Analogs of Cinchona Alkaloids Incorporating a 9,9′-Spirobifluorene Moiety

The Cinchona alkaloid analogs (+)- and (?)- 5 with a quinuclidine-2-methanol residue attached to C(2) of a 9,9′-spirobifluorene moiety were prepared as a racemic mixture by reacting lithiated 2-bromo-9,9′-spirobifluorene 7 with (2-ethoxycarbonyl)quinuclidine (±)- 6 to give ketone (±)- 8 , followed by diastereoselective reduction with diisobutylaluminum hydride (DIBAL-H). The absolute configuration at C(9) and C(8), i.e., at the methanol bridge and the adjacent quinuclidine C-atom, in the two enantiomers of 5 is identical to the configuration at the corresponding centers in (?)-quinine ( 1 ) and (+)-quinidine ( 2 ), respectively. For the optical resolution of (±)- 5 , a chiral stationary phase for HPLC was prepared by covalently bonding quinine via a thiol spacer to a silica-gel surface. The enantiomer separation was accomplished at an α value of 1.61 with (±)- 5 being eluted last, in agreement with ¹H-NMR studies in CDCl₃ which showed that (+)- 5 underwent a more stable host-guest association with quinine than (?)- 5 . ¹H{¹H} Nuclear Overhauser effect (NOE) difference spectroscopical analysis of the host-guest associations with quinine in CDCl₃, combined with computer-model examinations, allowed the assignment of the absolute configurations as (+)-(8R,9S)- 5 and (?)-(8S,9R)- 5 . A detailed conformational analysis displayed excellent agreement between the results of computational methods (Monte Carlo multiple minimum simulations, analyses of the total energy as a function of the flexible dihedral angles in the molecule) and ¹H{¹H}-NOE difference spectroscopical data. It was found that (?)- 5 and (+)- 5 differ significantly in their conformational preference from their natural counterparts quinine ( 1 ) and quinidine ( 2 ). Whereas the natural alkaloids prefer the ‘open’ conformation, with the quinuclidine N-atom pointing away from the quinoline ring, analog (±)- 5 adopts preferentially (by ca. 4 kcal mol^?1) a ‘closed’ conformation, in which the quinuclidine N-atom points into the cleft of the 9,9′-spirobifluorene moiety. Since the basic quinuclidine N-atom in the ‘closed’ conformation is sterically shielded from forming strong H-bonds, the new Cinchona alkaloid analogs form less stable host-guest associations via H-bonding than quinine or quinidine.