EFFICIENT AND SYSTEMATIC SYNTHESES OF ENANTIOMERICALLY PURE AND REGIOSPECIFICALLY PROTECTED MYOINOSITOLS

Efficient and systematic syntheses of a variety of enantiomerically pure and regiospecifically protected myo-inositols, which can be readily used as precursors for most natural and unnatural derivatives of myo-inositol, have been developed. The key strategies are the use of camphor as a protecting group and a chiral auxiliary and the development of regiospecific control in various steps. The diastereomerically pure 1D-2,3-O-(1'R,2'R,4'R-1',7',7'-trimethyl[2.2.1]bicyclohept-2'-ylidene)-myo-inositol (1a) was obtained in 31% yield via acetalization of myo-inositol with D-camphor dimethyl acetal followed by crystallization from methanol. In route A, silylation of tetrol 1a with tert-butyldiphenylsilyl chloride (TBDPS-Cl) afforded 1-O-TBDPS-4,5,6-triol 7 exclusively, which served as a key intermediate. Further protection with other reagents, exhaustively or regiospecifically, combined with selective deprotecting steps, led to protected myo-inositols with free hydroxyls at 1-, 5-, 6-, 1,4-, 4,5-, 5,6-, 1,4,5-, and 1,4,6-positions. In route B, the diastereomeric camphor-protected tetrols 1 were protected with a bifunctional silylating agent, 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDS-Cl2), to give diol 31. Subsequent protections/deprotections led to myo-inositols derivatives with free hydroxyls at 2-, 1,2-, 2,3-, 4,5-, 5,6-, 1,2,6-, and 1,3,4-positions. In route C the 4,5,6-triol 7 (from route A) was deacetalized to afford 1-TBDPS-inositol. 1-TBDPS-inositol after selective trisbenzoylation and alkylation followed by debenzoylation afforded 1,2,6-protected inositol (free hydroxyls at 3,4,5-positions). In route D the 4,5-diol 31 (from route B) was deacetalized to give 1,6-TIPDS-inositol. Alkylation or benzoylation of 1,6-TIPDS-inositol and subsequent desilylation afforded 1,6-diols (protected at 2,3,4,5-positions). Overall, the various precursors of phosphoinositides were obtained in 4-8 steps from inositol in 5-25% yields.