Resolution deracemization

Asymmetric synthesis can refer to any process which accesses homochiral products. We will focus on asymmetric synthesis from racemic or prochiral starting materials in the presence of an enantioselective catalyst (enzyme). There are four general methodologies commonly applied kinetic resolution, dynamic kinetic resolution, deracemization and... 

Oxidations of C-N bonds with synthetic relevance. A kinetic resolution, deracemization and stereoinversion (Sects. 16.7.2.1 and 16.7.3.1) ... 

Figure 5.1 Schematic illustration of (a) dynamic kinetic resolution, (b) deracemization, and (c) enantioconvergent processes.

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. 

Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer. This is not quite the same as the methods of resolution previously mentioned, though an outside optically active substance is required. 

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]. 

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

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. 

Unlike kinetic resolution, catalytic desymmetrization and asymmetrization can afford enantiopure products in theoretical yields of 100 % and are more generally applicable than DKR or deracemization techniques. 

This section will only discuss examples of catalytic kinetic resolution, DKR, desymmetrization and asymmetrization. Deracemization will not be considered because, although an important developing technology, examples of its application to the production of chiral late-stage intermediates in API production have yet to appear. 

Scheme 8. Resolution and deracemization of styrene oxide by fungal cells... 

Scheme 10. Resolution-inversion sequence for the deracemization of 2,2-disubstituted oxiranes...

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

During the past few years great efforts have been made to overcome the 50% threshold of enzyme-catalyzed KRs. Among the methods developed, deracemization processes have attracted considerable attention. Deracemizations are processes during which a racemate is converted into a non-racemic product in 100% theoretical yield without intermediate separation of materials [5]. This chapter aims to provide a summary of chemoenzymatic dynamic kinetic resolutions (DKRs) and chemoenzymatic cyclic deracemizations. 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

Abstract It is well known that spontaneous deracemization or spontaneous chiral resolution occasionally occurs when racemic molecules are crystallized. However, it is not easy to believe such phenomenon will occur when forming liquid crystal phases. Spontaneous chiral domain formation is introduced, when molecules form particular liquid crystal phases. Such molecules possess no chiral carbon but may have axial chirality. However, the potential barrier between two chiral states is low enough to allow mutual transformation even at room temperature. Therefore the systems are essentially not racemic but nonchiral or achiral. First, enhanced chirality by doping chiral nematic liquid crystals with nonchiral molecules is described. Emphasis is made on ester molecules for their anomalous behavior. Second, spontaneous chiral resolution is discussed. Three examples with rod-, bent-, and diskshaped molecules are shown to give such phenomena. Particular attention will be paid to controlling enantiomeric excess (ee). Actually, almost 100% ee was obtained by applying some external chiral stimuli. This is very noteworthy in the sense that we can create chiral molecules (chiral field) without using any chiral species. 

In 2005, Kajitani et al. reported a striking observation rod shaped mesogens show spontaneous deracemization using the same ester molecules shown in Fig. 6 [48]. Soon after this report, however, Walba et al. claimed that the observation must be a surface effect [49]. We repeated the same experiments as they did and concluded that spontaneous deracemization does not occur in this particular compound, but may occur in other compounds. However, since ester molecules seem to have some particular feature in chirality as described in Sect. 2.4, we continued to search for compounds showing chiral resolution and found two homologous series of achiral ester molecules that do [50]. 

Extensive studies have been conducted to investigate the formation of chiral columns or helical superstructures in chiral and nonchiral disk- [53], star- [54, 55], and board-shaped [56] molecules. However, spontaneous deracemization has never been unambiguously demonstrated in discotic columnar phases consisting of nonchiral or racemic molecules. We recently observed clear evidence showing chiral resolution in a disk-like molecules with a dibenzo[g,p]chrysene core [57]. 

Stecher, H. Faber, K. Biocatalytic deracemization techniques. Dynamic resolutions and stereoinversions. Synthesis 1997, 1, 1-16. 

For other biological resolution methods see Section 2.5.2.3 and Chapter 19. Another deracemization method uses radical chemistry. This topic is discussed in detail in Chapter 27. 

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