Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Regioselective Insertion of o‐Carborynes into the α‐CH Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C? H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C? H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Rhodium‐catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐amino Ketones

Rhodium/DuanPhos‐catalyzed asymmetric hydrogenation of aliphatic α‐dehydroamino ketones has been achieved and afforded chiral α‐amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β‐amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α‐amino ketones and chiral β‐amino alcohols.     

Conformational analysis of the disaccharide methyl α‐d‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d‐mannopyranoside monohydrate

The crystal structure of methyl α‐d ‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d ‐mannopyranoside monohydrate, C₁₅H₂₆O₁₂·H₂O, ( II ), has been determined and the structural parameters for its constituent α‐d ‐mannopyranosyl residue compared with those for methyl α‐d ‐mannopyranoside. Mono‐O‐acetylation appears to promote the crystallization of ( II ), inferred from the difficulty in crystallizing methyl α‐d ‐mannopyranosyl‐(1→3)‐β‐d ‐mannopyranoside despite repeated attempts. The conformational properties of the O‐acetyl side chain in ( II ) are similar to those observed in recent studies of peracetylated mannose‐containing oligosaccharides, having a preferred geometry in which the C2—H2 bond eclipses the C=O bond of the acetyl group. The C2—O2 bond in ( II ) elongates by ～0.02 Å upon O‐acetylation. The phi (?) and psi (ψ) torsion angles that dictate the conformation of the internal O‐glycosidic linkage in ( II ) are similar to those determined recently in aqueous solution by NMR spectroscopy for unacetylated ( II ) using the statistical program MA′AT, with a greater disparity found for ψ (Δ = ～16°) than for ? (Δ = ～6°).     

Fluorinative Rearrangements of Substituted Phenylallenes Mediated by (Difluoroiodo)toluene: Synthesis of α‐(Difluoromethyl)styrenes

Phenylallenes undergo fluorinative rearrangement upon the action of (difluoroiodo)toluene in the presence of 20 mol % BF₃⋅OEt₂ to yield α‐difluoromethyl styrenes. This unprecedented reaction was entirely chemoselective for the internal allene π bond, and showed remarkable regioselectivity during the fluorination event. Substituted phenylallenes, phenylallenes possessing both phenyl‐ and α‐allenyl substituents, and diphenylallenes were investigated, and good functional‐group compatibility was observed throughout. The ease with which allenes can be prepared on a large scale, and the operational simplicity of this reaction allowed us to rapidly access fluorine‐containing building blocks that have not been accessed by conventional deoxyfluorination strategies.     

N‐(tert‐Butoxycarbonyl)‐α‐aminoisobutyryl‐α‐aminoisobutyric acid methyl ester: two polymorphic forms in the space group P21/n

The title compound (systematic name: methyl 2‐{2‐[(tert‐butoxycarbonyl)amino]‐2‐methylpropanamido}‐2‐methylpropanoate), C₁₄H₂₆N₂O₅, (I), crystallizes in the monoclinic space group P2₁/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α‐aminoisobutyric acid (Aib) residues adopting ϕ and ψ values characteristic of α‐helical and mixed 3₁₀‐ and α‐helical conformations. The helical handedness of the C‐terminal residue (Aib2) is opposite to that of the N‐terminal residue (Aib1). In contrast to (I), the closely related peptide Boc‐Aib‐Aib‐OBn (Boc is tert‐butoxycarbonyl and Bn is benzyl) adopts an α_L‐P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen‐bonded parallel β‐sheet‐like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen‐bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α‐disubstituted residue.     

Ring‐opening polymerization of benzylated 1,6‐anhydro‐β‐D‐lactose and specific biological activities of sulfated (1→6)‐α‐D‐lactopyranans

A new anhydro disaccharide monomer, 1,6‐anhydro‐2,3‐di‐o‐benzyl‐4‐o‐(2′,3′,4′,6′‐tetra‐o‐benzyl‐β‐D ‐galactopyranosyl)‐β‐D ‐glucopyranose (benzylated 1,6‐anhydro lactose (LSHBE)), was synthesized from D ‐lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring‐opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 → 6)‐α‐D ‐lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH₂Cl₂ solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6‐anhydro‐β‐D ‐glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti‐HIV (EC₅₀ = 5.9 and 1.3 μg/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti‐HIV and blood anticoagulant activities of 0.3 μg/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti‐HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913–924, 2009     

The Regio‐ and Stereospecific Intermolecular Dehydrative Alkoxylation of Allylic Alcohols Catalyzed by a Gold(I) N‐Heterocyclic Carbene Complex

A 1:1 mixture of [AuCl(IPr)] (IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidine) and AgClO₄ catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio‐ and stereospecific with preferential addition of the alcohol nucleophile at the γ‐position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor α regioisomer is formed predominantly through a secondary reaction manifold involving regioselective γ‐alkoxylation of the initially formed allylic ether rather than by the direct α‐alkoxylation of the allylic alcohol.     

