Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N-methoxy-N-methylpropanamide (Fernholz Weinreb amide)

In research towards new antagonists against the Liver X receptor, the important intermediate Fernholz acid Weinreb amide has been synthesized and characterized.


Chemical context
In the nuclear receptor (NR) family, the two isoforms of the nuclear oxysterol receptor Liver X (LXR and LXR) are emerging new drug targets. They are key players for a number of important processes related to disease, such as metabolic and cardiovascular diseases, lipid metabolism, inflammation and cancer (Steffensen & Gustafsson, 2006;Laffitte et al., 2003). LXR modulators have been investigated as potential drugs in the therapy of cardiovascular diseases, metabolic syndrome, regulation of inflammatory response and immunity, skin diseases and are effective in the treatment of murine models of atherosclerosis, diabetes and Alzheimer's disease (Viennois et al., 2011(Viennois et al., , 2012Jakobsson et al., 2012). Further, such agents have been shown to affect anti-inflammatory activity (Zhu & Bakovic, 2008;Zhu et al., 2012;Solan et al., 2011) and cell proliferation in a number of major cancer forms such as LNCaP human prostate cancer cells. (Viennois et al., 2012;Jakobsson et al., 2012). The ligand-binding pocket (LBP) of LXR allows binding of side-chain-oxygenated sterols (OHCs).
Recently, OHCs with a specific stereochemistry at the 23hydroxyated side-chain carbon have also been shown to regulate the Hedgehog signalling pathway (Hh), a key developmental pathway playing multiple roles in embryonic development, including stem-cell differentiation (Corman et al., 2012). In our drug-design programme, our retrosynthetic analysis for the establishment of synthetic routes to the pharmacophores in different OHCs revealed that the aldehyde analogue of the title compound [Fernholz aldehyde, (II)] is a key compound leading to a number of new library

Supramolecular features
The unit-cell and the molecular packing of (I) are shown in Fig. 2. As a class, steroids display a pronounced tendency to form crystal structures with more than one molecule in the asymmetric unit; e.g. for about 35% of the 250 compounds mentioned above. The maximum Z 0 value of 16 is reached for the high-temperature polymorph of cholesterol itself (CHOEST21: Hsu et al., 2002). Compound (I) has a Z 0 value of 2, the two molecules differing in the way the hydroxy groups make intermolecular hydrogen bonds (Table 1)   (a) Unit-cell and crystal packing viewed along the a axis. The colour coding is as in Fig. 1. The orange circles highlight a series of methyl groups; the blue area shades a hydrogen-bonded chain in shape of a flat helix. The chain, as a pink shape, is shown in more detail in (b) (the view is along the b axis). Table 1 Hydrogen-bond geometry (Å , ). carbonyl group of molecule A is an acceptor, while the hydroxy groups of the B molecules are both donors and acceptors and thus serve to link adjacent A molecules along the a axis. In this process, stacks of either A or B molecules along the a axis expose all the methyl groups on the outside, giving distinct regions with methyl-methyl interactions (Fig. 2a). This is not a common molecular aggregation pattern for steroids, but some related Z 0 = 2 structures were found in the CSD, all hydrates without additional hydrogen-bond donors or acceptors in their C17 substituents (

Synthesis and crystallization
Compound (I) (348 mg) was dissolved in a minimum amount of boiling EtOAc (40 ml). The flask containing the solution was wrapped in aluminium foil and left overnight at room temperature to afford colourless crystalline needles.

tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N-methoxy-N-methylpropanamide
Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.