The first ring inversion of pyranoses induced by bulky silyl protections at the 2- and 3-positions

The pyranose rings of the 2,3-bis-O-tert-butyldiphenylsilyl-α- and β-d-glucopyranoses, and of the 2,3-bis-O-tert-butyldimethylsilyl-β-d-glucopyranose were in the ¹C₄ form. These findings indicate that the introduction of bulky silyl protecting groups at the 2- and 3-positions can flip a pyranose ring into the axial-rich chair form. Previous such ring inversions have been carried out by the silyl protections at the 3- and 4-positions.     

Synthesis and Conformational Analysis of 1, 2-Anhydro-3, 4-di-O-benzyl-6-deoxy-α-D-glucopyranose

Abstract

The title 1, 2-anhydro sugar (10) was synthesized from methyl 4, 6-O-benzylidene-α-D-glucopyranoside or from 1, 2-O-ethylidene-α-D-glucopyranose. The key intermediate for the synthesis was 2-O-acetyl-3, 4-di-O-benzyl-6-deoxy-β-D-glucopyranosyl fluoride (8)which was transformed into the target compound by ring closure with potassium tert-butoxide. Calculations by the modified Karplus equation from vicinal coupling constants of 10 suggested that the conformation of 10 was almost an ideal ⁴ H ₅ for the pyranose ring. Conformational analysis for the 1, 2-O-(R)-ethylidene intermediates 17 and 20 revealed that their pyranose ring basically adopted a B₂,₅ conformation.     

Non-chair six-membered-ring conformations. Preference for a twist-boat (or skew) structure in α- -sorbopyranose derivatives

The conformational preferences for 2,3-O-isopropylidene-α- -sorbopyranose derivatives 3–6 were determined by using ¹H NMR data and empirical force field calculations. Proton NMR studies of 3–6 indicate that a twist-boat (or skew) conformation (³S₀) prevails over possible chair forms for each compound. Force-field calculations (MM2, MNDO, AM1) on a model 2,3-O-isopropylidene-α- -sorbopyranose system (18) indicate that the ³S₀ conformation is among the low-energy structures. X-Ray crystallographic analysis of α- -sorbopyranose sulfamate 3, a compound with potent anticonvulsant activity, demonstrates that the ³S₀ skew conformation is manifested in the solid state, as well.     

2-Deoxy-2-C-(2,3-dideoxy-α-d-erythro-hexopyranosyl)-β-d-glucopyranoses: Reinvestigation of Synthesis,Use in Glycosylation,and Conformational Analyses by NMR

Abstract

Conformational investigations using 1D TOCSY and ROESY ¹H NMR experiments on 1,3,4,6-tetra-O-acetyl-2-C-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexopyranosyl)-2-deoxy-β-D-glucopyranose (8) and related disaccharides showed that for steric reasons the C-linked hexopyranosyl ring occurs in the usually unfavoured ¹C₄ conformation and reconfirmed the structure of 1,3,4,6-tetra-O-acetyl-2-C-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranosyl)-2-deoxy-β-D-glucopyranose (5). Glycosylation of 2,3,6-tri-O-benzyl-α-D-glucopyranosyl 2,3-di-O-benzyl-4,6-(R)-O-benzylidene-α-D-glucopyranoside (13) with acetate 8 using trimethylsilyl triflate as a catalyst afforded the α-D-linked tetrasaccharide 14. A remarkable side product in this reaction was the unsaturated tetrasaccharide 2,3,6-tri-O-benzyl-4-O-[4,6-di-O-acetyl-2,3-dideoxy-2-C-(4,6-di-O-acetyl-2,3-dideoxy-β-D-erythro-hexopyranosyl)-α-D-erythro-hex-2-enopyranosyl]-α-D-glucopyranosyl 2,3-di-O-benzyl-4,6-(R)-O-benzylidene-α-D-glucopyranoside (16) where in the C-linked hexopyranosyl ring an isomerization to the β-anomer had taken place to allow for the favoured ⁴C₁ conformation. The tetrasaccharide 14 was deacetylated and hydrogenolyzed to form the fully deprotected tetrasaccharide 18. The ¹ C ₄ conformation of the C-glycosidic pyranose of this tetrasaccharide was maintained as shown by an in depth NMR analysis of its peracetate 19.     