Polymerization of α‐amino acid N‐carboxyanhydrides catalyzed by rare earth tris(borohydride) complexes: Mechanism and hydroxy‐endcapped polypeptides

In this work, rare earth tris(borohydride) complexes, Ln(BH₄)₃(THF)₃ (Ln = Sc, Y, La, and Dy), have been used to catalyze the ring‐opening polymerization of γ‐benzyl‐L ‐glutamate N‐carboxyanhydride (BLG NCA). All the catalysts show high activities and the resulting poly(γ‐benzyl‐L ‐glutamate)s (PBLGs) are recovered with high yields (≥90%). The molecular weights (MWs) of PBLG can be controlled by the molar ratios of monomer to catalyst, and the MW distributions (MWDs) are relatively narrow (as low as 1.16) depending on the rare earth metals and reaction temperatures. Block copolypeptides can be easily synthesized by the sequential addition of two monomers. The obtained P(γ‐benzyl‐L ‐glutamate‐b‐ε‐carbobenzoxy‐L ‐lysine) [P(BLG‐b‐BLL)] and P(γ‐benzyl‐L ‐glutamate‐b‐alanine) [P(BLG‐b‐ALA)] have been well characterized by NMR, gel permeation chromatography, and differential scanning calorimetry measurements. A random copolymer P(BLG‐co‐BLL) with a narrow MWD of 1.07 has also been synthesized. The polymerization mechanisms have been investigated in detail. The results show that both nucleophilic attack at the 5‐CO of NCA and deprotonation of 3‐NH of NCA in the initiation process take place simultaneously, resulting in two active centers, that is, an yttrium ALA carbamate derivative [H₂BOCH₂(CH)NHC(O)OLn? ] and a N‐yttriumlated ALA NCA. Propagation then proceeds on these centers via both normal monomer insertion and polycondensation. After termination, two kinds of telechelic polypeptide chains, that is, α‐hydroxyl‐ω‐aminotelechelic chains and α‐carboxylic‐ω‐aminotelechelic ones, are formed as characterized by MALDI‐TOF MS, ¹H NMR, ¹³C NMR, ¹H–¹H COSY, and ¹H–¹³C HMQC measurements. By decreasing the reaction temperature, the normal monomer insertion pathway can be exclusively selected, forming an unprecedented α‐hydroxyl‐ω‐aminotelechelic polypeptide. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

A novel azocompound, 2‐(4‐phenylazoaniline)‐4‐phenylphenol: Spectroscopic and quantum‐chemical approach

A novel azocompound with two nonequivalents azo groups, 2‐(4‐phenylazoaniline)‐4‐phenylphenol, was synthesized and characterized by spectroscopic and computational analysis. An intramolecular hydrogen bonding (HB), ? O₁? H₁ ··· N₁? , involving the ? N₁?N₂? group and the proton in a neighbor hydroxyl moiety, was identified. It was found responsible for a characteristic π‐conjugated H₁? O₁? C₁₈?C₁₃? N₂?N₁? six‐membered cyclic fragment. It is worth noting that this azo group is involved in an azo‐hydrazo equilibrium, being the azo form the most stable one. This resonance‐assisted HB was characterized using the OH‐related infrared bands and the corresponding signals in ¹H NMR. In addition, conformational studies and geometrical and electronic parameter calculations were performed using the density functional theory, at B3LYP/6‐311++G** level. Bond and ring critical points were identified using the atoms in molecules theory, which allowed confirming the intramolecular HB. The second azo‐group cannot be involved in HB, but it also presents two stereoisomerics forms corresponding to cis (Z) and trans (E) configurations, with the later being the one with the lowest energy. © 2013 Wiley Periodicals, Inc.     

Synthesis and Evaluation of Bioactivity of Thiazolo[3,2‐b]‐[1,2,4]‐triazoles and Isomeric Thiazolo[2,3‐c]‐[1,2,4]‐triazoles

Synthesis of 2‐(o‐nitrophenyl)‐6‐arylthiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 and its isomer 3‐(o‐nitrophenyl)‐5‐arylthiazolo[2,3‐c]‐[1,2,4]‐triazoles 6 has been achieved starting from the appropriate 1‐(o‐nitrobenzoyl)‐3‐thiosemicarbazide 1 . Compound 1 on condensation with α‐haloketones gives 2‐(o‐nitrobenzoyl)hydrazino‐4‐arylthiazole hydrobromide 5 , which, on cyclization with POCl₃, affords thiazolo[3,2‐b]‐[1,2,4]‐triazoles 6 and not the isomeric thiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 . This has been established by an unequivocal synthesis of 4 through polyphosphoric acid cyclization of 5‐aroylmethylmercapto‐3‐o‐nitrophenyl‐[1,2,4]‐triazole 3 . Compound 3 was synthesized by condensation of α‐haloketones with 5‐mercapto‐3‐(o‐nitrophenyl)‐[1,2,4]‐triazole 2 , obtained cyclization of 2‐(o‐nitrobenzoyl)hydrazinecarbothioamide 1 with NaOH. The antibacterial and antifungal activities of some of the compounds have also been evaluated.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

