Glycosylidene Carbenes. Part 10. Regioselective Glycosidation of 4,6-O-Benzylidene-D-altropyranosides

Glycosidation by the diazirine 1 , the trichloroacetimidate 4 , and the bromide 5 of the altro-diol 2 , possessing an intramolecular H-bond (HO? C(3) to O? C(1)) in solution, but not in the solid state, proceeds with high and complementary regioselectivity. From 2 and 1 , one obtains mostly the 1,2-linked disaccharides 10 and 11 (β-D > α-D ), together with the 1,3-linked isomers 12 and 13 (α-D > β-D ; 1,2-/1,3-linked products ca. 9:1), the demethylated 1,3-linked disaccharides 24–27 , the trisaccharides 19–22 , the lactone azines 23 , and the hydroxyglucal 18 , while 2 reacted with 4 or 5 to yield mostly the 1,3-linked disaccharides (1,2-/1,3-linked products ca. 1:9). The disaccharides were additionally characterized as acetates (→ 14–17, 28–31 ). Yields and stereoselectivity depended upon the donor, stoichiometry, solvent, temperature, and concentration. Glycosidation of the 1,3-linked disaccharides with 1 yielded the trisaccharides 19–22 . Reaction of the β-D -altro-diol 3 with 1 gave the 1,2- and 1,3-linked disaccharides 32/33 and 34/35 in a 1:1 ratio, characterized as the acetates 36–39 , while glycosidation with 5 according to Lemieux proceeded regioselectively (1,2-/1,3-linked products 91:9). The monotosylates 6 and 7 reacted with 1 to yield the anomeric pairs 40/41 , and 42/43 of the tosylated disaccharides; the oxiranes 44 and 45 were not observed.     

Synthesis of β‐1,4‐Linked Galactan Side‐Chains of Rhamnogalacturonan I

The synthesis of linear‐ and (1→6)‐branched β‐(1→4)‐d ‐galactans, side‐chains of the pectic polysaccharide rhamnogalacturonan I is described. The strategy relies on iterative couplings of n‐pentenyl disaccharides followed by a late stage glycosylation of a common hexasaccharide core. Reaction with a covalent linker and immobilization on N‐hydroxysuccinimide (NHS)‐modified glass surfaces allows the generation of carbohydrate microarrays. The glycan arrays enable the study of protein–carbohydrate interactions in a high‐throughput fashion, demonstrated herein with binding studies of mAbs and a CBM.     

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C_2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C¹-O-octyloxy glycans, α/β-glucoside ( α/β-Glc ), α/β-mannoside ( α/β-Man ), and β-galactoside ( β-Gal ), was studied by mass spectrometry, ¹H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to β-Glc. SCR019 (3-indole) binds only to β-Man. SCR020 (2-pyridine) binds β-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and β-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host–guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR , where the former are driven by positive allosteric cooperativity induced by glycan–glycan contacts.     

Glycosylidene Carbenes. Part 15. Synthesis of disaccharides from allopyranose-derived vicinal 1,2-diols. Evidence for the protonation by a H-bonded hydroxy group in the σ-plane of the intermediate carbene,followed by attack on the oxycarbenium ion in the π-plane

