Negishi Cross-coupling Reactions Research Articles

Fluorescent carbazole-derived α-amino acids: structural mimics of tryptophan.

Fluorescent tags are commonly used for imaging of proteins and peptides during biological events; however, the large size of dyes can disrupt protein structure and function, and typically require the use of a chemical spacer. Herein, we report the synthesis of a new class of fluorescent unnatural α-amino acid, containing carbazole side-chains designed to mimic l-tryptophan and thus, readily incorporated into peptides. The amino acids were constructed using a Negishi cross-coupling reaction as the key step and exhibited strong fluorescent emission, with high quantum yields in both organic solvents and water. Compatible with solid phase peptide synthesis, the carbazole amino acids were used to replace tryptophan in a β-hairpin model peptide and shown to be a close structural mimic with retention of conformation. They were also found to be effective fluorescent molecular reporters for biological events. Incorporation into a proline-rich ligand of the WW domain protein demonstrated that the fluorescent properties of a carbazole amino acid could be used to measure the protein-protein binding interaction of this important biological signalling process.

Atroposelective NiII -Catalyzed Cross-Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher-Order Zincates.

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3 ]2- Mg(THF)2 2+ . The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions.

Discovery of novel cannabidiol derivatives with augmented antibacterial agents against methicillin-resistant Staphylococcus aureus

Drug-resistant bacterium infections are a severe threat to public health and novel antimicrobial agents combating drug-resistant bacteria are an unmet medical need. Although cannabidiol (CBD) has been reported to show antibacterial effects, whether its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) can be improved remains unclear. Herein, a series of novel CBD derivatives were designed and synthesized using various chemical approaches including amidation, Friedel-Crafts alkylation, and Negishi cross-coupling reaction for the modifications at the C-7, C-2′, C-4′, and C-6′ positions of CBD skeleton. Derivative 21f showed augmented antibacterial activity against MRSA with a minimum inhibitory concentration of 4 μM without cytotoxic effect in microglia BV2 cells. Further mechanistic studies suggested that 21f inhibited the formation of biofilms, induced excess reactive oxygen species, and reduced bacterial metabolism, which collectively led to the acceleration of bacterial death. Findings from this study expand the understanding of CBD derivatives as promising antibacterial agents, which provides useful information for the development of cannabinoid-based antibacterial agents.

Feed-Forward Neural Network for Predicting Enantioselectivity of the Asymmetric Negishi Reaction.

Density functional theory (DFT) is a powerful tool to model transition state (TS) energies to predict selectivity in chemical synthesis. However, a successful multistep synthesis campaign must navigate energetically narrow differences in pathways that create some limits to rapid and unambiguous application of DFT to these problems. While powerful data science techniques may provide a complementary approach to overcome this problem, doing so with the relatively small data sets that are widespread in organic synthesis presents a significant challenge. Herein, we show that a small data set can be labeled with features from DFT TS calculations to train a feed-forward neural network for predicting enantioselectivity of a Negishi cross-coupling reaction with P-chiral hindered phosphines. This approach to modeling enantioselectivity is compared with conventional approaches, including exclusive use of DFT energies and data science approaches, using features from ligands or ground states with neural network architectures.

Construction of Five Tryptophan Isomers and Application of the Isomers to Solid-Phase Total Syntheses of Lysocin E Derivatives.

Tryptophan (Trp) plays a unique role in peptides and proteins as its indole ring possesses an electron-rich character and an N1-H hydrogen-bond donor. Because of its non-rotationally symmetric structure, synthetic alterations of the orientation of the indole ring would modulate the intrinsic structures and functions of peptides and proteins. Here we developed synthetic routes to the five Trp isomers in which the C3-substitution of the indole ring was changed to the C2/4/5/6/7-substitutions, and applied the five monomers to Fmoc-based solid-phase peptide synthesis. Specifically, the five monomers were prepared via Negishi cross-coupling reactions of C2/4/5/6/7-iodoindoles. To demonstrate the applicability of the monomers to the solid-phase synthesis, the five Trp isomers of macrocyclic antibiotic lysocin E were selected as target molecules and synthesized through peptide elongation, on-resin macrocyclization, and global deprotection. The Trp isomers displayed markedly weaker antibacterial activity than the parent natural product, revealing the biological importance of the precise three-dimensional shape of the original Trp residue of lysocin E. The present methods for the preparation and application of these five Trp isomers provide a new strategy for analyzing and modifying the specific functions of numerous Trp-containing peptides and proteins beyond this study.

