Dehalogenation/enantioselective

SCHEME 31.41. Dehalogenation/enantioselective protonation transfer and a-fluoro carboxylic acid synthesis by Rovis and co-workers. 

Cleavage Gem-dihalides and monohalides have been dehalogenated to chiral monohalides in the presence of alkaloids [397, 398]. l,l-Diphenyl-2-bromo-2-carboxyl (bromo or methyl carboxylate) cyclopropanes are cathodically debromi-nated in the presence of alkaloid cations with enantioselectivities up to 45% ee. A mechanism is proposed whereby the alkaloid is adsorbed at the Hg cathode, which protonates face selectively the carbanion generated by 2e reduction from the bromide [399]. 

Recently it was described that the halohydrin dehalogenases can be employed for the enantioselective formation of a new carbon-carbon bond. Their natural task is the dehalogenation of halohydrins, however this reaction can be reversed. When utilizing cyanide instead of a halide as the nucleophile in the reverse reaction the desired /ttiydroxynitrile is formed with good to excellent enantioselectivity (Scheme 5.34) [60]. 

Optically active l,l -binaphthols are among the most important chiral ligands of a variety of metal species. Binaphthol-aluminum complexes have been used as chiral Lewis acid catalysts. The l,T-binaphthyl-based chiral ligands owe their success in a variety of asymmetric reactions to the chiral cavity they create around the metal center [107,108]. In contrast with the wide use of these binaphthyls, the polymer-supported variety has been less popular. The optically active and sterically regular poly(l,l -bi-naphthyls) 96 have been prepared by nickel-catalyzed dehalogenating polycondensation of dibromide monomer 95 (Sch. 7) [109] and used to prepare the polybinaphthyl aluminum(III) catalyst 97 this had much greater catalytic activity than the corresponding monomeric catalyst when used in the Mukaiyama aldol reaction (Eq. 29). Unfortunately no enantioselectivity was observed in the aldol reaction. 

S)-2-chloropropionic acid by enantioselective dehalogenation racemate (R)-specific dehalogenase... 

Attempts were also made to develop an enantioselective process for the benzaz-epinone building block of benazepril by selective dehalogenation of the dichloro precursor, as depicted in Scheme 12.9. However, despite an extensive screening of various modifiers, the catalyst and bases enantioselectivities never exceeded 50%, which was insufficient for a technical application even though excellent yields of the mono-dehalogenated product were achieved [27]. 

Figure 15-11. Improvement of enantioselectivity by substituting iodide at the para position yeast reduction followed by dehalogenation (dh)[6S1.

Other types of ketones can also be modified to improve the enantioselectivities, and various functionalities can be used to modify the substrate to produce the corresponding alcohol with higher enantioselectivities. For example, the reduction of acetophenone by yeast results in the formation of phenylethanol in 69 % ee, whereas the reduction of p-iodoacetophenone followed by the dehalogenation results in a product of 96% ee (Fig. 15-11) 165l... 

Reductions. The reduction of a-alkoxyketones with Sml2 in the presence of fluorous BINOL (chiral) derivative shows that the protonation step is enantioselective. The use of fluorous tin hydrides that are highly soluble in fluorinated solvents facilitates dehalogenation. ... 

Hydrodehalogenation. A synthesis of chiral epoxides from trichloromethyl ketones is through enantioselective reduction to the trichloromethyl carbinols and tinhydride-mediated conversion to the chlorohydrins before base treatment to close the three-membered ring. Dehalogenation of halocarboxylic acids in water is apparently a method that deserves wide application. 

Dravis BC, LeJeune KE, Hetro AD et al. (2000) Enzymatic dehalogenation of gas phase substrates with haloalkane dehalogenase. Biotechnol Bioeng 69(3) 235—241 D Souza S (1999) Immobdized enzymes in bioprocess. Curr Sci 77 69—78 Durand J, Teuma E, Gomez M (2007) Ionic liquids as a medoium for enantioselective catalysis. C R Chimie 10 152-177... 

Bicyclic haloketones, which were used for the synthesis of antiviral 6 -fluoro-carbocyclic nucleoside analogs, were resolved by using the same technique [1222] (Scheme 2.163). Both enantiomers were obtained with >95% optical purity. The exquisite enantioselectivity of the microbial oxidation is due to the presence of the halogen atoms since the dehalogenated bicyclo[2.2.1]heptan-2-one was... 

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