Stereoselective Coupling Research Articles

Synergistic Homogeneous Asymmetric Cu Catalysis with Pd Nanoparticle Catalysis in Stereoselective Coupling of Alkynes with Aldimine Esters.

Understanding the nature of a transition-metal-catalyzed process, including catalyst evolution and the real active species, is rather challenging yet of great importance for the rational design and development of novel catalysts, and this is even more difficult for a bimetallic catalytic system. Pd(0)/carboxylic acid combined system-catalyzed allylic alkylation reaction of alkynes has been used as an atom-economical protocol for the synthesis of allylic products. However, the asymmetric version of this reaction is still rather limited, and the in-depth understanding of the nature of active Pd species is still elusive. Herein we report an enantioselective coupling between readily available aldimine esters and alkynes using a synergistic Cu/Pd catalyst system, affording a diverse set of α-quaternary allyl amino ester derivatives in good yields with excellent enantioselectivities. Mechanistic studies indicated that it is most likely a synergistic asymmetric molecular Cu catalysis with Pd nanoparticle catalysis. The Pd catalyst precursor is transformed to soluble Pd nanoparticles in situ, which are responsible for activating the alkyne to an electrophilic allylic Pd intermediate, while the chiral Cu complex of the aldimine ester enolate provides chiral induction and works in synergy with the Pd nanoparticles.

Borane-Catalyzed Coupling of Diazooxindoles and Difluoroenoxysilanes to Tetrasubstituted Monofluoroalkenes.

A highly stereoselective coupling reaction of diazooxindoles with difluoroenoxysilanes catalyzed by Lewis acidic boranes has been developed. The reaction proceeded at ambient temperature under transition metal-free conditions with wide functional group tolerance. By using this simple procedure, a series of tetrasubstituted monofluoroalkenes can be accessed in good yield with high selectivity.

Stereoselective synthesis of 2-deoxy-α-C-glycosides from glycals

2-Deoxy-α-C-Glycosides are a significant class of carbohydrates found in numerous bioactive molecules and medicines. Developing a concise strategy for the assembly of these α-configured C-glycosides is crucial in the field of carbohydrate chemistry. However, current methods are restricted to the utilization of glycosyl radical precursors, which are required for pre-syntheses. Herein, we present a novel approach for the synthesis of 2-deoxy-α-C-glycosides using a nickel-catalyzed stereoselective coupling reaction with commercially available glycals. Notably, this method circumvents the preparation for diverse glycosyl radical precursors. The developed protocol exhibits a broad substrate scope and remarkable stereoselectivity under mild reaction conditions. Furthermore, the raw materials required for this process are readily accessible, eliminating the necessity for pre-functionalization modifications of the glycosyl substrates and ensuring high atomic economy.

Ni-catalyzed regioselective C–C bond formation of 1,1-disubstituted allenes with aldehydes

A regio- and stereoselective coupling process between allenes and aldehydes has been developed to obtain a linear homoallylic secondary alcohols by photoredox/Ni dual catalysis.

Nickel-Catalyzed Migratory Cross-Coupling Reactions: New Opportunities for Selective C-H Functionalization.

