MM3 Conformational Analysis and X‐ray Crystal Structure of 2,3,4,5‐Tetra‐O‐Acetyl‐N,N′‐Dimethyl‐D‐Glucaramide as a Conformational Model for the d‐Glucaryl Unit of Poly(Alkylene 2,3,4,5‐Tetra‐O‐Acetyl‐d‐Glucaramides)

This report describes the MM3 conformational analysis and X‐ray crystal structure of tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide as a conformational model for the D‐glucaryl monomer unit of poly(alkylene tetra‐O‐acyl‐d‐glucaramides). The driving force for this study was to determine the conformational preferences for the diacid unit as a function of the increasing steric bulk of pendant O‐acyl groups: acetyl, propanoyl, 2‐methylpropanoyl, and 2,2‐dimethylpropanoyl. The model dialkyl d‐glucaramides all displayed a large vicinal proton coupling between the central backbone glucaryl hydrogens, indicating an essentially fixed anti conformational arrangement of these protons. The MM3 molecular mechanics program was then applied to calculate the corresponding low‐energy conformations of the structurally simplest of these molecules, tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide (4). Given the large number of dihedral angles to be considered and the apparent rigidity of these molecules around the central carbons of the glucaryl backbone, a number of conformational approximations based upon model compounds were applied regarding the rotameric disposition of the pendant O‐acetyl and terminal N‐methyl groups. The calculated, and dominant, lowest energy conformer has a sickle structure very similar to the global minimum conformation previously calculated for unprotected d‐glucaramide. The x‐ray crystal structure data from 4 indicated an extended conformation in the solid state and gave solid‐state torsion angle information that was comparable to that obtained computationally.     

Synthesis of C‐Glycosyl Phosphate and Phosphonate,Analogues of N‐Acetyl‐α‐d‐Glucosamine 1‐Phosphate

Synthesis of α‐C‐ethylene phosphate and phosphonate as well as α‐C‐methylene phosphate analogues of N‐acetyl‐α‐d‐glucosamine 1‐phosphate is reported starting from the common perbenzylated 2‐acetamido‐2‐deoxy‐α‐C‐allyl glucoside. Anomerisation of the corresponding amino α‐C‐glucosyl aldehyde to the β‐aldehyde was observed. Thus, both amino α‐ and β‐C‐glucosyl methanol were obtained after reduction.     

Synthesis of the C‐Glycoside of Methyl α‐d‐Altropyranosyl‐(1→4)‐α‐d‐glucopyranoside

The C‐glycoside of methyl α‐d‐altropyranosyl‐(1→4)‐α‐d‐glucopyranoside 2 was prepared in a convergent fashion, from readily available precursors, 4‐O‐tert‐butyldiphenylsilyl‐1,2‐O‐isopropylidene‐d‐erythro‐S‐phenyl monothiohemiacetal 13 (five steps from D‐ribose) and the known acid, methyl 2,3,6‐tri‐O‐benzyl‐4‐C‐(carboxymethyl)‐4‐deoxy‐α‐d‐glucopyranoside 17 (seven steps from methyl α‐d‐glucopyranoside). The key reactions in the synthesis are the oxocarbenium ion cyclization of thioacetal‐enol ether 19 to a C1 substituted glycal 20, and the stereoselective hydroboration of 20 to the α‐C‐altroside 21.     

Synthesis of Per‐acetyl d‐fucopyranosyl Bromide and Its Use in Preparation of Diphyllin d‐fucopyranosyl Glycoside

The per‐O‐acetyl‐d‐fucosyl bromide (9) was expediently prepared for C‐6 deoxygenation of d‐galactose in six steps in 32.5% yield. Employing phase transfer catalysis glycosylation (PTC), d‐fucopyranosyl diphyllin (4), the analog of natural diphyllin glycoside, was synthesized by using 9 as the glycosyl donor in 67.1% in two steps. The product was identified by ¹H NMR, ¹³C NMR, and HRMS. Its abilities to inhibit the growth of cancer cells in vitro also are discussed.     

