Enantioselective Palladium‐Catalyzed Insertion of α‐Aryl‐α‐diazoacetates into the OH Bonds of Phenols

A palladium‐catalyzed asymmetric O? H insertion reaction was developed. Palladium complexes with chiral spiro bisoxazoline ligands promoted the insertion of α‐aryl‐α‐diazoacetates into the O? H bond of phenols with high yield and excellent enantioselectivity under mild reaction conditions. This palladium‐catalyzed asymmetric O? H insertion reaction provided an efficient and highly enantioselective method for the preparation of synthetically useful optically active α‐aryl‐α‐aryloxyacetates.     

Enantioselective Palladium‐Catalyzed C?H Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

A palladium‐catalyzed enantioselective C H functionalization of indoles was achieved with an axially chiral 2,2′‐bipyridine ligand, thus providing the desired indol‐3‐acetate derivatives with up to 98 % ee. Moreover, the reaction protocol was also effective for asymmetric O H insertion reaction of phenols using α‐aryl‐α‐diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium‐catalyzed carbene migratory insertion reactions.     

Enantioselective Palladium‐Catalyzed C?H Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

A palladium‐catalyzed enantioselective C H functionalization of indoles was achieved with an axially chiral 2,2′‐bipyridine ligand, thus providing the desired indol‐3‐acetate derivatives with up to 98 % ee. Moreover, the reaction protocol was also effective for asymmetric O H insertion reaction of phenols using α‐aryl‐α‐diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium‐catalyzed carbene migratory insertion reactions.     

Enantioselective Palladium‐Catalyzed Insertion of α‐Aryl‐α‐diazoacetates into the O?H Bonds of Phenols

A palladium‐catalyzed asymmetric O H insertion reaction was developed. Palladium complexes with chiral spiro bisoxazoline ligands promoted the insertion of α‐aryl‐α‐diazoacetates into the O H bond of phenols with high yield and excellent enantioselectivity under mild reaction conditions. This palladium‐catalyzed asymmetric O H insertion reaction provided an efficient and highly enantioselective method for the preparation of synthetically useful optically active α‐aryl‐α‐aryloxyacetates.     

Synthesis of Chlamydia Lipopolysaccharide Haptens through the use of α‐Specific 3‐Iodo‐Kdo Fluoride Glycosyl Donors

A scalable approach towards high‐yielding and (stereo)selective glycosyl donors of the 2‐ulosonic acid Kdo (3‐deoxy‐D ‐manno‐oct‐2‐ulosonic acid) is a fundamental requirement for the development of vaccines against Gram‐negative bacteria. Herein, we disclose a short synthetic route to 3‐iodo Kdo fluoride donors from Kdo glycal esters that enable efficient α‐specific glycosylations and significantly suppress the elimination side reaction. The potency of these donors is demonstrated in a straightforward, six‐step synthesis of a branched Chlamydia‐related Kdo‐trisaccharide ligand without the need for protecting groups at the Kdo glycosyl acceptor. The approach was further extended to include sequential iteration of the basic concept to produce the linear Chlamydia‐specific α‐Kdo‐(2→8)‐α‐Kdo‐(2→4)‐α‐Kdo trisaccharide in a good overall yield.     

Enantioselective Palladium‐Catalyzed Cross‐Coupling of α‐Bromo Carboxamides and Aryl Boronic Acids

We herein report an enantioselective palladium‐catalyzed cross‐coupling between α‐bromo carboxamides and aryl boronic acids, generating a series of chiral α‐aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium‐catalyzed coupling of α‐bromo carbonyl compounds.     

Palladium‐Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals

Palladium(II) in combination with a monodentate phosphine ligand enables the unprecedented direct and α‐stereoselective catalytic synthesis of deoxyglycosides from glycals. Initial mechanistic studies suggest that in the presence of N ‐phenyl‐2‐(di‐tert‐butylphosphino)pyrrole as the ligand, the reaction proceeds via an alkoxy palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is demonstrated with a wide range of glycal donors and acceptors, including substrates bearing alkene functionalities.     

Enantioselective Organocatalytic Addition of Oxazolones to 1,1‐Bis(phenylsulfonyl)ethylene: A Convenient Asymmetric Synthesis of Quaternary α‐Amino Acids

A new, easy, and highly enantioselective method for the synthesis of quaternary α‐alkyl‐α‐amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1‐bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords α,α‐disubstituted α‐amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary α‐amino acids and allows the synthesis of α‐phenyl‐α‐alkyl‐α‐amino acids and α‐tert‐butyl‐α‐alkyl‐α‐amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large‐scale reactions.     

