotal to ensure the competitive competence in reactivity and stereocontrol when the heteroatom handle is absent from the anthracenylidene skeleton. Both C10 mono- and disubstituted substrates were compatible for the established catalytic system, and structurally diverse anthracenylidene-based frameworks were forged with good-to-high enantiocontrol. The subsequent derivatization of the obtained products yielded a valuable array of centrally and axially chiral molecules, thus emphasizing the practicality of this chemistry. DFT calculations shed light on the catalytic mechanism and provided insights into the origin of the experimentally observed enantioselectivity for this reaction.