The efficacy of the heterogeneous polystyrene-bound triphenylphosphine gold(I) catalyst 3 (PS-[Ph₃PAu^INTf₂]; PS=polystyrene; Tf=trifluoromethanesulfonyl) in the activation of glycosyl ortho-hexynylbenzoates for glycosylation is demonstrated. The shelf-stable catalyst 3 (and its precursor 2, PS-[Ph₃PAu^ICl]) were fully characterized by elemental analysis, X-ray photoelectron spectroscopy (XPS), energy dispersive spectroscopy (EDS), and scanning electron microscopy (SEM), and showed remarkable catalytic activities and recyclability in glycosylation reactions as well as in the skeletal rearrangement of the 1,6-enyne 4. EDS analysis demonstrated that the phosphine ligand binds the gold strongly and prevents the leaching of the metal.

An effective glycosylation procedure for the stereoselective construction of the α-d-GlcN-(14)-d-GlcA/l-IdoA glycosidic linkage found in heparin and heparan sulfate is reported. The condensation occurs between 2-deoxy-2-azido-d-glucopyranosyl (d-GlcN) ortho-hexynylbenzoate donors and uronate acceptors (d-GlcA/l-IdoA) under mild gold(I)-catalyzed conditions. Optimal results are obtained when performing the reaction in CH₂Cl₂, from −72 °C to room temperature in the presence of 4 Å molecular sieves and under the promotion of [Ph₃PAuCl]/AgOTf or [(1,1-bis-(diphenylphosphino)methane)(AuCl)₂]/AgOTf as a source of the gold(I) catalyst. A donor/acceptor ratio of 3:1 as well as a loading of 0.6 equivalents of the gold(I) catalyst are essential to attain high yields and α selectivity, particularly for the [1+1] and [1+2] glycosylations.

While the gold(I)-catalyzed glycosylation reaction with 4,6-O-benzylidene tethered mannosyl ortho-alkynylbenzoates as donors falls squarely into the category of the Crich-type β-selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α-triflates are invoked, replacement of the ⁻OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ⁻NTf₂, ⁻SbF₆, ⁻BF₄, and ⁻BAr₄^F) leads to complete loss of β-selectivity with the mannosyl ortho-alkynylbenzoate β-donors. Nevertheless, with the α-donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) are especially highly β-selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6-di-O-benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho-alkynylbenzoate β-donors, an anomerization and glycosylation sequence can also ensure the highly β-selective mannosylation. The 1-α-mannosyloxy-isochromenylium-4-gold(I) complex (Cα), readily generated upon activation of the α-mannosyl ortho-alkynylbenzoate (1 α) with Ph₃PAuBAr₄^F at −35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β-selectivity in the present mannosylation.

The tunicamycins constitute a delicate mimic of the bisubstrate intermediates of N-acetyl-D-hexosamine-1-phosphate translocases and thus inhibit bacterial cell-wall synthesis and the N glycosylation of eukaryotic proteins. An efficient approach to the synthesis of this unique type of nucleoside antibiotics is now reported and features the assembly of five modules in a highly stereoselective and robust manner. A Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final N acylation were used as the key steps.

The tunicamycins constitute a delicate mimic of the bisubstrate intermediates of N-acetyl-D-hexosamine-1-phosphate translocases and thus inhibit bacterial cell-wall synthesis and the N glycosylation of eukaryotic proteins. An efficient approach to the synthesis of this unique type of nucleoside antibiotics is now reported and features the assembly of five modules in a highly stereoselective and robust manner. A Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final N acylation were used as the key steps.

In a previous study we reported a class of compounds with a 2H-thiazolo[3,2-a]pyrimidine core structure as general inhibitors of anti-apoptotic Bcl-2 family proteins. However, the absolute stereochemical configuration of one carbon atom on the core structure remained unsolved, and its potential impact on the binding affinities of compounds in this class was unknown. In this study, we obtained pure R and S enantiomers of four selected compounds by HPLC separation and chiral synthesis. The absolute configurations of these enantiomers were determined by comparing their circular dichroism spectra to that of an appropriate reference compound. In addition, a crystal structure of one selected compound revealed the exocyclic double bond in these compounds to be in the Z configuration. The binding affinities of all four pairs of enantiomers to Bcl-x_L, Bcl-2, and Mcl-1 proteins were measured in a fluorescence-polarization-based binding assay, yielding inhibition constants (K_i values) ranging from 0.24 to 2.20 μM. Interestingly, our results indicate that most R and S enantiomers exhibit similar binding affinities for the three tested proteins. A binding mode for this compound class was derived by molecular docking and molecular dynamics simulations to provide a reasonable interpretation of this observation.

The twists and turns toward the total synthesis of landomycin A, a prominent angucycline hexasaccharide antibiotic, in particular those toward the stereoselective construction of the di- and trideoxyglycosidic linkages, are described.