Metallkomplexe mit biologisch wichtigen Liganden. CLXV N,O‐Chelat‐Komplexe von α‐Aminosäureanionen mit cyclopalladiertem N,N‐Dimethylferrocencarbothiamid

Metal Complexes of Biologically Important Ligands. CLXV N,O‐Chelate Complexes of α‐Amino Acid Anions with Cyclopalladated N,N‐Dimethylferrocenecarbothioamide A short literature review on the reactions of various chlorobridged complexes with α‐aminoacidates, α‐amino acid esters, peptide ester or derivatives of amino acids is given. The chloro bridged o‐palladated N,N‐dimethylferrocenecarbothioamide [(fct)Pd(μ‐Cl)₂Pd(fct)] reacts with the anions of glycine, L‐alanine, L‐proline, L‐valine, L‐phenylalanine, L‐leucine, L‐isoleucine to give the N,O‐chelates [(fct)Pd(N,O‐α‐aminocarboxylate)] ( 1 – 7 ). Due to the planary chirality of the unsymmetrically disubstituted cyclopentadienyl iron moiety of fct the complexes 2 – 7 with optically active amino acidate ligands are formed as a mixture of two diastereoisomers, which can be detected by their NMR spectra.     

Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

A highly enantioselective Pd‐catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α‐aryl‐β‐keto esters employing the (R,R)‐ANDEN‐phenyl Trost ligand has been developed. The product (S)‐α‐allyl‐α‐arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all‐carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)‐tanikolide.     

Fluorinated Carbohydrates as Lectin Ligands: Dissecting Glycan–Cyanovirin Interactions by Using 19F NMR Spectroscopy

NMR spectroscopy and isothermal titration calorimetry (ITC) are powerful methods to investigate ligand–protein interactions. Here, we present a versatile and sensitive fluorine NMR spectroscopic approach that exploits the ¹⁹F nucleus of ¹⁹F‐labeled carbohydrates as a sensor to study glycan binding to lectins. Our approach is illustrated with the 11 kDa Cyanovirin‐N, a mannose binding anti‐HIV lectin. Two fluoro‐deoxy sugar derivatives, methyl 2‐deoxy‐2‐fluoro‐α‐D ‐mannopyranosyl‐(1→2)‐α‐D ‐mannopyranoside and methyl 2‐deoxy‐2‐fluoro‐α‐D ‐mannopyranosyl‐(1→2)‐α‐D ‐mannopyranosyl‐(1→2)‐α‐D ‐mannopyranoside were utilized. Binding was studied by ¹⁹F NMR spectroscopy of the ligand and ¹H–¹⁵N HSQC NMR spectroscopy of the protein. The NMR data agree well with those obtained from the equivalent reciprocal and direct ITC titrations. Our study shows that the strategic design of fluorinated ligands and fluorine NMR spectroscopy for ligand screening holds great promise for easy and fast identification of glycan binding, as well as for their use in reporting structural and/or electronic perturbations that ensue upon interaction with a cognate lectin.     

Stereoselective Synthesis of Fluoroalkenoates and Fluorinated Isoxazolidinones: N‐Substituents Governing the Dual Reactivity of Nitrones

α‐Fluoroalkenoates and 4‐fluoro‐5‐isoxazolidinones are of vast interest due to their potential biological applications. We now demonstrate the syntheses of (E)‐α‐fluoroalkenoates and 4‐fluoro‐5‐isoxazolidinones by the reactions between nitrones and α‐fluoro‐α‐bromoacetate. By altering N‐substituents in nitrones, (E)‐α‐fluoroalkenoates and 4‐fluoro‐5‐isoxazolidinones can be achieved, respectively, with high chemo‐ and stereoselectivities. Experimental and computational studies have been conducted to elucidate the reaction mechanisms. Linear free energy relationship studies further revealed that the N‐substituent effects are primarily of electronic origin.     

Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

An activated catalyst RhH(PPh3)4‐dppe‐ Me2S2 for α‐methylthiolaton of α‐phenyl ketones

In the presence of catalytic amounts of RhH(PPh₃)₄, 1,2‐bis(diphenylphosphino)ethane (dppe), and dimethyl disulfide, cyclic and acyclic α‐phenyl ketones reacted with p‐cyano‐α‐methylthioa‐ cetophenone giving α‐methylthio‐α‐phenylketones. The activated catalyst containing dimethyl disulfide was effective for the α‐methylthiolation reaction of these less reactive substrates. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 22:18–23, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20650     

Structural and Kinetic Dissection of the endo‐α‐1,2‐Mannanase Activity of Bacterial GH99 Glycoside Hydrolases from Bacteroides spp.

