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Department of Pharmacology

Dohle, W, Su, X, Mills, SJ, Rossi, AM, Taylor, CW, Potter, BVL

Reactions that form sec-sec ethers are well known, but few lead to compounds with dense functionality around the O-linkage. Replacement of the α-glucopyranosyl unit of adenophostin A, a potent d-myo-inositol 1,4,5-trisphosphate (IP3R) agonist, with a d-chiro-inositol surrogate acting substantially as a pseudosugar, leads to "d-chiro-inositol adenophostin". At its core, this cyclitol-nucleoside trisphosphate comprises a nucleoside sugar linked via an axial d-chiro-inositol 1-hydroxyl-adenosine 3'-ribose ether linkage. A divergent synthesis of d-chiro-inositol adenophostin has been achieved. Key features of the synthetic strategy to produce a triol for phosphorylation include a new selective mono-tosylation of racemic 1,2:4,5-di-O-isopropylidene-myo-inositol using tosyl imidazole; subsequent conversion of the product into separable camphanate ester derivatives, one leading to a chiral myo-inositol triflate used as a synthetic building block and the other to l-5-O-methyl-myo-inositol [l-(+)-bornesitol] to assign the absolute configuration; the nucleophilic coupling of an alkoxide of a ribose pent-4-ene orthoester unit with a structurally rigid chiral myo-inositol triflate derivative, representing the first sec-sec ether formation between a cyclitol and ribose. Reaction of the coupled product with a silylated nucleobase completes the assembly of the core structure. Further protecting group manipulation, mixed O- and N-phosphorylation, and subsequent removal of all protecting groups in a single step achieves the final product, avoiding a separate N6 protection/deprotection strategy. d-chiro-Inositol adenophostin evoked Ca2+ release through IP3Rs at lower concentrations than adenophostin A, hitherto the most potent known agonist of IP3Rs.

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Published date: 
2 May 2019
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Publication type: 
Journal articles
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Chem Sci
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