Diketone kinetic resolution

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

This indeed verifies the dynamic kinetic resolution of roc-3 through enzymatic reduction, representing the first example for the dynamic kinetic resolution of an open-chain 2-alkyl-substituted 1,3-diketone through reduction under neutral conditions. 

The desymmetrization of meso diols requires selective chemical transformation of one of the two enantiotopic hydroxyl functions. Among other possibilities this transformation can consist in acylation or - less commonly - oxidation to a ketone (Scheme 13.19). It should be noted that the enantiomeric purity of the initial reaction products can be upgraded by subsequent conversion of the unwanted enantiomer into the diacylated compound (or diketone), i.e. by subsequent kinetic resolution. 

Fig. 15.11 Synthesis of highly functionalized enantiopure [7]thiahelicenes via kinetic resolution of axially chiral diketones and McMurry annelation.

The mechanism of the proline-catalyzed enantioselective aldol reaction has been studied. An extension of the asymmetric aldolization deals with the cyclization of diketones. Also investigated was the dehydration of racemic p-ketols in the presence of (S)-proline and a kinetic resolution was observed. ... 

Recently, diacetyl reductase (Acetoin reductase, E.C. 1.1.1.5) from Bacillus stearo-thermophilus (BSDR) was reported to be a powerful catalyst in the oxidative kinetic resolution of vic-diols (Fig. 16.2-22)1901. All syn-diols tested yielded the enantiopure (R,R) diols in almost maximum theoretical yields, a-hydroxy ketones were largely further oxidized to the corresponding diketones. Oxidation of vic-anti diols only gave ee values in the range of 62-76%. 

Pentanediol [(R,/ )-28] has been used for the formation of chiral acetals and as a precursor for chiral alkenes (Sections D.1.5.1. and 1.6.1.5.). The original procedure for the resolution of the phenylboronic acid derivative with brucine39 was impractical, but recently a kinetic resolution by lipase-catalyzed esterification and hydrolysis has been developed40. In addition, a good method for catalytic reduction of 1,3-diketones with Raney nickel modified with sodium bromide and tartaric acid (for a procedure, see Section D.2,3.1.) allowed the production for commercial purposes41. Similarly, sterically more hindered and less water-soluble 2,6-dimethyl-3,5-heptanediol (29) has been introduced for the same purpose. It is obtained in the same way from the diketone and separated from the meio-compound by simple recrystallization42. 

Every kinetic resolution of bi- and polycyclic ketones suffers from mie particular drawback because the bridgehead carbon atoms make it impossible to recycle the undesired wrong enantiomer via racemization. Hence the desymmetrizatiOTi of prochiral diketones, making use of the enantioface- or enantiotopos-specificity of HLADH, is of advantage. For instance, both the cis- and tran -forms of the decali-nediones shown in Scheme 2.117 were reduced to give (5)-alcohols with excellent optical purity. Similar results were obtained with unsamrated derivatives [743, 795]. 

Moreover, unsaturated keto silanes and diketones obtained according to eq 1 can be easily reduced to saturated keto silanes or 1,6-dicarbonyl confounds unsaturated keto silanes can be transformed into enantiomerically enriched hydroxy derivatives by reduction and enzymatic kinetic resolution. MonosUylated unsaturated sulfides, precursors of a variety of dienylsilanes, can be also obtained by chemoselective electrophilic substitutions. ... 

Scheme 4.7 Parallel kinetic resolution of racemic diketones 13a-b catalyzed by engineered Saccharomyces cerevisiae overexpressing ADHs. While one enantiomer affords derivative 14a-b, the second one provides compound 15a-b.

Scheme 12.21 One-pot synthesis of the corresponding 1,3 diols through dynamic kinetic resolution of diketone 40.

Eustache F, Dalko PI, Cossy J. Enantioselective monoreduction of 2-alkyl-1,3-diketones mediated by chiral ruthenium catalysts, dynamic kinetic resolution. Org. Lett. 2002 4 1263-1265. 

Fig. 8.40 One-pot reactions sequence, including hydrogenation of prochiral diketone 1,2-indanedione (I) with chemoenzymatic dynamic kinetic resolution of the resulting rac-2-hydroxy-l-indanone by racemization of (S)-2-hydroxy-l-indanone into (ff)-2-hydroxy-l-indanone and acylation of the latter to (ff)-2-acetoxy-l-indanone. (From O. Langvik, T. Sandberg, J. Wdrnd, D.Yu. Murzin, R. Leino, One-pot synthesis of (R)-2-acetoxy-l-indanone from 1,2-indanedione combining metai cataiyzed hydrogenation and chemoenzymatic dynamic kinetic resoiution, dynamic kinetic resoiution, Catai. Sci. Technoi 5 (2015) 150—160. Copyright the Royai Society of Chemistry).

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