Synthesis of Heteroanellated Pyranosides Starting from Methyl 4,6‐O‐benzylidene‐2,3‐dideoxy‐α‐d‐erythro‐hexopyranosid‐2‐ylidenemalononitrile

The hexopyranosid‐2‐ylidenemalononitrile 1 reacted with phenyl isothiocyanate in the presence of triethylamine to furnish (2R,4aR,6S,10bS)‐8‐amino‐4a,6,10,10b‐tetrahydro‐6‐methoxy‐2‐phenyl‐10‐phenylimino‐4H‐thiopyrano[3′,4′:4,5]pyrano[3,2‐d][1,3]dioxine‐7‐carbonitrile (2). Starting from 1, cyclization with sulphur and diethylamine yielded (2R,4aR,6S,9bR)‐8‐amino‐4,4a,6,9b‐tetrahydro‐6‐methoxy‐2‐phenylthieno[2′,3′:4,5]pyrano[3,2‐d][1,3]dioxine‐7‐carbonitrile (3), which could be transformed into the corresponding aminomethylenamino derivative 4 by treatment with triethyl orthoformate and ammonia. Intramolecular cyclization of 4 to yield (2R,4aR,6S,11bR)‐4,4a,6,11b‐tetrahydro‐6‐methoxy‐2‐phenyl[1,3]dioxino[4″,5″:5′,6′]pyrano[3′,4′:4,5]thieno [2,3‐d]pyrimidin‐7‐amine (5) was achieved by using NaH as base. (2R,4aR,6S,9bS)‐8‐Amino‐4a,6,9,9b‐tetrahydro‐6‐methoxy‐9‐(4‐methylphenyl‐sulfonyl)‐2‐phenyl‐4H‐[1,3]dioxino[4′,5′:5,6]pyrano[4,3‐b]pyrrole‐7‐carbonitrile (6) was prepared by treatment of compound 1 with tosylazide and triethylamine.     

Synthesis of (Methyl 3‐O‐Benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thiophene Derivatives as Precursors of New Iso‐C‐nucleoside Analogues

Treatment of 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)ethanal (3) with malononitrile in the presence of aluminium oxide provided 2‐cyano‐4‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)crotononitrile (4). Starting from 4, cyclization with sulphur and triethylamine yielded 2‐amino‐5‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thiophene‐3‐carbonitrile (5). Further cyclization could be achieved with triethyl orthoformate/ammonia to furnish 4‐amino‐6‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thieno[2.3‐d]pyrimidine (8).     

Practical Preparation of Z‐α‐(N‐Acetylamino)‐ and Z‐α‐(N‐Benzoylamino)‐α,β‐unsaturated Acids

An efficient two‐step synthetic procedure for the preparation of numerous variations of N‐protected α,β‐unsaturated α‐amino acids and their corresponding esters from N‐protected glycine and either aliphatic or aromatic aldehydes was developed. The reaction involved cyclization of the N‐protected glycine into oxazolone, condensation with the aldehyde, and ring opening with a base.     

Crystal Structures of β‐1‐N‐Chloroacetamido Derivatives of d‐Glucose and d‐Galactose

Crystal structures of 1‐N‐(β‐d‐glucopyranosyl)chloroacetamide (1), an inhibitor of glycogen phosphorylase, and the corresponding galactopyranosyl amide (2) have been determined. Both crystals belong to P2₁2₁2₁ space group with 1 having the unit cell dimensions of a = 7.939(3), b = 9.547(3) and c = 14.157(2) Å, while those of 2 are, a = 7.636(10), b = 9.004(8) and c = 14.807(5) Å. The sugar ring takes a ⁴ C ₁ conformation and the amide linkage exists in Z‐anti conformation in both crystals. The torsion angle O5–C1–N1–C1′ is ? 93.9(5) for 1 and ? 111.5(3)° for 2. The conformational preference of Cl and N1 in 1 and 2 is found to be between anti and gauche. The molecular assembly in both 1 and 2 is stabilized by a finite chain of hydrogen bonds starting from N1H and ending at O1′, whereas a ten membered hydrogen‐bonded ring involving O4H and O5 is observed in 1.     

Application of a Model Building Approach to Molecular Mechanics (MM3) for Calculating Low‐Energy Conformations of Tetra‐O‐Acyl‐N,N′‐Dialkyl‐D‐Glucaramides

A model building approach was used in conjunction with the MM3 molecular mechanics program to find the low‐energy conformations of three tetra‐O‐acyl‐N,N′‐dimethyl‐d‐glucaramide molecules: tetra‐O‐propanoyl‐(2), 2‐methylpropanoyl‐(3) and 2,2‐dimethylpropanoyl‐N,N′‐dimethyl‐d‐glucaramide (4), and tetra‐O‐acetyl‐N,N′‐dihexyl‐d‐glucaramide (5). A set of models was chosen for calculation of the low‐energy conformations of parent tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide (1), with additional models required to simulate conformationally more complex diamides 2–5. The dominant low‐energy conformations of 2 and 3 were very similar to that from 1, whereas very sterically constrained 4, with four bulky pendant O‐2,2‐dimethylpropanoyl groups, and 5, with terminal n‐hexyl groups, adopted different conformations. Stereoregular alternating head tail–tail head and repeating head tail–poly(hexamethylene 2,3,4,5‐tetra‐O‐acetyl‐D‐glucaramide) oligomers were graphically generated to provide some insight into the possible conformations of the actual acylated polyamides in nonpolar solution.     

