Enantioselective Ketone Reduction

Keywords ketone, enantioselective reduction, BH3-ethylenediamin complex, inclusion complex, alcohol... 

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of a,p-Unsaturated Ketones. Enantioselective reductions of a,p-unsaturated ketones afford optically active ally lie alcohols which are useful intermediates in natural product synthesis. Enantioselective reduction of a,p-unsaturated ketones with LiAlH4 modified with chiral amino alcohol (1) affords optically active (S)-allylic alcohols with high ee s. When 2-cyclohexen-l-one is employed, (5)-2-cyclohexen-l-ol with 100% ee is obtained in 95% yield (eq 2). This is comparable with the results obtained using LiAlH4-chiral binaphthol and chiral 1,3,2-oxazaborolidine. ... 

The next addition of the reagent 5 was to the aldehyde 10. The adduct 11 was deproto-nated with -Btii to effect a limination, providing, after protection of the alcohol, the aU e. up g of 12 with the amide 7 gave a ketone, enantioselective reduction of which under Itsnno-Corey conditions led, again after protection of the alcohol, to the alkyne 13. 

COREY Enalioselaclive borane reduction Enantioselective reduction ol ketones by borane or catecholborane catalyzed by oxazaborolldine 3... 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

Enantioselective reductions of prochiral ketones by means of oxazaborolidines 97CLY9. 

In 2001, a screening study for the enantioselective reduction of various aryl ketones was developed by Petra et al. in the presence of amino sulfide... 

Table 5.5 gives some typical results for enantioselective reduction of ketones by alkylborohydrides and chloroboranes. 

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

Scheme 5.6. Enantioselective Reduction of Ketones Using CBS-Oxazaborolidine... 

The following reducing agents effect enantioselective reduction of ketones. Propose a transition structure that is in accord with the observed enantioselec-tivity. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

The crystal structure of (232) is reported. Ir complexes bound to the multidentate ligand as in (232) have proved successful in the enantioselective reduction of a,/3-unsaturated ketones to allylic alcohols.404... 

Prochiral aryl and dialkyl ketones are enantioselectively reduced to the corresponding alcohols using whole-cell bioconversions, or an Ir1 amino sulfide catalyst prepared in situ.695 Comparative studies show that the biocatalytic approach is the more suitable for enantioselective reduction of chloro-substituted ketones, whereas reduction of a,/ -unsaturated compounds is better achieved using the Ir1 catalyst. An important step in the total synthesis of brevetoxin B involves hydrogenation of an ester using [Ir(cod)(py) P(cy)3 ]PF6.696... 

On the other hand a direct hydrogen transfer through a Meerwein-Ponndorf mechanism, involving coordination of both the donor alcohol and the ketone to the copper site may also be considered. In this case, by using alcohols other than 2-propanol, we could expect some difference in stereochemistry. This would also imply the possibility of carrying out the enantioselective reduction of a prochiral ketone with a chiral alcohol as donor. 

The carbonyl reductase from Candida magnoliae catalyzed the enantioselective reduction of a diversity of ketones, including aliphatic and aromatic ketones and a- and /3-ketoesters (Figure 7.17), to anti-Prelog configurated alcohols in excellent optical purity (99% ee or higher) [56]. 

Groeger, H., Chamouleau, F., Orologas, N. et al. (2006) Enantioselective reduction of ketones with designer cells at high substrate concentrations highly efficient access to functionalized optically active alcohols. Angewandte Chemie-Intemational Edition, 45 (34), 5677-5681. 

The synthesis of both enantiomers of vasicinone has been carried out using almost entirely polymer-supported reagents. The route was based on functionalisation of deoxyvasicinone by a highly selective bromination then via enantioselective reduction of the derived ketone <06SL2609>. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

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