Green aldose isomerisation: 2-C-methyl-1,4-lactones from the reaction of Amadori ketoses with calcium hydroxide

Saccharinic acids, branched 2-C-methyl-aldonic acids, may be accessed via a green procedure from aldoses by sequential conversion to an Amadori ketose and treatment with calcium hydroxide; d-galactose and d-glucose are converted to 2-C-methyl-d-lyxono-1,4-lactone (with a small amount of 2-C-methyl-d-xylono-1,4-lactone) and 2-C-methyl-d-ribono-1,4-lactone. Inversion of configuration at C-4 of the branched lactones allows access to 2-C-methyl-l-ribono-1,4-lactone and 2-C-methyl-l-lyxono-1,4-lactone, respectively. d-Xylose affords 2-C-methyl-d-threono-1,4-lactone and 2-C-methyl-d-erythrono-1,4-lactone, whereas l-arabinose, under similar conditions, gave the enantiomers 2-C-methyl-l-threono-1,4-lactone and 2-C-methyl-l-erythrono-1,4-lactone.     

Kiliani reactions on ketoses: branched carbohydrate building blocks from D-tagatose and D-psicose

D-Tagatose and D-psicose on treatment with sodium cyanide gave mixtures of branched sugar lactones; extraction of the crude products by acetone in the presence of acid permits direct access to branched carbohydrate diacetonides, likely to be of value as new chirons. In both cases, the major lactone products—diacetonides with a 2,3-cis-diol relationship—can be crystallised in around 40-50% yield from the ketohexose. A practical procedure for the conversion of 30 g of D-tagatose to give 24 g of 2,3:5,6-di-O-isopropylidene-2-C-hydroxymethyl-D-talono-1,4-lactone is reported.     

Carbon-branched carbohydrate chirons: synthesis of C-3 and C-4-branched sugar lactones derived from d-erythronolactone

Two carbon chain extensions using a Wittig reaction on both a 1-deoxy ribulose derivative and a C-2-branched erythrose derivative are reported. Subsequent dihydroxylation resulted in the synthesis of C-3 and C-4 methyl-branched sugar lactones, the useful synthetic building blocks. Control of the stereoselectivity of both the Wittig reaction and the dihydroxylation is investigated, and 3-C-methyl and 4-C-methyl d-altrono-1,4-lactones and d-glucono-1,4-lactone and 4-C-hydroxymethyl-d-altrono-1,4-lactone were synthesised.     

(3R,4S)-3,4,5-Trihydroxy-4-methylpentylphosphonic acid, an isosteric phosphonate analogue of 2-C-methyl-d-erythritol 4-phosphate, a key intermediate in the new pathway for isoprenoid biosynthesis

2-C-Methyl-d-erythritol 4-phosphate (MEP) is the first intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis presenting the branched C₅ isoprene skeleton. Enantiopure (3R,4S)-3,4,5-trihydroxy-4-methylpentylphosphonic acid (MEP_N), an isosteric phosphonate analogue of MEP was synthesized from 1,2-O-isopropylidene-α-d-xylofuranose.     

Practical and convenient modifications of the A,C-secondary hydroxyl face of cyclodextrins

A practical and convenient method for the preparation of α-, β-, and γ-cyclodextrin derivatives, in which the secondary hydroxyl faces of A- and C-glucose units are regioselectively modified, has been developed. Reactions of α-, β-, and γ-cyclodextrins with 1,4-dibenzoylbenzene-3′,3″-disulfonyl imidazole in N,N-dimethylformamide in the presence of molecular sieves regioselectively afforded the corresponding cyclic 2^A,2^C-(1,4-dibenzoylbenzene-3′,3″-disulfonyl)-cyclodextrins. Subsequent treatment of the sulfonylated cyclodextrins with sodium hydroxide or aqueous ammonia afforded the corresponding 2^A,3^A:2^C,3^C-di-manno-epoxy-cyclodextrins or 3^A,3^C-diamino-3^A,3^C-dideoxy-(2^AS,2^CS,3^AS,3^CS)-cyclodextrins, respectively, which can serve as important intermediates for further functionalizations of the cyclodextrins.     

