Dynamic kinetic resolution methodology

Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

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 kinetic resolution is a technique that combines a racemization with a simultaneous resolution to overcome the inherent 50 % yield limit of kinetic resolution allowing a theoretical 100 % yield. Recently, a novel chemoenzymatic system has been developed for the dynamic kinetic resolution of 6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydroisoquino-hne, building on kinetic resolution methodology developed by Breen. The corresponding (/f)-carbamate was isolated in high yield and enantiomeric excess (Figure 4.2). 

Dynamic kinetic resolution is an excellent methodology to prepare enantiomeri-cally pure compounds and, in this context, chiral 4-(dimethylammo)pyridine (DMAP) iron and ruthenium " complexes have been reported to catalyze the... 

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. 

There are occasions when a resolution method can be useful. On the chemical side, this approach usually comes into play when small amounts of material are required and alternative methodology is under development. However, if a dynamic kinetic resolution can be achieved, then the approach can be very cost effective, as illustrated by D-phenylglycine (Chapters 7 and 25). In contrast,... 

Alternatively, enantiopure 2-hydroxycarboxylic acids can be obtained via a dynamic kinetic resolution of the (chemically synthesized) cyanohydrin in the presence of an enantioselective nitrilase (EC 3.5.5.1) (see Figure 16.1, route b). Racemization of the cyanohydrin, via reversible dehydrocyanation, takes place readily at pH 7 or above. The methodology [1] is attractive on account of the mild reaction conditions and is industrially applied in the multiton-scale synthesis of (R)-mandehc acid [2]. 

This nitrilase dynamic kinetic resolution (DKR) methodology depends on the availability of highly enantioselective biocatalysts that generate a minimum amount of amide. This latter issue may seem trivial and has long been disregarded somewhat, but reports of modest amounts of amide co-products date back to the early days of nitrilase enzymology. Only recently has the subject come under more intense scrutiny [3-5] and has a relationship with the stereochemistry of the nitrile been demonstrated [3, 5]. Hence, we set out to investigate the enantiomer and chemical selectivity of nitrilases in the hydrolysis of a representative set of cyanohydrins. 

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]. 

In polymer chemistry, one of the most challenging tasks is to efficiently synthesize optically active synthetic polymers. The extraordinary enantioselectivity of lipases offers new perspectives towards these materials, and it is therefore not surprising that some research efforts have focused on the use of lipases to synthesize chiral polymers from racemic monomers. Methodologies like kinetic resolution and even chemoenzymatic dynamic kinetic resolution (DKR) have already been exploited on the industrial scale to afford chiral intermediates for the pharmaceutical and agrochemical industry. Recently, these methodologies have been successfully applied in the synthesis of chiral polymers. 

As an extension, Fletcher and co-workers evaluated their methodology towards the performance of vinylzirconium compounds under these conditions [96]. However, despite extensive optimisation of reaction conditions, only moderate enantioselectivities could be reached (up to 19 81 e.r.). Nonetheless this demonstrated the possibility of using these sp -hybridised reagents in the context of copper-catalysed allylic alkylation via dynamic kinetic resolution. 

This highly efficient DKR methodology was applied to the synthesis of the selective serotonin reuptake inhibitor, norsertraline (Scheme 1.4), which is used to treat depression. For the application of enzymatic dynamic kinetic resolution in stereoselective synthesis, see chapter 57. 

For the synthesis of each enantiomer of both norephedrine and norpseudoephedrine, the appropriate and well-defined chiral Rh-complexes, (5,5)- or (R,/ )-Cp RhCl (TsDPEN), and have been employed. The ATH processes are carried out under mild conditions (room temperature, 15 minutes) using HCOiH/EtaN as a hydrogen source, and they are accompanied by dynamic kinetic resolution. Using this methodology, enantiomeric excess up to >99% ee can be achieved. ... 

Stereoselective Reductive Amination Using Chiral Ketones as Auxiliary The first report of asymmetric reductive amination using chiral ketone was published by Nugent and co-workers in 2004. The current methodology includes dynamic kinetic resolution of a racemic ketone 128 producing a chiral ketone 129,... 

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