Enantioselective nucleophilic addition

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

Enantioselective nucleophilic addition to imines has been carried out with a planar-chiral Lewis acid based on a 1,2-azaborolyl framework. 64 ... 

The enantioselective nucleophilic addition of prochiral C=0 and C=N moieties to the corresponding saturated chiral products is one of the most important stereoselective transformations on both the laboratory and the industrial scale. Although, over the past few decades, remarkable scientific achievements have been made in these research areas by using a variety of transitional metal-based catalysts, the sensitivity of the reaction to moisture and oxygen, as well as the toxic metal contamination of the product, usually restrict its practical application. Thus, currently, there is much interest in chiral organocatalysts, as they tend to be less toxic and more environmental friendly than traditional metal-based catalysts [1]. They are usually robust and thus tolerate moisture and oxygen, so that they usually do not demand any special reaction conditions. 

In this chapter, the current state of the art on the applications of cinchona alkaloids and their derivatives as chiral catalysts in the enantioselective nucleophilic addition of prochiral C=0 and C=N bonds is discussed. The schemes exemplified in this chapter demonstrate the indispensable role of cinchona alkaloids as catalysts in these important research areas. 

The chiral, proline-derived a-aminoalcohol ligand (606) was applied to the enantioselective, nucleophilic addition of trimethylsilylacetylene (605) to aromatic, heteroaromatic and aliphatic A-(diphenylphosphinoyl)imines (603) to give optically active propargylic phosphinoamides (605) in good yields (up to 92%) and enantioselectivities (up to 95%) (Scheme 150). ° ... 

Optically active sulfur containing compounds play a very important role in biochemistry as well as synthetic chemistry. The asymmetric conjugate addition of sulphur nucleophiles, or sulfa-Michael addition [379], provides a direct and versatile approach toward optically active sulfur compounds. This strategy is particularly valuable, since enantioselective nucleophilic additions to a C-S double bond, unlike those to carbonyls and imines, are not synthetically feasible. 

Alternatively, enantioselective nucleophilic addition to imines followed by intramolecular trapping of the transient amino intermediate with creation of a new C-N bond constitutes a powerful strategy for the synthesis of various heterocycles of synthetic and biologic interest. In this field, the formation of six-membered rings largely leads the way, and one of the first examples was reported in 2(X)3 by Ohsawa s group [4a] for the direct synthesis of the 3-carboline core via a Mannich/aza-Michael cascade promoted by (5)-proline and subsequentiy applied to the total synthesis of e t-dihydrocorynantheol (Scheme 16.3) [4b]. 

The first organocatalytic enantioselective nucleophilic addition to a, i-unsaturated ketones was reported by Kawara and Taguchi in 1994 [9]. In this report they stated that chiral proHne-derived ammonium hydroxides catalyzed the reaction between malonates and a,(i-unsaturated ketones in good yields and moderate enantioselectivities (up to 71%). 

Catalytic enantioselective nucleophilic addition of organolithium derivatives has been reviewed in terms of effects of additives on the degree of aggregation of oligomeric structures. ... 

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