Glycal Donors Research Articles

Influence of C-4 Axial/Equatorial Configuration and Neighboring Group/Remote Group Participation (NGP/RGP) Driven Conformational Evidence in Chemoselective Activation of Glycals.

We herein reveal the possibility of the C-4 neighboring group/remote group participation (NGP/RGP) facilitating the stabilization of the anomeric center via dioxolenium intermediates in the chemoselective activation of glycal donors. We further realized that the axial/equatorial configuration of the C-4 group in the galacto- and gluco-glycal series enables diverse pathways to give direct 1,2-addition or Ferrier rearrangement, respectively. A proof-of-principle for stereoselective glycosylation was amply illustrated by employing carbohydrates, amino acids, natural products, and bioactive molecules to develop 2-deoxy-glycan analogs.

Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals

C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki–Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp2)-C(sp), C(sp2)-C(sp2), and C(sp2)-C(sp3) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

Reagent-controlled chemo/stereoselective glycosylation of ʟ-fucal to access rare deoxysugars

2,6-Dideoxy sugars constitute an important class of anticancer antibiotics natural products and serve as essential medicinal tools for carbohydrate-based drug discovery and vaccine development. In particular, 2-deoxy ʟ-fucose or ʟ-oliose is a rare sugar and vital structural motif of several potent antifungal and immunosuppressive bioactive molecules. Herein, we devised a reagent-controlled stereo and chemoselective activation of ʟ-fucal, enabling the distinctive glycosylation pathways to access the rare ʟ-oliose and 2,3-unsaturated ʟ-fucoside. The milder oxo-philic Bi(OTf)3 catalyst induced the direct 1,2-addition predominantly, whereas B(C6F5)3 promoted the allylic Ferrier-rearrangement of the enol-ether moiety in ʟ-fucal glycal donor, distinguishing the competitive mechanisms. The reagent-tunable modular approach is highly advantageous, employing greener catalysts and atom-economical transformations, expensive ligand/additive-free, and probed for a diverse range of substrates comprising monosaccharides, amino-acids, bioactive natural products, and drug scaffolds embedded with susceptible or labile functionalities.

Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Glycals: A Facile Synthesis of Allyl and Alkynyl Glycosides

AbstractIn modern advances, tris(pentafluorophenyl)borane (commonly known as BCF) catalyst has risen to prominence owing to its extensive versatility in the use of myriad of organic reactions. An efficient and highly stereoselective α-C-glycosylation strategy is presented by employing a catalytic amount of B(C6F5)3 under mild reaction conditions en route to 2,3-unsaturated C-glycosides. The reaction features a broad functional group tolerance including a variety of glycals coupled with allyltrimethylsilane and trimethylsilylphenylacetylene to access the corresponding 2,3-unsaturated allyl- and alkynyl-C-glycosides with excellent α-selectivity. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor under mild conditions.

A Short Route to the Synthesis of Digoxose Trisaccharide Glycal Donor via Mislow-Evans Rearrangement.

The Mislow-Evans rearrangement was used as a key reaction to construct digitoxose-derived glycals. The same rearrangement was iteratively performed on di- and trisaccharides to form the digoxose glycal donor component present in the cardenolides digitoxin, digoxin, and gitoxin. The scalability of the trisaccharide synthesis was shown by performing the reactions on a multigram scale. Glycosylation reactions were also performed between the synthesized digoxin glycal donor and aglycons digoxigenin and gitoxigenin to synthesize novel cardenolide derivatives.

L‐Proline Derived Thioamide Small Organic Molecule for the α‐Stereoselective Synthesis of 2‐Deoxyglycosides

AbstractL‐Prolinethioamide catalyzes direct stereoselective glycosylation of glycal donors to access 2‐deoxyglycosides under moderate reaction conditions. This proposed glycosylation protocol produced the desired products in up to 88% yield and shows greater tolerance of glycosyl acceptors and a broad substrate scope with better stereoselectivity. This method is also applicable for less nucleophilic acceptors such as phenol. In addition, 1,1′‐linked trehalose‐type analogues can also be accessed through this methodology. Further, mechanistic studies suggest that, in this glycosylation, L‐prolinethioamide operates via Brønsted acid/base catalysis.

Stereoselective Synthesis of O-Glycosides with Borate Acceptors.