Reductive Ring‐Opening Reaction of 1,2‐O‐Benzylidene and 1,2‐O‐p‐Methoxybenzylidene‐α‐D‐glucopyranose Using Diisobutyl Aluminum Hydride

Abstract

Regioselectivity in the reductive ring‐opening reaction of 3,4,6‐tri‐O‐benzyl‐1,2‐O‐benzylidene and 3,4,6‐tri‐O‐benzyl‐1,2‐O‐p‐methoxybenzylidene‐α‐D‐glucopyranose using diisobutyl aluminum hydride (DIBAH) was examined. The ratio of the 1‐O‐ and 2‐O‐p‐methoxybenzyl ethers, which were generated from endo‐type 1,2‐O‐p‐methoxybenzylidene, was variable by the change of solvent.     

Preparation of Methyl 6‐O‐p‐Nitrobenzoyl‐β‐d‐Glucoside

Methyl 6‐O‐p‐nitrobenzoyl‐β‐d‐glucoside was synthesized by reacting methyl 4,6‐O‐p‐nitrobenzylidine‐β‐d‐glucoside with N‐bromosuccinimide (NBS). First, methyl β‐d‐glucoside was converted into methyl 4,6‐O‐p‐nitrobenzylidine‐β‐d‐glucoside with p‐nitrobenzaldehyde. Later, methyl 4,6‐O‐p‐nitrobenzylidine‐β‐d‐glucoside was opened oxidatively with NBS to give methyl 6‐O‐p‐nitrobenzoyl‐β‐d‐glucoside.     

Regioselectivity in Alkylation Reactions of 1,2‐O‐Stannylene Acetals of d‐Arabinofuranose

The synthesis of β‐arabinofuranosides via alkylation of 1,2‐O‐stannylene acetal intermediates has been studied. With reactive alkyl halides (benzyl bromide, allyl bromide, and p‐methoxybenzyl chloride), the method provides a mixture of β‐arabinofuranosides and 2‐O‐alkylated lactols in ratios of 4:1 to 1:1.5. However, with carbohydrate‐derived electrophiles, no alkylated products are produced. It appears, therefore, that the method is limited to the preparation of β‐arabinofuranosides of simple alcohols. Through the use of computational chemistry, we have explored the conformational properties of one of these stannylene acetals and propose that these species exist in more than one conformation in solution and that this contributes to the relatively poor regioselectivity in these reactions.     

Alternative Route for the Synthesis of 6‐Methoxy‐5‐methyl‐α‐tetralone and 6‐Methoxy‐2,5‐dimethyl‐α‐tetralone

The ketoesters 3 and 4, obtained by the condensation of 2‐cyclohexanone carboxylate and 1‐chloro‐3‐pentanone, were heated with 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) to yield the dienones 5 and 6, which on hydrolysis with potassium t‐butoxide and dimethyl sulfoxide afforded tetralin 8. These were converted to tetralone 10 by methylation and oxidation respectively. Further methylation of 10 yielded tetralone 11.     

Synthesis of Acylated Methyl 2‐Acetamido‐2‐Deoxy‐α‐D‐Mannopyranosides

Abstract

2‐Acetamido‐2‐deoxy‐β‐D‐mannopyranose (1) was glycosylated by the Fischer method using an acidic ion‐exchange resin as the catalyst to give α‐methyl glycoside 2. Selective pivaloylations of methyl 2‐acetamido‐2‐deoxy‐α‐D‐mannopyranoside (2) have been studied under various reaction conditions. Two partially pivaloylated products were submitted to additional acetylations. All structures were established by NMR spectroscopy. Structure of the methyl 2‐acetamido‐2‐deoxy‐3,6‐di‐O‐pivaloyl‐α‐D‐mannopyranoside (4) was determined by X‐ray analysis.     

Structures of N—（2,3,4,6—Tetra—O—acetyl—β—D—glycosyl） thiocarbamic Benzoyl Hydrazine

The crystal structure of N-(2,3,4,6-tetra-O-acetyl-β-D-gly-cosyl)-thiocarbamic benzoyl hydrazine(C22H27N3O9S) was determined by X-ray diffracton method.The hexopyranosyl ring adopts a chair conformation.All the ring substituents are in the equatorial positions.The acetoxyl-methyl group is in synclinal conformation.The S atom is in synperiplanar conformation while the benzoyl hydrazine moiety is anti-periplanar.The thiocarbamic moiety is almost companar with the benzoyl hydrazine group.There are two intramolecular hydrogen bonds and one intermolecular hydrogen bond for each molecule in the crystal structure.The molecules form a network structure through intermolecular hydrogen bonds.     