Ring conformations of d-glucose derivatives possessing two bulky silyl protecting groups at the 3,4-positions; the first observation of a stable full-axial chair conformer without bridge structures

The ring conformations of 3,4-bis-O-tert-butyldimethylsilyl- and 3,4-bis-O-tert-butyldiphenylsilyl-d-glucopyranoses as well as the corresponding phenyl 1-thio-d-glucopyranosides were investigated. Observations showed that the introduction of the two tert-butyldiphenylsilyl groups can flip the pyranose-ring into the ¹C₄ conformation possessing more axial substituents. All the substituents of the 3,4-bis-O-tert-butyldiphenylsilyl-β-d-glucopyranose were axially oriented.     

PMR investigation into the structure of some n-substituted 1-amino-1-deoxy-D-fructoses (amadori rearrangement products) : Evidence for a preferential conformation in solution

The PMR spectra at 220 MHz of some Amadori rearrangement products deduced from D-glucose with p-toluidine (1), N-methylphenylamine (2), di-butylamine (4), piperdine (5), and morpholine (6) have been studied in detail.Compounds 1-6 appear to exist in solution predominantly as an equilibrium mixture of the furanose and pyranose ring. The pyranose ring occurs exclusively in the β(D)-²C₅-conformation (corresponds to Reeves 1C-conformation). The furanose ring probably exists as a mixture of both the β- and α-anomer, in which the β-anomer is favoured.     

Conformational analysis of 2-OAryl-2-oxo-4,6-dimethyl- and -4-methyl-1,3,2λ5-dioxaphosphorinanes. Spectroscopic,X-Ray,and solid-state 13C and 31P studies

Results of IR and ¹H, ¹³C, and ³¹P NMR studies of the anancomeric title compounds ( 2–5 ) and compound 1 (Scheme 1) are analyzed to search for the existence of high-energy boat or twist-boat conformations in the equatorial epimers. While the difference in frequencies (Δν)_P=O between the axial and equatorial compounds and ¹³C NMR J_POCC and anti J_POCCH3 values suggest the participation of twist-boat conformations for the equatorial isomers, coupling constants in ¹H NMR J_H4H5a or J_H6H5a and J_H4H5e or J_H6H5e of the equatorial isomers 2e–4e along with the lack of a large ³J_PH in ³¹P NMR are consistent with predominant chair conformations. In addition, an X-ray structure of the equatorial 2-p-nitrophenoxy-2-oxo-cis-4,6-dimethyl-1,3,2-dioxaphosphorinane ( 4e ) showed that the molecule adopts a chair conformation with no severe ring flattening in the OPO region in the solid state. X-ray structures of trans- 4 and trans- 5 displayed chair conformations with mild ring flattening especially in the axial methyl region, presumably as a result of the steric methyl-oxygen interaction. CPMAS ¹³C and ³¹P NMR spectra of 4a and 4e provide evidence against the presence of a significant contribution of a twist-boat conformation in solid equatorial 4e . The NMR spectral analysis of 1e , on the other hand, suggests a substantial contribution of a twist conformation as well as, possibly, some contribution of the inverted chair. © 1997 John Wiley & Sons, Inc. Heteroatom Chem 8: 509–516, 1997     

On the Way to Glycoprocessing Inhibitors. Synthesis of an imidazo-L-xylo-piperidinose derivative

An eight-step synthetic sequence led from the known D -xylo-pentodialdose 8 to imidazo-L -xylo-piperidinose 15 , the key steps being the build-up of imidazole compound 12 by a van Leusen methodology and the intramolecular S_N2 ring closure of the O-triflated benzylidene derivative 13 . xylo-Piperidinose 15 appears in a half-chair conformation like the oxocarbonium ions which are the postulated intermediates in the glycoprocessing of the pyranose polysaccharides. This bicyclic azasugar should be a glycosidase inhibitor.     