A DFT and AIM analysis of the spin–spin couplings across the hydrogen bond in the 2‐fluorobenzamide and related compounds

In 1975 a large number of coupling constants were measured in 2‐fluorobenzamide labeled with ¹⁵N. Some of them were assigned to couplings through intramolecular N? H···F hydrogen bonds (HBs). These couplings change dramatically when CDCl₃ is replaced by DMSO‐d₆. In this theoretical paper we provide density functional theory (DFT) calculations that justify the existence of a weak HB in the absence of solvent, while solvents that act as HB acceptors break down the intramolecular hydrogen bond (IMHB) of 2‐fluorobenzamide. Atoms in molecules (AIM) analyses and Steiner‐Limbach plots were used to analyze the structure of the compounds. Copyright © 2009 John Wiley & Sons, Ltd.     

A facile and efficient synthesis of diethyl α,α‐chlorofluoroalkanephosphonates

A facile and efficient synthetic methodo‐ logy for the preparation of diethyl α,α‐chlorofluoro‐ alkanephosphonates is described. A wide variety of diethyl α‐hydroxyphosphonates were investigated by a two‐step halogenation procedure, which includes nucleophilic chlorination with PPh₃ and CCl₄ and electrophilic fluorination with N‐fluorobisbenzene‐ sulfonimide. Aromatic and aliphatic α,α‐chlorofluoro‐ phosphonates could be prepared by this method with acceptable yields. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:250–255, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20604     

Hydrogen‐bonded sheet structures in methyl 4‐(4‐chloroanilino)‐3‐nitrobenzoate and methyl 1‐benzyl‐2‐(4‐chlorophenyl)‐1H‐benzimidazole‐5‐carboxylate

In methyl 4‐(4‐chloroanilino)‐3‐nitrobenzoate, C₁₄H₁₁ClN₂O₄, (I), there is an intramolecular N—H...O hydrogen bond and the intramolecular distances provide evidence for electronic polarization of the o‐quinonoid type. The molecules are linked into sheets built from N—H...O, C—H...O and C—H...π(arene) hydrogen bonds, together with an aromatic π–π stacking interaction. The molecules of methyl 1‐benzyl‐2‐(4‐chlorophenyl)‐1H‐benzimidazole‐5‐carboxylate, C₂₂H₁₇ClN₂O₂, (II), are also linked into sheets, this time by a combination of C—H...π(arene) hydrogen bonds and aromatic π–π stacking interactions.     

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene: A Remarkable Base in the Debromination of 4‐ or 5‐Substituted N‐Benzyl α‐Bromo‐α‐p‐Toluenesulfonylglutarimide

Debromination of N‐benzyl 4‐ or 5‐substituted α‐bromo‐α‐p‐toluenesulfonylglutarimides is achieved with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) to give the N‐benzyl 4‐ or 5‐substituted α‐p‐toluenesulfonylglutarimides. The DBU/THF system is applied to a new methodology for the synthesis of bicyclic glutarimide skeleton in moderate yields.     

The α‐Glycosidation of Partially Unprotected N‐Acetyl and N‐Glycolyl Sialyl Donors in the Absence of a Nitrile Solvent Effect

The synthesis of α‐sialosides is one of the most difficult reactions in carbohydrate chemistry and is considered to be both a thermodynamically and kinetically disfavored process. The use of acetonitrile as a solvent is an effective solution for the α‐selective glycosidation of N‐acetyl sialic acids. In this report, we report on the α‐glycosidation of partially unprotected N‐acetyl and N‐glycolyl donors in the absence of a nitrile solvent effect. The 9‐O‐benzyl‐N‐acetylthiosialoside underwent glycosidation in CH₂Cl₂ with a good α‐selectivity. On the other hand, the 4,7,8‐O‐triacetyl‐9‐O‐benzyl‐N‐acetylthiosialoside was converted to β‐sialoside as a major product under the same reaction conditions. The results indicate that the O‐acetyl protection of the sialyl donor was a major factor in reducing the α‐selectivity of sialylation. After tuning of the protecting groups of the hydroxy groups at the 4,7,8 position on the sialyl donor, we found that the 9‐O‐benzyl‐4‐O‐chloroacetyl‐N‐acetylthiosialoside underwent sialylation with excellent α‐selectivity in CH₂Cl₂. To demonstrate the utility of the method, straightforward synthesis of α(2,9) disialosides containing N‐acetyl and/or N‐glycolyl groups was achieved by using the two N‐acetyl and N‐glycolyl sialyl donors.     

()‐Tartaric acid

()‐Tartaric acid, C₄H₆O₆, crystallized from ethanol in space group P. The structure is characterized by five hydrogen bonds, including the formation of a centrosymmetric carbox­ylic acid dimer which forms infinite chains along the body diagonal. These chains form sheets via hydrogen bonding between α‐hydroxyl groups. The sheets are connected through a bifurcated hydrogen bond. Structural comparisons are made with homochiral (2R,3R)‐(+)‐tartaric acid.