Synthesis of 7‐Alkoxy/Hydroxy‐α‐methyltryptamines

Abstract

A simple method for the preparation of 7‐alkoxy/hydroxy‐α‐methyl‐DL‐tryptamines is reported. The key steps of the synthesis are the Japp–Klingemann coupling of 2‐piperidone‐3‐carboxylic acid 3 with diazonium salts 4, the Fischer‐type cyclization of hydrazones 5 to β‐carboline derivatives 6 and their hydrolysis to title compounds 8.     

Selective Reductions of C‐(4,6‐O‐Benzylidene‐β‐d‐glucopyranosyl) Nitromethane

Abstract

The nitromethyl group of C‐(4,6‐O‐benzylidene‐β‐d‐glucopyranosyl) nitromethane was manipulated by various reduction and oxidation methods and further functionalizations into –CH₂NHOH, –CH?NOH, –CN, –CH?O, and –CH₂NHCONH₂, all with retention of the 4,6‐O‐benzylidene group. Certain reduction methods gave rise to a novel secondary amine via an unusual dimeric aminal.     

Synthesis of Novel Anellated Pyranosides as Precursors of C‐Nucleoside Analogues Using Isopropyl 6‐O‐Acetyl‐3‐deoxy‐4‐S‐ethyl‐4‐thio‐α‐D‐threo‐hexopyranosid‐2‐ulose

Abstract

Isopropyl 6‐O‐acetyl‐3‐deoxy‐4‐S‐ethyl‐4‐thio‐α‐D‐threo‐hexopyranosid‐2‐ulose (3) was converted to the corresponding 3‐[bis(methylthio)methylene] derivative 4 with a push–pull activated C–C double bond. Treatment of 4 with hydrazine and methylhydrazine afforded the pyrano[3,4‐c]pyrazol‐5‐ylmethyl acetates 5a and 5b, respectively. Desulfurization of compound 4 with sodium boron hydride yielded the 3‐[(methylthio)methylene]hexopyranosid‐2‐ulose 7. Compound 7 was reacted with amines to furnish 3‐aminomethylene‐hexopyranosid‐2‐uloses 8, 9. Reaction of 7 with hydrazine hydrate, hydrazines, hydroxylamine, and benzamidine afforded the pyrazolo, isoxazalo, and pyrimido anellated pyranosides (10–13).     

Isolation and Structure Characterization of a (4‐O‐Methyl‐d‐glucurono)‐d‐xylan from the Skin of Opuntia ficus‐indica Prickly Pear Fruits

A slightly water soluble (4‐O‐methyl‐d‐glucurono)‐d‐xylan was isolated from the skin of Opuntia ficus‐indica (OFI) fruits by alkaline extraction, followed by ethanol precipitation and ion‐exchange chromatography. The structure of this xylan was determined by sugar determination coupled with a ¹H and ¹³C NMR spectroscopy analysis. The xylan consisted of a linear (1→4)‐β‐d‐xylopyranosyl backbone decorated with 4‐O‐methyl‐α‐d‐glucopyranosyluronic acid groups linked to the C‐2 of the xylopyranosyl residues, in the ratio of one uronic acid for six neutral sugar units.     

An Exceptionally Simple Chemical Synthesis of O‐Glycosylated d‐Glucosamine Derivatives by Heyns Rearrangement of the Corresponding O‐Glycosyl Fructoses

2‐N‐Acetyl‐4‐O‐(β‐d‐galactopyranosyl)‐d‐glucosamine (N‐acetyl‐d‐lactosamine), a very important building block of biologically relevant oligosaccharides such as sialyl Lewis^x, is easily accessible via the Heyns rearrangement of the corresponding O‐glycosylated ketohexose, d‐lactulose. This approach can also be extended to other glucosamine derivatives employing suitable O‐glycosylated ketoses many of which are commercially available. For example, nigerosamine (3‐O‐α‐d‐glucopyranosyl‐d‐glucosamine) was prepared from turanose (3‐O‐α‐d‐glucopyranosyl‐d‐fructose). In combination with a recently introduced vinylogous amide type N‐protecting group, [1,3‐dimethyl‐2, 4, 6 (1H, 3H, 5H)‐trioxopyrimidine‐5‐ylidene] methyl (DTPM), this access is clearly superior to other routes and eminently suitable for scaling up.