Showing papers on "Nucleophile published in 2017"

Transition metal-catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry.

Abstract: BACKGROUND The development of useful new methods for the construction of carbon-carbon bonds has had an impact on the many scientific disciplines (including materials science, biology, and chemistry) that use organic compounds. Tremendous progress has been made in the past several decades in the creation of bonds between sp 2 -hybridized carbons (e.g., aryl-aryl bonds), particularly through the use of transition metal catalysis. In contrast, until recently, advances in the development of general methods that form bonds between sp 3 -hybridized carbons (alkyl-alkyl bonds) had been rather limited. A variety of approaches, such as classical S N 2 reactions and transition metal catalysis, typically led to side reactions rather than the desired carbon-carbon bond formation. With transition metal catalysis, the unwanted but often facile β-hydride elimination of alkylmetal complexes presented a key impediment to efficient cross-coupling of alkyl electrophiles. In the case of many alkyl-alkyl bonds, there is an additional challenge beyond construction of the carbon-carbon bond itself: controlling the stereochemistry at one or both carbons of the new bond. It is important to control the stereochemistry of organic molecules because of its influence on properties such as biological activity. Each of these two challenges is difficult to solve individually; addressing them simultaneously is even more demanding. Until recently, the methods for achieving alkyl-alkyl bond formation were comparatively limited in scope, typically involving the use of unhindered (e.g., primary) electrophiles and unhindered, highly reactive nucleophiles (e.g., Grignard reagents, which have relatively poor functional group compatibility). With respect to enantioconvergent reactions, there were virtually no examples. ADVANCES In recent years, it has been established that, through the action of an appropriate transition metal catalyst, it is possible to achieve a broad range of alkyl-alkyl bond-forming processes; nickel-based catalysts have proved to be especially effective. With respect to the electrophilic coupling partner, a wide range of secondary alkyl halides are now suitable. This has enabled the development of enantioconvergent reactions of readily available racemic secondary electrophiles. In view of the abundance of tertiary stereocenters in organic molecules, this is a noteworthy advance in synthesis. With respect to the nucleophilic partner, alkylboron and alkylzinc reagents (Suzuki- and Negishi-type reactions, respectively) can now be used in a wide variety of alkyl-alkyl couplings, which greatly increases the utility of such processes, as these nucleophiles are more readily available and have much improved functional group compatibility relative to Grignard reagents. These new methods for alkyl-alkyl bond formation have been applied to the synthesis of natural products and other bioactive compounds. OUTLOOK A number of major challenges remain. For example, with regard to the electrophilic coupling partner, there is a need to develop general methods that are effective for tertiary alkyl halides, including enantioconvergent processes. With regard to the nucleophilic partner, there is a need to discover more versatile catalysts that can use a wide range of hindered (e.g., secondary and tertiary) alkylmetal reagents, as well as to achieve a broad spectrum of enantioconvergent couplings of racemic nucleophiles. These advances can enable the doubly stereoconvergent coupling of a racemic electrophile with a racemic nucleophile. The synthesis of alkyl-alkyl bonds is arguably the most important bond construction in organic synthesis. The ability to achieve this bond formation at will, as well as to control the product stereochemistry, would transform organic synthesis and empower the many scientists who use organic molecules. Recent work has provided evidence that transition metal catalysis can address this exciting challenge.

Recent developments in and perspectives on three-coordinate boron materials: a bright future.

Abstract: The empty pz-orbital of a three-coordinate organoboron compound leads to its electron-deficient properties, which make it an excellent π-acceptor in conjugated organic chromophores. The empty p-orbital in such Lewis acids can be attacked by nucleophiles, so bulky groups are often employed to provide air-stable materials. However, many of these can still bind fluoride and cyanide anions leading to applications as anion-selective sensors. One electron reduction generates radical anions. The π-acceptor strength can be easily tuned by varying the organic substituents. Many of these compounds show strong two-photon absorption (TPA) and two-photon excited fluorescence (TPEF) behaviour, which can be applied for e.g. biological imaging. Furthermore, these chromophores can be used as emitters and electron transporters in OLEDs, and examples have recently been found to exhibit efficient thermally activated delayed fluorescence (TADF). The three-coordinate organoboron unit can also be incorporated into polycyclic aromatic hydrocarbons. Such boron-doped compounds exhibit very interesting properties, distinct from their all-carbon analogues. Significant developments have been made in all of these areas in recent years and new applications are rapidly emerging for this class of boron compounds.