Borate esters have been applied widely as coupling partners in organic synthesis. However, the direct utilization of borate acceptors in O-glycosylation with glycal donors remains underexplored. Herein, we describe a novel O-glycosylation resulting in the formation of 2,3-unsaturated O-glycosides and 2-deoxy O-glycosides mediated by palladium and copper catalysis, respectively. This O-glycosylation method tolerated a broad scope of trialkyl/triaryl borates and various glycals with exclusive stereoselectivities in high yields. All the desired aliphatic/aromatic O-glycosides and 2-deoxy O-glycosides were generated successfully, without the hemiacetal byproducts and O→C rearrangement because of the nature of borate esters. The utility of this strategy was demonstrated by functionalizing the 2,3-unsaturated glycoside products to form saturated β-O-glycosides, 2,3-deoxy O-glycosides, and 2,3-epoxy O-glycosides.

Reversible-Hydrogen-Transfer-Mediated Anomerization of Azaheterocyclyl 2-Deoxy-C-glycosides and Mechanistic Studies

Mutarotation of O-glycans and O-glycosides has long been well-established and exploited in the stereocontrolled chemical synthesis of O-glycosides, while few examples of C-glycoside anomerization are known to date. During the development of a simple iridium catalyst-promoted α-stereoselective C-glycosylation of 2-indoly-pyridine with glycal donors, we serendipitously discovered the occurrence of 2-deoxy-C-glycoside anomerization, enabling α-to-β configuration conversion. Control experiments and density functional theory calculations were performed to explore the mechanistic details of the anomerization of the C-glycosylation products, which could tolerate C-aryl and C-alkyl-glycosides. The anomerization reaction plausibly proceeds through the pathway involving the activation of the C(sp3)–H bond mediated by the iridium catalyst and reversible hydrogen transfer, rather than the classical anomerization mechanisms involving the endocyclic cleavage of the C1–O5 bond or exocyclic cleavage of the glycosidic bond.

Switchable reactivity of 2-benzoyl glycals towards stereoselective access of 1-3 and 1-1 S/O linked disaccharides.

We have developed a synthesis of 1-3 and 1-1 disaccharides from 2-benzoyl glycal and anomeric thiol and/or hydroxy sugar acceptors under mild conditions at room temperature. The regio and stereo-selectivity of the newly formed inter-glycosidic linkages are dependent on the nature of the glycal donor (D or L) and anomeric acceptor.

Acid Catalyzed Stereocontrolled Ferrier-Type Glycosylation Assisted by Perfluorinated Solvent.

Described herein is the first application of perfluorinated solvent in the stereoselective formation of O-/S-glycosidic linkages that occurs via a Ferrier rearrangement of acetylated glycals. In this system, the weak interactions between perfluoro-n-hexane and substrates could augment the reactivity and stereocontrol. The initiation of transformation requires only an extremely low loading of resin-H+ and the mild conditions enable the accommodation of a broad spectrum of glycal donors and acceptors. The 'green' feature of this chemistry is demonstrated by low toxicity and easy recovery of the medium, as well as operational simplicity in product isolation.

Synthesis of 2-deoxy mucin-type O-glycan analogues as biological probes

Access to mucin-type O-glycans as tools to help further our understanding of the biological role of these complex molecules is of importance. Herein, we report the efficient stereoselective synthesis of four novel 2-deoxyglycosidemucin-type O-glycan analogues. The strategy relies on the use of two common glycoside acceptors bearing a free OH at either C-3 or C-6 and two different orthogonally protected glycal donors, which can be activated using organocatalytic methods or Brønsted acid catalysis in good yields and stereocontrol.

Bismuth-Catalyzed Stereoselective 2-Deoxyglycosylation of Disarmed/Armed Glycal Donors

Bi(OTf)3 promoted direct and highly stereoselective glycosylation of "disarmed" and "armed" glycals to synthesize 2-deoxyglycosides has been reported. The tunable and solvent-controlled chemoselective activation of deactivated glycal donors distinguishing the competitive Ferrier and 1,2-addition pathways was discovered to improve substrate scope. The practical versatility of the method has been amply demonstrated with the oligosaccharide syntheses and 2-deoxyglycosylation of high-value natural products and drugs.

O-Cyanobenzoate: A Recyclable and Reusable Stereo-directing Group for β-O-Glycosylation via Pd(0)-catalyzed Ferrier Rearrangement.

Inner sphere Tsuji-Trost reaction has found recent application for β-selective Ferrier rearrangement of glycal substrates with alcohol nucleophiles. Herein, we report an efficient and stereoselective synthesis of 2,3-dideoxy-β-O-glycosides from C3-(o-cyanobenzoate) ester protected glycal donors via Ferrier rearrangement under Pd(0)-catalyzed Tsuji-Trost conditions. The synthesized donors indeed reacted with a variety of acceptors to afford the corresponding glycosides in good yields and excellent β-stereoselectivity. The stereochemical outcome of the reactions has been found to be independent of the nature of protecting groups or conformational flexibility of the glycal donors. Furthermore, regeneration of ortho-cyanobenzoic acid post rearrangement makes it a recyclable and reusable stereodirecting group. A preliminary mechanistic study demonstrates the importance of cyano-group for the observed rearrangement and stereoselectivity. Incorporation of the directing group on the benzoate ester has altered the reactivity of the ester group as a leaving group for Tsuji-Trost as well as Ferrier Rearrangement pathway.

