Diastereoselective Synthesis of D- and L-myo-Inositol 3,4,5,6-Tetrakisphosphates from D-Glucose via Dihydroxylation of (+)-Conduritol B Derivatives

Abstract

Phosphorylated phosphatidyl-myo-inositols and myo-inositol phosphates play important roles as second messengers in intracellular signal transduction. 1) We have previously reported on the synthesis of various lipid analogs as artificial second messengers and biochemical probes. [2][3][4][5][6][7][8][9][10][11][12] Recently, D-and L-myo-inositol 3,4,5,6-tetrakisphosphates (D-1 and L-1) were identified as novel bioactive molecules ( Fig. 1), which play distinct but critical roles in cellular signaling.13-23) D-1 is responsible for the inhibition of the calcium-mediated chloride section. It may have therapeutic implications for diseases like cystic fibrosis and secretory diarrhea. In contrast, L-1 inhibits insulin-like growth factor 1 (IGF-1) induced thymidine incorporation in human breast cancer cells and thus prevents the ability of these cells to grow. Recent studies have revealed that L-1 is also involved in nuclear processes since it is required for gene regulation and may control gene expression. Their mechanisms of action are far from being elucidated but appear to be closely related to the number and position of the phosphate groups on the inositol ring. Thus, a new area of design of anticancer drugs can be envisaged for the future.In order to synthesize suitably protected optically active myo-inositol derivatives with appropriate stereogenic centers, Ferrier rearrangement, 24,25) pinacol coupling [26][27][28][29][30] and ringclosing metathesis (RCM) 12,31) of chiral intermediates derived from precursors such as carbohydrates and tartaric acid derivatives, have been performed in addition to optical resolution 32-34) of racemic myo-inositol derivatives. In this article, we describe the efficient syntheses of both enantiomers of myo-inositol 3,4,5,6-tetrakisphosphates via ring-closing metathesis of 1,7-diene with Grubbs catalyst followed by catalytic OsO 4 dihydroxylation of (ϩ)-conduritol B derivatives (Chart 1).The 1,2-addition of vinylcopper to the known aldehyde (3) 35) derived from D-glucose gave the desired allyl alcohol (4) with high diastereoselectivity (Ͼ99%de). 36) In order to synthesize both D-1 and L-1 from common intermediate 4, its hydroxyl group was protected as 4-methoxybenzyl ether (R 1 ϭPMB, 5a) for D-1 and 2-methoxybenzyl ether (R 1 ϭOMB, 5b) for L-1. Acidic hydrolysis of isopropylidene acetal with aqueous 3 N-H 2 SO 4 in THF, gave an anomeric mixture of the hemiacetal (6a, b), which was subjected to Wittig methylenation to give the 1,7-diene (7a, b). RCM of 7a or 7b using Grubbs catalyst gave the conduritol B derivatives (8a, b) in good yield. To confirm the relative and absolute stereochemistry of 8a, PMB ether was hydrolyzed June 2004 Chem. Pharm. Bull. 52(6) 727-732 (2004) 727 * To whom correspondence should be addressed. Bunkyo-ku, Tokyo 113-0032, Japan. Received February 13, 2004; accepted March 9, 2004; published online March 11, 2004 Syntheses of D-and L-myo-inositol 3,4,5,6-tetrakisphosphates were achieved via diastereoselective 1,2-addition of vinylcopper reagent with t...

Structure–Reactivity Relationships of Conformationally Armed Disaccharide Donors and Their Use in the Synthesis of a Hexasaccharide Related to the Capsular Polysaccharide from Streptococcus pneumoniae Type 37

“…To a solution of A3p (163 mg) in CH 2 Cl 2 (3 mL) were added water (0.3 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 76 mg, 1.5 equiv) . The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with CH 2 Cl 2 , washed twice with a solution of saturated NaHCO 3 , and then dried over Na 2 SO 4 .…”

“…13 To a solution of A3p (163 mg) in CH 2 Cl 2 (3 mL) were added water (0.3 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 76 mg, 1.5 equiv). 43 The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with CH 2 Cl 2 , washed twice with a solution of saturated NaHCO 3 , and then dried over Na 2 SO 4 . The solvent was evaporated, and the oil obtained was purified by flash chromatography (TLC: R f = 0.65, pentane/EtOAc, 1:2) to yield the acceptor methyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1 → 2)-4,6-O-benzylidene-α-D-glucopyranoside (A3) in 88% yield (120 mg) as a white powder.…”

Synthetic Strategies for Converting Carbohydrates into Carbocycles by the Use of Olefin Metathesis

“…myo ‐Inositol forms the major component of inositol phosphates and phosphatidylinositols which play important roles as secondary messengers in intracellular signal transduction. Shirai and co‐workers developed a synthesis of D ‐ myo ‐inositol 3,4,5,6‐tetrakisphosphate ( 107 ) from D ‐glucose by the use of ring‐closing metathesis 57. Furanose aldehyde 103 was prepared in 3 steps from diisopropylidene glucofuranose and subjected to a completely diastereoselective Grignard reaction with vinylmagnesium bromide (Scheme ).…”

“…Protecting group manipulations and a Wittig reaction then gave diene 104 , which was cyclized with catalyst C to afford cyclohexene 105 . Further protecting group transformations and dihydroxylation gave protected myo ‐inositol 106′ , which was converted into 107 in 3 steps 57…”