Quinuclidine nitrogen

Theoretical studies aimed at rationalizing the interaction between the chiral modifier and the pyruvate have been undertaken using quantum chemistry techniques, at both ab initio and semi-empirical levels, and molecular mechanics. The studies were based on the experimental observation that the quinuclidine nitrogen is the main interaction center between cinchonidine and the reactant pyruvate. This center can either act as a nucleophile or after protonation (protic solvent) as an electrophile. In a first step, NH3 and NH4 have been used as models of this reaction center, and the optimal structures and complexation energies of the pyruvate with NH3 and NHa, respectively, were calculated [40]. The pyruvate—NHa complex was found to be much more stable (by 25 kcal/mol) due to favorable electrostatic interaction, indicating that in acidic solvents the protonated cinchonidine will interact with the pyruvate. 

In earlier kinetic and computer modeling [1,2, 14] the open form of CD (CDopen) was used to illustrate the adsorbed [CD - a-keto ester] complex. In this complex the quinuclidine nitrogen was involved in the interaction with the substrate directly or via a proton bridge. 

We have modelled the [CDopen - methyl pyruvate] complex. The result is shown in Figure 2. In this complex there is no steric hindrance to prevent the free rotation of the substrate around the quinuclidine nitrogen. Thus, in complex shown in Figure 2. there is no preferential stabilization of the substrate. In earlier computer modeling it was suggested that Pt is involved in the stabilization of the [CDopew-a-lfeto ester] complex, i.e. the Pt surface prevent the free rotation of the substrate, however the driving force for enantio-differentiation, i.e. for preferential adsorption of the substrate, was not discussed [14]. 

The above comparison indicates that the rate acceleration induced by CD is more pronounced than that of the other tertiary nitrogen bases. This fact also indicates that in CD a cooperative effect should exist between the quinuclidine nitrogen and the quinoline ring, The cooperative effect is in force if the modifier is in a shielded form. 

The conformational analysis of methyl pyruvate shows that it can have two conformers. In the second conformer the two carbonyls are in syn position. The anti-syn conformational change requires 3 kcal. The [CDqIq qJ - methyl pyruvate ] complex ((R) form) was also calculated and shown in Figure 8. In the above complex the "directionality" of the lone pair of electrons of the quinuclidine nitrogen is advantageous for interactions with both the keto and the ester carbonyl groups. 

Figure 14.11 Example of the chiral pocket for the tilted surface open(5) conformation. Functional groups 1 and 2 are able to give bonding interactions, while the hydrocarbon skeleton of the alkaloid gives repulsive interactions, allowing only some molecular shapes to adjust themselves in the proximity of the quinuclidine nitrogen [244],...

A third variation on this theme was recently reported by Hodge (48), who alkylated the cinchona alkaloids on the quinuclidine nitrogen using the well-known chloromethylated cross-linked polystyrenes. Optical yields were low (10 to 30%) and no significant conclusions were drawn. 

The notable mode of stereoselectivity of Cinchona alkaloids is presented by its psendoenantiomeric pairs which can be employed to generate either enantiomer of chiral prodnct. Key moieties that are central to Cinchona alkaloids are the quinuclidine nitrogen and the adjacent C(9)-OH (the N-C(8)-C(9)-OH moiety) (Fig. 2). In psendoentiomeric alkaloids in the natural open conformation, the torsion angle N-C(8)-C(9)-0 are opposite in sign Q and CD are (-), and thereby induce selectivity for one enantiomer, whereas QD and C are (-I-) and afford the other enantiomer [28, 29],... 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Scheme 6.147 visualizes two proposals for the mechanism of the 131-catalyzed Henry addition of nitromethane to benzaldehyde. In (A), benzaldehyde is achvated by the thiourea moiety through double hydrogen bonding to the carbonyl funchon, while the nitromethane is deprotonated and activated by the basic quinuclidine nitrogen [298] proposal (B), however, based on detailed DFT computations... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

Ease of protonation of the quinuclidine nitrogen makes competitive reactions such as carbonium ion isomerization and substitution and elimination processes unimportant. 

The quinuclidine complex of Eu(DPM)3 gives rise to a polyhedron consisting of a distorted octahedron formed by six oxygen atoms with quinuclidine nitrogen located above the center of one of the faces, resulting in overall threefold symmetry. The molecular structure [71] of [Eu(DPM)3 quinuclidine] is shown in Fig. 5.10. 

The presence of the quinuclidine base functionality makes them effective ligands for a variety of metal-catalyzed processes (Chapters 2-4). The most representative example is the osmium-catalyzed asymmetric dihydroxylation of olefins [9]. The metal binding properties of the quinuclidine nitrogen also allow to use cinchona alkaloids as metal surface modifiers, for example, in the highly enantioselective heterogeneous asymmetric hydrogenation of a-keto esters (Chapter 2). Both... 

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