Macrotricyclic Steroid Receptors by Pd°‐Catalyzed Cross‐Coupling Reactions: Dissolution of cholesterol in aqueous solution and investigations of the principles governing selective molecular recognition of steroidal substrates

Abstract Three double‐decker cyclophane receptors, (±)‐ 2 , (±)‐ 3 , and (±)‐ 4 with 11–13‐Å deep hydrophobic cavities were prepared and their steroid‐binding properties investigated in aqueous and methanolic solutions. Pd°‐Catalyzed cross‐coupling reactions were key steps in the construction of these novel macrotricyclic structures. In the synthesis of D 2 ‐symmetrical (±)‐ 2 , the double‐decker precursor (±)‐ 7 was obtained in 14% yield by fourfold Stille coupling of equimolar amounts of bis(tributylstannyl)acetylene with dibromocyclophane 5 ( Scheme 1 ). For the preparation of the macrotricyclic precursor (±)‐ 15 of D 2 ‐symmetrical (±)‐ 3 , diiodocylophane 12 was dialkynylated with Me 3 SiCCH to give 13 using the Sonogashira cross‐coupling reaction; subsequent alkyne deprotection yielded the diethynylated cyclophane 14 , which was transformed in 42% yield into (±)‐ 15 by Glaser‐Hay macrocyclization ( Scheme 2 ). The synthesis of the C 2 ‐symmetrical conical receptor (±)‐ 4 was achieved via the macrotricyclic precursor (±)‐ 25 , which was prepared in 20% yield by the Hiyama cross‐coupling reaction between the diiodo[6.1.6.1]paracyclophane 19 and the larger, dialkynylated cyclophane 17 ( Scheme 4 ). Solid cholesterol was efficiently dissolved in water through complexation by (±)‐ 2 and (±)‐ 3 , and the association constants of the formed 1:1 inclusion complexes were determined by solid‐liquid extraction as K a = 1.1 × 10 6 and 1.5 × 10 5 l mol −1 , respectively (295 K) ( Table 1 ). The steroid‐binding properties of the three receptors were analyzed in detail by 1 H‐NMR binding titrations in CD 3 OD. Observed steroid‐binding selectivities between the two structurally closely related cylindrical receptors (±)‐ 2 and (±)‐ 3 ( Table 2 ) were explained by differences in cavity width and depth, which were revealed by computer modeling ( Fig. 4 ). Receptor (±)‐ 2 , with two ethynediyl tethers linking the two cyclophanes, possesses a shallower cavity and, therefore, is specific for flatter steroids with a C(5)C(6) bond, such as cholesterol. In contrast, receptor (±)‐ 3 , constructed with longer buta‐1,3‐diynediyl linkers, has a deeper and wider hydrophobic cavity and prefers fully saturated steroids with an aliphatic side chain, such as 5α‐cholestane ( Fig. 7 ). In the 1:1 inclusion complexes formed by the conical receptor (±)‐ 4 ( Table 3 ), testosterone or progesterone penetrate the binding site from the wider cavity side, and their flat A ring becomes incorporated into the narrower [6.1.6.1]paracyclophane moiety. In contrast, cholesterol penetrates (±)‐ 4 with its hydrophobic side chain from the wider rim of the binding side. This way, the side chain is included into the narrower cavity section shaped by the smaller [6.1.6.1]paracyclophane, While the A ring protrudes with the OH group at C(3) into the solvent on the wider cavity side ( Fig. 8 ). The molecular‐recognition studies with the synthetic receptors (±)‐ 2 , (±)‐ 3 , and (±)‐ 4 complement the X‐ray investigations on biological steroid complexes in enhancing the understanding of the principles governing selective molecular recognition of steroids.