Selected Copper-Based Reactions for C-N, C-O, C-S and C-C Bond Formation

Abstract: Metal-catalyzed cross-coupling reactions belong to the most important transformations in organic synthesis Copper catalysis has received great attention owing to the low toxicity and low cost of copper However, traditional Ullmann-type couplings suffer from limited substrate scopes and harsh reaction conditions The introduction of several bidentate ligands, such as amino acids, diamines, 1,3-diketones, and oxalic diamides, over the past two decades has totally changed this situation as these ligands enable the copper-catalyzed coupling of aryl halides and nucleophiles at both low reaction temperatures and catalyst loadings The reaction scope has also been greatly expanded, rendering this copper-based cross-coupling attractive for both academia and industry In this Review, we have summarized the latest progress in the development of useful reaction conditions for the coupling of (hetero)aryl halides with different nucleophiles Additionally, recent advances in copper-catalyzed coupling reactions with aryl boronates and the copper-based trifluoromethylation of aromatic electrophiles will be discussed

Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes

Abstract: Classical methods for achieving nucleophilic substitutions of alkyl electrophiles (SN1 and SN2) have limited scope and are not generally amenable to enantioselective variants that employ readily available racemic electrophiles. Radical-based pathways catalyzed by chiral transition-metal complexes provide an attractive approach to addressing these limitations.

Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis

Abstract: ConspectusMetal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, and copper. The palladium- and the iridium-catalyzed versions have turned out to be particularly versatile in organic synthesis because of the very broad scope of the nucleophile and great functional group compatibility. Assets of the iridium-catalyzed reaction are the formation of branched, chiral products from simple monosubstituted allylic substrates, high degrees of regio- and enantioselectivity, and use of modular, readily available chiral ligands. The possibility to use carbon, nitrogen, oxygen, and sulfur compounds as well as fluoride as nucleophiles allows a wide range of chiral building blocks to be prepared.Our Account begins with the presentation of fundamental reaction schemes and chiral ligands. We will focus our discussion ...

An Adventure in Sustainable Cross-Coupling of Phenols and Derivatives via Carbon–Oxygen Bond Cleavage

Abstract: Aryl halides are very useful electrophiles for synthesizing various substituted aromatic compounds via metal-catalyzed cross-coupling reactions. Because of the high cost associated with their synthesis and the stoichiometric halide waste produced when using aryl halide feedstocks, cheaper and more sustainable alternatives have been explored, such as phenols. However, phenols have a very reactive hydroxyl group and a C–O bond with high dissociation energy. To overcome such challenges, earlier studies focused on finding ways to reduce the energy of the C–O bond while removing the active proton by transforming phenols into phenol derivatives (e.g., sulfonates, esters, carbamates, ethers, and metal salts). A greater ambition is to directly cross-couple phenols with nucleophiles via C–O cleavage. In this Perspective, we briefly summarize efforts and accomplishments concerning the cross-coupling of phenol derivatives and phenols.

Electrocatalytic Radical Dichlorination of Alkenes with Nucleophilic Chlorine Sources

Abstract: We report a Mn-catalyzed electrochemical dichlorination of alkenes with MgCl2 as the chlorine source. This method provides operationally simple, sustainable, and efficient access to a variety of vicinally dichlorinated compounds. In particular, alkenes with oxidatively labile functional groups, such as alcohols, aldehydes, sulfides, and amines, were transformed into the desired vicinal dichlorides with high chemoselectivity. Mechanistic data are consistent with metal-mediated Cl atom transfer as the predominant pathway enabling dual C–Cl bond formation and contradict an alternative pathway involving electrochemical evolution of chlorine gas followed by Cl2-mediated electrophilic dichlorination.

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

Abstract: Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

Organocalcium-mediated nucleophilic alkylation of benzene

Abstract: The electrophilic aromatic substitution of a C–H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n -alkyl derivatives—synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride—react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C–D/H bond. These reactions produce the n- alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C–H activation transition state.

Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation.

