Stereoselective gold(I)-catalyzed approach to the synthesis of complex α-glycosyl phosphosaccharides.

Glycosyl phosphosaccharides represent a large and important family of complex glycans. Due to the distinct nature of these complex molecules, efficient approaches to access glycosyl phosphosaccharides are still in great demand. Here, we disclose a highly efficient and stereoselective approach to the synthesis of biologically important and complex α-glycosyl phosphosaccharides, employing direct gold(I)-catalyzed glycosylation of the weakly nucleophilic phosphoric acid acceptors. In this work, the broad substrate scope is demonstrated with more than 45 examples, including glucose, xylose, glucuronate, galactose, mannose, rhamnose, fucose, 2-N3-2-deoxymannose, 2-N3-2-deoxyglucose, 2-N3-2-deoxygalactose and unnatural carbohydrates. Here, we show the glycosyl phosphotriester prepared herein was successfully applied to the one-pot synthesis of a phosphosaccharide from Leishmania donovani, and an effective preparation of a trisaccharide diphosphate of phosphosaccharide fragments from Hansenula capsulate via iterative elongation strategy is realized.

An Approach to the Synthesis of Electron-Rich and Hindered Esters and Its Application to the Synthesis of Acteoside.

Electron-rich esters are ubiquitously distributed in natural products and play a central role in bioactivities. Herein, we disclose an efficient, mild, and general esterification approach to the synthesis of these esters by employing gold(I)-catalyzed acylation reaction with alkyne-tethered mixed anhydrides and alcohols. This method can be applied to ester-bond formation in complex substrates and facilitates efficient synthesis of acteoside, which belongs to the family of phenylethanoid glycosides and possesses a broad range of bioactivities.

Enantioselective Tandem Cyclization of Alkyne-Tethered Indoles Using Cooperative Silver(I)/Chiral Phosphoric Acid Catalysis.

Reported is the enantioselective synthesis of tetracyclic indolines using silver(I)/chiral phosphoric acid catalysis. A variety of alkyne-tethered indoles are suitable for this process. Mechanistic studies suggest that the in situ generated silver(I) chiral phosphate activates both the alkyne and the indole nucleophile in the initial cyclization step through an intermolecular hydrogen bond and the phosphate anion promotes proton transfer. In addition, further modifications of the cyclization products enabled stereochemistry-function studies of a series of bioactive indolines.

Tetracyclic indolines as a novel class of ß-lactam-selective resistance-modifying agent for MRSA.

Antibiotic-resistant bacterial infections have seen a marked increase in recent years, while antibiotic discovery has waned. Resistance-modifying agents (RMA) offer an intriguing alternative strategy to fight against resistant bacteria. Here we report the discovery, antibiotic profiling, and structure-activity relationships of a novel class of RMAs, tetracyclic indolines. These selectively potentiate ß-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) without antibacterial or ß-lactamase inhibitory activity on their own. The most potent analogue, 6a, showed strong potentiation of amoxicillin/clavulanic acid in a variety of hospital-acquired and community-acquired MRSA strains with low mammalian toxicity. These compounds may be further developed to extend the clinic life span of ß-lactam antibiotics.

Stereoselective synthesis of ß-rhamnopyranosides via gold(I)-catalyzed glycosylation with 2-alkynyl-4-nitro-benzoate donors.

Stereoselective ß-rhamnopyranosylation remains a challenge, due to the unfavorable anomeric effect and steric hindrance of the C2-substituent; herein, this challenge is addressed with a gold(I)-catalyzed SN2-like glycosylation protocol employing α-rhamnopyranosyl 2-alkynyl-4-nitro-benzoates as donors.

Highly stereoselective ß-mannopyranosylation via the 1-α-glycosyloxy-isochromenylium-4-gold(I) intermediates.

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 ß-selective mannosylation when Ph3 PAuOTf 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 ß-selectivity with the mannosyl ortho-alkynylbenzoate ß-donors. Nevertheless, with the α-donors, the mannosylation reactions under the catalysis of Ph3 PAuBAr4 (F) (BAr4 (F) =tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) are especially highly ß-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 ß-donors, an anomerization and glycosylation sequence can also ensure the highly ß-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 Ph3 PAuBAr4 (F) at -35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high ß-selectivity in the present mannosylation.

Mechanistic insights into the gold(I)-catalyzed activation of glycosyl ortho-alkynylbenzoates for glycosidation.

Anomerization, which involves cleavage and formation of the anomeric C-O bond, is of fundamental importance in the carbohydrate chemistry. Herein, the unexpected gold(I)-catalyzed anomerization of glycosyl ortho-alkynylbenzoates has been studied in detail. Especially, crossover experiments in the presence of an exogenous isochromen-4-yl gold(I) complex confirm that the anomerization proceeds via the exocleavage mechanism, involving (surprisingly) the addition of the isochromen-4-yl gold(I) complex onto a sugar oxocarbenium (or dioxolenium) and an elimination of LAu(+) from the vinyl gold(I) complex. The inhibitory effect of the exogenous isochromen-4-yl gold(I) complex when in stoichiometric amount on the anomerization has guided us to disclose an isochromen-4-yl gem-gold(I) complex, which is inactive in catalysis but in equilibrium with the monogold(I) complex and the LAu(+) catalyst. The proposed key intermediate in the anomerization, a transient glycosyloxypyrylium species, is successfully trapped via a cycloaddition reaction with n-butyl vinyl ether as a dienophile. SN2-like substitution of the initially formed glycosyloxypyrylium intermediate has then been achieved to a large extent via charging with acceptors in an excess amount to lead to the corresponding glycosides in a stereoselective manner.

A dramatic concentration effect on the stereoselectivity of N-glycosylation for the synthesis of 2'-deoxy-ß-ribonucleosides.

A dramatic concentration effect on the stereoselectivity of N-glycosylation, which is attributable to a low-concentration-facilitated remote-participation, has been disclosed, leading to convenient synthesis of the 2'-deoxy-ß-ribonucleosides of biological significance.