The α-D -allo-diol 9 possesses an intramolecular H-bond (HO? C(3) to O? C(1)) in solution and in the solid state (Fig. 2). In solution, it exists as a mixture of the tautomers 9a and 9b (Fig. 3), which possess a bifurcated H-bond, connecting HO? C(2) with both O? C(1) and O? C(3). In addition, 9a possesses the same intramolecular H-bond as in the solid state, while 9b is characterized by an intramolecular H-bond between HO? C(3) and O? C(4). In solution, the β-D -anomer 12 is also a mixture of tautomers, 12a and presumably a dimer. The H-bonding in 9 and 12 is evidenced by their IR and ¹H-NMR spectra and by a comparison with those of 3–8, 10 , and 11 . The expected regioselectivity of glycosidation of 9 and 12 by the diazirine 1 or the trichloroacetimidate 2 is discussed on the basis of the relative degree of acidity/nucleophilicity of individual OH groups, as governed by H-bonding. Additional factors determining the regioselectivity of glycosidation by 1 are the direction of carbene approach/proton transfer by H-bonded OH groups, and the stereoelectronic control of both the proton transfer to the alkoxy-alkyl carbene (in the σ-plane) and the combination of the thereby formed ions (π-plane of the oxycarbenium ion). Glycosidation of 9 by the diazirine 1 or the trichloroacetimidate 2 proceeded in good yields (75–94%) and with high regioselectivity. Glycosidation of 9 and 12 by 1 or 2 gave mixtures of the disaccharides 14–17 and 18–21 , respectively (Scheme 2). As expected, glycosidation of 12 by 1 or by 2 gave a nearly 1:1 mixture of regioisomers and a slight preference for the β-D -anomers (Table 4). Glycosidation of the α-D -anomer 9 gave mostly the 1,3-linked disaccharides 16 and 17 (α-D β-D ) along with the 1,2-linked disaccharides 14 and 15 (α-D < β-D , 1,2-/1,3-linked glycosides ca. 1:4), except in THF and at low temperature, where the β-D -configurated 1,2-linked disaccharide 15 is predominantly formed. Similarly, glycosidation of 9 with 2 yielded mainly the 1,3-linked disaccharides (1,2-/1,3-linked products ca. 1:3 and α-D /β-D ca. 1:4). Yields and selectivity depend upon the solvent and the temperature. The regioselectivity and the unexpected stereoselectivity of the glycosidation of 9 by 1 evidences the combined effect of the above mentioned factors, which also explain the lack of regio-complementarity in the glycosidation of 9 by 1 and by 2 (Scheme 3). THF solvates the intermediate oxycarbenium ion, as evidenced by the strong influence of this solvent on the regio- and stereoselectivity, particularly at low temperatures, where kinetic control leads to a stereoelectronically preferred axial attack of THF on the oxycarbenium ion.     

Methyl β‐allolactoside [methyl β‐d‐galactopyranosyl‐(1→6)‐β‐d‐glucopyranoside] monohydrate

Methyl β‐allolactoside [methyl β‐d ‐galactopyranosyl‐(1→6)‐β‐d ‐glucopyranoside], (II), was crystallized from water as a monohydrate, C₁₃H₂₄O₁₁·H₂O. The βGalp and βGlcp residues in (II) assume distorted ⁴C₁ chair conformations, with the former more distorted than the latter. Linkage conformation is characterized by ϕ′ (C2_Gal—C1_Gal—O1_Gal—C6_Glc), ψ′ (C1_Gal—O1_Gal—C6_Glc—C5_Glc) and ω (C4_Glc—C5_Glc—C6_Glc—O1_Gal) torsion angles of 172.9 (2), −117.9 (3) and −176.2 (2)°, respectively. The ψ′ and ω values differ significantly from those found in the crystal structure of β‐gentiobiose, (III) [Rohrer et al. (1980). Acta Cryst. B 36 , 650–654]. Structural comparisons of (II) with related disaccharides bound to a mutant β‐galactosidase reveal significant differences in hydroxymethyl conformation and in the degree of ring distortion of the βGlcp residue. Structural comparisons of (II) with a DFT‐optimized structure, (II_C), suggest a link between hydrogen bonding, pyranosyl ring deformation and linkage conformation.     

Regio- and stereo-controlled synthesis of β-Xyl(1–4)Rbo-5P1-Rbo,the partial structure of O-mannosyl glycan

O-mannosyl glycan is a pivotal glycan part of α-dystroglycan, which serves as a transmembrane linker connecting the intracellular cytoskeleton and extracellular matrix, such as laminin in skeletal muscle. We synthesized β-d-Xyl-(1–4)-d-Rbo-5P (1), β-d-Xyl-(1–4)-d-Rbo (2), and β-d-Xyl-(1–4)-d-Rbo-5P1-d-Rbo (3), partial structures of O-mannosyl glycan, in regio- and stereo-controlled manners, and demonstrated compatibility with the natural product.     

