Dynamic kinetic resolutions DKRs

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Kim and co-workers recently reported an excellent example of dynamic kinetic resolution (DKR) using lipase-ruthenium combo catalyst in an IE solvent system (Fig. 7). Applied to this protocol, the authors succeeded in preparing (R)-ester or (5 )-ester using lipase PS or subtilisin, respectively. An IE solvent system is truly appropriate for DKR because racemizafion takes place easily in a highly polar solvent. 

The novel phenomenon of converting racemic substrates into a single enantiomer of the product hy dynamic kinetic resolution (DKR) via racemization of the substrates has been a formidable challenge in asymmetric synthesis. Recently, DKR has been receiving increasing attention since it can overcome the limitations... 

The dynamic kinetic resolution (DKR) of a-sulfur-substituted ketones such as 31 and 33 was investigated. When the MOM protected mercaptol ketone 31 was treated with the BINOL-LiAlH4 complex, a moderate diastereoselectivity of 5 1 favoring the desired anti isomer was observed. The major diastereomer had 70%... 

Scheme 9.10 Proposed dynamic kinetic resolution (DKR) of ketone rac-13.

The use of an enzyme in a cascade using nanoencapsulation has also been demonstrated [23]. In this case, the dynamic kinetic resolution (DKR) of secondary alcohols was achieved with an acidic zeolite and an incompatible enzyme, Candida antarctica lipase B (CALB) (Scheme 5.8). 

Dynamic kinetic resolution (DKR) is an extension to the kinetic resolution process, in which an enantioselective catalyst is usually used in tandem with a chemoselective catalyst. The chemoselective catalyst is used to racemize the starting material of the kinetic resolution process whilst leaving the product unchanged. As a consequence, the enantioselective catalyst is constantly supplied with fresh fast-reacting enantiomer so that the process can be driven to theoretical yields of up to 100 %. There are special cases where the starting material spontaneously racemizes under the reaction conditions and so a second catalyst is not required. 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Dynamic kinetic resolution (DKR) is a process in which the resolution process is coupled with in situ racemization of unreacted substrate. This has been shown to be a potential and feasible method to produce 100 % theoretical yield. We have developed a chemo-enzymatic DKR to obtain higher desired yield for (5)-ibuprofen. The combined base catalyst with lipase has resulted in high conversion and excellent ee of the product. 

Chapter 3 describes the application of lipases, proteases and sulfatases for the kinetic resolution of a range of interesting molecules. A selection of dynamic kinetic resolution (DKR) procedures is disclosed in Chapter 4. DKRs are attracting a significant amount of... 

Cp Ir(NHC) complexes are a very versatile type of catalyst, with a wide range of applications. In a chemoenzymatic application, Cp Ir complexes activated by fluo-rinated and nonfluorinated NHC ligands were shown to be catalysts for racemiza-tion in the one-pot chemoenzymic dynamic kinetic resolution (DKR) of secondary... 

Dynamic kinetic resolution (DKR) is an attractive protocol for the production of enantiopure compounds from racemic mixtures [45]. The concept of DKR is illustrated in Scheme 5.13. In many cases, DKRs are accomplished by the combination of enzymatic resolution and transition-metal-catalyzed racemization based on hydrogen transfer. Thus, the use of Cp Ir complexes as catalysts for racemization in DKR can be anticipated. 

Dynamic Kinetic Resolution (DKR) of Azlactones Thioureas Can Act as Oxyanion Holes Comparable to Serine Hydrolases... 

There are basically two approaches to the synthesis of enantiomerically pure alcohols (i) kinetic resolution of the racemic alcohol using a hydrolase (lipase, esterase or protease) or (ii) reduction mediated by a ketoreductase (KRED). Both of these processes can be performed as a cascade process. The first approach can be performed as a dynamic kinetic resolution (DKR) by conducting an enzymatic transesterification in the presence of a redox metal [e.g. a Ru(ll) complex] to catalyze in situ racemization of the unreacted alcohol isomer [11] (Scheme 6.1). We shall not discuss this type of process in any detail here since it forms the subject of Chapter 1. 

A prominent example of chemoenzymatic catalysis in bio-organic chemistry is the dynamic kinetic resolution (DKR) of secondary alcohols (Scheme 9) [94, 95] and amines [96-99], In this process, a lipase is employed as an enantioselective acylation catalyst, and a metal-based catalyst ensures continuous racemization of the unreactive enantiomer. 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

Limitations of kinetic resolutions. If one is interested in preparing a single enantiomer, the major drawback of hydrolase-catalyzed kinetic resolutions is that only 50% yield of the desired enantiomer is possible from a racemic starting material. The introduction of dynamic kinetic resolution (DKR, see Chapter 6) provides one solution to this problem. Another one is to invert the configuration of the product or the remaining substrate after the hydrolase-mediated resolution, and examples of this approach are discussed below (Section 4.2.1.2). 

It is worth noting here that with two enzymes displaying opposite enantioselec-tivity it is possible to produce both enantiomers of the ester products. If the remaining alcohols can be continuously and rapidly racemized during the much slower acylation reaction, either the R- or S-esters can be obtained in high yields (>>5096) from reactions catalyzed by two hydrolases that display opposite enantio-preference. The combined process of racemization and simultaneous resolution, dynamic kinetic resolution (DKR), is described in Chapter 6. 

The pentanoates 32-37 are obtained with fair enanhoselectivity (E > 47) (Scheme 4.17, bottom half) [74]. When the kinetic resolution conditions were established, efficient conditions for dynamic kinetic resolutions (DKR) were also established (see Chapter 6) [74]. 

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. 

---