Synthesis, biological activity and crystal structure of ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate

The compound ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate (C₁₄H₂₂N₄O₄S₂) has been synthesized by multicomponent reactions, and characterized by ¹H NMR, IR, and X-ray diffraction. The crystal structure analysis shows that the thiazinane ring displays a half-chair conformation. The benzene ring is almost vertical to the tetrahydro-pyridine ring. Intramolecular H-bonding of N–H···O type exists and completes an S (6) ring. In the crystal, the molecules are connected into a 3D network by a N–H···O and C–H···O intermolecular hydrogen bond. The bioassay indicates that the compound shows moderate insecticidal activity against Aphis craccivora.     

2‐Propynyl 2,3,4,6‐tetra‐O‐acetyl‐α‐d‐mannopyranoside

The 2‐propynyl group in the title compound, C₁₇H₂₂O₁₀, adopts an exoanomeric conformation, with the acetylenic group gauche with respect to position C1. Comparison of ¹³C NMR chemical shifts from solution and the solid state suggest that the acetylenic group also adopts a conformation anti to C1 in solution. The pyranose ring adopts a ⁴C₁ conformation. Of the three secondary O‐acetyl groups, that on position O4, flanked by two equatorial groups, adopts a syn conformation, in agreement with recent generalizations [González‐Outeiriño, Nasser & Anderson (2005). J. Org. Chem. 70 , 2486–2493]. The acetyl group on position O3 adopts a gauche conformation, also in agreement with the recent generalizations, but that on position O2 adopts a syn conformation, not in agreement with the recent generalizations.     

Structure cristalline et moléculaire d'un dérivé méthyl-hexopyranoside à C(4) hybridé sp2

The derivative C₁₃H₁₉NO₅ crystallizes in space group P2₁2₁2₁ with a = 9.371, b = 11.815, c = 13.207 Å and Z = 4. The structure was solved by direct methods and refined by full-matrix least-squares to R = 0.058. The pyranose ring exists in the ³S₁ conformation (or in the equivalent, but here structurally less consistent, ⁰S₄ conformation). The dioxolane ring has an envelope conformation. Strong intramolecular interactions between the bulky substituents suggest that the ensuing strain energy is assumed, for a significant part, by the twisted-boat conformation of the pyranose ring.     

Conformational analysis of cyclic phosphates derived from 5-C′ substituted 1,2-O-isopropylidene-α-d-xylofuranose derivatives

Twelve 2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes fused with a 1,2-O-isopropylidene-α-d-xylofuranose moiety in cis orientation and substituted at the C′5 position were prepared in two steps from commercially available diacetone-α-d-glucose. Their conformations, and configurations were determined by ¹H and ³¹P NMR and X-ray crystallographic techniques. Both, chair-twisted-chair and chair-boat equilibria were observed in solution. We observed that the strong anisotropic shielding effect of the benzene ring in the phenoxy group generates an upfield shift of the H¹ hydrogen atom, when the cyclic phosphates adopt a boat conformation. This is due to a relative cis-orientation of the P-phenoxy group and the H¹ proton of the 1,2-O-isopropylidene-α-d-xylofuranose moiety. Therefore, the configuration of the phosphorus center (S_P or R_P) can be determined by ¹H NMR spectroscopy. Interestingly, the crystal structure of one of the cyclic phosphates exhibits two independent molecules in the asymmetric unit, one with a chair and the other one with a boat conformation.     

Highly beta-selective O-glucosidation due to the restricted twist-boat conformation

[reaction: see text] Ethyl 1-thio-2,3,4,6-tetrakis-O-triisopropylsilyl-beta-d-glucopyranoside, ethyl 6-O-benzyl-1-thio-2,3,4-tris-O-triisopropylsilyl-beta-d-glucopyranoside, and ethyl 6-O-pivaloyl-1-thio-2,3,4-tris-O-triisopropylsilyl-beta-d-glucopyranoside induced highly beta-selective O-glucosidations. Among them, the 6-O-pivaloylated substrate provided the best selectivity up to alpha/beta = 3:97 with cyclohexylmethanol, and the substrate was used for glucosidations with secondary and tertiary alcohols in a highly beta-selective manner. The selectivity would be caused by the twist-boat conformation of the pyranose; this is the first beta-selective O-glucosidation based on conformational control of the pyranose ring.     