Convergent Synthesis of a Bisecting N‐Acetylglucosamine (GlcNAc)‐Containing N‐Glycan

The chemical synthesis of a bisecting N‐acetylglucosamine (GlcNAc)‐containing N‐glycan was achieved by a convergent synthetic route through [4+2] and [6+2] glycosylations. This synthetic route reduced the number of reaction steps, although the key glycosylations were challenging in terms of yields and selectivities owing to steric hindrance at the glycosylation site and a lack of neighboring group participation. The yields of these glycosylations were enhanced by stabilizing the oxocarbenium ion intermediate through ether coordination. Glycosyl donor protecting groups were explored in an effort to realize perfect α selectivity by manipulating remote participation. The simultaneous glycosylations of a tetrasaccharide with two disaccharides was investigated to efficiently construct a bisecting GlcNAc‐containing N‐glycan.     

Glycosylidene Carbenes. Part 16. Glycosidation of methyl 6-O-trityl-α-D-altropyranoside

Hydrogen bonding of the triol 4 in chlorinated solvents was studied by IR (CH₂Cl₂ and CCl₄) and ¹H-NMR spectroscopy (CDCl₃), and the regioselectivity of the glycosidation of the triol 4 by the diazirine 1 is predicted on the basis of two assumptions: preferred protonation of the intermediate glycosylidene carbene by the OH group involved in the weakest intramolecular H-bond, and attack in the π-plane of the thereby generated oxycarbenium cation either by the reoriented oxy anion, or by a properly oriented vicinal OH group. Glycosidation led to the disaccharides 5–10 (Scheme) which were separated and characterized as their acetates 11–16 , to the lactone azines 17 and to the 2-(benzyloxy)glucal 18 . In agreement with the predictions, glycosidation in non-coordinating solvents gave the 1,2-, 1,3-, and 1,4-linked disaccharides in decreasing relative amounts. Glycosidation in THF proceeded with a lower degree of regioselectivity and led preferentially to the β -D -anomers, except for the minor, 1,4-linked disaccharides, where THF had only a weak influence on stereoselectivity at room temperature and led to a slight increase of the α -D -anomer at ?80°.     

Methyl β‐d‐galactopyranosyl‐(1→4)‐β‐d‐allopyranoside tetrahydrate

The title compound, C₁₃H₂₄O₁₁·4H₂O, (I), crystallized from water, has an internal glycosidic linkage conformation having ϕ′ (O5_Gal—C1_Gal—O1_Gal—C4_All) = −96.40 (12)° and ψ′ (C1_Gal—O1_Gal—C4_All—C5_All) = −160.93 (10)°, where ring‐atom numbering conforms to the convention in which C1 denotes the anomeric C atom, C5 the ring atom bearing the exocyclic hydroxymethyl group, and C6 the exocyclic hydroxymethyl (CH₂OH) C atom in the βGalp and βAllp residues. Internal linkage conformations in the crystal structures of the structurally related disaccharides methyl β‐lactoside [methyl β‐d ‐galactopyranosyl‐(1→4)‐β‐d ‐glucopyranoside] methanol solvate [Stenutz, Shang & Serianni (1999). Acta Cryst. C 55 , 1719–1721], (II), and methyl β‐cellobioside [methyl β‐d ‐glucopyranosyl‐(1→4)‐β‐d ‐glucopyranoside] methanol solvate [Ham & Williams (1970). Acta Cryst. B 26 , 1373–1383], (III), are characterized by ϕ′ = −88.4 (2)° and ψ′ = −161.3 (2)°, and ϕ′ = −91.1° and ψ′ = −160.7°, respectively. Inter‐residue hydrogen bonding is observed between O3_Glc and O5_Gal/Glc in the crystal structures of (II) and (III), suggesting a role in determining their preferred linkage conformations. An analogous inter‐residue hydrogen bond does not exist in (I) due to the axial orientation of O3_All, yet its internal linkage conformation is very similar to those of (II) and (III).     

Exploration of the Oxazolidinthione Protecting System for the Synthesis of Sialic Acid Glycosides

An N-acetyl oxazolidinthione-protected sialyl thioglycoside was synthesized and its use as a sialyl donor studied. The strongly electron-withdrawing nature of the oxazolidinthione moiety is such that activation could not be achieved at ?78°C. Couplings were therefore conducted at the lowest convenient temperature (?50°C). Glycosides were formed in good yield but in two out of three cases studied selectivities were lower than those seen with the corresponding N-acetyl oxazolidinone-protected donor. The resulting N-acetyl oxazolidinthione-protected disaccharides were converted to the corresponding N-acetyl oxazolidinones by treatment with N-iodosuccinimide and triflic acid in the presence of water at 0°C.     

