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The design and total synthesis of DL-6-deoxy-6-(hydroxymethyl)-scyllo-inositol 1:7-cyclic 2,4-trisphosphate (4), a conformationally restricted cyclic phosphate analogue of the second messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ], is described. The protected inosose 2,4,6/3,5-pentahydroxy-3,5-bis-O-(p-methoxybenzyl)-2,4,6-O- methylidynecyclohexanone (7) was obtained from myoinositol orthoformate in two steps, and Wittig methylenation and then hydroboration-oxidation using 9-BBN-H/OH - /H 2 O 2 gave the axial hydroxymethyl derivative 9. A series of protection/ deprotection steps provided the diol 13, which was converted into two cyclic phosphate esters 14a and 14b, epimeric at phosphorus, by reaction with (benzyloxy)bis(N,N-diisopropylamino)phosphine/ 1H-tetrazole followed by m-CPBA. Two other hydroxyl groups were then exposed and phosphorylated, and total deprotection gave racemic 4. NMR studies confirmed that in 4 the phosphate group equivalent to the 4-phosphate of Ins(1,4,5)P 3 is held in the positive gauche orientation and that the inositol ring maintains a chair conformation from pH 2 to 12. Investigation of the acid-base properties of 4 using potentiometric and 31 P NMR techniques showed that, over the physiological pH range, 4 behaves as a diprotic acid and that the ionization of the phosphate group equivalent to the 5-phosphate of Ins(1,4,5)P 3 is enhanced. In biological assays, 4 appears to behave as a weak full agonist at the platelet Ins(1,4,5)P 3 receptor, and the possible interpretation of this result is discussed.

Original publication

DOI

10.1021/jo9714425

Type

Journal article

Journal

Journal of Organic Chemistry

Publication Date

23/01/1998

Volume

63

Pages

295 - 305