Chiral Pharmaceutical Intermediaries Obtained by Reduction of 2-Halo-1-(4-substituted phenyl)-ethanones Mediated by Geotrichum candidum CCT 1205 and Rhodotorula glutinis CCT 2182
Enantioselective reductions of p-R1-C6H4C(O)CH2R2 (R1 = Cl, Br, CH3, OCH3, NO2 and R2 = Br, Cl) mediated by Geotrichum candidum CCT 1205 and Rhodotorula glutinis CCT 2182 afforded the corresponding halohydrins with complementary R and S configurations, respectively, in excellent yield and enantiomeric excesses. The obtained (R)- or (S)-halohydrins are important building blocks in chemical and pharmaceutical industries. 1. Introduction Chiral halohydrins are important and valuable intermediates in the synthesis of fine chemicals and pharmaceuticals as optically active 1,2-aminoalcohols. The halohydrin (R)-1-aryl-2-haloethanol may be used for the preparation of (R)-1-aryl-2-aminoethanols that are used as α- and β-adrenergic drugs. An interesting chemoenzymatic synthetic route to obtain optically active 1-aryl-2-ethanolamines is from the enantioselective reduction of the correspondent α-haloacetophenones giving halohydrins that are transformed into an epoxy that reacts with the appropriate amine (Scheme 1) [1, 2]. Scheme 1: (a) reduction using chiral catalytic reagent or biocatalytic process; (b) base; (c) amine. An enormous potential of the use of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio-, and enantioselectivity has been increasing in the pharmaceutical industry [3]. The dehydrogenases in the form of whole cells for the production of chiral styrene oxides have been used on a pilot-plant scale [4]. Therefore, a large number of papers have appeared reporting the enantiomeric reduction of？？α-bromoacetophenone [5–10] and α-chloroacetophenone [4, 6, 7, 11–17] by whole cells of microorganism and also by isolated enzyme [18] giving halohydrins in high enantiomeric excesses (ee). There are few examples of biocatalytic reduction of α-haloacetophenone having suitable substituted group attached to the aromatic ring for enantioselective preparation of some target 1-aryl-2-ethanolamines [2, 19]. It is known that some examples of biocatalytic reductions of α-haloacetophenone that have substituted groups like 3-chloro [20, 21], 4-nitro [10, 22], and 3,4-methylenedioxy [23–25] were mediated by a number of microorganisms. Also, isolated enzymes have been used to reduce α-haloacetophenone having various kinds of substituted groups [26, 27]. The performances of Rhodotorula glutinis CCT 2182 and Geotrichum candidum CCT 1205 in bioreduction of α-haloacetophenones have been calling our attention due to the efficiency and complementary enantioselectivity of these microorganisms giving the corresponding (R)- and
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