Binding structures of tri‐N‐acetyl‐β‐glucosamine in hen egg white lysozyme using molecular dynamics with a polarizable force field

Lysozyme is a well‐studied enzyme that hydrolyzes the β‐(1,4)‐glycosidic linkage of N‐acetyl‐β‐glucosamine (NAG)_n oligomers. The active site of hen egg‐white lysozyme (HEWL) is believed to consist of six subsites, A‐F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all‐atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)₃. MD trajectories are applied to analyze structures and conformation of the complex as well as protein–ligand interactions, including the hydrogen‐bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)₃ are investigated independently based on a fixed‐charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM‐GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root‐mean‐squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed‐charge models. © 2012 Wiley Periodicals, Inc.     

A 3,4‐trans‐Fused Cyclic Protecting Group Facilitates α‐Selective Catalytic Synthesis of 2‐Deoxyglycosides

A practical approach has been developed to convert glucals and rhamnals into disaccharides or glycoconjugates with high α‐selectivity and yields (77–97 %) using a trans‐fused cyclic 3,4‐O‐disiloxane protecting group and TsOH?H₂O (1 mol %) as a catalyst. Control of the anomeric selectivity arises from conformational locking of the intermediate oxacarbenium cation. Glucals outperform rhamnals because the C6 side‐chain conformation augments the selectivity.     

Glycosylidene Carbenes. Part 19. Regioselective glycosidation of allyl 2-deoxy-2-phthalimido-D-allopyranosides

The regio- and stereoselectivity of the glycosidation of the partially protected mono-alcohols 3 and 7 , the diols 2 and 8 , and the triol 4 by the diazirine 1 have been investigated. Glycosidation of the α-D -diol 2 (Scheme 2) gave regioselectively the 1,3-linked disaccharides 11 and 12 (80%, α-D /β-D 9:1), whereas the analogous reaction with the βD -anomer 8 led to a mixture of the anomeric 1,3- and 1,4-linked disaccharides 13 (12.5%), 14 (16%), 15 (13%), and 16 (20.5%; Table 2). Protonation of the carbene by OH–C(4) of 2 is evidenced by the observation that the α-D -mono-alcohol 3 did not react with 1 under otherwise identical conditions, and that the β-D -alcohol 7 yielded predominantly the β-D -glucoside 18 (52%) besides 14% of 17 . Similarly as for the glycosidation of the diol 2 , the influence of the H-bond of HO? C(4) on the direction of approach of the carbene, the role of HO? C(4) in protonating the carbene, and the stereoelectronic control in the interception of the ensuring oxycarbenium cation are evidenced by the reaction of the triol 4 with 1 (Scheme 3), leading mostly to the α-D -configurated 1,3-linked disaccharide 19 (41%), besides its anomer 20 (16%), and some 4-substituted β-D -glucoside 21 (9%). No 1,6-linked disaccharides could be detected. In agreement with the observed reactivity, the ¹H-NMR and IR spectra reveal a strong H-bond between HO? C(3) and the phthalimido group in the α-D -, but not in the β-D -allosides. The different H-bonds in the anomeric phthalimides are in keeping with the results of molecular-mechanics calculations.     

1H-NMR Studies on (6R)- and (6S)-deuterated (1–6)-linked disaccharides: assignment of the preferred rotamers about C5–C6 bond of (1–6)-disaccharides in solution

Conformational properties of the C5–C6 bond in the α- and β(1–6)-linked disaccharides in solution were clarified based on the ¹H-NMR spectra of the (6R)- and (6S)-deuterated derivatives.     

