STRUCTURAL SYSTEMATICS OF MYO-INOSITOL DERIVATIVES. Carl H. Schwalbe & Ian D. Spiers, Pharmaceutical Sciences Institute, Dept. of Pharmaceutical & Biological Sciences, Aston University, Birmingham B4 7ET, U.K

Myo-inositol 1,2,3-trisphosphate may act biologically as an iron chelator and anti-oxidant. While developing an efficient synthesis of this biochemical we obtained crystal structures of four key intermediates, the final product, and a related derivative of myo-inositol (MI):

1. D/L-1,2;4,5-di-O-cyclohexylidene MI,

2. D/L- 1 -O-(t-butyldiphenylsilyl)-2,3-O-cyclohexylidene MI,

3. 4,5,6-tri-O-benzoyl-2,

4. 4,5,6-tri-O-benzoyl MI 1,2,3-tris(dibenzyl phosphate),

5. monosodium tetra(cyclohexylammonium) MI 1,2,3-trisphosphate,

6. D/L-cis-1,2-O-cyclohexylidene-3,4,5,6-tetra-O-benzyl MI.

Related structure determinations describe 23 independent molecules.

MI itself (MYINOL) exhibits a near-perfect chair conformation with five OH groups equatorial, one (at C2) axial. Even when all OH groups are individually substituted with bulky groups as in 4, or with charged groups as in 5, the chair is maintained with average pseudorotation amplitude parameters q2 = 0.059, q3 = 0.584 for 19 molecules. Imposition of one acetal five-membered ring as in 2,3, and 6 distorts the chair: <q2> = 0.161, <q3> = 0.533, n= 4; and a second acetal ring as in 1 heightens the distortion: <q2> = 0.222, <q3> = 0.546, n= 4. The chair may retain a plane of symmetry by flattening one vertex and puckering the opposite one, or it may preserve a twofold axis while twisting. In one more extreme case 1,2;5,6-di-O-isopropylidene MI (PINMII) the chair form is lost entirely. Restrictive bridges and interaction of MI phosphates with metal ions as in sodium phytate (NAMIHP10) can change the substituent conformation to 5-axial/1-equatorial, where <q2> = 0.127, <q3> = 0.549, n= 3. Semi-empirical AM1 molecular orbital calculations were validated against ab initio results and used to compare conformational energies. For myo-inositol itself the 5-axial/1-equatorial OH conformer is 3 kcal/mol higher in energy than the normal 5-equatorial/1-axial; for fully ionised 5 the difference increases to 23 kcal/mol. This work was supported by the Science and Engineering Research Council. Reference codes and parameter calculations are taken from the Cambridge Crystallographic Database.