Towards cyclic,conformationally constrained,fluorine-containing β-amino acid derivatives from d-glucose

Novel, potentially bioactive, fluorinated branched-chain monosaccharides were obtained by reaction of diethylaminosulphur trifluoride (DAST) with a series of methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside derivatives, including the 4,6-O-benzylidene derivative and their 3-C-(N-protected aminomethyl) reduction products, as well as the phenyl 3-C-cyano-3-ethoxycarbonyl-1-thio-α-d-(and β-d-)glucopyranosides. The absolute configuration at C(3) was unambiguously assigned for all compounds on the basis of X-ray crystallographic analysis of methyl 4,6-O-benzylidene-3-C-cyano-3-deoxy-3-ethoxycarbonyl-β-d-glucopyranoside, corroborating the previous tentative assignment by other authors for the 4,6-unprotected compound. The course of the fluorination depended on the reaction temperature and the substitution pattern of the substrate. Thus, for methyl 3-C-cyano-3-ethoxycarbonyl-β-d-glucopyranoside, fluorination occurred exclusively at C(6), but for the phenylthio analogue, a 2-deoxy-2-phenylthio-α-d-manno-configured glycosyl fluoride and its 6-fluoro derivative were obtained, resulting from the expected rearrangement reaction, whilst starting from the phenylthio α anomer, only the unrearranged 6-fluoro compound was formed. Rearrangement was also observed in the fluorination of methyl 4,6-O-benzylidene-3-C-(N-protected aminomethyl)-β-d-glucopyranoside, which led to the 2-O-methyl-α-d-mannopyranosyl fluoride derivative as the sole product. This methodology may constitute a simple route to enantiopure conformationally constrained cyclic fluorinated β-amino acids having the α carbon atom shared with a pyranose ring, although only moderate yields were achieved, particularly in the fluorination step.     

Coupling Reactions of Anhydro-Aldose Tosylhydrazones with Boronic Acids

A catalyst-free coupling reaction between O-peracetylated, O-perbenzoylated, O-permethylated, and O-permethoxymethylated 2,6-anhydro-aldose tosylhydrazones (C-(β-d-glycopyranosyl)formaldehyde tosylhydrazones) and aromatic boronic acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope. The main products in most of the transformations were open-chain 1-C-aryl-hept-1-enitol type compounds while the expected β-d-glycopyranosylmethyl arenes (benzyl C-glycosides) were formed in subordinate yields only. A mechanistic rationale is provided to explain how a complex substrate may change the well-established course of the reaction.     

Concise and practical route to tri- and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from d-(+)-glucurono-γ-lactone

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

Untersuchungen an Polypseudohalogeniden. 3. Darstellung und Kristallstruktur von Kaliumdicyanoiodat(I)-Diiminooxalsäurediethylester (1/1), K[I(CN)2] · C6H12N2O2

Studies on Polypseudohalides. 3. Preparation and Crystal Structure of K[I(CN)₂] · C₆H₁₂N₂O₂ The new compound K[I(CN)₂] · C₆H₁₂N₂O₂, C₈H₁₂IKN₄O₂, may be prepared by reaction of an aqueous solution of potassium cyanide and an ethanolic solution of iodine cyanide at 255 K. The direct formation from the components potassium cyanide, iodine cyanide and diimino oxalic acid diethyl ester is possible in different solvents, too. The compound has been investigated by chemical analysis, spectroscopic methods and structural analysis based on single crystal X-ray data. At room temperature it crystallizes in the triclinic space group P1 (No. 2) with a = 428.5 pm, b = 925.9 pm, c = 1035.0 pm, α = 63.41°, β = 76.33°, γ = 78.58° and Z = 1. The compound may be described as a solvated salt built up by a potassium ion, a trihalide-analogous dicyanoiodate(I)-ion and a molecule C₆H₁₂N₂O₂. The anion (point symmetry 1 ) is nearly linear. The distance d(I? C) = 230.2 pm is lengthened compared with the corresponding distance in iodine cyanide. The geometry of the for the first time characterized molecule diimino oxalic acid diethyl ester is as expected. The crystal structure can be interpreted as a sequence of ionic and molecular layers along [0 1 0].     

