Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

The crystal and molecular structures of a series of structurally related analogues of 1,25-dihydroxyvitamin D₂ and of the first analogue with all hydroxyl groups protected were established with single crystal X-ray structural analysis. With the use of the new structural data, we proposed that the A-ring conformation depends on hydrogen bonding of the hydroxyl groups of the A-ring. The A-ring of the 1α-hydroxylated vitamin D analogues exists in the solid state in a preferred chair β-conformation induced by direct hydrogen bonds between the 1-OH and 3-OH hydroxyl groups. In the same A-ring conformation, the vitamin D analogue interacts with the vitamin D receptor. Indirect hydrogen bonds between the A-ring hydroxyl groups, such as the ones through the water molecule, or hydrogen bonds between the A-ring hydroxyl groups and side-chain hydroxyl groups, induce the α-conformation. Theoretical calculations performed in vacuo showed that the β-form has a slightly lower energy than the α-form. Not only the hydroxyl groups but also the exocyclic methylene highly influences intermolecular interactions including the hydrogen bond pattern in the crystal lattices.