Abstract
Abstract In the course of our search for new anti-inflammatory glucocorticosteroids with improved therapeutic index, the 6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione was synthesised, and the conformation, configuration and crystallisation behaviour of one of its C(22) epimers, rofleponide, was studied by X-ray single-crystal diffraction. The crystals, grown from a 2-propanol solution, had a body-centred tetragonal (I4, No. 79) unit cell with a = b = 27.952(2) Å, c = 6.3299(3) Å, V c = 4945.6(6) Å3, D c = 1.2989(2) g cm−3 and F(000) = 2064, containing eight steroid and two solvent molecules. The alcoholic guest molecules were found to be disordered, each one occupying two partly overlapping disorder positions with equal probability. The structure model was refined to R = 0.045 for 1199 observations with I > 2σ(I). The basic cyclopentanoperhydrophenanthrene steroid skeleton, containing four (A, B, C and D) rings, has a flat shape with the trans-anti-trans-anti-trans stereochemistry, like the naturally occurring steroid hormones. The dioxolane (E) ring is fused to the cyclopentane (D) ring (at the 16α, 17α-positions) in a cis manner, with the angular hydroxyacetyl substituent at C(17) approximately equatorially oriented to the D and axially to the E rings, and with the C(22)-propyl chain equatorially attached to the dioxolane ring. Hence, the stereogenic centre at C(22), created during the formation of the cyclic 16α,17α-acetal, has the absolute R configuration. The rofleponide molecules in the crystal are linked via hydrogen bonds [O(21) ⋯ HO(3)] into infinite helical chains winding around the four-fold screw axes. The helices are tied to each other by additional hydrogen bonds [O(11) ⋯ HO(20)], thus forming a three-dimensional H-bonded framework. This packing arrangement is stabilised by inclusion of the 2-propanol solvent, yielding a singular type of ‘tubulato clathrate’, where the alcoholic guests reside in channel-like cavities not inside but between the host helices without any noticeable interaction with the steroid molecules.
Published Version
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