ConspectusMigratory cross-coupling via metal migration is a process of significant academic and industrial interest. It provides an attractive alternative for the selective installation of a functional group at remote C-H positions from simple precursors, thus enabling the direct synthesis of challenging structures not accessible with traditional cross-coupling. In particular, with the merger of 1,n-Ni/H shift and cross-coupling of nickel, the Ni-catalyzed migratory functionalization of simple precursors has undergone particularly intense development and emerged as a valuable field of research in the past few years. This Account will outline the recent progress made in this arena in terms of migration-functionalization modes, diverse functionalizations, and strategies for regio- and stereocontrol. Mechanistic studies and synthetic applications are also discussed.In detail, we systematically categorize our work into two parts based on the migration modes. In the first part, a platform is created for Ni-catalyzed migratory sp3 C-H functionalization of alkenes or alkyl halides via iterative 1,2-Ni/H shift-selective cross-coupling. The key reactive Ni(II)H species for chain-walking could be generated in situ either in a polarity-reversed fashion relying on stoichiometric reductants (X-Ni(II)-H) or in a redox-neutral fashion with the participation of nucleophilic coupling partners (FG-Ni(II)-H). One significant advantage associated with the polarity-reversed NiH system is the use of relatively stable, abundant, and safe olefin surrogates or alkyl halides instead of the sensitive organometallics required in traditional cross-coupling reactions. Another advantage is that diverse functionalizations, including carbonation and more challenging amination and thiolation could be smoothly achieved with suitable electrophiles or their precursors. Finally, to address the challenging multifaceted selectivity and reactivity issues in asymmetric migratory cross-coupling reactions, we have developed a feasible ligand relay catalytic strategy. In this dynamic ligand exchange process, one ligand promotes rapid migration while the other promotes highly regio- and stereoselective coupling. This innovative strategy overcomes the formidable challenge stemming from the difficulty of designing a single ligand to efficiently promote both steps of chain-walking and asymmetric coupling. In the second part, a new platform for Ni-catalyzed migratory sp2 C-H functionalization via 1,4-Ni/H shift-selective cross-coupling has been reported. Starting from readily available aryl or vinyl coupling partners, the in situ-generated aryl- or vinylnickel(II) species could undergo a rapid and reversible 1,4-Ni/H shift along an sp2 backbone, and subsequent selective coupling with various coupling partners would allow regio- and stereoselective access to diverse 1,4-migratory functionalization products. The key to success was the discovery of an appropriate ligand to efficiently promote both migration and subsequent selective cross-coupling. A vinyl-to-aryl 1,4-Ni/H shift successfully enables the modular ipso/ortho difunctionalization of aryl coupling partners, while an aryl-to-vinyl 1,4-Ni/H shift enables regio- and stereoselective access to functionalized trisubstituted alkenes.We hope that this Account will inspire broad interest and future development of migratory cross-coupling reactions. We strongly believe that continued efforts in this fascinating field will overcome many of the remaining challenges, including cutting-edge ligand/catalyst design to enhance reactivity and selectivity, conceptually new migration modes for additional transformations, and in-depth mechanistic studies for rational reaction design.

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives.

ConspectusNickel-catalyzed reactions of alkyl alcohol derivatives leverage the high prevalence of hydroxyl groups in natural products, medicinal agents, and synthetic intermediates to provide access to C(sp3)-rich frameworks. This Account describes our laboratory's development of stereospecific and stereoconvergent C-C bond forming reactions employing C(sp3)-O and C(sp3)-N electrophiles. In the context of development of new transformations, we also define fundamental characteristics of the nickel catalysts.Part I details the nickel-catalyzed cross-coupling reactions developed by our group which hinges on stereospecific formation of stable π-benzyl intermediates. Acyclic and cyclic ethers, esters, carbamates, lactones, and sulfonamides undergo Kumada-, Suzuki-, and Negishi-type coupling reactions to produce enantioenriched products with high fidelity of stereochemical information. We describe extension to include ring-opening reactions of saturated heterocycles to afford acyclic 1,3-fragments in high diastereomeric ratios. We also describe our advances in stereospecific nickel-catalyzed cross-electrophile coupling reactions. Tethered C-O and C-X electrophiles proved fruitful for construction of a variety of carbocyclic frameworks. We report an intramolecular cross-electrophile coupling of benzylic pivalates with aryl bromides for the synthesis of indanes and tetralins. We found that 4-halotetrahydropyrans and 4-halopiperidines readily undergo stereospecific ring contraction to afford substituted cyclopropanes. Mechanistic investigations are consistent with closed-shell intermediates, a Ni(0)/Ni(II) cycle, and an intramolecular SN2-type reaction of a key organonickel intermediate to form the cyclopropane. Building toward more complex cascade reactions, we have demonstrated that 2-alkynyl piperidines incorporate MeMgI in a dicarbofunctionalization of the alkyne to afford highly substituted vinyl cyclopropanes.In Part II we present our development of stereoconvergent reactions of alkyl alcohol derivatives. In order to expand the utility of the intramolecular XEC reaction, we sought to employ unactivated alkyl electrophiles. Specifically, alkyl dimesylates engage in intramolecular XEC reactions to form alkyl cyclopropanes. In contrast to our previous work, these reactions proceed through open-shell intermediates and favor stereoconvergent formation of the trans-cyclopropane. Enantioselective aldol reactions can be employed in syntheses of 1,3-diols which furnish enantioenriched cyclopropanes in high ee. Experimental and computational evidence reveals that MeMgI mediates formation of alkyl iodides in situ. The coupling reaction initiates with halogen atom abstraction at the secondary alkyl iodide. The alkyl Ni(II) complex then proceeds through a stereospecific SN2-type ring closure to form cyclopropane. In an effort to increase functional group compatibility in the synthesis of cyclopropanes from alkyl dimesylates we developed a zinc-mediated reaction of 1,3-dimesylates prepared from medicinal analogues. In challenging nickel-catalyzed intramolecular cross-electrophile coupling we were also able to show that vicinal carbocycles can be prepared under similar conditions, affording vicinal cyclopentyl-cyclopropyl motifs in high yield.In Part III we discuss our recent findings on the role of ligand identity in catalyst selectivity for stereospecific vs stereoablative mechanisms for oxidative addition. We demonstrate multivariable control of mechanism, where the choice of substrate and ligand work together to promote open- or closed-shell intermediates. In divergent reactions of 4-halotetrahydropyrans we observe distinct ligand preference for reactions at the C(sp3)-O center or the C(sp3)-Cl center. These findings are the source of continued investigations in our laboratory.

