Quinine conjugate addition

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706) syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing the asymmetry of the target molecule was the enantioselective conjugate addition developed by the Jacobsen group. 

Both the cis- and the trans-disubstituted spiranes resulted, in different ratios, depending on the reaction conditions. Clearly, the trans spiranes are chiral. The first conjugate addition to the Michael acceptors 75a-c is intermolecular in nature and defines the sense of chirality at the first chiral center. Subsequent intramolecular ring closure to the spiranes 76 defines the cis or trans configuration of the product. When cyclohexane-1,3-dione (74a) was reacted with dibenzalacetone (75a) in the presence of ca 5 mol% (—)-quinine (3a, Scheme 4.3), a 2.5 1 trans/cis mixture resulted, with the trans isomer 76 having optical purity of ca 30% (Scheme 4.37) [61] (the absolute configuration of the predominant enantiomer was not assigned). 

The acid itself was chosen for the conjugate addition as the intermediate can then be resolved by crystallisation of the quinine salt. Conjugate addition of HC1 was successful and the acid was reduced to the alcohol with UAIH4 before esterification in the usual way.1... 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

When the Michael donors have a sufficiently low pKa, the Michael addition can be catalyzed by a base. The first catalytic asymmetric conjugate addition was achieved by Wynberg et al. in 1975 using cinchona bases [la]. They performed the reaction of cyclic P-ketoesters such as 1 with methyl vinyl ketone in the presence of quinine and... 

CONJUGATE ADDITIONS Bis(methylthio)(trimethylsilyl)methyllithium. Diethylalum-inum cyanide. Di(a-methoxyvinyl)copperlithium. Ethyl diethoxyacetate. Ethyl methylsulfinylacetate. Lithium a-carboethoxy vinyl(l-hexynyl)cuprate. Potassium fluoride. Quinine, chinchonine. Titanium tetrachloride. Trimethylaluminum. Tris-(phenylthio)methyllithium. 

Quinine 84a has also been found to be an excellent catalyst for the conjugate addition of p-ketoesters to quinones. In this case, the reaction proceeded in the usual way, but the obtained conjugate addition products, in which the quinone... 

With respect to the use of Cinchona alkaloid-derived organocatalysts, the first example of asymmetric Michel addition of ketones to enones appeared in 1979 when Trost illustrated, during the total synthesis of the sesquiterpene ( )-hirsutic acid C [101], a stereoselective (30% ee) quinine (59)-catalyzed intramolecular conjugate addition of an intermediate functionalized cyclohexanone (Scheme 2.32). 

After Takemoto s studies, Bartoli and Melchiorre have successfully used 3-ketoesters and 1,3-diketones in the conjugate addition to iV-benzyl maleimides employing the natural cinchona alkaloids quinine or quinidine as catalysts [267]. The reaction, which is one of the few reported examples of a very stereoselective conjugate addition catalyzed by quinine (or quinidine), affords highly functionalized products with two adjacent stereogenic carbon atoms in high diastereo- (up to 92/2 dr) and enantioselectivity (up to 98% ee) with cyclic and acyclic P-ketoesters... 

A bifunctional iminiumyhydrogen-bonding catalysis has been very recently employed for the first enantioselective organocatalytic conjugate addition of a phosphorous nucleophile (diarylphosphane oxides) to a,ji-unsaturated ketones [370]. The process, which allows efficient additions to cyclic and linear enones as well as the generation of quaternary stereocenters, is catalyzed by quinine-derived thiourea... 

Cyclopentenone as well as acyclic enones have been productively used in the conjugate addition with aromatic and aliphatic thiols employing catalysts 203 [383] and 204 [384] (Fig. 2.28). Quinine-derived urea catalyst 203 is a very active organocatalyst for the addition of aromatic nucleophiles to cyclic and acyclic enones working at rt under very low loading conditions (0.1 mol%) [383]. 

Most reports on organocatalytic sulfa-Michael reactions are based on Br0nsted base catalysis, in order to activate pro-nucleophiles containing a S H or a Se—H bond. The early works, appeared in the lates 1970s, featured natural cinchona alkaloids 1-4 as basic catalysts (Figure 14.1). In their seminal works, Wynberg and co-workers employed less than 1 mol% of quinine 1 as chiral catalyst for the conjugated addition of arenethiols to 2-cyclohexen-l-ones. The enantiocontrol was unsatisfactory with benzyhnercaptan [6]. The quasi-enantiomeric catalyst quinidine 2 furnished the... 

In a similar manner, conjugate addition of azlactones possessing isopropyl or isobutyl groups at the C4-position to a series of acyl phosphonates proceeded with y-selectivity and high stereoselectivity under the catalysis of quinine-derived thiourea 19c. The phosphonate moiety of the resulting adducts was readily replaced with various heteronucleophiles such as alcohols and amines in situ under the influence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 17) [33]. The synthetic utility of azlactones as an acyl anion equivalent in this y-selective addition... 

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