Dynamic kinetic resolution alcohols

Another example of dynamic kinetic resolution is the reduction of a sulfur-substituted ketone. Thus, yeast reduction of (R/S)-2-(4-methoxyphenyl)-l, 5-benzothiazepin-3,4(2H, 5H)-dione gave only (2S, 3S)-alcohol as a product out of four possible isomers as shown in Figure 8.39c [29kj. Only (S)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded... 

Other biocatalysts were also used to perform the dynamic kinetic resolution through reduction. For example, Thermoanaerobium brockii reduced the aldehyde with a moderate enantioselectivity [30b,c], and Candida humicola was found, as a result of screening from 107 microorganisms, to give the (Jl)-alcohol with 98.2% ee when ester group was methyl [30dj. 

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. 

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and BackvalP used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering... 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

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). 

Hydrogen transfer reactions are reversible, and recently this has been exploited extensively in racemization reactions in combination with kinetic resolutions of racemic alcohols. This resulted in dynamic kinetic resolutions, kinetic resolutions of 100% yield of the desired enantiopure compound [30]. The kinetic resolution is typically performed with an enzyme that converts one of the enantiomers of the racemic substrate and a hydrogen transfer catalyst that racemizes the remaining substrate (see also Scheme 20.31). Some 80 years after the first reports on transfer hydrogenations, these processes are well established in synthesis and are employed in ever-new fields of chemistry. 

The next step in the use of transfer hydrogenation catalysts for recycling of the unwanted enantiomer is the dynamic kinetic resolution. This is a combination of two reaction systems (i) the continuous racemization of the alcohol via hydrogen transfer and (ii) the enantioselective protection of the alcohol using a... 

It is important that the catalysts are stable in each other s presence. Typically, kinetic resolution of the reaction is performed with an enzyme, which always will contain traces of water. Hence, MPVO catalysts and water-sensitive transition-metal catalysts cannot be used in these systems. The influence of the amount of the hydrogen acceptor in the reaction mixture during a dynamic kinetic resolution is less pronounced than in a racemization, since the equilibrium of the reaction is shifted towards the alcohol side. 

Scheme 20.31 The dynamic kinetic resolution of a racemic alcohol.

Transfer hydrogenation is a mild and efficient means of reducing aldehydes, and can be advantageous over other reagents such as sodium borohydride. Clearly, the product is a primary alcohol and therefore not chiral, but a chiral center might be alpha to the aldehyde, in which case a resolution can be effected. Indeed, under the appropriate conditions the chiral center can be race-mized and a dynamic kinetic resolution effected [57]. 

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. 

Zhu, Y-.Z., Fow, K.L., Chuah, G.K. and Jaenicke, S., Dynamic kinetic resolution of secondary alcohols combining enzyme-catalyzed transesterification and zeolite-catalyzed racemisation. Chem. Eur. J. 2007, 13, 541. 

Synthesis of the (/ )-Butyrate Esters of Secondary Alcohols hy Dynamic Kinetic Resolution Employing a Bis(tetrafluorosuccinato)-hridged Ru(II) Complex... 

Van Nispen, S.E.G.M., van Buijtenen, J., Vekemans, J.A.J.M., Meuldijk, J. and Hulshof, L.A., Efficient dynamic kinetic resolution of secondary alcohols with a novel tetrafluorosuccinato ruthenium complex. Tetrahedron Asymm., 2006, 17, 2299. 

Verzijl, G.K.M., de Vries, J.G. and Broxterman, Q.B., Removal of the acyl donor residue allows the use of simple alkyl esters as acyl donors for the dynamic kinetic resolution of secondary alcohols. Tetrahedron Asymm., 2005, 16, 1603. 

The reversibility of hydrogen transfer reactions has been exploited for the racemi-zation of alcohols and amines. By coupling the racemization process with an enantioselective enzyme-catalyzed acylation reaction, it has been possible to achieve dynamic kinetic resolution reactions. The combination of lipases or... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

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. 

Kinetic and Dynamic Kinetic Resolution of Allylic Alcohols... 

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