Dynamic Kinetic Resolution Through Reduction

Dynamic kinetic resolution of racemic substrate proceeds through asymmetric reduction when the substrate racemizes and the product does not under the applied experimental conditions. For example, by dynamic kinetic resolution of 

75% yield, 99% ee (from ddtetone) [69, 69] 90% yield, 99% ee (from recemic monoalcohol) 

FASTER racemization than enzymatic reduction in aqueous buffer 00 J-L 0 0 

Possible products of dynamic kinetic resolution of a-methyl p-keto ester through reduction. 

Synthesis of important compounds by dynamic kinetic resolution through reduction. 

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Other biocatalysts were also used to perform the dynamic kinetic resolution through reduction. For example, Thermoanaerobium brockii reduced the aldehyde with a moderate enantioselectivity [30b,c], and Candida humicola was found, as a result of screening from 107 microorganisms, to give the (Jl)-alcohol with 98.2% ee when ester group was methyl [30dj. 

Dynamic kinetic resolution (DKR) of racemic substrate proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. For example, by dynamic kinetic resolution of a-alkyl S-keto ester, one isomer, out of the four possible products for the unselective reduction (Scheme 33.18), can be selectively synthesized. Various examples of biocatalytic kinetic resolution through reduction are summarized in Scheme 33.19. A recent development in dynamic kinetic resolution has been reviewed. 

Ji, A., Wolberg, M., Wandrey, C. et al. (2001) Dynamic kinetic resolution of tert-butyl 4-methyl-3,5-dioxohexanoate through enzymatic reduction. Chemical Communications (Cambridge) (1), 57-58. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

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. 

DYNAMIC KINETIC RESOLUTION OF RACEMIC KETONES THROUGH ASYMMETRIC REDUCTION... 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions.29 For example, baker s yeast reduction of (/ /5)-2-(4-methoxyphenyl)-l,5-benzothiazepin-3,4(2H,5H)-dione gave only (25, 35)-alcohol as a product out of four possible isomers as shown in Figure 28 (a).29a Only (5)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded enantioselectively. The resulting product was used for the synthesis of (25, 35)-Diltiazem, a coronary vasodilator. 

List and coworkers developed an excellent approach to synthesize p branched amines in optically active forms by combining the enamine and reductive amination processes (Scheme 3.45) [96]. The reductive amination of unsymmetrically a,a disubstituted aldehydes and aniline derivatives proceeded through a tautomerization between imine and enamine forms. Dynamic kinetic resolution occurred under the... 

The tethered catalyst 24a proved to be superior over its untethered version 26 in the reduction of functionalised acetylenic ketones 27 with FA-TEA as hydrogen donor (Fig. 8) [59]. High enantioselectivity and substituent tolerance of these ketones indicate that the alkyne group has a dominating stereo-controlling effect through C-Wn interaction. Additionally, an efficient dynamic kinetic resolution was observed with substrates 27 favouring the syn products. The table in Fig. 8 shows selected examples of the reduction of acetylenic p-keto esters. 

Dynamic kinetic resolution of racemic ketones through asymmetric reduction... 

A., Gucciardo, G., and Paradisi, F. (2007) Highly efficient asymmetric reduction of arylpropionic aldehydes by horse liver alcohol dehydrogenase through dynamic kinetic resolution. Chem. Commun., 4038 040. 

List and coworkers developed an excellent application of this method to a dynamic kinetic resolution approach (Scheme 11.12) [23]. In the presence of phosphoric acid catalyst la and 39, the reductive amination of racemic a,a-disubstituted aldehydes 46andpara-anisidine (17) proceeded through a tautomerization between enamine 48 and imine 49. The essential point of this protocol is that the hydrogenation of (R)-49 proceeded more rapidly than that of (S)-49 to give P-branched amine 47 in 87% yield with 96% ee. 

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