An efficient route to optically active inositol derivatives via the resolution of myo-inositol 1,3,5-orthoformate: a short synthesis of D -myo-inositol-4-phosphate Kana M. Sureshan and Yutaka Watanabe * Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan Received 9 February 2004; accepted 20 February 2004 Abstract—Anefficientmethodfortheresolutionof myo-inositol1,3,5-orthoformatehasbeendeveloped.Thetriol, 1 wasconverted todiastereomersviareactionwith(S)-O-acetylmandeloylchloride.Conditionswereoptimizedforadiastereomericratioof7:3.Both thediastereomerscouldbeseparatedbycolumnchromatography.Theabsoluteconfigurationsofthediastereomersweredetermined by converting the less polar diastereomer to the known L -2,4-di-O-benzyl-myo-inositol. The utility of the resolved derivatives is illustrated by a short and efficient synthesis of D-myo-inositol-4-phosphate in four steps from myo-inositol. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Recently, there have been significant advances in the chemistry and biology of myo-inositol and its deriva- tives due to their important biological roles. 1 The real- ization that phosphatidylinositol phospholipase C (PIPLC) mediates hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] to the second messengers D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DAG), has augmented the pace of research in this field. Many phosphoinositols are involved in the myo-inositol cycle, through which Ins(1,4,5)P 3 recycles back to the lipid PI(4,5)P 2 . Addi- tionally, many other phosphatidylinositol phosphates (PIPns) have recently been found in living cells. How- ever a clear understanding of the biological significance of these phosphoinositols has been lacking mainly due to difficulties in isolating these derivatives from natural resources. As the isolation of these phosphorylated derivatives from natural sources is impracticable, bio- logical studies rely on the efficient synthesis of these phosphoinositol derivatives. On the other hand, the judicious design and synthesis of structurally modified natural substrates of different enzymes as prospective effectorsorinhibitorsisalsooneofthemajorfocusesof inositol chemistry. The increased interest in the biology of phosphoinositols has necessitated better synthetic strategies for their preparation. Furthermore, the dis- closed therapeutic potential 2 of inositol derivatives and the recent use of inositol as a synthon for the synthesis of many natural products 3 havegivenfurtherimpactto the myo-inositol chemistry. This multi-faceted impor- tance of inositol demands better methods for resolution and selective protection–deprotection 4 for this meso cyclohexane hexol. The most commonly used intermediates for the synthe- ses of phosphoinositols are the orthoformate 1 and diketal derivatives 2 and 3 (Fig. 1). Following Kishi’s first report, 5 the efforts of different groups to improve the yield of triol 1 has culminated in various excellent methods 6 fortheisolationoftriol 1 inverygoodyields. Such a high yield (90%) of triol, 1 from myo-inositol unlikediketals 2 and 3 (around25%asamixtureoffour or more components) promote 1 as the preferred start- ing material for various phosphoinositol syntheses. A good distinction can also be made between the reactiv- itiesofthethreehydroxylgroups[C-2-OHandC-4-OH (C-6-OH)] of this triol. For instance, methods for the selectiveprotectionof(a)onlytheC-4(orC-6)hydroxyl group, 7 (b)onlytheC-2hydroxylgroup, 5;7b;8 (c)C-2and C-4 (or C-6) hydroxyl groups 9 simultaneously, and (d) C-4 and C-6 hydroxyl groups 7c;10 simultaneously, in 1 havebeendeveloped.Thusbychoosingtheappropriate reagent, any required protection of the three hydroxyl groups can be achieved. Acidic deprotection of the *Correspondingauthor.Tel.:+81-89-927-9921;fax:+81-89-927-9944; e-mail: wyutaka@dpc.ehime-u.ac.jp 0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2004.02.020 Tetrahedron: Asymmetry 15 (2004) 1193–1198 Tetrahedron: Asymmetry