Studies on the Selectivity Between Nickel-Catalyzed 1,2-<i>cis</i>-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene <i>N</i>‑Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-<i>cis</i>-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-<i>cis</i>-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-<i>cis</i>-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-<i>cis</i>-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with <i>N</i>-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors

Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates

The amination of racemic secondary and tertiary allylic trichloroacetimidates possessing β-nitrogen substituents and proximal nitrogen-containing heterocycles, via chiral diene-ligated rhodium-catalyzed dynamic kinetic asymmetric transformations (DYKAT), provides branched allylic 1,2-diamines with high enantioselectivity. The catalytic system can be applied to the synthesis of 1,2-diamines possessing two contiguous stereocenters with excellent diastereoselectivity. Furthermore, the nitrogen-containing heterocycles suppress competing vinyl azirdine formation, allowing for the high enantioselective syntheses of 1,2-diamines possessing tertiary and quaternary centers

Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Trichloroacetimidates with Anilines

The rhodium-catalyzed regio- and enantioselective amination of racemic tertiary allylic trichloroacetimidates with a variety of aniline nucleophiles is a direct and efficient route to chiral α,α-disubstituted allylic <i>N</i>-arylamines. We describe the first dynamic kinetic asymmetric transformations of racemic tertiary allylic electrophiles with anilines utilizing a chiral diene-ligated rhodium catalyst. The method allows for the formation of α,α-disubstituted allylic <i>N</i>-arylamines in moderate to good yields with good to excellent levels of regio- and enantioselectivity

Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and T_N Antigen via Nickel Catalysis

The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-threonine amino acid and T_N antigen in gram scale (0.5–1 g) is described. The challenging 1,2-<i>cis</i>-2-amino glycosidic bond is addressed through a coupling of threonine residues with C(2)-<i>N</i>-<i>ortho</i>-(trifluoro­methyl)­benzyliden­amino trihaloacetimidate donors mediated by Ni­(4-F-PhCN)₄(OTf)₂. The desired 1,2-<i>cis</i>-2-amino glycoside was obtained in 66% yield (3.77 g) with α-only selectivity and subsequently transformed into the Fmoc-protected GalNAc-threonine and T_N antigen. This operationally simple procedure no longer requires utilization of the commonly used C(2)-azido donors and overcomes many of the limitations associated with the synthesis of 1,2-<i>cis</i> linkage

Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates

A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et₃N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [¹⁸F]KF·Kryptofix allowed ¹⁸F^– incorporation in 10 min

Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry

Preparations of the highly ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary neoglycopolymers of α-d-mannose and β-d-glucose residues were achieved via ring-opening metathesis polymerization. Isothermal titration calorimetry measurements of these synthetic neoglycopolymers with Concanavalin A (Con A), revealed that heterofunctional diantennary architectures bearing both α-mannose and nonbinding β-glucose units, poly­(Man-Glc), binds to Con A (<i>K</i>_a = 16.1 × 10⁶ M^–1) comparably to homofunctional diantennary neoglycopolymer (<i>K</i>_a = 30 × 10⁶ M^–1) bearing only α-mannose unit, poly­(Man-Man). In addition, poly­(Man-Glc) neoglycopolymer shows a nearly 5-fold increasing in binding affinity compared to monoantennary neoglycopolymer, poly­(Man). Although the exact mechanism for the high binding affinity of poly­(Man-Glc) to Con A is unclear, we hypothesize that the α-mannose bound to Con A might facilitate interaction of β-glucose with the extended binding site of Con A due to the close proximity of β-glucose to α-mannose residues in the designed polymerizable scaffold

Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates

A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et₃N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [¹⁸F]KF·Kryptofix allowed ¹⁸F^– incorporation in 10 min

Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic Allylic Trichloroacetimidates Catalyzed by a Chiral Diene-Iridium Complex

The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]­octadiene-ligated iridium-catalyzed asymmetric fluorination with Et₃N·3HF is described. The methodology represents an effective route to prepare a wide variety of α-linear, α-branching, and β-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (<i>R</i>,<i>R</i>) or (<i>S</i>,<i>S</i>)-bicyclo­[3.3.0]­octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

We report herein the first-time exploration of the attachment of well-defined saccharide units onto a synthetic polymer backbone for the inhibition of a glycosidase. More specifically, glycopolymers endowed with heparan sulfate (HS) disaccharides were established to inhibit the glycosidase, heparanase, with an IC₅₀ value in the low nanomolar range (1.05 ± 0.02 nm), a thousand-fold amplification over its monovalent counterpart. The monomeric moieties of these glycopolymers were designed in silico to manipulate the well-established glycotope of heparanase into an inhitope. Studies concluded that (1) the glycopolymers are hydrolytic stable toward heparanase, (2) longer polymer length provides greater inhibition, and (3) increased local saccharide density (monoantennary vs diantennary) is negligible due to hindered active site of heparanase. Furthermore, HS oligosaccharide and polysaccharide controls illustrate the enhanced potency of a multivalent scaffold. Overall, the results on these studies of the multivalent presentation of saccharides on bottlebrush polymers serve as the platform for the design of potent glycosidase inhibitors and have potential to be applied to other HS-degrading proteins

Overcoming the Potential Window-Limited Functional Group Compatibility by Alternating Current Electrolysis

The functional group compatibility of an electrosynthetic method is typically limited by its potential reaction window. Here, we report that alternating current (AC) electrolysis can overcome such potential window-limited functional group compatibility. Using alkene heterodifunctionalization as a model system, we design and demonstrate a series of AC-driven reactions that add two functional groups sequentially and separately under the cathodic and anodic pulses, including chloro- and bromotrilfuoromethylation as well as chlorosulfonylation. We discovered that the oscillating redox environment during AC electrolysis allows the regeneration of the redox-active functional groups after their oxidation or reduction in the preceding step. As a result, even though redox labile functional groups such as pyrrole, quinone, and aryl thioether fall in the reaction potential window, they are tolerated under AC electrolysis conditions, leading to synthetically useful yields. The cyclic voltammetric study has confirmed that the product yield is limited by the extent of starting material regeneration during the redox cycling. Our findings open a new avenue for improving functional group compatibility in electrosynthesis and show the possibility of predicting the product yield under AC electrolysis from voltammogram features