ortho-Methoxycarbonylethynylphenyl Thioglycosides (MCEPTs): Versatile Glycosyl Donors Enabled by Electron-Withdrawing Substituents and Catalyzed by Gold(I) or Cu(II) Complexes.

With easily accessible and operator-friendly reagents, shelf-stable ortho-methoxycarbonylethynylphenyl thioglycosides were efficiently prepared. Based on these MCEPT glycoside donors, a novel glycosylation protocol featuring mild and catalytic promotion conditions with Au(I) or Cu(II) complexes, expanded substrate scope encompassing challenging donors and acceptors and clinically used pharmaceuticals, and versatility in various strategies for highly efficient synthesis of glycosides has been established. The practicality of the MCEPT glycosylation protocol was fully exhibited by highly efficient and scalable synthesis of surface polysaccharide subunits of Acinetobacter baumannii via latent-active, reagent-controlled divergent orthogonal one-pot and orthogonal one-pot strategies. The underlying reaction mechanism was investigated systematically through control reactions, leading to the isolation and characterization of the vital catalyst species in MCEPT glycosylation, the benzothiophen-3-yl-gold(I) complex. Based on the results obtained both from control reactions and from studies leading to the glycosylation protocol establishment, an operative mechanism was proposed and the effect of the vital catalyst species reactivity on the results of metal-catalyzed alkyne-containing donor-involved glycosylation was disclosed. Moreover, the mechanism for C-glycosylation side product formation from ortho-(substituted)ethynylphenyl thioglycoside donors with electron-donating substituents was also illuminated.

Metallaphotoredox-Enabled Construction of the P(O)-N Bond from Aromatic Amines and P(O)-H Compounds.

We have developed a dual copper/photoredox-catalyzed approach for the construction of the P(O)-N bond from commercially available aromatic amines and P(O)-H compounds. This metallaphotoredox method avoids toxic or corrosive reagents and does not require prefunctionalized substrates. The reaction has a broad substrate scope and is suitable for the synthesis of phosphonamides and phosphinamides, thus complementing the previous nonphotochemical approaches. The reaction is amenable to the direct modification of drug molecules and can be conducted on a gram scale.

8-(Methyltosylaminoethynyl)-1-naphthyl (MTAEN) Glycosides: Potent Donors in Glycosides Synthesis.

With 8-(methyltosylaminoethynyl)-1-naphthyl (MTAEN) glycoside as donors, a novel and efficient glycosylation protocol has been established. The MTAEN glycosylation protocol exhibits the merits of shelf-stable donors, mild catalytic promotion conditions, considerably extended substrate scope encompassing both free alcohols, silylated alcohols, nucleobases, primary amides, and C-type nucleophile acceptors, and applicability to various one-pot strategies for highly efficient synthesis of oligosaccharides, such as orthogonal one-pot, single-catalyst one-pot, and acceptor reactivity-controlled one-pot strategies.

1,2-trans-Stereoselective Synthesis of C-Glycosides of 2-Deoxy-2-amino-sugars Involving Glycosyl Radicals.

We report for the first time that the imidate radical can be efficiently added to glycals to generate glycosyl radicals, based on which a general, toxic-reagent-free synthesis of C-glycosides of 2-deoxy-2-amino sugars has been developed. Complementary to previous strategies, the reaction is 1,2-trans-stereoselective and could use aryl alkenes as substrates. The late-stage functionalization and density functional theory calculations are reported.

Reagent-Controlled Divergent Synthesis of C-Glycosides.

By turning on or switching off the directing effect of the C3-OH-located o-diphenylphosphanylbenzoyl (o-DPPB) group in glycals, a reagent-controlled protocol for divergent and regio- and stereoselective syntheses of C-glycosides has been established. In particular, the silence of the directing effect of o-DPPB was achieved by the introduction of a ZnCl2 additive, which is operationally simple and efficient. The flexibility of the novel protocol was exhibited not only by the easy access of both α- and ß-C-glycosides but also by the versatility of the obtained formal Ferrier rearrangement products, which can be easily derivatized to various C-glycoside analogues owing to the embedded multifunctionalities.

Total Synthesis and Structural Revision of Rebaudioside S, a Steviol Glycoside.

The total synthesis of rebaudioside S, a minor steviol glycoside from the leaves of Stevia rebaudiana, was investigated via a modular strategy, culminating not only in the first and highly efficient synthesis of Reb-S and analogues thereof but also in the revision of the originally proposed structure. The modular strategy dictated the application of C2-branched disaccharide Yu donors to forge C-13 steviol glycosidic linkages, posing considerable challenges in stereoselectivity control. Through systematic investigations, the effect of the internal glycosidic linkage configuration on the glycosylation stereoselectivity of 1,2-linked disaccharide donors was disclosed, and the intensified solvent effect by the 4,6-O-benzylidene protecting group was also observed with glucosyl donors. Through the orchestrated application of these favorable effects, the stereoselectivity problems were exquisitely tackled.

The first total synthesis of rebaudioside R.