Direct N-Glycosylation of Amides/Amines with Glycal Donors.

Direct N-glycosylation between glycals and amides/amines was achieved with exclusive stereoselectivity in moderate to high yields. Various amides, amines, and 3,4-O-carbonate-glycals were tolerated, and unique β-N-glycosides were obtained. The strategy was based on palladium-catalyzed decarboxylative allylation, and the high 1,4-cis-selectivity was proposed because of the hydrogen bonding effect. Notably, all the synthesized products were subjected to preliminary bioactivity studies, revealing that three compounds were cytotoxic to tumor cells and nontoxic to normal human cells.

Copper-Catalyzed Stereoselective Synthesis of 2-Deoxygalactosides

An efficient glycosylation method to synthesize 2-deoxy-O-galactosides based on a Cu(II)-catalyzed reaction without additional ligand has been developed. The glycosylation was amenable to different protected glycal donors and a wide range of acceptors including alcohols, amino acids, sugars, and phenol, and proceeds with excellent yield and high α-selectivity under mild conditions. The reaction proceeds readily on a gram scale, and its versatility is exemplified in the synthesis of oligosaccharides.

Copper(ii)-catalyzed stereoselective 1,2-addition vs. Ferrier glycosylation of "armed" and "disarmed" glycal donors.

Selective activation of "armed' and ''disarmed" glycal donors enabling the stereo-controlled glycosylations by employing Cu(ii)-catalyst as the promoter has been realized. The distinctive stereochemical outcome in the process is mainly influenced by the presence of diverse protecting groups on the donor and the solvent system employed. The protocol is compatible with a variety of aglycones including carbohydrates, amino acids, and natural products to access deoxy-glycosides and glycoconjugates with high α-anomeric selectivity. Notably, the synthetic practicality of the method is amply verified for the stereoselective assembling of trisaccharides comprising 2-deoxy components. Mechanistic studies involving deuterated experiments validate the syn-diastereoselective 1,2-addition of acceptors on the double bond of armed donors.

Tris(Pentafluorophenyl)Borane‐Driven Stereoselective O‐Glycosylation with Glycal Donors under Mild Condition

AbstractActivation of glycal donors was achieved using tris(pentafluorophenyl)borane [B(C6F5)3] under mild reaction conditions. The glycosylation reaction proceeded efficiently with a wide range of sugar and non‐sugar acceptors and provided α‐selective glycosides in high yield. Interestingly, under different reaction conditions, Ferrier rearrangement products or 2‐deoxyglycosides (i. e. addition products) were obtained as major products with benzyl‐protected glycal donors.

Substrate-Controlled Direct α-Stereoselective Synthesis of Deoxyglycosides from Glycals Using B(C6F5)3 as Catalyst.

B(C6F5)3 enables the metal-free unprecedented substrate-controlled direct α-stereoselective synthesis of deoxyglycosides from glycals. 2,3-Unsaturated α-O-glycoside products are obtained with deactivated glycals at 75 °C in the presence of the catalyst, while 2-deoxyglycosides are formed using activated glycals that bear no leaving group at C-3 at lower temperatures. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor and nucleophile acceptor. The method is exemplified with the synthesis of a series of rare and biologically relevant glycoside analogues.

A Glycal Approach to the Synthesis of Pregnane Glycoside P57

AbstractPregnane glycoside P57 is known as an active component of Hoodia gordonii, which has long been used as a diet with appetite suppressant property. Chemical synthesis of P57 demands installation of β‐cymarosyl linkage onto the steroid aglycone. The stereoselective formation of this special 2‐deoxy‐β‐glycosidic linkage has previously been proven to be difficult and thus a limiting step in the synthesis of P57 and its congeners. Herein, we report the glycosylation reactions with glycals as donors and TPHB (triphenylphosphine hydrobromide) as promoter and a convergent synthesis of P57 via a β‐selective glycosylation with a trisaccharide glycal donor.

Gold(I)-Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals

Au(I) in combination with AgOTf enables the unprecedented direct and α-stereoselective catalytic synthesis of deoxyglycosides from glycals. Mechanistic investigations suggest that the reaction proceeds via Au(I)-catalyzed hydrofunctionalization of the enol ether glycoside. The room temperature reaction is high yielding and amenable to a wide range of glycal donors and OH nucleophiles.