Electronic spectra and first‐order hyperpolarizability of 4‐(dicyanomethylene)‐2,6‐bis‐ (2′‐thiophene‐vinyl)‐pyran derivatives

On the basis of the ZINDO program, we have designed a program to calculate the first‐order hyperpolarizability β_ijk and β_μ according to the sum‐over‐states (SOS) expression. The first‐order hyperpolarizability of 4‐(dicyanomethylene)‐2,6‐bis‐(2′‐thiophene‐vinyl)‐pyran derivatives were studied. The calculated results were that the 4‐(dicyanomethylene)‐2,6‐bis‐(2′‐thiophene‐vinyl)‐pyran derivatives exhibit good nonlinearity with their β₀ values, which are slightly less than that of the corresponding 2,6‐bis‐styryl‐4‐(dicyanomethylene)‐pyran derivatives. It does not agree with the auxiliary donor–acceptor effects theory. The 4‐(dicyanomethylene)‐2,6‐bis‐(2′‐thiophene‐vinyl)‐pyran derivatives, having two low‐lying electronic excited states that contribute to the molecular hyperpolarizability in an additive manner, are good candidates as chromophores due to their high nonlinearities and good thermal stability. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 65–72, 2001     

Glycosylidene Carbenes. Part 17. Glycosidation of benzyl β-D- and β-L-ribopyranosides. Further evidence for the effect of stereoelectronic control on the regioselectivity of glycosidation

The H-bonds of the enantiomeric ribosides 4 and 5 and their glycosidation by the diazirine 1 are described. HO–C(2) and HO? C(4) of 4 and 5 form a ‘flip-flop’ H-bonding system, with HO? C(3) acting as a H-bond donor to O? C(2) or O? C(4). HO? C(2) and HO? C(4) of monomeric 4 and 5 are thus the most strongly acidic OH groups. Glycosidation of 4 and 5 by 1 depends on the solvent, the temperature, and the concentration. It yields up to 91% of a mixture of anomeric pairs of the 1,2-, 1,3-, and 1,4-linked disaccharides 8–13 and 20–25 , respectively, which were characterized as their diacetates 14–19 and 26–31 (Scheme). Glycosidation in CH₂Cl₂ and in dioxane yielded mostly the 1,3-linked disaccharides 10/11 and 22/23 (α/β ca. 4:1), while glycosidation in THF leads mostly to the 1,2- and 1,4-linked regioisomers (β>α). There are small, but significant differences in the glycosidation of 4 and 5 . These, the regio-, and the stereoselectivities are rationalized as the consequences of the stereoelectronic control of both the H-transfer from HO? C(2) or HO? C(4) to the intermediate carbene and of the formation of the glycosidic C? O bond, and of the coordination of the intermediate oxycarbenium ion with THF.     

Homodimerization of hyaluronan and heparan sulfate derivatives by olefin metathesis reaction

Hyaluronan and heparan sulfate disaccharides of the type β-d-glucuronic acid-(1→3)-N-acetyl-β-d-glucosamine and α-l-iduronic acid-(1→4)-N-acetyl-β-d-glucosamine, respectively, with an n-pentenyl group at the reducing end have been synthesized. Homodimerization of these derivatives using Grubbs catalyst furnished dimerized disaccharides separated by a C₈ spacer arm.     

Structure and reactivity of α,β-unsaturated ethers. VIII. Cationic copolymerizations and acetal additions of propenyl and isobutenyl ethyl ethers

Cationic copolymerizations of cis- and trans-propenyl ethyl ethers (PEE) with isobutenyl ethyl ether (IBEE) were carried out in methylene chloride at ?78°C with the use of boron trifluoride etherate as catalyst. Monomer reactivity ratios were r₁ = 24.0 ± 2.4 and r₂ = 0.02 ± 0.02 for the cis-PEE (M₁)–IBEE (M₂) system and r₁ = 19.1 ± 1.8 and r₂ = 0.04 ± 0.02 for the trans-PEE (M₁)–IBEE (M₂) system, indicative of the reactivity order: cis-PEE > trans-PEE ? IBEE. In separate experiments, these β-methyl-substituted vinyl ethers were allowed to react with various acetals in the presence of boron trifluoride etherate. The relative reactivities of these ethers were generally found to decrease in the order: cis-β-monomethylvinyl > vinyl > trans-β-monomethylvinyl > β,β-dimethylvinyl. Comparisons of these results with previously published copolymerization data have permitted the conclusion that, in both the copolymerizations and acetal additions, the single β-methyl substitution on vinyl ethers exerts little steric effect against their additions toward any alkoxycarbonium ion, whereas the β,β-dimethyl substitution results in a large adverse steric effect toward both β-monomethyl- and β,β-dimethyl-substituted alkoxycarbonium ions.     