Pictet Spengler-type reactions in 3-arylmethylpiperazine-2,5-diones. Synthesis of pyrazinotetrahydroisoquinolines

The behavior of aldehydes and acetals as N-alkylating agents of 1-acetyl-3-arylmethylpiperazine-2,5-diones and the subsequent cyclization of the N-alkylated products was studied. Use of paraformaldehyde in different reaction conditions gave 6-unsubstituted 3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-diones and, in some cases, benzo[f]pyrazino[1,2-c]1,3-oxazepine-1,4-diones. Succesful reactions with benzaldehyde required a first activation of the lactam function and a catalyzed N-alkylation with the aldehyde dimethyl acetal. The isolated O,N-amidoacetals thus obtained were submitted to a diastereoselective Pictet Spengler-type reaction that worked with arenes at several degrees of ring activation and with thiophene to give 6-phenylpyrazinoisoquinolinediones and the corresponding thieno analog.     

Two epimerisations in the formation of oxetanes from l-rhamnose: towards oxetane-containing peptidomimetics

The methyl group in (R)-3,5-O-benzylidene-l-rhamnono-1,4-lactone 2, prepared from l-rhamnose 1 in 41% yield without need for chromatography, is axial and provides a good example of Mills’ rule that the ‘O-inside’ conformations are, in general, more stable than alternative ‘H-inside’ conformations. The lactone 2 may be converted in two steps in an overall 57% yield to the rhamnono-oxetane 3, which should be useful in generating oxetane dipeptide isosteres and oxetane β-amino acids and in determining the value of the oxetane ring in inducing secondary structure in small peptidomimetics. Methyl 2,4-anhydro-(S)-3,5-O-benzylidene-l-rhamnonate 11, in which both the phenyl and methyl groups are equatorial, is slightly more thermodynamically stable than 3, providing a rare exception to Mills’ rule. X-ray crystal structures of 2 and 11 are reported.     

Identification,composition, thermodynamic and structural properties of a pyroaurite-like iron(II)-iron (III) hydroxy-oxalate green rust

The aerial oxidation of aqueous suspensions of ferrous hydroxide precipitated from ferrous oxalate and caustic soda can lead to an iron (II)-iron (III) hydroxy-oxalate of the pyroaurite group, a GR(C₂O₄^2-) Green Rust. As other GR compounds, it is unstable with respect to the action of oxygen and oxidises later on. Its chemical composition was determined to be [Fe^II₆ Fe^III₂(OH)₁₆]²⁺[C₂O₄^2- · nH₂O], with n more likely equal to 3 on the basis of structural considerations. The composition does not vary and the Fe (II) / Fe (III) ratio in the compound is measured by means of transmission Mössbauer spectroscopy at 78 K and 20 K in the range from 2.8 to 3.2 for various samples at various stages of the reaction. GR(C₂O₄^2-) is paramagnetic at both temperatures and is unambiguously distinguished from ferrous hydroxide, the initial reactant, and magnetite, the main final product, which are magnetically ordered at 20 K. The spectrum of the GR compound is composed of three quadrupole doublets, one due to the Fe(III) cations characterised by a small quadrupole splitting ΔE_Q of 0.40 mm s⁻¹, and two due to the Fe(II) cations, characterised by larger ΔE_Q values of about 2.55 and 2.85 mm s⁻¹. Finally, from the observed equilibrium conditions between ferrous hydroxide and GR(C₂O₄^2-), the standard free enthalpy of formation of GR(C₂O₄^2-) was computed to be : ΔG°_f[Fe^II₆ Fe^III₂ (OH)₁₆]²⁺[C₂O₄^2- · 3H₂O] = −5383 ± 3 kJ mol⁻¹.     

One-pot inversion of d-mannono-1,4-lactone for the practical synthesis of l-ribose

l-Ribose was synthesized in a concise manner from d-mannono-1,4-lactone using one-pot inversion conditions. Treatment of d-mannono-1,4-lactone with piperidine, followed by mesylation-induced S_N2-type O-alkylation, afforded the desired one-pot inversion in an optimum yield, and the following straightforward transformations provided l-ribose in good yields.     

Novel synthesis of 1,4-thiazin-2-one O-(tert-butyl) oximes and benzo[b][1,4]thiazin-2-one O-(tert-butyl) oximes in the presence of K2CO3/SiO2

A simple and efficient method was developed for the synthesis of 1,4-thiazin-2-one O-(tert-butyl) oximes and benzo[b][1,4]thiazin-2-one O-(tert-butyl) oximes from N-tert-butoxy acyl imidoyl bromides and 2-aminothiols in the presence of K₂CO₃/SiO₂. Twenty five novel compounds were readily synthesized in excellent yields using this procedure. The products possessed Z-stereochemistry with regard to the CN double bond. The reaction proceeded with initial substitution of bromine in the N-tert-butoxy acyl imidoyl bromides by mercapto groups in the presence of K₂CO₃/SiO₂, and subsequent intramolecular Schiff base formation.     

