Enantioselective synthesis of inositols as intermediates for the preparation of deoxy-inositol phosphates from D-galactose

Abstract Optically pure 6-deoxy-inososes, 6-deoxy-inositols and 6-deoxy-inositol-1,4,5-trisphosphates were synthesized from D-galactose by the carbohydrate-inosose Ferrier rearrangement. 6-Deoxy-inositolphosphates exhibit a tight binding to the Ins-P 3 -receptor making such compounds an interesting tool for studying the intracellular signalling. It is now well established that receptor stimulated hydrolysis of inositol phospholipids is a common mechanism for transmembrane signalling when cells respond to external stimuli such as hormones, neurotransmitters, antigens, light, growth factors and insulin 1 . It was also shown that phosphatidylinositol-4,5-bisphosphate [(Ptd)Ins(4,5)P 2 ] is a major inositol lipid hydrolysed by activated phospholipase C, resulting into the simultaneous generation of two “second messengers”, D- myo -inositol-1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DG) 2 . Ins(1,4,5)P 3 triggers the mobilization of Ca ++ from intracellular stores and DG stimulates protein phosphorylation via the activation of protein kinase C 3,4 . In addition (Ptd)Ins(4,5)P 2 contains a high percentage of arachidonic acid in the sn-2 position, which is released for lipoxygenase and cyclooxygenase pathways. These “second messengers” and their metabolites control and modulate vital physiological processes by their independent, additive and synergestic effects. 5 Therefore, it is conceivable that inhibitors of the key enzymes of the phosphoinositide cascade could be of medicinal interest and could be also useful tools to elucidate the individual role of the inositol metabolites in regulation of cell functions. 6,7 In view of difficulties in the isolation of inositol phosphate metabolites from natural sources and the need for structural analogues, several synthetic studies have been reported 8 . However, these have employed mostly the optically inactive myo inositol as a logical and cheap starting material. The crucial role of the phosphate esters at positions 1, 3, 4, and 5 of the myo inositol nucleus in the “second messengers” Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 is well established. For analogue synthesis, modifications of the centers C-1, C-3, C-4 and C-5 or alteration of the hydroxyl functions at neighboring carbons (C-2 or C-6), not involved at first glance in cellular processes, seemed justified. With these considerations in mind we have initiated a synthetic program aimed to proxide access to the hitherto unknown partially protected 6-deoxy-cyclitols 8 and 9, appropriate precursors of a variety of chiral deoxy-inositol phosphates 9 . Our approach to the deoxy-inositols 8 and 9 has been envisaged from the chiral deoxy-inososes 6 and 7 which could be obtained by mercury(II) mediated carbohydrate-inosose Ferrier rearrangement 10 from hex-5- ene -pyranoside 5. Olefin 5 was readily prepared in a four steps sequence from methyl-β-D-galactopyranoside 1 in 60% overall yield 11 . Treatment of 1 with 1,1-dimethoxycyclohexane in DMF in presence of sulfuric acid afforded acetal 2 in 90% yield. The latter was selectively brominated with triphenylphosphine-carbontetrabromide, leading to 3 (m.p. 122–123°C). Benzylation of 3 by a phase transfer process (powdered KOH, benzyltriethylammonium chloride, benzyl bromide in CH 2 Cl 2 ) furnished benzyl ether 4 (m.p. 94–95°C,[ α ] rmD 20 + 46). Access to olefin 5 (m.p. 61–62°C, [ α ] rmD 20 − 55) was achieved by two methods. Initially the bromo compound 4 was dehydrobrominated with sodium hydride in DMF (3h, 100°C) giving 5 in 90% yield 12. An alternative route for the