Acid‐Assisted Direct Olefin Metathesis of Unprotected Carbohydrates in Water

Abstract

The ability to use unprotectedc arbohydrates in olefin metathesis reactions in aqueous media is demonstrated. By using water-soluble, amine-functionalized Hoveyda-Grubbs catalysts under mildly acidic aqueousc onditions, the self-metathesis of unprotecteda lkene-functionalized a-dmanno-and a-d-galactopyranosides could be achieved through minimization of nonproductive chelation and isomerization. Cross-metathesis with allyl alcoholc ould also be achieved with reasonable selectivity. The presence of small quantities (2.5vol %) of acetic acid increased the formation of the self-metathesis product while significantly reducing the alkenei somerization process. The catalytic activityw as furthermore retained in the presenceo fl arge amounts (0.01 mm)o fp rotein, underlining the potential of this carbon-carbon bond-formingr eactionu nder biological conditions. These results demonstrate the potential of directly using unprotectedc arbohydrates tructures in olefin metathesis reactions under mild conditions compatible with biological systems, and therebye nabling their use in, for example, drug discovery and protein derivatization.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

Developing a Library of Mannose-Based Mono- and Disaccharides: A General Chemoenzymatic Approach to Monohydroxylated Building Blocks

“…Column chromatography (SiO 2 , ethyl acetate/n-hexane 5:5) gave the desired product as a colorless oil (610 mg, 61%). 1 H-NMR was in agreement with that previously reported [47]. was synthesized as previously reported [34].…”

Anionic Olefin Metathesis Catalysts Enable Modification of Unprotected Biomolecules in Water

“…In comparison, RCM of related mannosides by Ru-2 in the absence of acid caused nearly 90% isomerization at 60 °C, with the desired dimer being formed in just 5% yield. 15 Finally, motivated by the explosion in interest in oligonucleotide therapeutics, 49 and the enhanced activity demonstrated for nucleoside dimers accessed via click chemistry, 50 we examined metathetical coupling of uridinetagged 7 (Table 1, entry 5). Prior examples of nucleoside metathesis employ protected glycosylamines in organic solvent, and proceed in low yields.…”

“…Olefin metathesis catalysts capable of modifying unprotected biomolecules hold great potential as a tool that bridges chemistry and biology. − Modification of peptides or proteins (Figure ) has seen much study. , Other, emerging applications include drug discovery via DNA-encoded libraries (DEL), , and in vivo metathesis in blood or living cells. − Most of these applications require metathesis in water. Surprising, therefore, is the widespread preference for neutral catalysts such as HII (the second-generation Hoveyda–Grubbs catalyst; Chart a), − despite the availability of water-soluble analogues (Chart b). − In several comparative studies, water-soluble catalysts (e.g., Aquamet, AM ; Ru-1 ) proved less effective than HII in mixed organic-aqueous media, ,,, notwithstanding superior phase homogeneity …”

“…5% isomerization prior to metathesis. In comparison, RCM of related mannosides by Ru-2 in the absence of acid caused nearly 90% isomerization at 60 °C, with the desired dimer being formed in just 5% yield …”

“…At RT, <10% dimer is observed even at 1 mol % Ru, perhaps because the electron-withdrawing sulfonate ligand exacerbates the slow propagation characteristic of CAAC catalysts. , Nevertheless, the TON of 1,520 for nucleoside substrate 7 is the highest yet reported for metathesis of terminal olefins in water. The improvement over RCM of the simpler substrates 2 and 5 may reflect the extended “tether length” to the terminal olefin (the incipient site of Ru installation), which is beneficial in related contexts. , …”