A polystyrene-(benzotriazole)(triphenylphosphine)gold(I) [Btz⋅Au(I)PPh₃] resin, representing the first polystyrene-immobilized homogeneous gold(I) complex, was conveniently prepared, and showed remarkable catalytic activities and recyclability in three model transformations, including the tandem 3,3-rearrangement and Nazarov reaction of an enynyl acetate, the cyclization of a 1,6-enyne, and the rearrangement of an alkyne-furan.

A class of compounds with a common thiazolo[3,2-a]pyrimidinone motif has been developed as general inhibitors of Bcl-2 family proteins. The lead compound was originally identified in a random screening of a small compound library using a fluorescence polarization-based competitive binding assay. Its binding to the Bcl-x_L protein was further confirmed by ¹⁵N-HSQC NMR experiments. Structural modifications on the lead compound were guided by the outcomes of molecular modeling studies. Among the 42 compounds obtained, a number of them exhibited much improved binding affinities to Bcl-2 family proteins as compared to the lead compound. The most potent compound, BCL-LZH-40, inhibited the binding of BH3 peptides to Bcl-x_L, Bcl-2, and Mcl-1 with inhibition constants (K_i) of 17, 534, and 200 nM, respectively.

GH20 β-N-acetyl-D-hexosaminidases are enzymes involved in many vital processes. Inhibitors that specifically target GH20 enzymes in pests are of agricultural and economic importance. Structural comparison has revealed that the bacterial chitindegrading β-N-acetyl-D-hexosaminidases each have an extra +1 subsite in the active site; this structural difference could be exploited for the development of selective inhibitors. N,N,Ntrimethyl-D-glucosamine (TMG)-chitotriomycin, which contains three GlcNAc residues, is a natural selective inhibitor against bacterial and insect β-N-acetyl-D-hexosaminidases. However, our structural alignment analysis indicated that the two GlcNAc residues at the reducing end might be unnecessary. To prove this hypothesis, we designed and synthesized a series of TMG-chitotriomycin analogues containing one to four GlcNAc units. Inhibitory kinetics and molecular docking showed that TMG-(GlcNAc)₂, is as active as TMG-chitotriomycin [TMG-(GlcNAc)₃]. The selective inhibition mechanism of TMG-chitotriomycin was also explained.

A new type of sugar-fused isoxazoline N-oxides was synthesized from 2-nitroglycals via [1+4] condensation with bromomalonate under the action of DBU. In addition, 1,3-dipolar cycloaddition of these isoxazoline N-oxides with alkene and alkyne dipolarophiles were also investigated.

Talosin A and B, namely genistein 7-O-α-L-6-deoxy-talopyranoside and genistein 4′,7-di-O-α-L-6-deoxy-talopyranoside, which show excellent antifungal and anti-inflammatory activities, were synthesized concisely.

Glycosyl ortho-alkynylbenzoates have emerged as a new generation of donors for glycosidation under the catalysis of gold(I) complexes such as Ph₃PAuOTf and Ph₃PAuNTf₂ (Tf=trifluoromethanesulfonate). A wide variety of these donors, including 2-deoxy sugar and sialyl donors, are easily prepared and shelf stable. The glycosidic coupling yields with alcohols are generally excellent; even direct coupling with the poorly nucleophilic amides gives satisfactory yields. Moreover, excellent α-selective glycosylation with a 2-deoxy sugar donor and β-selective sialylation have been realized. Application of the present glycosylation protocol in the efficient synthesis of a cyclic triterpene tetrasaccharide have further demonstrated the versatility and efficacy of this new method, in that a novel chemoselective glycosylation of the carboxylic acid and a new one-pot sequential glycosylation sequence have been implemented.

Candicanoside A (1) and its 4″-O-(p-methoxybenzoate) derivative 2 are congeners of the novel 24(2322)abeo-cholestane glycosides that occur in the genus Ornithogalum indigenous to Southern Africa and have remarkable cytostatic activities. These two saponins have been synthesized starting from dehydroisoandrosterone, D-glucose, and L-rhamnose in 37 and 44 steps, respectively. The reaction protocols feature a stereocontrolled stepwise glycosylation with glycosyl imidates as the donors. The synthesis of the rearranged steroid aglycon employs a 20-alkoxy radical-mediated functionalization of the angular 18-methyl group, a Johnson–Claisen rearrangement for the alkylation at C-20, an aldol condensation at C-22, and a photodeconjugation of an α,β-unsaturated lactone as the key steps. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

On the basis of the structure of 4′,7,8-trihydroxyisoflavone 7-O-α-D-arabinofuranoside (namely A-76202, 1), a Rhodococcus metabolite showing potent inhibitory activities againstthe α-glucosidases of rat liver microsome (IC₅₀ = 0.46 ng/mL), 26 analogs, each with minor variations at the sugar moiety and the isoflavone A and B rings, were readily synthesized. Notably, a new and efficient method was developed for the divergent synthesis of the B-ring congeners of the isoflavone glycosides by using Suzuki–Miyaura coupling as the final step. Modifications at the sugar moiety and the isoflavone A ring significantly diminish the activity, whereas variations at the B ring are largely tolerated for retaining the potent α-glucosidase inhibitory activity.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)