A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic

Abstract

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 an ether linkage between the axial 1-hydroxyl position of D-chiro-inositol and the 3′-hydroxyl group of an adenosine ribose sugar. 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-1-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.