An improved method for synthesizing antennary β-d-mannopyranosyl disaccharide units

The merits of an indirect protecting method for hydroxyl groups using allyl groups via allyloxycarbonyl groups in the synthesis of antennary β-d-mannopyranosyl disaccharides from β-d-galactopyranosyl disaccharides were studied. Regioselective allyloxycarbonylation and conversion reactions involving simultaneous double S_N2 nucleophilic substitution at C-2′ and C-4′ of benzyl O-[β-d-galactopyranosyl]-(1-4)-3,6-di-O-benzyl-2-deoxy-2-N-phthalimido-β-d-glucopyranoside were examined for comparison with the direct allylation method. The required β-d-mannopyranosyl disaccharide having proper protecting groups was obtained using this indirect method in 52% yield. In contrast, the reported direct allylation method using methyl O-(β-d-galactopyranosyl) disaccharide gave the corresponding β-d-mannopyranosyl disaccharide in only 7.5% yield.     

Glycosylidene Carbenes. Part 14. Glycosidation of partially protected galactopyranose-, glucopyranose-, and mannopyranose-derived vicinal diols

The relation between H-bonding in diequatorial trans-1,2 and axial, equatorial cis-1,2-diols and the regioselectivity of glycosidation by the diazirine 1 was examined. H-Bonds were assigned on the basis of FT-IR and ¹H-NMR spectra (Fig. 1). Glycosidation by 1 of the gluco-configurated diequatorial trans-2,3-diols 4–7 yielded the mono-glucosylated products 16/17/20/21 (69–89%); 1,2-/1,3-linked products (37–46:63–54), 24/25/28/29 (60–63%; 1,2-/1,3-linked products 46–51:54–49), 32–35 (69–94%; 1,2-/1,3-linked products 45–52:55–48), and 36/37/40/41 (59–63%; 1,2-/1,3-linked products 52–59:48–41), respectively (Scheme 1, Table 3). The disaccharides derived from 4, 5 , and 7 were characterized as their acetates 18/19/22/23, 26/27/30/31 , and 38/39/42/43 , respectively. Glycosidation of the galacto-configurated diequatorial 2,3-diols 8 and 9 and the manno-configurated diequatorial 3,4-diol 10 by 1 (Scheme 2, Table 3) also proceeded in fair yields to give the disaccharides 44–47 (69–80%;1,2-/1,3-linked products ca. 1:1), 48–51 (51–61%;1,2/-1,3-linked products 54–56:56–54), and 56/57/60/61 (71–80%; 1,3-/1,4-linked products 49–54:51–46), respectively. The 1,3-linked disaccharides 56/57 derived from the diol 10 were characterized as the acetates 58/59 . The regio- and stereoselectivities of the glycosidation by 1 were much better for the α-D -manno-configurated axial, equatorial cis-2,3-diol 11 and the galacto-configurated axial, equatorial cis-3,4-diol 13 (1,2-/1,3-linked disaccharides ca. 3:7 for 11 and 1,3-/1,4-linked disaccharides ca. 4:1 for 13 ; Scheme 3, Table 4). The regio- and stereoselectivity for the β-D -manno-configurated cis-2,3-diol 12 were, however, rather poor (1,2-/1,3-linked products 48:52). The 1,2-linked disaccharides 66/67 derived from 12 were characterized as the acetates 70/71 . Koenigs-Knorr-type glycosidation of the cis-diols 11–13 by 2 or 3 proceeded with a similar regio- and a higher stereoselectivity (α-D > β-D with the donor 2 and α-D < β-D with the donor 3 ) than with 1 , with the exception of 12 which did not react with 2 . The regioselectivity of the glycosidations by 1 agrees fully with the H-bonding scheme of the diols and with the hypothesis that the intermediate carbene is preferentially protonated by the most weakly H-bonded OH group. The regioselectivity of the glycosidation by 2 and by 3 is determined by a higher reactivity of the equatorial OH groups and by H-bonding. Several H-bonded and equilibrating isomers of a given diol may intervene in the glycosidation by 1 , or by 2 and 3 , resulting in the same regioselectivity. The low nucleophilicity of 12 and the low degree of regioselectivity in its reaction with 3 show that stereoelectronic effects may also profoundly influence the nucleophilicity of OH groups.