With easily available monosaccharides and steviol as starting materials, the first total synthesis of rebaudioside R with a xylosyl core in the C13-OH linked sugar chain was accomplished via two distinct approaches. The first approach features the stepwise installation of branch-sugar residues via an order of C2-OH first and then C3-OH of the xylosyl core, laying a firm foundation for the synthesis of analogues with different branch sugars, while the second route features the introduction of the C13 trisaccharide sugar chain via a convergent strategy, securing the overall synthetic efficiency. Through the synthetic study, the effect of protecting groups (PGs) at the vicinal hydroxy group on the reactivity of OH acceptors was illustrated.

Palladium-Catalyzed Cross-Coupling of 2-Iodoglycals with N-Tosylhydrazones: Access to 2-C-Branched Glycoconjugates and Oxadecalins.

A convenient and straightforward synthesis of diverse 2-C-alkenyl-glycosides through a palladium-catalyzed cross-coupling reaction between 2-iodoglycals and N-tosylhydrazones has been developed. Further transformation of 2-C-branched sugars by Diels-Alder reactions provided oxadecalins in good yields.

Diversity-Oriented Synthesis of Steviol Glycosides.

With cheap and easily available mixtures of steviol glycosides as starting materials, a practical method for steviol acquisition has been developed, on the basis of which a facile, diversity-oriented, and economic protocol for the synthesis of structurally defined steviol glycosides was established. The novel approach is featured by the highly efficient glycosylation of sterically hindered and acid-sensitive steviol via orchestrated application of Yu glycosylation, Schmidt glycosylation, and PTC glycosylation. Hence, these high-intensity sweeteners and potential lead compounds for drug development are now readily accessible.

Cu-Catalyzed/mediated synthesis of N-fluoroalkylanilines from arylboronic acids: fluorine effect on the reactivity of fluoroalkylamines.

An oxidative coupling reaction of fluoroalkylamines with arylboronic acids has been achieved for the first time. Fluorine has profound influence on the reactivity and fluoroalkylated amines have the following reactivity trend: difluoroethylamine > trifluoroethylamine > pentafluoropropylamine ≈ heptafluorobutylamine.

The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives.

Under the effect of a catalytic amount of Au(I) complex, 4-O-(2-cyclopropylethynyl)benzoyl-(epi)-podophyllotoxins, easily prepared via dehydrative condensation between (epi)-podophyllotoxin and ortho-cyclopropylethynylbenzoic acid, could efficiently couple with a variety of nucleophiles including alcohol, phenol, aniline, and carbon nucleophiles, all to provide (epi)-podophyllotoxin derivatives. Thus, the first catalytic and lignan-activation-based approach for (epi)-podophyllotoxin derivatization was established. Based on the new methodology, as well as the judicious choice of N3, AZMB, and Cbz protecting groups, an efficient approach forward was set. NK-611, an antitumoral agent at a phase II clinical trial was established, featuring an in situ anomerization of the hemiacetal OHs in the critical condensation step. Commencing from easily available starting material, the target molecule was obtained using the longest linear sequence of six steps and a 38% overall yield.

Synthetic Access Toward Cycloastragenol Glycosides.

The first efficient synthetic approach toward four types of the cycloartane glycosides, the cycloastragenol 25-O; 3-O; 3,6-O-bis; and 3,25-O-bisglycoside, have been established, which featured the PPY-mediated, concentration-controlled acetylation and Au(I)-catalyzed Yu glycosylation. Through the synthetic investigation, the reactivity sequence of the four OHs in cycloastragenol was fixed for the first time and a detour strategy for the highly efficient removal of bulky pivaloyl protecting groups was discovered.

Synthetic investigation toward apigenin 5-O-glycoside camellianin B as well as the chemical structure revision.

Capitalizing on the Au(i)-catalyzed ortho-alkynylbenzoate glycosylation method, the first total synthesis of the proposed structure of apigenin-5-O-glycoside camellianin B was achieved, wherein three approaches, one linear and two convergent, were established, through which the synthetic structures were firmly corroborated. Meanwhile, through the synthesis of anthentic camellianin B via commercially available camellianin A, the misassigned structures of camellianins A and B were revised.

A Highly Efficient Approach To Construct (epi)-Podophyllotoxin-4-O-glycosidic Linkages as well as Its Application in Concise Syntheses of Etoposide and Teniposide.

By taking full advantage of the mild promotion conditions of an ortho-alkynylbenzoate glycosylation protocol, a highly efficient approach to construct the challenging (epi)-podophyllotoxin 4-O-glycosidic linkages was devised under the activation of a catalytic amount of a Au(I) complex. The novel method enjoys a quite broad substrate scope in terms of both glycosyl donors and podophyllotoxin derivative acceptors, providing the desired glycosides in excellent yields. Based on the new approach, concise syntheses of clinically used anticancer reagents etoposide and teniposide were accomplished, and the overall yields counting from easily available starting materials could reach as high as 18% and 9%, respectively.

Highly efficient synthesis of flavonol 5-O-glycosides with glycosyl ortho-alkynylbenzoates as donors.

With glycosyl ortho-alkynylbenzoates as donors, the highly efficient glycosylation of flavonoid 5-OH which are notorious for their low reactivity due to their involvement in the formation of strong intramolecular H-bonds was achieved under the catalysis of a Au(i) complex. Thus, a series of flavonoid 5-O-glycosides, including a kaempferol 5-O-disaccharide, were synthesized with good to excellent yields.