Dioxamethylene intramolecular bridging of p-tert-butylcalix[8]arene

The first examples of dioxamethylene bridged calix[8]arenes 2-6 have been obtained by Cs₂CO₃-promoted direct O-alkylation of p-tert-butylcalix[8]arene with BrCH₂Cl. Assignment of the 1,2-, 1,2:3,4-, 1,2:3,4:6,7-, 1,4:2,3:5,6:7,8-, and 1,2:3,4:5,6:7,8-bridging pattern of 2-6, respectively, was mainly based on chemical shift of OH groups and chemical correlations. Dynamic ¹H NMR studies and MM3 calculations indicated that in these compounds the dioxocine subunit adopts a boat-chair conformation.     

Synthesis, Conformational Studies and Inclusion Properties of Tetrakis[(2-pyridylmethyl)oxy]thiacalix[4]arenes

An attempted O-alkylation of the flexible macrocycle 1with 2-(chloromethyl)pyridine in the presence of Cs₂CO₃ under THF reflux afforded a mixture of twoconformers of tetra-O-alkylated product 4a in a ratio of 91:9 (cone-4a:1,2-alternate-4a)in 70% yield, while other possible isomers were not observed. In the case of Na₂CO₃, there was no reaction product,only the starting compound 1, whereasonly monoalkylated compound 3 was obtained when usingK₂CO₃ as the base. The distribution of cone conformer decreased in the case of O-alkylation of tetraol 1with 4-(chloromethyl)pyridine or benzyl bromide in the presence of Cs₂CO₃ in comparison with that ofO-alkylation with 2-(chloromethyl)pyridine, while the 1,2-alternate conformer increased in the same sequence. The larger Cs⁺might increase the contribution of the metal template effect, which can hold the 2-pyridylmethyl group(s) and theoxide group(s) on the same side of the tetrathiacalix[4]arene 1 through the cation-O^- and -N-interaction in the caseof O-alkylation of tetraol 1 with 2-(chloromethyl)pyridine.Only when the template metal can hold the 2-pyridyl group(s) andthe oxide group(s) on the same side of the tetrathiacalix[4]arene is the conformation immobilized to thecone. The template effect of the cesium cation plays an important role in this alkylation reaction. The structuralcharacterization of these products is also discussed.The two-phase solvent extraction data indicated thattetrakis[(2-pyridylmethyl)oxy]thiacalix[4]arenes 4a show strong Ag⁺ affinity and a high Ag⁺ selectivity wasobserved for cone-4a. A good Job plot proves 1:1 coordination of cone-4a with Ag⁺ cation.¹H-NMR titration of cone-4a with AgSO₃CF₃ also clearly demonstrates that a 1:1complex is formed with retention of the original symmetry. In contrast, the 1,2-alternate-4a can form a 2:1 metal/thiacalix[4]arene complex and the two metal-binding sites display positive allostericity. The conformational changes ofpyridine moiety from the original outward orientation of the ring nitrogen to the inside orientation toward thethiacalixarene cavity were observed in the processof Ag⁺ complexation.     

Synthesis and X-ray single crystal structure of first aromatic ortho-di-tert-butyl azolo[1,2,4]triazine

Oxidation of 3,4-di-tert-butyl-8-methyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine with NBS/K₂CO₃ furnished 3,4-di-tert-butyl-8-methylpyrazolo[5,1-c][1,2,4]triazine, a mildly strained heteroaromatic compound. X-Ray single crystal diffraction analysis indicated that the conjugated 1,2,4-triazine ring adopts a twist-boat configuration, while the two t-Bu substituents are located on the opposite sides of the azole plane. The related 3-tert-butyl-4-(o-C-carboranyl)-8-methyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine was also synthesized, however, its oxidative aromatization was unsuccessful.     

Synthesis of 13c-labelled [s]-proline and its conformational analysis by nuclear magnetic resonance

In order to analyze completely the ring conformation of [S]-Proline (l-thiazolidine-4-carboxylic acid) this compound has been synthesized with its C_δ atom enriched at 90% in ¹³C. The ¹H-¹H, ¹³C-¹H, ¹³C-¹³C vicinal coupling constants measured at several pH values describe well the geometry of the thiazolidine ring. The results suggest that the ring has an average planar conformation only in a narrow range of pH close to the pK of the amine group. Above and below this pH the ring tends to adopt preferentially the S_γendo and S_γexo puckered conformations respectively. It is concluded that a good correlation exists between the value of the dihedral angle ø and the character S_γendo or S_γexo of the ring.     