Abstract: An intermolecular 1,2-carboamination of unactivated alkenes proceeding via a Pd(II)/Pd(IV) catalytic cycle has been developed. To realize this transformation, a cleavable bidentate directing group is used to control the regioselectivity of aminopalladation and stabilize the resulting organopalladium(II) intermediate, such that oxidative addition to a carbon electrophile outcompetes potential β-hydride elimination. Under the optimized reaction conditions, a broad range of nitrogen nucleophiles and carbon electrophiles are compatible coupling partners in this reaction, affording moderate to high yields. The products of this reaction can be easily converted to free γ-amino acids and γ-lactams, both of which are common structural motifs found in drug molecules and bioactive compounds. Reaction kinetics and DFT calculations shed light on the mechanism of the reaction and explain empirically observed reactivity trends.

Nucleophilic Deoxyfluorination of Phenols via Aryl Fluorosulfonate Intermediates

Abstract: This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe4F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO2F2 and NMe4F. Ab initio calculations suggest that carbon–fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.

Recent Advances of Oxidative Radical Cross-Coupling Reactions: Direct α-C(sp3)–H Bond Functionalization of Ethers and Alcohols

Abstract: Oxygen-containing heterocycles are an important class of compounds with diverse biological activities. In recent years, direct α-C–H functionalization of inexpensive and abundant readily available ethers and alcohols by oxidative radical cross-coupling with different nucleophilic partners (C–H, N–H, O–H and S–S), leading to the construction of C–C and C–X (X=C, N, O, S) bonds, has emerged as one of the vital strategies among oxidative cross-coupling reactions. Owing to the features of being atom-economic, environmentally benign, having a simple operation and biologically properties, a series of ether α-C(sp3)–H bond activation reactions have been developed by metal or metal-free systems via the radical oxidative coupling pathway, since the radical oxidative coupling reactions have wide range of applications. This review aims to highlight the recent advances in direct α-C(sp3)–H bond functionalization of ethers and alcohols via radical oxidative process.

Ascorbic Acid as a Bifunctional Hydrogen Bond Donor for the Synthesis of Cyclic Carbonates from CO2 under Ambient Conditions

Abstract: Readily available ascorbic acid was discovered as an environmentally benign hydrogen bond donor for the synthesis of cyclic organic carbonates from CO2 and epoxides in the presence of nucleophilic cocatalysts. The ascorbic acid/TBAI (TBAI: tetrabutylammonium iodide) binary system could be applied for the cycloaddition of CO2 to various epoxides under ambient or mild conditions. Density functional theory calculations and catalysis experiments revealed an intriguing bifunctional mechanism in the step of CO2 insertion involving different hydroxyl moieties (enediol, ethyldiol) of the ascorbic acid scaffold.

Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis

Abstract: Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles. Squaramides are shown to interact with silyl triflates by binding the triflate counterion to form a stable, yet highly Lewis acidic, complex. The silyl triflate-chiral squaramide combination promotes the generation of oxocarbenium intermediates from acetal substrates at low temperatures. Enantioselectivity in nucleophile additions to the cationic intermediates is then controlled through a network of noncovalent interactions between the squaramide catalyst and the oxocarbenium triflate.

Electrophilic Aromatic Substitution with Silicon Electrophiles: Catalytic Friedel–Crafts C−H Silylation

Abstract: Electrophilic substitution of arenes is a fundamental reaction in synthetic chemistry. It converts C-H bonds of sufficiently nucleophilic arenes into C-X and C-C bonds using either stoichiometrically added or catalytically generated electrophiles. These reactions proceed through Wheland complexes, that is cationic intermediates that rearomatize by proton release. Hence, these high-energy intermediates are nothing but protonated arenes and are as such strong Bronsted acids. The formation of protons is an issue in those rare cases when the electrophilic aromatic substitution is reversible. This situation arises in the electrophilic silylation of C-H bonds where the energy of the intermediate Wheland complex is lowered by the beta-silicon effect. As a consequence, protonation of the silylated arene is facile, and the reverse reaction usually occurs to afford the desilylated arene. Several new approaches to overcome that inherent challenge of C-H silylation by SEAr were recently disclosed, and this Minireview summarizes this progress.

Study of Intermediates in Iridium-(Phosphoramidite,Olefin)-Catalyzed Enantioselective Allylic Substitution

Abstract: Experimental mechanistic studies of iridium-catalyzed, enantioselective allylic substitution enabled by (phosphoramidite,olefin) ligands are reported. (η2-Allylic alcohol)iridium(I) and (η3-allyl)iridium(III) complexes were synthesized and characterized by NMR spectroscopy as well as X-ray crystallography. The substrate complexes are catalytically and kinetically competent to be intermediates in allylic substitutions of branched, racemic allylic alcohols with various nucleophiles. In addition, we have identified an off-cycle pathway involving reversible binding of molecular oxygen to iridium, which contributes to the air tolerance of the catalyst system.

