Chiral catalysis, nucleophilic addition

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Based on nucleophilic addition, racemic allenyl sulfones were partially resolved by reaction with a deficiency of optically active primary or secondary amines [243]. The reversible nucleophilic addition of tertiary amines or phosphanes to acceptor-substituted allenes can lead to the inversion of the configuration of chiral allenes. For example, an optically active diester 177 with achiral groups R can undergo a racemization (Scheme 7.29). A 4 5 mixture of (M)- and (P)-177 with R = (-)-l-menthyl, obtained through synthesis of the allene from dimenthyl 1,3-acetonedicar-boxylate (cf. Scheme 7.18) [159], furnishes (M)-177 in high diastereomeric purity in 90% yield after repeated crystallization from pentane in the presence of catalytic amounts of triethylamine [158], Another example of a highly elegant epimerization of an optically active allene based on reversible nucleophilic addition was published by Marshall and Liao, who were successful in the transformation 179 — 180 [35], Recently, Lu et al. published a very informative review on the reactions of electron-deficient allenes under phosphane catalysis [244]. 

The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

The use of chiral Brpnsted acid catalysis as a mode of asymmetric activation burgeoned dramatically in the early part of the twenty first century [35]. The role of hydrogen in this process is, in essence, similar to that of Lewis acid catalysts - i.e. activation of the C=X bond (X=0, NR, CR ) by decreasing the LUMO energy and ultimately leading to promotion of nucleophilic addition to the C=X bond (Fig. 1.5). 

The emergence of catalytic asymmetric methods to effect the Staudinger reaction appears to have largely displaced further efforts to identify new methodology based on the use of chiral auxiliaries. These methods rely on the nucleophilic activation of the ketene to form a zwitterionic enolate, which then undergoes nucleophilic addition to the imine, followed by cyclization. While the assembly of enantiodifferentiated transition states using Lewis acid catalysis has been well developed, the use of Lewis base catalysts to accomplish the same purpose is a relatively recent development and well suited to the Staudinger reaction. 

Domino nucleophilic addition-dehydration-reduction reaction catalysed by chiral phosphoric acid catalysis and palladium catalysis. 

Chiral amine-mediated organocaialytic cascade reactions have become a benchmaik in contemporary organic synthesis, as wimessed by a number of cascade processes developed in the past decade [1]. The great success is attributed to two unique interconveilible activation modes, enamine [2] and iminium activations [3]. Enamine catalysis has been widely applied to the a-functionalizations of aldehydes and ketones. Mechanistically, dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate, 2, which undergoes an enantioselective a-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 1.1). Hydrolysis affords the products and, meanwhile, releases the chiral amine catalyst. 

As for the base-promoted thioetheriiication, Shen and Wang reported in 2005 that highly electrophilic alkenes such as fluorinated vinylstannanes 172 could be converted to fluorinated vinyl sulfides 173 with ( )-selectivity via a nucleophilic addition of thiols to alkenes and defluorination 174 followed by destannylation (Scheme 46.22). In 2008, Cordova developed an organocatalytic enantioselec-tive aminosulfenylation of a,(3-unsaturated aldehydes 175 using A -(benzylthio)succinimides 176 in the presence of a TMS-protected chiral diarylprolinol. ° The reaction proceeded with low diastereoselectivities but with excellent enantioselectivities. The reason for the low diastereoselec-tivity might lie in the rapid epimerzation of Ca-H bond under the enamine catalysis 178. 

Because imine has a basic nitrogen atom, a Bronsted acid turned out to be effective as the activator of imines. The seminal work of Akiyama and Terada in 2004 paved the way for chiral Bronsted acid catalysis in nucleophilic addition to imines. 

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