Synthesis of the first per(3-deoxy)-cyclooligosaccharide: hepta(manno-3-deoxy-6-O-t-butyldimethylsilyl)-β-cyclodextrin

Reduction of hepta(manno-2,3-anhydro-6-O-t-butyldimethylsilyl)-β-cyclodextrin with lithium triethylborohydride gives hepta(manno-3-deoxy-6-O-t-butyldimethylsilyl)-β-cyclodextrin. This compound plus the hepta(2-O-methyl)- and hepta(2-O-benzyl)-derivatives all have the ⁴C₁ conformation. Capillary GC columns manufactured with hepta(manno-2,3-anhydro-, hepta(manno-3-deoxy-2-O-methyl- and hepta(manno-2-O-benzyl-6-O-t-butyldimethylsilyl)-β-cyclodextrin stationary phases were evaluated for enantio-discrimination with 39 non-polar racemic analytes. The GC column coated with the benzyl derivative showed enantioselectivity comparable to, and in some cases superior to, a commercial per(methyl)-β-cyclodextrin column. The other columns showed little or no enantio-discrimination. A thermodynamics study established a linear enthalpy–entropy compensation effect for two series of analytes on the commercial permethyl-β-cyclodextrin column, but not for the column coated with the benzyl derivative.     

C-Glycosylidene derivatives (exo-glycals): their synthesis by reaction of protected sugar lactones with tributylphosphonium ylids, conformational analysis and stereoselective reduction

Stabilised tributylphosphonium ylids Bu₃PCHCH(EWG), where EWG is CO₂Me, CO₂^tBu or CN, react with protected sugar lactones under mild conditions to give high yields of glycosylidene derivatives (4 and 5) with good Z/E selectivity. X-Ray crystallography shows that in the solid state the tetra-O-benzyl protected (Z)-glucosylideneacetonitrile (Z)-4c adopts a conformation intermediate between a boat and a twist-boat, whereas the isomeric galactose derivative (Z)-5c exists as a distorted chair. NMR data suggest that in solution chair-like conformations are again more favoured for galactosylidene derivatives than for their glucosylidene analogues. Solution phase NMR studies and molecular modelling show that the (E)-double bond geometry disfavours the chair-like geometry of the ring, even in the galactose series; this is consistent with the avoidance of allylic 1,3-strain. Reduction of the glycosylidene double bond to give stereoselective formation of β-C-glycoside derivatives may be achieved by using Et₃SiH-CF₃CO₂H or Et₃SiH-BF₃·Et₂O.     

3,4,6‐Tri‐O‐acetyl‐1,2‐O‐[1‐(exo‐ethoxy)ethylidene]‐β‐d‐mannopyranose 0.11‐hydrate

The title compound, C₁₆H₂₄O₁₀·0.11H₂O, is a key intermediate in the synthesis of 2‐deoxy‐2‐[¹⁸F]fluoro‐d ‐glucose (¹⁸F‐FDG), which is the most widely used molecular‐imaging probe for positron emission tomography (PET). The crystal structure has two independent molecules (A and B) in the asymmetric unit, with closely comparable geometries. The pyranose ring adopts a ⁴C₁ conformation [Cremer–Pople puckering parameters: Q = 0.553 (2) Å, θ = 16.2 (2)° and ϕ = 290.4 (8)° for molecule A, and Q = 0.529 (2) Å, θ =15.3 (3)° and ϕ = 268.2 (9)° for molecule B], and the dioxolane ring adopts an envelope conformation. The chiral centre in the dioxolane ring, introduced during the synthesis of the compound, has an R configuration, with the ethoxy group exo to the mannopyranose ring. The asymmetric unit also contains one water molecule with a refined site‐occupancy factor of 0.222 (8), which bridges between molecules A and B via O—H...O hydrogen bonds.