39 Synthesis of Optically Active myo-Inositol Derivatives
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Phosphorylated phoshoinositides(PI Pn) and inositol phosphates(IPn) play pivotal roles as second messengers in intracellular signal transduction. D- and L-myo-inositol 3,4,5,6-tetrakisphosphate (D-IP4, and L-IP4) and phosphatidylinositol 3,5-bisphosphate(PI 3,5-P2) were recently identified as novel second messengers. 1. Total synthesis of D- and L-IP4 from D-glucose The 1,2-addition of vinyl copper reagent to the chiral aldehyde derivative from D-glucose gave the desired allyl alcohol as the sole diastereomer. Protection of hydroxyl group, acid hydrolysis, Wittig methylenation and ring-closing metathesis(RCM) gave the conduritol B derivatives(3). The catalytic OsO_4 dihydroxylation of C_2 symmetric conduritol B derivative(4) gave the single diastereomer which was successfully converted to D-IP4 by established amidite procedure. On the other hand, L-IP4 was stereoselectively synthesized by OsO_4 catalyzed diastereoselective dihydroxylation of non-C_2 symmetric conduritol B derivatives(6j). Oxidation of allylic benzoate gave the desired cis-diol with high diastereofacial selectivity, and 7 was converted to L-IP4. 2. Synthesis of PI 3,5-P2 By catalytic OsO_4 oxidation of non-C2 symmetric conduritol B derivatives(6c), we synthesized desired key intermediate of PI 3,5-P2. Finally, this diol was successfully converted to PI 3,5-P2 by established amidite procedure. 3. Enantioselective desymmetrization of meso-1,2,3-Triol Recently, Matsumura and co-workers reported the CuCl_2-Ph_2box catalyzed asymmetric acylation of racemic and meso-1,2-diols. We could succeed the highly enatioselective one-pot desymmetrization of meso-1,2,3-triol derivatives of myo-inositol by asymmetric acylation followed by successive kinetic resolution catalyzed by CuCl_2-chiral diamine complexes. When 18c was used as the chiral diamine, benzoylation of 14 gave D-15 in 81% and 100%ee, respectively. Kinetic resolution of DL-15 under the same reaction condition gave the less reactive D-enantiomer in 45.3% (90.6% theoretical) and 99.4%ee, respectively. 4. Improved synthesis of PI 3,5-P2 by enantioselective desymmetization Enantioselective desymmetrization of meso-myo-inositol derivative(19) under the same condition provided the benzoate (20) in 81% 100%ee. The synthetic intermediate of our previous total synthesis of PI 3,5-P2.
