Ketones enantioselective halogenation

A number of chiral ketones have been developed that are capable of enantiose-lective epoxidation via dioxirane intermediates.104 Scheme 12.13 shows the structures of some chiral ketones that have been used as catalysts for enantioselective epoxidation. The BINAP-derived ketone shown in Entry 1, as well as its halogenated derivatives, have shown good enantioselectivity toward di- and trisubstituted alkenes. 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Typically, solvents are screened to identify one that gives optimal results. Assuming that the substrate and catalyst are soluble, solvent polarities varying from alkanes, aromatics, halogenated, ethers, acetonitrile, esters, alcohols, dipolar aprotic to water have been used. An example of this, using a ketone and the rhodium cp TsDPEN catalyst, is shown in Table 35.3. Further optimization of this reaction improved the enantiomeric excess to 98%. A second example involved the reduction of 4-fluoroacetophenone in this case the enantioselectivity was largely unaffected but the rate of reduction changed markedly with solvent. Development of this process improved the optical purity to 98.5% e.e. 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

Halo-substituted acetophenones such as m-bromo- [74] or p-chloroacetophe-none [46] were reduced with borane in high enantioselectivity in the presence of oxazaborolidines 4b and 47, respectively. Other important halogen-containing ketones are chloromethyl or bromomethyl ketones. Oxazaborolidine reduction of co-chloro- or co-bromoacetophenone gives enantio-enriched halohydrins that can be converted into chiral oxiranes [20]. Martens found that the sulfur-containing oxazaborolidine catalysts 60 show high enantioselectivity in this kind of reduction [44, 86, 87]. Enantiopure halohydrins were obtained as shown in Scheme 8. 

Halogenations. Fluorination of ketones can make use of 7, although the enantioselectivity is only moderate. Of the active methylene compounds, fluorination in the presence of dihydroquinine esters is adequate. A synthesis of p-amino-a-hydroxy acids involves iodination of substrates such as 8, which is attended by spontaneous cyclization. ... 

The third subsection of this chapter discusses the a-funtionalisation of aldehydes and ketones. a-Oxidation, amination and halogenation have recently been achieved with high levels of enantioselectivity using enantiopure Lewis acids, or by generation of chiral nonracemic metal enolates, in the presence of a suitable electrophilic heteroatom source. Similar levels of selectivity in this transformation are obtained via the intermediacy of chiral enamines generated using organocatalysts. 

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