Kinetic resolution reactions With racemisation

Kellogg, Feringa and co-workers have achieved successful dynamic kinetic resolution reactions using cyclic hemiacetals as substrates[13, 14l The enzyme-catalyzed acetylation of 6-hydroxypyranone shown in Fig. 9-6 has been achieved with reasonable enantioselectivity with essentially complete conversion. The racemisation of the hemiacetal is presumed to proceed via reversible ring-opening of the pyranone1 1. The rate of reaction was found to greatly increase when the enzyme, lipase PS (Pseudomonas sp.) was immobilized on Hyflo Super Cell (HSC). 

An elegant way to avoid the low yields and the need for recycling half of the material in the case of kinetic resolutions is a dynamic kinetic resolution (DKR). The dynamic stands for the dynamic equilibrium between the two enantiomers that are kinetically resolved (Scheme 6.6A). This fast racemisation ensures that the enzyme is constantly confronted with an (almost) racemic substrate. At the end of the reaction an enantiopure compound is obtained in 100% yield from racemic starting material. Mathematical models describing this type of reaction have been published and applied to improve this important reaction [32, 33]. There are several examples, in which the reaction was performed in water (see below). In most cases the reaction is performed in organic solvents and the hydrolase-catalysed reaction is the irreversible formation of an ester (for example see Figs. 9.3, 9.4, 9.6, 9.12) or amide (for example see Figs. 9.13, 9.14, 9.16). 

When looking at the above described dynamic kinetic resolution from a green point of view, then one thing can immediately be noticed This reaction would be unnecessary if the starting material had been synthesized enantioselectively. A much more efficient way of performing a dynamic kinetic resolution is thus to start with a prochiral material. The reversible addition of another building block to this prochiral starting material is not only the formation of a new bond but at the same time a pathway for the rapid racemisation of the intermediate... 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

A straightforward approach to avoid low yields is to perform the reaction as a dynamic kinetic resolution. Racemisation can be achieved chemically [33] or enzymatically, indeed a number of N-acyl amino acid racemases have been described and it has been demonstrated that they could be employed together with the l-N-acyl amino acylase for the production of optically pure methionine [81]. 

DSM developed a slightly different approach towards enantiopure amino acids. Instead of performing the Strecker synthesis with a complete hydrolysis of the nitrile to the acid it is stopped at the amide stage. Then a stereoselective amino acid amidase from Pseudomonas putida is employed for the enantioselective second hydrolysis step [83], yielding enantiopure amino acids [34, 77, 78]. Although the reaction is a kinetic resolution and thus the yields are never higher than 50% this approach is overall more efficient. No acylation step is necessary and the atom efficiency is thus much higher. A drawback is that the racemisation has to be performed via the Schiff s base of the D-amide (Scheme 6.23). 

Lipases have also been combined with palladium catalysts to provide the dynamic aspect of the kinetic resolution.30 In the example below the unreacted allyl acetate (5)-49 is racemised. The formation and reactions of Pd-allyl cations are discussed in chapter 18. 

Fu has demonstrated that a dynamic kinetic resolution using the nonenzy-matic catalyst (12.95) can be achieved. The azlactone (12.114) is very prone to racemisation, whilst the ring-opened product (12.115) is stable under the reaction conditions. Thus the product is formed by methanolysis under dynamic resolution conditions (see Section 3.1), albeit with moderate enantioselectivity so far. 

Dynamic Kinetic Resolution. Another typical acid-catalysed reaction is the racemisation of chiral alcohols, due to inversion at the chiral carbon. This can actually be made use of in the formation of enantiopure compounds, by dynamic kinetic resolution using an enzyme, such as a lipase, that catalyses enantioseleetive esterification in an organic medium. By coupling zeolite Beta-catalysed intereonversion of benzylic alcohol enantiomers with enzyme-catalysed esterifieation of only one of the enantiomeric alcohols, almost complete eon version to enantiopure ester ean be achieved. ... 

It is the combination of these twin goals that has led to the evolution of classical kinetic resolution into dynamic kinetic resolution (DKR). In such a process, it is possible in principle to obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution, with in situ equilibration or racemisation of the chirally labile substrate (Figure i.2). In DKR, the enantiomers of a racemic substrate are induced to equilibrate at a rate faster than that of the slow-reacting enantiomer in reaction with the chiral reagent (Curtin-Hammett kinetics). If the enantioselectivity is sufficient, then isolation of a highly enriched non-racemic product is possible with a theoretical yield of 100% based on the racemic substrate. 

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