Merging Iridium-Catalyzed Stereoselective Coupling from Alcohols with Organocatalytic Functionalization at the Aldehyde Oxidation Level

Merging Iridium-Catalyzed Stereoselective Coupling from Alcohols with Organocatalytic Functionalization at the Aldehyde Oxidation Level

Synthesis of the branched tetrasaccharide fragment of saccharomicin B

A synthesis of the branched tetrasaccharide fragment of saccharomicin B through a [2+2] strategy is reported. Stereoselective coupling of a saccharosamine ortho-alkynyl benzoate to a digitoxose thioglycoside acceptor afforded the Sac-11-Digi-10 donor in 50% yield. This latter compound was then united with our previously reported Fuc-8-Eva-9 disaccharide under AgPF6 promotion to afford the target tetrasaccharide in 20% yield. The resulting tetrasaccharide can serve as a linchpin for assembling the target molecule.

Identification and functional characterization of the dirigent gene family in Phryma leptostachya and the contribution of PlDIR1 in lignan biosynthesis

BackgroundFurofuran lignans, the main insecticidal ingredient in Phryma leptostachya, exhibit excellent controlling efficacy against a variety of pests. During the biosynthesis of furofuran lignans, Dirigent proteins (DIRs) are thought to be dominant in the stereoselective coupling of coniferyl alcohol to form ( ±)-pinoresinol. There are DIR family members in almost every vascular plant, but members of DIRs in P. leptostachya are unknown. To identify the PlDIR genes and elucidate their functions in lignan biosynthesis, this study performed transcriptome-wide analysis and characterized the catalytic activity of the PlDIR1 protein.ResultsFifteen full-length unique PlDIR genes were identified in P. leptostachya. A phylogenetic analysis of the PlDIRs classified them into four subfamilies (DIR-a, DIR-b/d, DIR-e, and DIR-g), and 12 conserved motifs were found among them. In tissue-specific expression analysis, except for PlDIR7, which displayed the highest transcript abundance in seeds, the other PlDIRs showed preferential expression in roots, leaves, and stems. Furthermore, the treatments with signaling molecules demonstrated that PlDIRs could be significantly induced by methyl jasmonate (MeJA), salicylic acid (SA), and ethylene (ETH), both in the roots and leaves of P. leptostachya. In examining the tertiary structure of the protein and the critical amino acids, it was found that PlDIR1, one of the DIR-a subfamily members, might be involved in the region- and stereo-selectivity of the phenoxy radical. Accordingly, LC–MS/MS analysis demonstrated the catalytic activity of recombinant PlDIR1 protein from Escherichia coli to direct coniferyl alcohol coupling into ( +)-pinoresinol. The active sites and hydrogen bonds of the interaction between PlDIR1 and bis-quinone methide (bisQM), the intermediate in ( +)-pinoresinol formation, were analyzed by molecular docking. As a result, 18 active sites and 4 hydrogen bonds (Asp-42, Ala-113, Leu-138, Arg-143) were discovered in the PlDIR1-bisQM complex. Moreover, correlation analysis indicated that the expression profile of PlDIR1 was closely connected with lignan accumulations after SA treatment.ConclusionsThe results of this study will provide useful clues for uncovering P. leptostachya's lignan biosynthesis pathway as well as facilitate further studies on the DIR family.

