Asymmetric nucleophilic catalysis

In the preceding examples, the asymmetric catalyst is a Lewis acid and hence the catalytic processes reported so far involve electrophilic activation by a metal-centred chiral Lewis acid. There is another strategy, although less explored, which consists of designing chiral Lewis bases for nucleophilic catalysis. It is well known that Lewis bases such as nitrogen heterocycles and tertiary phosphines and amines catalyse a variety of important chemical processes. For instance 4-(dimethylamino)pyridine (DMAP) catalyses the acylation of alcohols by anhydrides the mechanism by which DMAP accelerates this process provides an instmctive illustration of how nucleophiles can 

In kinetic resolution, the key parameter is the selectivity factor s, which measures the relative rate of reaction of the two enantiomers. A selectivity factor greater than 10 is required for a kinetic resolution to be synthetically useful. 

Fu and coworkersshowed that acylations catalysed by 3.62 in the presence of tert-amyl alcohol allowed the resolution of a wide array of arylalkyl carbinols with excellent stereoselection (Table 3.3). 

Other nucleophile catalysed reactions using chiral ferrocene scaffolds have been investigated by different groups but with lower enantioselectivity compared with those 

PAryl PAIkyl NEt0, f-amyl alcohol, 0°C PAryl PAIkyl 

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Attempts to convert prochiral ketenes such an 33 (Scheme 13.15) into enantio-enriched derivatives of a-chiral carboxylic acids (34, Scheme 13.15) are among the earliest examples of asymmetric nucleophilic catalysis in general. 

The lone pair in the T] -pyrrolyI ligands is the most basic site in V azolyl complexes, and is the site of protonation and electrophilic attack. Novel planar chiral catalysts have been prepared, based on the azaferrocene unit, and these complexes have been used for asymmetric nucleophilic catalysis. One example of such a complex is shown on the left in Figure 4.5. Some linked versions of azaferrocenes possessing C synunetry create an unconventional chiral environment. The ligand on the right in Figure 4.5 has been used for several asymmetric copper-catalyzed transformations. ... 

Seidel and coworkers have developed a new concept for asymmetric nucleophilic catalysis, in which an achiral nucleophile is used in combination with a chiral hydrogen-bonding catalyst. The application of this concept to the Steglich rearrangement implied the use of simple DMAP as the achiral nucleophile and of the thiourea 17 as the chiral hydrogen-bond donor co-catalyst (Scheme 40.24) [30]. 

Seitzberg, J.G., Dissing, C., Sotofte, L, Norrby, P.-O., and Johannsen, M. (2005) Design and synthesis of a new type of ferrocene-based planar chiral DMAP analogues. A new catalyst system for asymmetric nucleophilic catalysis. J. Org. Chem., 70, 8332-8337. 

Keywords Acylation Asymmetric desymmebisation resolution Nucleophilic catalysis... 

Miller and co-workers have exploited the highly modular nature of peptide structures, along with mechanistic knowledge regarding peptide conformational control and the principles of nucleophilic catalysis to develop an assortment of synthetically unique, useful, and practical asymmetric transformations [22]. Representative examples are illustrated in Scheme 7. Particularly noteworthy is the asymmetric phosphorylation the resultant phosphate ester can be readily... 

Silyl enolates are useful carbon nucleophiles in the asymmetric tandem Michael addition and lactonization (Scheme 3.3). Mukaiyama recently reported that cinchona-derived ammonium phenoxides act as activators (nucleophilic catalysis), to give highly stereocontrolled products [18-20]. In a typical PTC manner, most of the... 

Enders D (1993) Enzymemimetic C-C and C-N bond formations. In Stereoselective synthesis. Springer-Verlag, Berlin Heidelberg New York, p 63 Enders D, Balensiefer T (2004) Nucleophilic carbenes in asymmetric organo-catalysis. Acc Chem Res 37 534—541... 

Recently, the asymmetric variants of the Stetter [114-118], crossed-benzoin [114, 117-120], and transeslerification [121] reactions have attracted great interest as asymmetric nucleophilic acylation processes. A prerequisite for asynunetric catalysis is the availability of a chiral catalyst. Introduction of chirahty into the thiamin framewoik follows the same principles as that for the related imidazoUum systems, mainly the introduction of a chiral centre next to the nitrogen atom of the thiazole ring [117]. 

Lewis base or nucleophilic catalysis by chiral amines, amine or phosphine iV-oxides, sulfides, and phosphines has been intensively exploited in asymmetric organocatalysis [122]. Representative catalysts are shown in Figure 2.27. 

Nucleophilic catalysts are able to promote several different types of asymmetric transformations, taking place via specific mechanisms. A number of these processes have been studied by theoretical methods [3]. In general, nucleophilic catalysis can be classified into two reaction types, depending on whether the process is initiated through interaction of a nonbonding electron pair of the catalyst with a Jt orbital ( -jt interaction. Figure 2.28) or with a a orbital (n-a interaction) of the substrate (Figure 2.29). 

Although Diels-Alder reactions provided the first examples for the great potential of asymmetric iminium catalysis, it must be pointed out that by far the most applications of this type of catalysis in natural product syntheses have been reported for conjugate additions of different nucleophiles to iminium-activated a, 3-tmsatu-rated acceptor molecules. The following sections will give an overview based on the type of nucleophiles employed in such transformations. 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

With the natural product (—)-sparteine as chelating N-donor ligand, asymmetric Pd catalysis can be achieved in this way via kinetic resolution of PhCH(OH)Me with krei ratios up to 25. BackvalP obtained oxidative 1,4-addition of nucleophiles to dienes with good control of stereochemistry in the product. The hydroquinone/benzoquinone pair is the redox partner that couples the Pd catalyst with air as primary oxidant. 

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. ... 

Dual activation of nucleophile and epoxide has emerged as an important mechanistic principle in asymmetric catalysis [110], and it appears to be particularly important in epoxide ARO reactions. Future work in this area is likely to build on the concept of dual substrate activation in interesting and exciting new ways. 

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