Alkynes as Electrophilic or Nucleophilic Allylmetal Precursors in Transition Metal Catalysis

Abstract: Diverse late transition metal catalysts convert terminal or internal alkynes into transient allylmetal species that display electrophilic or nucleophilic properties. Whereas classical methods for the generation of allylmetal species often form stoichiometric by-products, the recent use of alkynes as allylmetal precursors enables completely atom-efficient catalytic processes to be carried out, including enantioselective transformations.

Iron-Catalyzed Intermolecular 1,2-Difunctionalization of Styrenes and Conjugated Alkenes with Silanes and Nucleophiles

Abstract: The first iron-catalyzed 1,2-difunctionalization of styrenes and conjugated alkenes with silanes and either N or C, using an oxidative radical strategy, is described. Employing FeCl2 and di-tert-butyl peroxide allows divergent alkene 1,2-difunctionalizations, including 1,2-aminosilylation, 1,2-arylsilylation, and 1,2-alkylsilylation, which rely on a wide range of nucleophiles, namely, amines, amides, indoles, pyrroles, and 1,3-dicarbonyls, thus providing a powerful platform for producing diverse silicon-containing alkanes.

Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds

Abstract: Methods utilizing renewable feedstocks are critical to accessing molecules of industrial importance in light of the present ecological and economic climate. Here, it is shown that umpolung reactivity of carbonyl compounds can be used for nucleophilic additions to yield a diverse array of valuable alcohols as an alternative to using stoichiometric organometallic reagents.

The influence of acceptor nucleophilicity on the glycosylation reaction mechanism

Abstract: A set of model nucleophiles of gradually changing nucleophilicity is used to probe the glycosylation reaction mechanism. Glycosylations of ethanol-based acceptors, bearing varying amounts of fluorine atoms, report on the dependency of the stereochemistry in condensation reactions on the nucleophilicity of the acceptor. Three different glycosylation systems were scrutinized, that differ in the reaction mechanism, that - putatively - prevails during the coupling reaction. It is revealed that the stereoselectivity in glycosylations of benzylidene protected glucose donors are very susceptible to acceptor nucleophilicity whereas condensations of benzylidene mannose and mannuronic acid donors represent more robust glycosylation systems in terms of diastereoselectivity. The change in stereoselectivity with decreasing acceptor nucleophilicity is related to a change in reaction mechanism shifting from the SN2 side to the SN1 side of the reactivity spectrum. Carbohydrate acceptors are examined and the reactivity-selectivity profile of these nucleophiles mirrored those of the model acceptors studied. The set of model ethanol acceptors thus provides a simple and effective "toolbox" to investigate glycosylation reaction mechanisms and report on the robustness of glycosylation protocols.

Catalytic Asymmetric N-Alkylation of Indoles and Carbazoles through 1,6-Conjugate Addition of Aza-para-quinone Methides.

Abstract: Catalytic asymmetric N-alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza-para-quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N-protective group, the intermolecular C−N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional-group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides

Abstract: Despite the long history of SN2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex se...

Copper-Catalyzed Alkene Aminoazidation as a Rapid Entry to 1,2-Diamines and Installation of an Azide Reporter onto Azahetereocycles

Abstract: A copper-catalyzed aminoazidation of unactivated alkenes is achieved for the synthesis of versatile unsymmetrical 1,2-diamine derivatives. This transformation offers an effective approach to installing an amide and an azide from two diffenent amino precursors onto both terminal and internal alkenes, with remarkable regio- and stereoselectivity. Mechanistic studies show that this diamination reaction proceeds via a nucleophilic amino cyclization followed by an intermolecular C–N bond formation using electrophilic azidoiodinane. This pathway differs from previous azidoiodinane-initiated alkene functionalization, suggesting new reactivity of azidoiodinane. Furthermore, this aminoazidation reaction provides an efficient strategy to introduce azide, one of the most useful chemical reporters, onto a broad range of bioactive azaheterocycles, offering new opportunities in bioorthogonal chemistry and biological studies. Rapid syntheses of 5-HT2C agonist, (−)-enduracididine and azido-cholesterol derivatives demonst...