Cobalt(II)‐Catalyzed C(sp3)−C(sp3) Coupling for the Direct Stereoselective Synthesis of 2‐Deoxy‐C‐Glycosides from Glycals

AbstractWe report a ligand‐controlled CoII‐catalyzed C(sp3)−C(sp3) coupling hydroalkylation for direct and β‐selective synthesis of 2‐deoxy‐C‐glycosides from glycals. This reaction proceeds by a radical pathway for alkyl halide activation and is β‐selective through ligand control. This approach may inspire the development of further stereoselective coupling reactions with potential application in the field of carbohydrates.

Cobalt(II)-Catalyzed C(sp3 )-C(sp3 ) Coupling for the Direct Stereoselective Synthesis of 2-Deoxy-C-Glycosides from Glycals.

We report a ligand-controlled CoII -catalyzed C(sp3 )-C(sp3 ) coupling hydroalkylation for direct and β-selective synthesis of 2-deoxy-C-glycosides from glycals. This reaction proceeds by a radical pathway for alkyl halide activation and is β-selective through ligand control. This approach may inspire the development of further stereoselective coupling reactions with potential application in the field of carbohydrates.

Simultaneous Dual Cu/Ir Catalysis: Stereodivergent Synthesis of Chiral β-Lactams with Adjacent Tertiary/Quaternary/Tertiary Stereocenters

A stereodivergent synthesis of chiral β-lactams with contiguous tertiary/quaternary/tertiary stereocenters has been achieved by a Cu/Ir-catalyzed three-component interrupted Kinugasa allylic alkylation reaction. The two catalysts independently exert high local stereocontrol, providing access to four of the eight possible stereoisomers in high yields with >99% ee. The features of this strategy are the asymmetric simultaneous dual metal-catalyzed cascade reactions with stereoselective coupling of highly transient organometallic intermediates.

Cloning and Expression Analysis of <i>PeDIR19</i> Gene in Poplar

Dirigent ( DIR ) gene plays an important role in the formation of lignin and lignans by controlling the stereoselective coupling of pineperin alcohol monomers in plants during the polymerization of lignin and lignans. In this study, we take the ‘Nanlin 895’ ( Populus deltoides × P. euramericana  cv ‘Nanlin 895’) as the material, and clone the PeDIR19  gene. PeDIR19 , the whole length of 588 bp, has a length of 555 bp in ORF region and has only a length of 33 bp intron in the middle. PeDIR19 protein codes 185 amino acids and is a hydrophobic protein. It has four conservative motifs and has a highly conservative structural functional domain between 50 bp ~ 142 bp. PeDIR19  gene was found to have the highest homology with Populus trichocarpa   PtDIR19 ( Potri.001G009100 ), with only four bases differences. By phylogenetic analysis, PeDIR19  gene belongs to DIR -B/D subfamily. Through tissue specific expression analysis of ‘Nanlin 895’ with different growth stages, it was found that PeDIR19  gene expression level was the highest in the root during the tissue culture seedlings and in the stem during the pot seedlings. PeDIR19  gene had a strong response after 1 d under the induction of Yangpan Erbaojun ( Marssonina brunnea ). Under the induction of salicylic acid, methyl jasmonate and abscisic acid stress, PeDIR19  gene can strongly respond to the stress of methyl jasmonate and abscisic acid and weakly respond to the salicylic acid stress. This study provides a solid foundation for further study on the function identification of DIR  gene in the biosynthetic pathway of plant resistance.

Stereocontrolled Synthesis of the Fully Glycosylated Monomeric Unit of Lomaiviticin A.

We describe a stereocontrolled synthesis of 3, the fully glycosylated monomeric unit of the dimeric cytotoxic bacterial metabolite (-)-lomaiviticin A (2). A novel strategy involving convergent, site- and stereoselective coupling of the β,γ-unsaturated ketone 6 and the naphthyl bromide 7 (92%, 15:1 diastereomeric ratio (dr)), followed by radical-based annulation and silyl ether cleavage, provided the tetracycle 5 (57% overall), which contains the carbon skeleton of the aglycon of 3. The β-linked 2,4,6-trideoxy-4-aminoglycoside l-pyrrolosamine was installed in 73% yield and with 15:1 β:α selectivity using a modified Koenigs-Knorr glycosylation. The diazo substituent was introduced via direct diazo transfer to an electron-rich benzoindene (4 → 27). The α-linked 2,6-dideoxyglycoside l-oleandrose was introduced by gold-catalyzed activation of an o-alkynyl glycosylbenzoate (75%, >20:1 α:β selectivity). A carefully orchestrated endgame sequence then provided efficient access to 3. Cell viability studies indicated that monomer 3 is not cytotoxic at concentrations up to 1 μM, providing conclusive evidence that the dimeric structure of (-)-lomaiviticin A (2) is required for cytotoxic effects. The preparation of 3 provides a foundation to complete the synthesis of (-)-lomaiviticin A (2) itself.

