Reduction of a-haloketones

Researchers at Sepracor later disclosed the use of a new class of chiral oxazaborolidines derived from r/. v-aminoindanol in the enantioselective borane reduction of a-haloketones.6,7 The 5-hydrogen oxazaborolidine ligand 10 was prepared in situ from d,v-aminoindanol 1 and BH3 THF.8 Stock solutions of 5-methyl oxazaborolidine 11-16 were obtained by reaction of the corresponding N-alkyl aminoindanol with trimethyl boroxine.6,7 5-Methyl catalyst 11 was found to be more selective (94% ee at 0°C) than the 5-hydrogen catalyst 10 (89% ee at 0°C), and enantioselectivities with 11 increased at lower temperatures (96% ee at -20°C). The catalyst structure was modified by introduction of A-a I kyI substituents. As a general trend, reactivities and selectivities decreased as the steric bulk or the chelating ability of the A -alkyl substituent increased (Scheme 17.4). 

Reduction. Chromous chloride is useful also for reduction of a-haloketones to the parent ketones, for the reduction of epoxides to olefins, and reduction of... 

For the enantioselective preparations of chiral synthons, the most interesting oxidations are the hydroxylations of unactivated saturated carbons or carbon-carbon double bonds in alkene and arene systems, together with the oxidative transformations of various chemical functions. Of special interest is the enzymatic generation of enantiopure epoxides. This can be achieved by epoxidation of double bonds with cytochrome P450 mono-oxygenases, w-hydroxylases, or biotransformation with whole micro-organisms. Alternative approaches include the microbial reduction of a-haloketones, or the use of haloperoxi-dases and halohydrine epoxidases [128]. The enantioselective hydrolysis of several types of epoxides can be achieved with epoxide hydrolases (a relatively new class of enzymes). These enzymes give access to enantiopure epoxides and chiral diols by enantioselective hydrolysis of racemic epoxides or by stereoselective hydrolysis of meso-epoxides [128,129]. 

The Fukuzumi group later investigated the mechanism of reduction of a-haloketones using NADH model compounds [249, 250], This non-enzymatic model system was developed to investigate the role of Brpnsted acids in enzymatic ketone... 

DIP-Cl has also been employed in the reduction of a-haloketones which can subsequently be converted to chiral epoxides that, of course, can be very useful synthetic building blocks. A good example of their use is in the synthesis of a cholesteryl ester transfer protein (CETP) inhibitor from Pharmacia (Scheme 14.46). In this case, the chemists reduced 3-bromo-l,l,l-trifluoro-propan-2-one with (+)-DIP-Cl to yield (S )-3-bromo-l,l,l-tri-fluoro-propan-2-ol which upon treatment with sodium hydroxide yielded (i )-2-(trifluoromethyl)oxirane in 99% ee. 

Conversion of a-haloketones to olefins using hydrazine (via enedlitnides C-C-N NH). Also reduction of o,3-epoxy ketones to allyl alcohols. 

Borane reduction of a variety of aromatic ketones using 5-10 mol% of 5-methyl catalyst 11 proceeded in >95% yield and in 80-97% ee. a-Haloketones were generally more reactive (90-97% ee) than simple ketones, which required higher temperatures (0°C compared to -20°C) to react to completion and led to lower enantioselectivities (80-90% ee).118 A complementary study by Umani-Ronchi and co-workers37 described the borane reduction of cyclic and acyclic ketones using catalyst 10. All products were obtained in >89% yield and >85% ee. Cyclic and hindered ketones led to the highest enantioselectivities (up to 96% ee) at room temperature. 

Carbon - heteroatom bonds can be cleaved by an appropriate combination of a hard acid and a soft nucleophile. Synthetically useful selective C-0 bond cleavage in the presence of other C-0 bond(s) is described. Reductive dehalogenation of a-haloketones is presented as an example that illustrates the concept of hard-soft affinity inversion. Finally, regio- and stereoselective functionalization of 1,3-di-enes is demonstrated by the thienium cation Diels-Alder cyclization involving the C-S bond cleavage. 

Dehalogenation of a-haloketones. The reduction can be conducted in 57% HI without solvent. 

The most plausible mechanism for the interconversion of la and Ih is shown in Scheme 2. Similar mechanism has been put forward for epimerization of a-substituted ketones under basic conditions and for the equilibration via an enolate prior to nucleophilic substitution was observed by Numazawa et al. (ref. 13). The same mechanism seems to operate in the reduction of some steroid a-haloketones (ref. 14) or tra/ty-3-chloroflavanone (ref. 15) with sodium borohydride where an inversion of configuration takes place at the a carbon parallel to the reduction of the... 

Scheme 9.23 Ru-catalysed DKR-reductions of cyclic a-haloketones with TsDPEN ligand.

Finally, it is noteworthy that Lewis base adducts of gallane (I.GalL) reduce cyclic ketones, enones and w-haloketones to the corresponding alcohols in excellent yields254. These reagents show some promise as a new extension of the boron-type reductions of carbonyl compounds. 

Since Et3B-initiated radical reactions with Bu3SnH under aerobic conditions, can be carried out at 0 °C or lower temperature, stereoselective reduction of reactive a-haloesters or a-haloketones can be performed. Eq. 10.1 shows Et3B-mediated Bu3SnH reduction of p-methoxy-a-bromo ester in the presence and absence of MgBr2 (Lewis acid) at 0 °C. Anti/syn diastereoselectivity depends on the absence or presence of a Lewis... 

Halogen substituents in a "-haloketones are easily removed even by zinc dust, because of the greater tendency of the halogen to ionisation. The reduction may be represented by a mechanism like that for acetoxy ketones, the ease of removal of halogens following their usual order of reactivity F < Cl < Br < I. In one case the intermediacy of an enolate anion was revealed by direct isolation of an enol acetate aa-chloro-Sa-cholestan 3 One was dechlorinated with zinc in acetic anhydride to give 3-acetoxycholest-2 ene [ 112]. 

This unusual reduction by halide ion of the vinylog of an a-acyloxyketone, presumably via an -haloketone intermediate, finds analogy in the reduction of simple a-haloketones by halogen acid (Newman, 1951 Meyer, 1911 Backes et al., 1921). 

The reaction of an a-haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities first in the solution phase <1996BML1409> and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB-CHO resins (Scheme 55) <1998JOG196>. 

Reformatsky-type reactions and reductions. Enolates generated from a-bromoketones by reaction with BiClj-Al in an aqueous medium condense with various aldehydes to give J-hydroxy ketones." A modification of reaction conditions (BiClj-NaBH ) and in the absence of aldehydes leads to hydrodehalogenation of the haloketones. ... 

Fig. 8. Chemoenzymatic synthesis of chiral epoxides via the a-haloketone reduction route...

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