Graphene loaded with metal nanoparticles/complexes catalyzed cross-coupling reactions: A review

Various catalytic reactions under suitable conditions were used for the carbon-carbon (C-C) bond formation, such as the Kumada, Mizoroki-Heck, Sonogashira, Negishi, Stille, Suzuki-Miyaura, Hiyama, and Fukuyama cross-coupling reactions. Supporting metal nanoparticles or complexes on functionalized graphene oxide (GO) or reduced graphene oxide (rGO) compounds provides new heterogeneous catalysts with enhanced aptitude for the formation of C-C bonds. This review highlights the applications of metal decorated on modified GO and rGO derivatives to form C-C bonds. We discuss briefly the general mechanistic cycle of each reaction and the recent applications of the graphene-based nanocatalysts for the coupling reactions, along the advantages of each catalyst.

Surfactant Micellar and Vesicle Microenvironments and Structures under Synthetic Organic Conditions.

Fluorescence lifetime imaging microscopy (FLIM) reveals vesicle sizes, structures, microenvironments, reagent partitioning, and system evolution with two chemical reactions for widely used surfactant-water systems under conditions relevant to organic synthesis, including during steps of Negishi cross-coupling reactions. In contrast to previous investigations, the present experiments characterize surfactant systems with representative organohalide substrates at high concentrations (0.5 M) that are reflective of the preparative-scale organic reactions performed and reported in water. In the presence of representative organic substrates, 2-iodoethylbenzene and 2-bromo-6-methoxypyridine, micelles swell into emulsion droplets that are up to 20 μm in diameter, which is 3-4 orders of magnitude larger than previously measured in the absence of an organic substrate (5-200 nm). The partitioning of reagents in these systems is imaged through FLIM─demonstrated here with nonpolar, amphiphilic, organic, basic, and oxidative-addition reactive compounds, a reactive zinc metal powder, and a palladium catalyst. FLIM characterizes the chemical species and/or provides microenvironment information inside micelles and vesicles. These data show that surfactants cause surfactant-dictated microenvironments inside smaller micelles (<200 nm) but that addition of a representative organic substrate produces internal microenvironments dictated primarily by the substrate rather than by the surfactant, concurrent with swelling. Addition of a palladium catalyst causes the internal environments to differ between vesicles─information that is not available through nor predicted from prior analytical techniques. Together, these data provide immediately actionable information for revising reaction models of surfactant-water systems that underpin the development of sustainable organic chemistry in water.

Well-Defined Ni(0) and Ni(II) Complexes of Bicyclic (Alkyl)(Amino)Carbene (Me BICAAC): Catalytic Activity and Mechanistic Insights in Negishi Cross-Coupling Reaction.

Negishi cross-coupling reaction of organozinc compounds as nucleophiles with aryl halides has drawn immense focus for C-C bond formation reactions. In comparison to the well-established library of Pd complexes, the C-C cross-coupling of this particular approach is largely primitive with nickel-complexes. Herein, we describe the syntheses of Ni(II) complexes, [(Me BICAAC)2 NiX2 ] (X=Cl (1), Br (2), and I (3)) by employing the bicyclic (alkyl)(amino)carbene (Me BICAAC) ligand. The reduction of complexes 1-3 using KC8 afforded the two coordinate low valent, Ni(0) complex, [(Me BICAAC)2 Ni(0)] (4). Complexes 1-4 have been characterized by spectroscopic techniques and their solid-state structures were also confirmed by X-ray crystallography. Furthermore, complexes 1-4 have been applied in a direct and convenient method to catalyze the Negishi cross-coupling reaction of various aryl halides with 2,6-difluorophenylzinc bromide or phenylzinc bromide as the coupling partner in the presence of 3 mol % catalyst. Comparatively, among all-pristine complexes, 1 exhibit high catalytic potential to afford value-added C-C coupled products without the use of any additive. The UV-vis studies and HRMS measurements of controlled stochiometric reactions vindicate the involvement of Ni(I)-NI(III) cycle featured with a penta-coordinated Ni(III)-aryl species as the key intermediate for 1 whereas Ni(0)/Ni(II) species are potentially involved in the catalytic cycle of 4.

Stereoselective Syntheses of trans-Anhydromevalonic Acid and trans-Anhydromevalonyl Group-Containing Natural Products.

Collective total syntheses of trans-anhydromevalonic acid (tAHMA) and trans-anhydromevalonyl (tAHM) group-containing natural products (pestalotiopin A, pestalotiopamide C, pestalotiopamide D, farinomalein E, eleutherazine B, and trichocyclodipeptide A) were achieved using tAHMA esters as key intermediates. To this end, tAHMA tert-butyl ester was newly prepared by Z-vinyltosylation of tert-butyl 3-oxo-5-((triisopropylsilyl)oxy)pentanoate followed by the Negishi cross-coupling reaction with Me2Zn. tAHMA esters were converted to the target natural products via esterification or amidation. Comparison of the spectroscopic data of synthetic and natural products confirmed the E-configuration of the tAHM moieties in the natural products.

Synthesis and crystal structures of unsymmetrical wave-shaped heptathienoacenes.

