Dynamic deracemization

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. 

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. 

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... 

DYNAMIC INSTABILITY DEPOLYMERIZATION, END-WISE MICROTUBULE TREADMILLING POLYMERIZATION RANDOM SCISSION KINETICS DEPOLYMERIZATION, END-WISE Deracemization,... 

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. 

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

Turner, N. J. 2004. Enzyme catalyzed deracemization and dynamic kinetic resolution reactions. Curr. Op. Chem. Biol., 8(2), 114-119. 

Chung M-K, Hebling CM, Jorgenson JW, Severin K, Lee SJ, Gagne MR (2008) Deracemization of a dynamic combinatorial library induced by (—Vcytidine and (—)-2-thiocytidine. J Am Chem Soc 130 11819-11827... 

The two more common strategies for achieving such an objective are deracemization by stereoinversion or deracemization by dynamic kinetic resoluhon DKR (Scheme 13.1). 

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

When resolution and racemization are carried out in the same vessel at the same time, the process has been termed deracemization or dynamic resolution.40 The maximum yield then becomes 100%, with no need to recycle an unwanted isomer. Several examples will be given to illustrate the scope of this approach. 

Simeo Y, KrontU W, Paber K. Biocatalytic deracemization dynamic resolution, stereoinversion, enantioconvergent processes, and cyclic deracemization. In Biocatalysis in the Pharmaceutical and Biotechnology Industries, Ed. Patel RN. CRC Press, Boca Raton, PL, 2007, p. 27. 

Stecher, H., and Faber, K. (1997) Biocatalytic Deracemization Techniques. Dynamic Resolutions and Stereoinversions, Synthesis 1,1-16. 

With their efficient procedure for deracemization of MBH adducts, Trost and coworkers have applied dynamic asymmetric kinetic transformation (DYKAT) to the total synthesis of furaquinodn E. As shown in Scheme 5.28, the asymmetric palladium-catalyzed alkylation of phenols combined with a reductive Heck reaction delivered an effident approach to the synthesis of the key synthon, which is the core structure of the furaquinocins. A general synthetic route to furaquinocin E was established in 14 steps from MBH adduct 159. Their work highlighted the ability to use racemic MBH adducts for asymmetric synthesis. They further extended the scope of their strategy by developing the synthesis of three more analogs of... 

DERACEMIZATION/DYNAMIC KINETIC RESOLUTION VIA ACYLATION-TYPE REACTIONS 1170... 

Application of Enzymes in Kinetic Resolutions, Dynamic Kinetic Resolutions and Deracemization Reactions... 

Deracemization of 3-phenyllactic acid and 2-hydroxy-4-phenylbutanoic acid was found to be feasible via a lipase-catalysed KR together with racemization using Lactobacillus paracasei DSM 20008 [98]. It was necessary to switch between aqueous-organic solvent systems, so it was not possible to achieve racemization in a dynamic process indeed attempts at in situ racemization in organic solvents were not successful (Scheme 4.45). 

Enzymes - and thus hydrolases - can realize all kinds of selectivities such as chemo-, regio-, diastereomer and diastereotopic selectivity, as well as enantiomer and enantiotopic selectivity [83]. Accordingly, lipases were apphed in all possible kinds of stereoselective biotransformations [29, 30, 79, 81, 83] such as KR [79, 84], deracemization, and dynamic kinetic resolution (DKR) [85]. In this review, we wish to concentrate on methods enabling the continuous-mode hydrolase-mediated production of compounds in high enantiomeric purity. 

Dynamic kinetic resolution of racemates to obtain 100% yield of products with 100% ee is theoretically possible when the substrate racemizes but the product does not. Some examples are shown in this section. Deracemization reactions where racemic compounds are converted to enantiomerically pure form without changing the chemical structure will also be discussed. 

In a similar dynamic kinetic resolution method, the DAAO from Rhodotorula gracilis was recently combined in a one-pot reaction with i-aspartate amino transferase (l-AAT) from Escherichia coli and used for the deracemization of racemic 2-naphthylalanine (DL-2-NAla) (Scheme 11.13b). After the oxidation of the D-amino acid catalyzed by DAAO, the formed 2-naphthyl pyruvate (2-NPA) served as a substrate of l-AAT in the presence of cysteine sulfinic acid (CSA) as an amino donor. Almost quantitative yields of the enantiomerically pure t-2-NAla were achieved by using this cascade reaction, thanks to the spontaneous degradation of the 3-keto sulfinic acid produced in the t-AAT-catalyzed transamination that drives the overall reaction equilibrium toward the desired direction [26]. 

Deracemization of a number of pharmaceutically valuable building blocks has been carried out by biocatalytic processes. They include epoxides, alcohols, amines, and acids [12,14,190-192]. Dynamic kinetic resolution (DKR) involves the combination of an enantioselective transformation with an in situ racemization process so that, in principle, both enantiomers of the starting material can be converted to the product with a high yield and ee. The racemization step can be catalyzed either enzymatically by racemases or nonenz3nnatically by transition metals. 

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