Cinchona conformational behavior

The pivotal role of the conformational behavior of a cinchona alkaloid (e.g., cinchonidine) in its enantioselectivity was nicely illustrated in the platinum-catalyzed enantioselective hydrogenation of ketopantolactone in different solvents [18]. The achieved enantiomeric excess shows the same solvent dependence as the fraction of anti-open conformer in solution, suggesting that this conformer plays a crucial role in the enantiodifferentiation. As a more dramatic example, the solvent affects the absolute chirality of the product in the 1,3-hydron transfer reaction catalyzed by dihydroquinidine [20]. An NMR study revealed that the changes in the ratio between the two conformers of dihydroquinidine can explain the observed reversal of the sense of the enantioselectivity for this reaction when the solvent is changed from o-dichlorobenzene (open/closed 60 40) to DMSO (open/dosed 20 80). 

Undoubtedly, the modification of the structure of the cinchona alkaloid also has a significant effect on its conformational behavior in solution esters [17] and 9-0-carbamoyl derivatives [21] exist as a mixture of two major anti-closed and anti-open conformers, while C9 methyl ethers prefer an anti-closed arrangement in noncoordinating solvents [17]. Here again, protonation provides the anti-open conformation as the sole stable form [16b]. In addition to the solvent polarity, many other factors such as intermolecular interactions are also responsible for the complex conformational behavior of cinchona alkaloids in solution. 

The catalytic properties of the natural cinchona alkaloids are related to the presence of a basic tertiary amine function (of the quinucUdtne ring) and the hydrogen bonding properties of the hydroxyl group of the C9 site. In addition, the conformational behavior of these molecules is essential for their reactivily as bifunctional catalysts [12]. Four low-energy conformers were identified with NMR spectroscopy and computational techniques and shown to be interrelated by rotations about the C4 -C9 and C9-C8 bonds (Figure 6.4) [13,14]. 

According to molecular modehng (MM) calculations, quinine and quinidine preferentially adopt the syn-closed conformation in the gas phase (Figure 6.4). In apolar solvents, however, anti-open conformations are observed in NMR spectroscopy for both quinine and quinidine [13]. More advanced ah initio calculations revealed that the anti-open conformer is preferred in apolar solvents, whereas polar solvents favor the two closed conformers, syn-closed and anti-closed [14]. However, many other factors (such as intermolecular interactions) are likely to influence the complex conformational behavior of cinchona alkaloids in solution. In addition, protonation of the quinucUdine nitrogen atom is reported to hinder rotation about the C4-C9 and C8-C9 bonds [15]. 

The next part of the specific behavior of the cinchona alkaloids as modifiers resides in their stable conformational structure. The molecules of cinchona alkaloids, e.g. cinchonidine or cinchonine (see Scheme 5.20.), consists of two relatively rigid parts an aromatic quinoline ring and an aliphatic bicyclic quinuclidine ring, both connected through the hydroxyl-bearing chiral carbon atom, C9. 

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