Asymmetric reduction of fluorinated

Baker s Yeast-mediated Asymmetric Reduction of Fluorinated Ketones. 

P. V. Ramachandran, H. C. Brown, Asymmetric reduction of fluorine-containing carbonyl compounds, in V. A. Soloshonok (Ed.) Enantiocontrolled Synthesis of Fluoro-Organic Compounds Stereochemical Challenges and Biomedical Targets, John Wiley Sons, Inc., Hoboken, 1999, pp. 179-228. 

Besides the above-mentioned catalytic asymmetric hydrogenation method for preparing fluorine-containing compounds, other reactions such as asymmetric reduction of achiral fluorine-containing ketones are also feasible methods for preparing chiral fluorinated compounds. For example, the oxazabor-olidine system, which has been discussed in Chapter 6, can also be employed in the catalytic reduction of trifluoromethyl ketones. Scheme 8 40 depicts some examples.85... 

In contrast, there are now many examples in the literature to indicate that, when presented with organic compounds already labelled with fluorine, enzymes may be tolerant to the presence of fluorine, depending on the number of C-F bonds and their location [89, 90]. For example, baker s yeast may lead to significant asymmetric reduction of carbonyl (Figure 1.7). 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

Lipase-catalyzed Asymmetric Hydrolysis of Fluorinated Esters. Yeast-mediated reductions form a single enantiomer predominantly and it is often difficult to find conditions which produce the opposite stereoisomer selectively. On the other hand, it is ideally possible to obtain both enantiomers in 50% yield in 100% ee via enzymatic optical resolution. Moreover, such a method could be readily optimized by use of an acyl group which facilitates stereoisomer differentiation by the employed... 

Ring-Substituted Acetophenones. Kirk and coworkers have shown the importance of fluorine substitution in the aromatic ting of several ring-fluorinated neutoactive amines (31). Due to their apparent importance, we undertook the asymmetric reduction of ring-fluorinated acetophenones with 1. The reduction of 2, 3, 4, 5, 6 -pentafluoroacetophenone with 1 provided the corresponding alcohol in... 

This section focuses on the preparation of fluorinated compounds through asymmetric hydrogenation/reduction reactions and nucleophilic additions by listing some examples. The first successful example of catalytic asymmetric hydrogenation of a fluoro-compound was reported by Konig et al.81... 

While nonracemic trifluoroalanines can easily undergo racemization or dehydro-fluorination, many asymmetric syntheses oftrifluoroalanines have been proposed. These syntheses generally involve an asymmetric reduction step of an imine or an enamine. This step can be performed by utilizing either chiral catalysts or chiral auxiliaries. 

Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes. The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1). In some cases oxidation rather than fluorination occurred. Stereospecifically deuterium-labelled allylic isoprenoid diphosphates, e.g. (1), have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and Sn2 displacement with pyrophosphate (Scheme 2). ... 

Recent employment of optically active fluorinated compounds for biologically active substances (7-2) or ferroelectric liquid crystals (3-5) has emphasized the versatility of these chiral molecules, while few methods have been reported for the preparation of such materials in a highly diastereo- as well as enantioselective manner. On the other hand, recent investigations in this field have opened the possibility for the introduction of chirality via asymmetric reduction or optical resolution by employing biocatalysts such as baker s yeast (6-75) or hydrolytic enzymes (16-20), respectively (27-23), along with the conventional chemical methodology (24-27). Chiral materials thus obtained may also be utilized in diastereoselective reactions which create new chiral centers (77). In this paper, the authors would like to discuss our recent progress in the preparation of optically active fluorinated compoounds and the effect of fluorine atom(s) on the reactivity and selectivity. 

Reduction of Alkyl Fluoroalkyl Ketones. Since 1 reduces non-fluorinated aralkyl ketones in high ee, a better understanding of the effects of fluorine atom in asymmetric induction with this reagent was sought from the reduction of a series of alkyl a-fluoroalkyl ketones. The fact that unhindered prochiral dialkyl ketones are typically reduced by 1 in relatively poor ee added value to this proj t. DBP-CMoride reduced alkyl trifluoromethyl ketones at a rate faster dwn that of the aryl derivatives... 

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