Enantioselective and Diastereodivergent Allylation of Propargylic C-H Bonds.

An iridium-catalyzed stereoselective coupling of allylic ethers and alkynes to generate 3,4-substituted 1,5-enynes is reported. Under optimized conditions, the coupling products are formed with excellent regio-, diastereo-, and enantioselectivities, and the protocol is functional group tolerant. Moreover, we report conditions that allow the reaction to proceed with complete reversal of diastereoselectivity. Mechanistic studies are consistent with an unprecedented dual role for the iridium catalyst, enabling the propargylic deprotonation of the alkyne through π-coordination, as well as the generation of a π-allyl species from the allylic ether starting material.

Palladium-Catalyzed Regio- and Stereoselective Coupling of Alkynylsulfones with Alkenes: Access to Dichlorinated Vinyl Sulfones.

A palladium-catalyzed coupling reaction of alkynylsulfones with alkenes has been described, which provides an efficient and practical entry to various functionalized dichlorinated vinyl sulfones. This method features excellent regio- and stereoselectivities, good functional group compatibility, as well as mild reaction conditions. Mechanistic studies suggest that the reaction goes through sequential syn-chloropalladation, alkene insertion, and C(sp3)-Cl bond formation processes, and the sulfonyl group is crucial to the stereoselectivity control of the reaction.

Amine-catalyzed site- and stereo-selective coupling of epoxy amines and carbon dioxide to construct oxazolidinones

NEt3catalyzed the cycloaddition of epoxy amine and CO2, which generated oxazolidinones. Reactions of chiral epoxy amine achieved 100% configuration inversion, enabling the synthesis of linezolid. DFT studies show that NEt3acted as a nucleophile.

α-Boryl Organometallic Reagents in Catalytic Asymmetric Synthesis.

Recent years have witnessed an increase in the popularity of α-boryl organometallic reagents as versatile nucleophiles in asymmetric synthesis. These compounds have been adopted in chemo- and stereoselective coupling reactions with a number of different electrophiles. The resulting enantioenriched boronic esters can be applied in stereospecific carbon-carbon or carbon-heteroatom bond construction reactions, enabling a two-step strategy for the construction of complex structures with high efficiency and functional group compatibility. Due to these reasons, tremendous effort has been devoted to the preparation of enantiomerically enriched α-boryl organometallic reagents and to the development of stereoselective reactions of related racemic or prochiral materials. In this review, we describe the enantio- or diastereoselective reactions that involve α-boryl organometallic reagents as starting materials or products and we showcase their synthetic utility.

Site- and Stereoselective C-H Alkylations of Carbohydrates Enabled by Cooperative Photoredox, Hydrogen Atom Transfer, and Organotin Catalysis.

Diorganotin dihalides act as cocatalysts for site-selective and stereoselective couplings of diol-containing carbohydrates with electron-deficient alkenes in the presence of an Ir(III) photoredox catalyst and quinuclidine, a hydrogen atom transfer mediator. Quantum-chemical calculations support a proposed mechanism involving the formation of a cyclic stannylene acetal intermediate that shows enhanced reactivity toward hydrogen atom abstraction by the quinuclidinium radical cation. Addition of the carbon-centered radical to the alkene partner results in C-alkylation of the carbohydrate substrate.

Hydroalkylation of Alkynes: Functionalization of the Alkenyl Copper Intermediate through Single Electron Transfer Chemistry.

We have developed a method for the stereoselective coupling of terminal alkynes and α-bromo carbonyls to generate functionalized E-alkenes. The coupling is accomplished by merging the closed-shell hydrocupration of alkynes with the open-shell single electron transfer (SET) chemistry of the resulting alkenyl copper intermediate. We demonstrate that the reaction is compatible with various functional groups and can be performed in the presence of aryl bromides, alkyl chlorides, alkyl bromides, esters, nitriles, amides, and a wide range of nitrogen-containing heterocyclic compounds. Mechanistic studies provide evidence for SET oxidation of the alkenyl copper intermediate by an α-bromo ester as the key step that enables the cross coupling.