Dynamic kinetic resolution processes

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Moreover, it is possible to open racemic azlactones by acyl bond cleavage to form protected amino acids in a dynamic kinetic resolution process. As azlactones suffer a fast racemization under the reaction conditions, eventually all starting material is converted [115]. 

May O., Verseck, S., Bommarius, A. and Drauz, K. (2002) Development of dynamic kinetic resolution processes for biocatalytic production of natural and nonnatural L-amino acids. Organic Process Research Development, 6 (4), 452-457. 

After some early examples of bio-chemo combinations in the 1980s, there was then over a decade of silence , followed by clearly increasing interest from the mid-1990s in the field of dynamic kinetic resolution processes (i.e., chemocata-lyzed racemization combined with enantioselective enzymatic conversion, giving, in principle, 100% yield of an optically pure compound). 

Dynamic kinetic resolution process was also applied to biocatalytic Baeyer-Villiger oxidations. The recombinant E. coli expressing the cyclohexanone monooxygenase from A. calcoaceticus was used for the oxidation of racemic... 

This methodology has been extended successfully to polymer-supported chiral (salen)Co complexes [88] and to intramolecular kinetic resolution of epoxy alcohols (with (R,R)-L Co OAc)) [82]. The ceiling of 50 % yield in kinetic resolution reactions can be extended if the starting material undergoes racemization under the reaction conditions. This has been shown to be possible with epichlorohydrin in reaction with TMSN3, the dynamic kinetic resolution process affording now a 76 % product yield (97 % ee) and 12 % each of the dichloro and diazido products [89]. 

The reaction concept with this new hydantoinase-based biocatalyst is economically highly attractive since it represents a dynamic kinetic resolution process converting a racemic hydantoin (theoretically) quantitatively into the enantiomerically pure L-enantiomer [19]. The L-hydantoinase and subsequently the L-carbamoylase hydrolyze the L-hydantoin, l-11, enantioselectively forming the desired L-amino acid, l-2. In addition, the presence of a racemase guarantees a sufficient racemiza-tion of the remaining D-hydantoin, d-11. Thus, a quantitative one-pot conversion of a racemic hydantoin into the desired optically active a-amino acid is achieved. The basic principles of this biocatalytic process in which three enzymes (hydan-toinase, carbamoylase, and racemase) are integrated is shown schematically in Fig. 9. 

Alternatively, the resolution reaction can be combined with rapid in situ racemi-zation of the substrate in dynamic kinetic resolution processes. Combinations of... 

The related dynamic resolutions of the furanone and pyrrolinone substrates were achieved with higher selectivities (Fig. 9-7) U). Again, these substrates underwent spontaneous racemization under the reaction conditions. Appropriate choice of enzyme afforded a good example of an essentially perfect dynamic kinetic resolution process in the case of the esterification of the hydroxypyrrolinone substrate. 

Most commonly used biocataiytic kinetic resolutions of racemates often provide compounds with high EE, but the maximum theoretical yield of product is only 50%. The reaction mixture contains about a 50 50 mixture of reactant and product that possess only slight differences in physical properties (e.g., a hydrophobic alcohol and its acetate), and thus separation may be very difficult. These issues with kinetic resolutions can be addressed by employing a dynamic kinetic resolution process involving a biocatalyst or biocatalyst with metal-catalyzed in situ racemiza-tion [112-114]. 

An advantage of this process is that it is possible to circumvent the racemiza-tion step if the unwanted isomer can be made to undergo spontaneous in situ racemization under the reaction conditions. In such a dynamic kinetic resolution process, a theoretical yield of 100% is possible as in asymmetric synthesis. Another example is the production of (/ )-phenylglycine. 

Scheme 35 Hydrogenation/dynamic kinetic resolution process for Ro 67-8867 (Roche)...

Dynamic kinetic resolution processes (DKR) [50] have been also carried out successfully using (5)-proline as catalyst. Thus, racemic atropisomeric W-diisopropyl-2-formylbenzamide derivatives reacted with excess of acetone (27.3 equiv.) in DMSO at room temperature to gave mixtures of diastereoisomers from 36% to 78% de, with the major diastereoisomer reaching up to 95% ee [51]. In a similar way, DKR of racemic l,4-dioxa-8-thia-spiro[4.5]decane-6-carbaldehyde (18) was performed with an excellent enantioselectivity using ketone 14 as the source of nucleophile (Scheme 4.7) [52]. The protocol has been successfully extended to the related 6,10-dicarbaldehyde, as a mixture of racemic and mexo-compounds. 

Using benzyloxyacetaldehyde in the trimerization process, the corresponding allose derivative 36 (R =OBn, R =CH20Bn) was obtained in 39% yield and 99% ee, with an important non-linear effect being detected [90]. This fact has been permitted the dynamic kinetic resolution processes of compounds of type anti-29 by... 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

This fundamental experiment has strong implications on related catalyst-controlled Mizoroki-Heck cyclizations of precursors of this type. As axial chirality in 113 sets the stereochemistry in 114, enantioinduction was rationalized to arise from a dynamic kinetic resolution of (at elevated temperature) rapidly interconverting enanhomers of 113 in the oxidative addition step, rather than in the alkene coordination-migratory insertion event. Such a dynamic kinetic resolution process has been previously proposed by Stephenson et al. within their mechanistic study regarding the conformations of helically chiral 2-iodoanilides in intramolecular asymmetric Mizoroki-Heck reactions [72],... 

Desymmetrization and Dynamic Kinetic Resolution Processes Using Covalent and Non-covalent Strategies... 

The product of a NHase/amidase cascade reaction is an acid, which is the same as the single enzymatic reaction performed by a nitrilase. However, the NHases usually have different substrate specificities than nitrilases, making them more suitable for the production of certain compounds. Although most organisms have both NHase and amidase activity (see earlier text), it is sometimes preferable, in a synthetic application, to combine enzymes from different organisms. The reasons for this are the enantioselectivity of the amidase or specific activity or substrate specificity of either of the enzymes. In this way, products with different enantiomeric purity can be obtained. Recently, a coupling of a NHase with two different amidases with opposite enantiopreference together with an -amino-a-caprolactam racemase that allows the formation of small aliphatic almost enantiopure (R)- or (S)-amino acids via dynamic kinetic resolution processes has been described [52]. 

Scheme 19.6 Chemoenzymatic dynamic kinetic resolution process of a secondary alcohol at room temperature.

Gutierrez M-C, Furstoss R, Alphand V (2005) Microbiological transformations 60. Enantioconvergent Baeyer-Villiger oxidation via a combined whole cells and ionic exchange resin-catalysed dynamic kinetic resolution process. Adv Synth Catal 347(7-8) 1051-1059. doi 10.1002/adsc.200505048... 

Enantioselective transformations catalyzed by nitrilases often suffer from poor chiral recognition. Exceptions from this trend are benzaldehyde and phenylac-etaldehyde cyanohydrins. As an additional advantage, these substrates racemize readily at near-neutral pH via reversible loss of hydrogen cyanide representing good starting materials for dynamic kinetic resolution processes. This was demonstrated using 22 substituted phenyl and heteroaryl derivates 25 with two recombinant nitrilases a preparative biotransformation yielded (S)-phenyllactic add 26 in 84% yield and 96% ee on 1 g scale (Scheme 9.7) [31]. 

N. Berezina, V. Alphand, R. Furstoss, Microbiological transformations. Part 51 The first example of a dynamic kinetic resolution process applied to a microbiological Baeyer-Villiger oxidation. Tetrahedron Asymmetry 13 (2002) 1953-1955. 

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