Three unsymmetrical wave-shaped heptathienoacenes (UHT-1, UHT-2 and UHT-3) with sulfur atoms at different isomeric locations in the two terminal thiophene rings were designed and synthesized. The synthetic strategy contains two crucial steps, including the cross-coupling of two different dithienothiophene isomers (DTT) from dithieno[2,3-b:3',2'-d]thiophene (bb-DTT), dithieno[2,3-b:2',3'-d]thiophene (bt-DTT) and dithieno[2,3-b:3',4'-d]thiophene (bs-DTT) as building blocks through the Negishi coupling and intramolecular cyclization reactions with (SnBu3)2S. X-ray crystal structures of UHT-1, UHT-2 and UHT-3 show that the molecules adopt a wave-shaped geometry with multiple intermolecular interactions, such as S-S, S-C and S-H, which result in different crystal packing patterns. The isomeric location of the sulfur atoms of the two terminal thiophene rings of UHT-1, UHT-2 and UHT-3 plays an important role in tuning π-electronic conjugation and spectroscopic behaviors.

Synthesis of desmosine-BSA/KLH conjugates via Sonogashira/Negishi cross-coupling reactions

Desmosine is an elastin crosslinking amino acid that is expected to be a useful biomarker of diseases related to elastin degradation including chronic obstructive pulmonary disease (COPD). In this study, conjugates of desmosine and carrier proteins, such as bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH), with linkers were designed and prepared for the creation of an effective antibody to be used in the development of an enzyme-linked immunosorbent assay (ELISA) system. Synthesis of desmosine along with the linkers having appropriate lengths was achieved via stepwise and chemo/regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions starting from an alkyne with protecting groups over nine steps. Subsequently, Michael addition with a thiolated carrier protein (BSA/KLH) was carried out using Traut’s reagent to afford seven types of desmosine-BSA/KLH conjugates.

Multicomponent Synthesis of Unsymmetrical 4,5-Disubstituted Imidazolium Salts as N-Heterocyclic Carbene Precursors: Applications in Palladium-Catalyzed Cross-Coupling Reactions.

Various novel (a)chiral 4,5-disubstituted 1-aryl-3-alkyl-imidazolium salts were synthesized via the multicomponent reaction of diketone derivatives, sterically congested arylamines, and alkylamines. Moreover, two novel unsymmetrical bulky cycloalkyl-based NHC-Pd complexes proved highly active as catalysts for Suzuki-Miyaura and Negishi cross-coupling reactions.

Reactivity of [Pt(P t Bu3)2] with Zinc(I/II) Compounds: Bimetallic Adducts, Zn-Zn Bond Cleavage, and Cooperative Reactivity.

Metal-only Lewis pairs (MOLPs) based on zinc electrophiles are particularly interesting due to their relevance to Negishi cross-coupling reactions. Zinc-based ligands in bimetallic complexes also render unique reactivity to the transition metals at which they are bound. Here we explore the use of sterically hindered [Pt(PtBu3)2] (1) to access Pt/Zn bimetallic complexes. Compounds [(PtBu3)2Pt → Zn(C6F5)2] (2) and [Pt(ZnCp*)6] (3) (Cp* = pentamethylcyclopentadienyl) were isolated by reactions with Zn(C6F5)2 and [Zn2Cp*2], respectively. We also disclose the cooperative reactivity of 1/ZnX2 pairs (X = Cl, Br, I, and OTf) toward water and dihydrogen, which can be understood in terms of bimetallic frustration.

Unexpected Substituent Effects in Aryl-Aryl Negishi Cross-Coupling Reactions Rationalized by Density Functional Theory and Natural Charges

While numerous studies consider substitution effects at the aromatic system in the arylzinc reactant during the transmetalation step in palladium-catalyzed Negishi cross-coupling reactions, the effects caused by varying substituents at the arylpalladium complex have not been the center of attention so far. Herein, we present results from competition experiments providing the counterintuitive observation that electron-withdrawing (donating) groups in the para position to the palladium center inhibit (accelerate) the transmetalation step in aryl-aryl Negishi cross-coupling reactions. Quantum-chemical calculations based on density functional theory provide mechanistic insights and show that an associative transmetalation mechanism is favored over a dissociative one. Foster–Boys localized orbitals and Mayer bond orders aid in rationalizing molecular and electronic structural features. Natural population analysis reveals that charge accumulation at the palladium center causes a destabilization of the transition state, which clearly correlates with the electronic properties of the substituents represented by their Hammett parameters.

Palladium-Catalyzed Allylic Carbonylative Negishi Cross-Coupling Reactions with Sterically Bulky Aromatic Isocyanides

Palladium-Catalyzed Allylic Carbonylative Negishi Cross-Coupling Reactions with Sterically Bulky Aromatic Isocyanides

Stereocomplementary and Parallel Syntheses of Multi-Substituted (E)-, (Z)-Stereodefined α,β-Unsaturated Esters: Application to Drug Syntheses.

