Abstract
Palladium-catalyzed hydrogenolysis is often the final step in challenging natural product total syntheses and a key step in industrial processes producing fine chemicals. Here, we demonstrate that there is wide variability in the efficiency of commercial sources of palladium on carbon (Pd/C) resulting in significant differences in selectivity, reaction times, and yields. We identified the physicochemical properties of efficient catalysts for hydrogenolysis: (1) small Pd/PdO particle size (2) homogeneous distribution of Pd/PdO on the carbon support, and (3) palladium oxidation state are good predictors of catalytic efficiency. Now chemists can identify and predict a catalyst’s efficiency prior to the use of valuable synthetic material and time.
Highlights
Palladium-catalyzed hydrogenolysis is often the ultimate step in challenging total syntheses to remove ether protecting groups to yield the desired target compound
Reports of the automated glycan assembly of Lewis type antigens,[2] and the largest glycan synthesized to date, a 151-mer,[3] reported final deprotection yields ranging from 17−54% depending on the glycan
Representing a challenging substrate as it assumes a branched tertiary structure[9] and contains 25 groups that need to be reduced under a hydrogen atmosphere, including benzyl ethers, naphthylmethyl ethers, and azides
Summary
Palladium-catalyzed hydrogenolysis is often the ultimate step in challenging total syntheses to remove ether protecting groups (e.g., benzyl or naphthylmethyl ethers) to yield the desired target compound While deceptively simple, this final step is often a major bottleneck. In the synthesis of glycans related to Cryptococcus neoformans, glucuronoxylomannan (GXM), naphthoxylosides, and high mannose N-glycans, saturation of aromatic protecting groups to saturated ethers has been reported.[4−8] Separation of these saturated side products from the desired compound complicates the final purification step To overcome these selectivity issues, we introduced a catalyst pretuning methodology (dimethylformamide (DMF):H2O, 37% HCl) that increases catalyst selectivity toward hydrogenolysis rather than hydrogenation through amine poisoning. The catalyst pretreatment inhibits these unwanted saturation by-products and gives access to pure synthetic oligosaccharides.[4,9,10] This methodology successfully tackled an issue we faced (catalyst selectivity) but another key question was how and why different palladium on carbon
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