Reactions of 1,4-bis(tetrazole)benzenes: formation of long chain alkyl halides

The reactions of 1,4-bis[2-(tributylstannyl)tetrazol-5-yl]benzene with α,ω-dibromoalkanes were carried out in order to synthesise pendant alkyl halide derivatives of the parent bis-tetrazole. This led to the formation of several alkyl halide derivatives, substituted variously at N1 or N2 on the tetrazole ring. The crystal structures of 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (2-N,2-N′), 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (1-N,2-N′) and 1,4-bis[(2-(8-bromooctyl)tetrazol-5-yl)]benzene (2-N,2-N′) are reported. Further discussion involves the structure of 1,4-bis[2-(6-bromohexyl)-2H-tetrazol-5-yl]benzene (2-N,2-N′) previously reported.     

A new methodology of annelation of five- and seven-membered heterocycles to quinoxalines

Pyrazolo[3,4-b]-, isoxazolo[4,5-b]-, benzo[2,3]-1,4-diazepino-, and benzo[2,3]-1,4-oxazepinoquinoxalines were prepared by reactions of 2-quinoxalinecarboxaldehyde with 1,2-N,N-, 1,2-N,O and 1,4-N,N- and 1,4-N,O-dinucleophiles.     

A new approach to Amadori ketoses via MoVI-catalyzed stereospecific isomerization of 2-C-branched sugars bearing azido function in a microwave field

A branched-chain aldose bearing an azido group at the C-2 position provides access to the corresponding 1-deoxy-1-azido- and 1-deoxy-1-amino ketoses in a single step via stereospecific isomerization. The isomerization exploited the catalytic effect of molybdate ions and microwave irradiation. The structures of the products were analyzed by NMR spectroscopy, IR, HRMS spectrometry and quantum-chemical DFT calculations. DFT-computed proton-proton coupling constants of the prepared Amadori ketose 1-deoxy-1-amino-d-gluco-heptulose were found to be comparable with the experimentally obtained coupling constants and were in agreement with the ⁴C₁ pyranose form in aqueous solution at room temperature.     

Unprecedented N→C[1,4] Boc migration: synthesis of 3-carboxyl functionalized 7-azaindolo[2,1-c][1,4]benzoxazine ring system

Use of 1 equiv excess n-BuLi in synthesis of azaindolo[2,1-c][1,4]benzoxazine heterocycles furnished the corresponding 3-(tert-butyloxycarbonyl) derivatives presumably via an unprecedented intramolecular N→C[1,4] Boc migration. Thus, treatment of N-Boc-2-aminopicoline 1a with 3 equiv of n-BuLi at ?15 °C, to generate the dianion Li₂-1a, followed by the reactions with Weinreb amides 2a–h at ?40 °C, and then allowing the reaction mixture to warm upto rt in a controlled manner (?40 to 0 °C, 2 h; 0 °C to rt, 16 h) led to formation of a series of Boc-group migrated products 7a–h generally in good yield (～70% isolated yield). Surprisingly, going from cyclopentylene to cyclohexylene cases (2d–e to 2g–h), the desired [1,4] Boc migration was found to be a minor fate (yield ～20%). In these instances, N→ortho-C[1,3] Boc-migrated compounds 9g–h (to ortho-aryl position) were obtained as major products. Plausible mechanisms have been invoked for the formation of tetracyclic heterocycle 3a, as well as for the observed N→C[1,4] Boc-group migration phenomena supported by data from anion quenching experiments.     

Confirmation of the structure of a glucono-1,4-lactone derivative obtained from silylation of glucono-1,5-lactone

Silylation reactions of glucono-1,5-lactone can give the persilylated glucono-1,5-lactone or the persilylated 1,4-lactone depending on the reaction conditions employed. The structure of 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-d-glucono-1,4-lactone, obtained in 84% yield from the reaction of glucono-1,5-lactone with TBSOTf and lutidine in dichloromethane, has been confirmed by X-ray crystallography. Formation of the glucono-1,5-lactone and manno-1,5-lactone derivatives and other possible products has also been ruled out by synthesis of possible exo-glycal derivatives of these lactones using the Ramberg–Bäcklund rearrangement of the corresponding sulfones.