Stereoinversion

Although the transformation from Sj + Sg to 2Sjj (or 2Sg) is energetically unfavourable due to entropy, the reaction can proceed if the stereochemistry of one enantiomer Sjj (or Sg) is specifically inverted to Sg (or Sjj) via a chemically 

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The anion is assumed to exist preferentially in the anti conformation A, which offers a stabilizing 7rc -> minimizes steric interactions69,71 11. The nonplanar nature of the carhanionic center and coordination of the lithium to the oxygen atom could be demonstrated for a related compound by an X-ray analysis72. Usually, the electrophile attacks the carhanionic center with stereoinversion. 

Assuming that the enzymatic reaction is highly enantioselective, then even after only four cycles the enantiomeric excess will have reached 93.4% whereas after seven catalytic cycles the enantiomeric excess is >99% (Figure 5.3). This type of deracemization is really a stereoinversion process in that the reactive enantiomer undergoes stereoinversion during the process. One of the challenges of developing this type of process is to find conditions under which the enzyme catalyst and chemical reactant can coexist, particularly in the case of redox chemistry in which the coexistence of an oxidant and reductant in the same reaction vessel is difficult to achieve. For this... 

An alternative approach to the microbial deracemization of secondary alcohols is to use two different microorganisms with complementary stereoselectivity. Fantin et al. studied the stereoinversion of several secondary alcohols using the culture supernatants of two microorganisms, namely Bacillus stearothermophilus and Yarrowia lipolytica (Figure 5.18) [31]. The authors tested three main systems for deracemization. First, they used the supernatant from cultures of B. stearothermophilus, to which they added Y. lipolytica cells and the racemic alcohols. Secondly, they used the culture supernatant of Y. lipolytica and added B. stearothermophilus cells and the racemic alcohols. Finally, they resuspended the cells of both organisms in phosphate buffer and added the racemic alcohols. The best results were obtained in the first system with 6-penten-2-ol (26) (100% ee and 100% yield). The phosphate buffer system gave... 

Figure 5.18 Stereoinversion of 6-hexen-2-ol (26) using two microorganism preparations.

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Deracemization via the biocatalytic stereoinversion is usually achieved by employing whole cells. In the case of secondary alcohols, it is believed that microbial stereoinversion occurs by an oxidation-reduction sequence... 

Scheme 5.12 Deracemization of secondary alcohols via resolution followed by chemical stereoinversion.

Scheme 5.13 Deracemization of secondary alcohols based on biocatalytic stereoinversion [26, 50b].

Biocatalytic Deracemization Dynamic Resolution, Stereoinversion, Enantioconvergent Processes and Cyclic Deracemization, in Biocatalysts in the Pharmaceutical and Biotechnology industries, (ed. R.N. Patel), CRC Press, Boca Raton, pp. 27-51. 

Figure 7.35 Stereoinversion of 2-hydroxy acids using sequential oxidation and reduction...

Pellissier, H., Recent developments in dynamic kinetic resolution. Tetrahedron, 2008, 64, 1563-1601 Turner, N.J., Enzyme catalysed deracemisation and dynamic kinetic resolution reactions. Curr. Opin. Chem. Biol., 2004, 8, 114-119 Gmber, C.C., Lavandera, I., Faber, K. and Kroutil, W., From a racemate to a single enantiomer deracemisation by stereoinversion. Adv. Synth. Catal., 2006, 348, 1789-1805 Pellissier, H., Dynamic kinetic resolution. Tetrahedron, 2003, 59, 8291-8327 Pmnies, O. and Backvall, J.-E., Combination of enzymes and metal catalysts. A powerful approach in asymmetric catalysis. Chem. Rev., 2003, 103, 3247-3261. 

Pogorevc, M. and Faber, K., Enantioselective stereoinversion of rec-alkyl sulfates by an alkyl-sulfatase from Rhodococcus ruber DSM 44541. Tetrahedron Asymm., 2002,13, 1435. 

Keywords Microbial, Stereoinversion, Deracemization, Redox, Epimerase. 

Deracemization Through Stereoinversion Using a Single Microorganism... 

A more complicated picture arises with substrates containing more than one stereocentre which could be subject to redox stereoinversion of the type described in the previous examples. With two carbinol stereocentres in a symmetrical substrate there exist a maximum of five stereoisomers (the R,R and S,S enantiomers and meso isomer of the diol and two enantiomers of the intermediate a-hydroxyketone) for the dehydrogenase enzyme(s) to discriminate and transform irreversibly to a single enantiomer. Of course for 1,2-diols the intermediate j -hydroxyketone may be spontaneously equilibrating through an... 

Metabolic stereoinversion R to S) C-2 hydro-xylation terminal methyl group oxidation... 

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