Cinchonidine conformations

The first approach applied for [cinchonidine (CD) - a-keto ester] complex was also unsuccessful. In the open conformation CD cannot provide the required steric shielding. In open form either the quinuclidine or the quinoline moiety of CD will interact with the substrate. It has already been demonstrated that the quinuclidine moiety has a crucial role both in the rate acceleration and the induction of ED [13]. 

Figure. 1, The principle of shielding effect. Cinchonidine in dosed conformation.

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

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). 

Fig. 9.12 Methyl pyruvate adsorbed by each of its enantiofaces at the enantioselective site adjacent to cinchonidine adsorbed in the open-3 conformation. On hydrogenation (a) gives R-lactate and (b) gives S-lactate.

The simplest cinchona alkaloids, cinchonidine and its 10,11-dihydro-derivative, have been shown by D-tracer studies and by NEXAFS and ATR-IR spectroscopy to adsorb by interaction of the quinoline moiety with the platinum surface. Mechanistic studies have established that a site exists adjacent to the open-3 conformation of adsorbed cinchonidine at which pyruvate ester can undergo selective enantioface adsorption. Hydrogenation of the preferred enantioface results in preferential formation of one enantiomer of the product, methyl lactate, MeC H(OH)COOMe. Pt modified by cinchonidine provides R-lactate preferentially, whereas the near enantiomer cinchonine provides 5-lactate in excess. Values of the enantiomeric excess of 75% can be obtained without optimisation, and of 98% under special conditions. In solution, conditions that achieve enantioselectivity normally promote the reaction rate by a factor of 2 to 100 depending on conditions. ... 

Cinchonidine in its lowest energy state is L-shaped and it can approach a Pt (100) or Pt (111) surface in a configuration that would permit adsorption by the quinoline moiety without conformational disturbance (22]. The model proposed by Wells involves the flat adsorption on the platinum surface in a non-close packed array, thus leaving exposed shaped ensembles of platinum atoms. 

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. 

Scheme 5.28. The structures of the [cinchonidine-ethyl pyruvate] intermediate complexes (a, b, c and/are in open -conformations, while d and e are in closed conformations (according to Bartok et al.

Buergi, T., Baiker, A. (1998) Conformational behavior of cinchonidine in different solvents a combined NMR and ab initio investigations, J. Amer. Chem. Soc. 120, 12920-12926. 

Figure 5.12 Calculated lowest energy conformations of cinchonidine.

Figure 5.6 Proposals for the structures of activated complexes on surfaces, (a) The cinchonidine adopts an open (3) conformation involved in an H-bond with the a-ketoester in the trans configuration, (b) The open(3) conformation involved in a bifurcating H-bonding interaction with the c/s-a-ketoester. (c) Cinchonidine in the closed configuration, (d) The proposed C-H-0 interaction providing a two-point stabilizing contact between the a-ketoester and the alkaloid. (Reprinted with permission from [63]. 2006, American Chemical Society.)...

Vargas A, Bonalumi N, Ferri D, Baiker A (2006) Solvent-induced conformational changes of O-phenyl-cinchonidine a theoretical and VCD spectroscopy study. J Phys Chem A 110 1118-1127... 

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