Nucleophilic quinuclidine

Cinchona alkaloids such as 121 possess a nucleophilic quinuclidine structure and can act as versatile Lewis bases to react with ketenes generated in situ from acyl halides in the presence of an add scavenger. By acting as nucleophiles, the resulting ketene enolates can react intermolecularly [53] or intramolecularly [54] with electrophilic C=0 or C=N bonds to deliver formal [2 + 2]-cycloadducts, such as chiral P-lactones or [1-lactams, via aldol (or Mannich)-i intramolecular cydization sequence reactions (Scheme 8.46). The nucleophilic ammonium enolate can also read with energetic... 

The fluoraza reagents consist of two types of compounds one in which a fluorine atom is bound to the nitrogen atom of an amide or, more often, a sulfonamide and one in which a fluorine atom is bound to the nitrogen atom of a tertiary amine such as pyridine, quinuclidine, or triethylenediamine 1,4-diaza-bicyclo[2 2.2]octane. The positive charge on the nitrogen is counterbalanced by a non-nucleophilic anion such as triflate or tetrafluoroborate. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

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. 

Full details on the phosphorylation of water and alcohols by 4-nitrophenyl dihydrogen phosphate and the NfC H ) - and N(CH3) -salts of its mono- and dianion have been published 146>. Phosphoryl group transfer from the monoanion and dianion is thought to proceed via the monomeric POf ion. Addition of the sterically unhindered amine quinuclidine to an acetonitrile solution containing the phosphate monoanion and tert-butanol produces t-butyl phosphate at a faster rate than does the addition of the more hindered diisopropylethylamine. This nucleophilic catalysis of the phosphorylation reaction is also explained by the intermediacy of the POf ion. 

Recently, Vayner and coworkers [239] have revisited the model proposed by Augustine et al. [34] which is based on the assumption that the QN can make a nucleophilic attack to an activated carbonyl. According to this model the two possible zwitterionic intermediates that can thus be formed have different energies, which leads to the selective formation of one of the two intermediates, and, therefore, to e.s. after hydrogenolysis by surface hydrogen. This model nevertheless does not explain the e.d. of nonbasic modifiers, such as the one reported by Marinas and coworkers [240], which have no quinuclidine moiety and no nitrogen atom, and thus no possibility to form zwitterionic intermediates. Furthermore, in situ spectroscopic evidence for hydrogen bond formation between the quinuclidine moiety of cinchonidine and the ketopantolactone has been provided recently [241], which supports the hypothesis of the role of weak bond formation rather than the formation of intermediates such as those proposed by Vayner and coworkers. 

Unfortunately, the same trend in kll/k14 is not observed in the triethylamine/quinuclidine reactions with methyl iodide. Here, identical UC/14C KIEs are found for both nucleophiles. It is possible that the identical... 

A recent study of the reactions of 2,4-dinitrochlorobenzene and of picryl chloride with a series of nucleophiles that are presented in Table 6 shows that a plot (not shown) of log k against the pK values of all the nucleophiles is badly scattered77. Differences of up to 108 are observed for bases with similar pKa values. Part of this scatter is due to deviations that result because different families of nucleophiles (with different nucleophilic atoms) give rise to different Br0nsted correlation lines. Thus, for the reactions of picryl chloride good correlations are observed for a family of oxyanions (ft = 0.38, plot not shown), primary and secondary amines (Figure 4, ft = 0.52) and quinuclidines (Figure 4, P = 0.66). 

FIGURE 4. (Top) plot of log k for the reactions of primary and secondary amine nucleophiles with picryl chloride against their pK3 values in aqueous solution at 25 °C. (Bottom) plot of log k for the reactions of a series of substituted quinuclidine ions with picryl chloride against the pA a values of the nucleophiles. In aqueous solution at 25 °C77. Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society... 

One aspect of asymmetric catalysis has become clear. Every part of the molecule seems to fulfill a role in the process, just as in enzymic catalysis. Whereas many of us have been used to simple acid or base catalysis, in which protonation or proton abstraction is the key step, bifunctional or even multifunctional catalysis is the rule in the processes discussed in this chapter.Thus it is not only the increase in nucleophilicity of the nucleophile by the quinine base (see Figures 6 and 19), nor only the increase in the electrophilicity of the electrophile caused by hydrogen bonding to the secondary alcohol function of the quinine, but also the many steric (i.e., van der Waals) interactions between the quinoline and quinuclidine portions of the molecule that exert the overall powerful guidance needed to effect high stereoselection. Important charge-transfer interactions between the quinoline portion of the molecule and aromatic substrates cannot be excluded. 

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. 

In the initial screening of various Cinchona alkaloids, the addition of diethyl phosphate 41 to IV-Boc imine 40 in toluene revealed the key role of the free hydroxyl group of the catalyst. Replacing the C(9)-OH group with esters or amides only results in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-hydroxyl group and quinuclidine base activation of the phosphonate into a nucleophilic phosphite species are key to the reactivity of this transformation (Scheme 9). 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Molecular modeling of the reaction predicts attack of the CN" ion on the re face of the iV-allyl benzaldimine carbon to provide an (5)-adduct. The aromatic ring of the imine and the quinuclidine hydrogen bond stabilizes the iminium above the pyridazine, blocking the rear face of the imine bond. Nucleophilic attack by CN is... 

Baylis-Hillman reactions, the protonated amine was the governing factor in determining catalyst efficiency, thus making quinuclidine itself a better catalyst than 3-heteroatom substituted analogs, which are of reduced basicity/nucleophilic-ity and consequently give lower reaction rates. 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Historically, the most effective N-based organic catalysts were nucleophilic unhindered tertiary amines such as DABCO (diazabicyclo[2.2.2]octane, 1) [23], qui-nuclidine (2), 3-hydroxy quinuclidine (3-HDQ, 3), 3-quinuclidone (4) and indoli-zine (5) (Fig. 5.1) [24]. A direct correlation has been found between pKa and the activity of the quinuclidine-based catalysts the higher the pKa, the faster the rate [25]. More recently, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6), considered as a hindered and non-nucleophilic base, was shown to be a better catalyst than DABCO, or 3-HDQ [26]. The reason for the increased reactivity for this catalyst was attributed to stabilization of the zwitterionic enolate by delocalization of the positive charge. Other N-based catalysts such as N,N-(dimethylamino)pyridine... 

Much more important in determining pJCjH is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (p H 11-2) and morpholine (p-K"aH 9.8) or piperazine (pfCan 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this... 

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