Glycoside hydrolase family 99 (GH99) was created to categorize sequence‐related glycosidases possessing endo‐α‐mannosidase activity: the cleavage of mannosidic linkages within eukaryotic N‐glycan precursors (Glc_1–3Man₉GlcNAc₂), releasing mono‐, di‐ and triglucosylated‐mannose (Glc_1–3‐1,3‐Man). GH99 family members have recently been implicated in the ability of Bacteroides spp., present within the gut microbiota, to metabolize fungal cell wall α‐mannans, releasing α‐1,3‐mannobiose by hydrolysing αMan‐1,3‐αMan→1,2‐αMan‐1,2‐αMan sequences within branches off the main α‐1,6‐mannan backbone. We report the development of a series of substrates and inhibitors, which we use to kinetically and structurally characterise this novel endo‐α‐1,2‐mannanase activity of bacterial GH99 enzymes from Bacteroides thetaiotaomicron and xylanisolvens. These data reveal an approximate 5 kJ mol^?1 preference for mannose‐configured substrates in the ?2 subsite (relative to glucose), which inspired the development of a new inhibitor, α‐mannopyranosyl‐1,3‐isofagomine (ManIFG), the most potent (bacterial) GH99 inhibitor reported to date. X‐ray structures of ManIFG or a substrate in complex with wild‐type or inactive mutants, respectively, of B. xylanisolvens GH99 reveal the structural basis for binding to D ‐mannose‐ rather than D ‐glucose‐configured substrates.     

The achiral tetrapeptide Z‐Aib‐Aib‐Aib‐Gly‐OtBu

The title achiral peptide N‐benzyloxycarbonyl‐α‐aminoisobutyryl‐α‐aminoisobutyryl‐α‐aminoisobutyrylglycine tert‐butyl ester or Z‐Aib‐Aib‐Aib‐Gly‐OtBu (Aib is α‐aminoisobutyric acid, Z is benzyloxycarbonyl, Gly is glycine and OtBu indicates the tert‐butyl ester), C₂₆H₄₀N₄O₇, is partly hydrated (0.075H₂O) and has two different conformations which together constitute the asymmetric unit. Both molecules form incipient 3₁₀‐helices. They differ in the relative orientation of the N‐terminal protection group and at the C‐terminus. There are two 4→1 intramolecular hydrogen bonds.     

Heteroannulation of Arynes with α‐Amino Imides: Synthesis of 2,2‐Disubstituted Indolin‐3‐ones and Application to the Enantioselective Total Synthesis of (+)‐Hinckdentine A

A novel heteroannulation reaction between α‐amino imides and in situ generated arynes has been developed for the synthesis of 2,2‐disubstituted indolin‐3‐ones. An enantioselective total synthesis of the marine alkaloid (+)‐hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α‐aryl‐α‐isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α‐quaternary α‐amino ester.     

Facile and Effective Synthesis of Glucopyranosyl Oligosacchardes with Alternative (1→3)-α- and -β-Linkages in the Presence of C-2 Ester Capable of Neighboring Group Participation

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Photoinduced and thermal reactions of α‐cyano‐β‐bromomethylcinnamide with 1‐benzyl‐1,4‐dihydronicotinamide

The photoinduced reaction of a mixture of (Z)‐α‐cyano‐β‐bromomethylcinnamide (1) and (E)‐α‐cyano‐β‐bromomethylcinnamide (2) with 1‐benzyl‐1, 4‐dihydronicotinamide produces a mixture of the (E)‐ and (Z)‐ isomers of α‐cyano‐β‐methylcinnamide (3 and 4). Using spin‐trapping technique for monitoring reactive intermediate, it is shown that the reaction proceeds via electron transfer‐debromination‐H abstraction mechanism. The thermal reaction of the same substrate with BNAH at 60°C in the dark gives three products: the (E)‐ and (Z)‐isomers of α‐cyano‐β‐methylcinnamide and a dehydrodimeric product; 2, 7‐dicyano‐3, 6‐diphenylocta‐2, 4, 6‐trien‐1, 8‐dioic amide (7). Based on product analysis, scavenger experiment and cyclic voltammetry, an electron transfer‐debromination‐disproportionation mechanism is proposed.