Ubiquitous α,β-unsaturated esters are well recognized as key structural olefin scaffolds in organic chemistry. (E)- and (Z)-steroselectivity is the most critical issue in their synthesis, however, (E)- and (Z)- stereocomplementary synthetic methods remain quite limited. The present account discloses general (E)-, (Z)-stereocomplementary syntheses of a variety of α,β-unsaturated esters from highly accessible (E)-, (Z)-stereodefined enol tosylates derived from β-ketoesters and α-formyl esters. Step 1 toward the stereocomplementary preparation of (E)-, (Z)-stereodefined enol tosylates is implemented by using inexpensive reagents under mild reaction conditions. Step 2 toward the highly stereoretentive synthesis of (E)- and (Z)-stereodefined α,β-unsaturated esters involves Suzuki-Miyaura, Negishi, Sonogashira, Iron-catalyzed, Mizoroki-Heck, and Buchwald-Hartwig cross-coupling reactions. Notably, this strategy was successfully applied for parallel drug syntheses of (E)- and (Z)-zimelidine, (E)- and (Z)-tamoxifen, and Merck's cyclopropane pharmacophore. Representative successful utilizations by other groups are also introduced.

Total Synthesis of Ajudazol A by a Modular Oxazole Diversification Strategy.

The total synthesis of the potent respiratory chain inhibitor ajudazol A was accomplished by a concise strategy in 17 steps (longest linear sequence). The modular approach was based on a direct oxazole functionalization strategy involving a halogen dance reaction for selective halogenation in combination with a challenging combination of sp2-sp2 and sp2-sp3 Negishi cross coupling reactions. The applicability of this strategy for analogue synthesis was demonstrated by the synthesis of a simplified as well as stabilized ajudazol analogue.

Toward prediction of the precatalyst activation mechanism through the cross-coupling reactions: Reduction of Pd(II) to Pd(0) in precatalyst of the type Pd-PEPPSI.

Pd-PEPPSI type complexes are widely used as precatalyst in a variety of organic reactions, including the Negishi, Kumada and Suzuki-Miyaura cross-coupling reactions. The aim of this research is to determine potential proposed reaction pathways 1, 2, or 2' (See Schemes 1 and S1-S4) for Pd-PEPPSI precatalyst activation in the presence of ethylene glycol as a solvent also in the gas phase at Cam-B3LYP-D3 method nominated among eight DFT methods examined. There is also investigation into the impact of promoter bases (NaOEt, NaOi Pr, NaOt Bu) on precatalyst activation of Pd-PEPPSI. Eventually, the most favorable proposed reaction pathway and promoter base for reducing Pd(II) to Pd(0) are predicted computationally. Notably, our findings are consistent with the organ Pd-PEPPSI type complexes that offer increased catalytic activity and provide basic information in the presence of solvents designing the monoligated Pd(0)-solvent.

Stereoselective Bromoboration of Acetylene with Boron Tribromide: Preparation and Cross-Coupling Reactions of (Z)-Bromovinylboronates.

The mechanism of acetylene bromoboration in neat boron tribromide was studied carefully by means of experiment and theory. Besides the syn-addition mechanism through a four-center transition state, radical and polar anti-addition mechanisms are postulated, both triggered by HBr, which is evidenced also to take part in the Z/E isomerization of the product. The proposed mechanism is well supported by ab initio calculations at the MP2/6-31+G* level with Ahlrichs' SVP all-electron basis for Br. Implicit solvation in CH2Cl2 has been included using the PCM and/or SMD continuum solvent models. Comparative case studies have been performed involving the B3LYP/6-31+G* with Ahlrichs' SVP for Br and MP2/Def2TZVPP levels. The mechanistic studies resulted in development of a procedure for stereoselective bromoboration of acetylene yielding E/Z mixtures of dibromo(bromovinyl)borane with the Z-isomer as a major product (up to 85%). Transformation to the corresponding pinacol and neopentyl glycol boronates and stereoselective decomposition of their E-isomer provided pure (Z)-(2-bromovinyl)boronates in 57-60% overall yield. Their reactivity in a Negishi cross-coupling reaction was tested. An example of the one-pot reaction sequence of Negishi and Suzuki-Miyaura cross-couplings for synthesis of combretastatin A4 is also presented.

Two approaches to the synthesis of planar chiral quinolinyl cymantrene

Two approaches to the synthesis of planar chiral (SMn,S)-[2-(quinolin-2-yl)cymantren-1-yl]-p-tolylsulfoxide have been developed. One of them is based on the Negishi cross-coupling reaction, while other one is based on the SNH cross-coupling.