Utilization of bench-stable and readily available nickel(II) triflate for access to 1,2-cis-2-aminoglycosides

Loka

et al. 2017

Biomacromolecules

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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.

Section: Resultsmentioning

confidence: 99%

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

Loka

et al. 2017

Biomacromolecules

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“…Due to the 1,2- cis -2-amino linkage nature of the GlcNS(6S)α(1,4)GlcA disaccharide unit, control of its stereoselective formation is quite challenging. 21 Capitalizing on our reported nickel-catalyzed 1,2- cis -2-aminoglycoside methodology, 22 we investigated the direct coupling of GlcA acceptor 7 with GlcN donors 4 – 6 (Scheme 1) having pivaloyl (Piv), triethylsilyl (TES), and benzyl (Bn) groups, respectively, at O -4. Under our nickel conditions, disaccharides 9–11 were formed in 52–85% yield with exclusive α-selectivity.…”

mentioning

confidence: 99%

Design, synthesis, and evaluation of heparan sulfate mimicking glycopolymers for inhibiting heparanase activity

Loka

et al. 2017

Chem. Commun.

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Heparanase is an enzyme which cleaves heparan sulfate (HS) polysaccharides of the extracellular matrix. It is a regulator of tumor behavior, plays a key role in kidney related diseases and autoimmune diabetes. We report herein the use of computational studies to extract the natural HS-heparanase interactions as a template for the design of HS mimicking glycopolymers. Upon evaluation, glycopolymer with 12 repeating units was determined to be the most potent inhibitor and to have tight-binding characteristics. This glycopolymer also lacks anticoagulant activity.

“…33 Therefore, in situ generated Ni(OTf) 2 became the catalyst of choice for the construction of several highly desired saccharide motifs containing 1,2- cis -2-amino linkages. 24,32…”

Section: Resultsmentioning

confidence: 99%

“…6,11 In order to study the concept of “hidden Brønsted acid catalysis” being the actual promoter for metal triflate-catalyzed glycosylation reactions and its impact on the stereoselectivity, we systematically probed the activation and operative mechanisms of our recently developed method for 1,2- cis -aminoglycoside synthesis via nickel triflate-catalyzed glycosylation with a C(2)-benzylideamino N -phenyl trifluoroacetimidate electrophile (Scheme 1). 24…”

Section: Introductionmentioning

confidence: 99%

Are Brønsted Acids the True Promoter of Metal-Triflate-Catalyzed Glycosylations? A Mechanistic Probe into 1,2-cis-Aminoglycoside Formation by Nickel Triflate

Schlegel

et al. 2019

ACS Catal.

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Metal triflates have been utilized to catalytically facilitate numerous glycosylation reactions under mild conditions. In some methods, the metal triflate system provides stereocontrol during the glycosylation, rather than the nature of protecting groups on the substrate. Despite these advances, the true activating nature of metal triflates remains unclear. Our findings indicated that the in situ generation of trace amounts of triflic acid from metal triflates can be the active catalyst species in the glycosylation. This fact has been mentioned previously in metal triflate-catalyzed glycosylation reactions; however, a thorough study on the subject and its implications on stereoselectivity has yet to be performed. Experimental evidence from control reactions and 19F NMR spectroscopy have been obtained to confirm and quantify the triflic acid released from nickel triflate, for which it is of paramount importance in achieving a stereoselective 1,2-cis-2-amino glycosidic bond formation via a transient anomeric triflate. A putative intermediate resembling that of a glycosyl triflate has been detected using variable temperature NMR (1H and 13C) experiments. These observations, together with density functional theory calculations and a kinetic study, corroborate a mechanism involving triflic acid-catalyzed stereoselective glycosylation with N-substituted trifluoromethylbenzylideneamino protected electrophiles. Specifically, triflic acid facilitates formation of a glycosyl triflate intermediate which then undergoes isomerization from the stable α-anomer to the more reactive β-anomer. Subsequent SN2-like displacement of the reactive anomer by a nucleophile is highly favorable for the production of 1,2-cis-2-aminoglycosides. Although there is a previously reported work regarding glycosyl triflates, none of these reports have been confirmed to come from the counter ion of the metal center. Our work provides supporting evidence for the induction of a glycosyl triflate through the role of triflic acid in metal triflate-catalyzed glycosylation reactions.