The valienamine (1) ring system is found in drugs such as arbacose and validamycin. These compounds work by either inhibition of alpha-glucosidases (α-GHs), alpha-amylase, or trehalase, respectively. Similarly, the aminocyclitol validamine (2) also shows inhibition of α-GHs and is key structural motif found within the drug voglibose. Keeping these activities in mind, we synthesized the α-1-4 linked pseudo-disaccharide congeners of valienamine (3) and validamine (4) for evaluation against the alpha-glycoside hydrolase-like enzyme Streptomyces coelicolor GlgEI. Synthesis of valienamine (1) was achieved using commercially available per-acetylated glucose. Key steps involved reprotection to a reducing sugar, Wittig homologation, and Moffatt oxidation to a known eneone. The eneone was converted to valienamine in five steps following reported literature. We successfully employed this general method to prepare α-1-4 linked pseudo-disaccharide congeners of valienamine and validamine starting from maltose. Similar to the synthesis of valienamine, key steps involved a Wittig homologation and an oxidation to an eneone. This latter compound was subjected to a diastereoselective vinylmagnesium bromide addition to form a 4:1 mixture of diastereomers. The two dienes were separated and transformed to cyclitols utilizing a ring closing metathesis reaction. At this point the structures of diastereomers could be discerned by spectroscopic methods. The major diastereomer possessed the desired gluco-configuration at the C-5 position. The C-5 hydroxyl was then transformed to an allyl cyanate and subjected to a [3,3]-sigmatropic rearrangement to afford a protected version of the α-1-4 linked pseudo-disaccharide congener of valienamine (3). After deprotection, the α-1-4 linked pseudo-disaccharide congener of validamine (4) was prepared by hydrogenolysis of the alkene. Biological evaluation against Streptomyces coelicolor GlgEI is ongoing.

Synthesis of aminocyclitol-based inhibitors of glycoside hydrolase-like enzymes

ACS Fall 2020 Virtual Meeting

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