Asymmetric Multicomponent Reactions Based on Trapping of Active Intermediates

Abstract: Metal carbenes derived from transition metal-catalyzed decomposition of diazo compounds react with nucleophiles with heteroatoms, such as alcohols and amines, to generate highly active oxonium/ammonium ylides intermediates. These intermediates can be trapped by appropriate electrophiles to provide three-component products. Based on this novel trapping process, we have developed novel multicomponent reactions (MCRs) of diazo compounds, alcohols/anilines, and electrophiles. The nucleophiles were also extended to electron-rich heterocycles (indoles and pyrroles)/arenes, in which the resulting zwitterionic intermediates were also trapped by electrophiles. By employing efficient catalysis strategy, the reactions were realized with excellent stereocontrol and wide substrate scope. In this personal account, we introduce our breakthroughs in the development of novel asymmetric MCRs via trapping of the active ylides and zwitterionic intermediates with a number of electrophiles, such as imines, aldehyde, and Michael acceptors, under asymmetric catalysis. Transition metal/chiral Lewis acid catalysis, transition metal/Bronsted acid catalysis, and chiral transition-metal catalysis, enable excellent stereocontrolled outcomes. The methodologies not only provide experimental evidence to support the existence of protic onium ylides intermediates/zwitterionic intermediates and the stepwise pathways of carbene-induced O-H, N-H and C-H insertions, but also offer a novel approach for the efficient construction of chiral polyfunctional molecules.

Living Ring-Opening Polymerization of Lactones by N-Heterocyclic Olefin/Al(C6F5)3 Lewis Pairs: Structures of Intermediates, Kinetics, and Mechanism

Abstract: The strong Lewis acid Al(C6F5)3, in combination with a strong Lewis base N-heterocyclic olefin (NHO), cooperatively promotes the living ring-opening (co)polymerization of lactones, represented by δ-valerolactone (δ-VL) and e-caprolactone (e-CL) in this study. Medium to high molecular weight linear (co)polyesters (Mw up to 855 kg/mol) are achieved, and most of them exhibit narrow molecular weight distributions (Đ as low as 1.02). Detailed investigations into the structures of key reaction intermediates, kinetics, and polymer structures have led to a polymerization mechanism, in that initiation involves nucleophilic attack of the Al(C6F5)3-activated monomer by NHO to form a structurally characterized zwitterionic, tetrahedral intermediate, followed by its ring-opening to generate active zwitterionic species. In the propagation cycle, this ring-opened zwitterionic species and its homologues attack the incoming monomer activated by Al(C6F5)3 to generate the tetrahedral intermediate, followed by the rate-deter...

Vanadium(V) Catalysts with High Activity for the Coupling of Epoxides and CO2: Characterization of a Putative Catalytic Intermediate

Abstract: Vanadium(V) complexes derived from aminotriphenolate ligands are demonstrated to be highly active catalysts for the coupling of various terminal and internal epoxides with carbon dioxide to afford a series of substituted organic carbonates in good yields. Intriguingly, a V(V) complex bearing peripheral chloride groups on the ligand framework allowed for the formation and isolation of a rare complex that incorporates a ring-opened epoxide with one of the phenolate-O atoms acting as a nucleophile and the metal center as a Lewis acidic site. This unusual structure was characterized by X-ray diffraction and 51V NMR and was shown to exhibit catalytic activity for the coupling of propylene oxide and CO2 when it was combined postsynthetically with these substrates. The results obtained herein clearly show that vanadium complexes in a high oxidation state are effective catalysts for the activation of challenging internal epoxides and their conversion into cyclic organic carbonates.

Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides

Abstract: Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities. We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic conditions with Pd2(dba)3 (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the β-elimination pathway. We demonstrated that the glycosyl cross-coupling resulted in consistently high anomeric selectivities for both anomers with mono- and oligosaccharides, deoxysugars, saccharides with free hydroxyl groups, pyranose, and furanose substrates. The versatility of the glycosyl cross-coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the β-elimination pathway is suppressed for biphenyl-type ligands due to the shielding of Pd(II) by sterically demanding JackiePhos, whereas smaller ligands, which allow for the formation of a Pd-F complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles, a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small molecules and biologics.

Iron-Catalyzed Intramolecular Aminations of C(sp3)−H Bonds in Alkylaryl Azides

Abstract: The nucleophilic iron complex Bu4 N[Fe(CO)3 (NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of unactivated C(sp3 )-H bonds in alkylaryl azides, which results in the formation of substituted indoline and tetrahydroquinoline derivatives.