Secondary alcohols, dynamic kinetic resolution

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). 

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. 

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 integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

The combination of Ru complex-catalyzed stereomutation of secondary alcohols with enzyme-catalyzed enantioselective acylation is an efficient procedure to obtain chiral acyloxy compounds with excellent optical purity from a variety of racemic secondary alcohols via dynamic kinetic resolution [112]. 

Enzymatic resolution of racemic secondary alcohols by enantiomer-selective acylation gives optically pure compounds with up to 50% yield [332], When this method is coupled with the principle of dynamic kinetic resolution (see Section 1.4.1.5), the theoretical yield increases to 100%. Thus a reaction system consisting of an achiral transition-metal catalyst for racemization, a suitable enzyme, acetophenone, and an acetyl donor allows the transformation of racemic 1-phenylethanol to the R acetates with an excellent ee (Scheme 1.93) [333]. The presence of one equiv. of acetophenone is necessary to promote the alcohol racemization catalyzed by the... 

Figure 5 Dynamic kinetic resolution of secondary alcohols...

The only difference is that in conventional kinetic resolution the enantiomer (5)-substrate is left behind as unreacted starting material while in case of dynamic kinetic resolution the substrate is continuously isomerised during the resolution process, thus (R) and ( )-substrates are in equilibrium, which allows for the possibility of converting all starting materials of (A)-substrate into (A)-product. Several conditions should be applied and are reviewed in literature.21 For instance, Backvall et al20 used a combination of enzyme and transition metal complex (Ru-catalyst) to perform the DKR of a set of secondary alcohols. Depending on the substrate, the chemical yield was ranging from 60 to 88 % with more... 

Dijksman, A. Elzinga, M., J. Li, Yu-Xin, Arends, I., Sheldon, R., A. Efficient ruthenium-catalyzed racemization of secondary alcohols application to dynamic kinetic resolution. Tetrahedron Asymmetry 2002, 13, 879-884. 

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

The remarkable activity of copper catalysts in carbonyl hydrogenation and alcohol dehydrogenation prompts their use also for the racemization of chiral secondary alcohols. Actually, since the first report on chemoenzymatic dynamic kinetic resolution [68], racemization of alcohols via the corresponding ketone has attracted considerably attention, owing to its role as backbone in this resolution [69, 70]. 

Zeolite beta has also been used for the racemization of secondary phenylic alcohols in a dynamic kinetic resolution however, in this case water elimination/ addition via a carbenium ion is involved rather than a redox mechanism [75, 76]. 

Subsequently the groups of Williams [7] and Backvall [8] showed, in 1996 and 1997, respectively, that lipase-catalyzed transesterification of alcohols could be combined with transition metal-catalyzed racemization to produce an efficient dynamic kinetic resolution of chiral secondary alcohols (Fig. 9.2). 

The kinetic resolution of racemic secondary alcohols by enzymatic acylation is a well-established method for obtaining optically pure alcohols or their esters in near-50% yield [293]. Coupling the enzymatic method with a catalytic redox ability of a Ru complex makes the process a dynamic kinetic resolution, increasing the theoretical yield from 50 to 100% [294]. Thus, a reaction system consisting of an achiral Ru catalyst for the chemical racemization of an alcoholic substrate, a suitable enzyme,... 

Kim M-J, Kim HM, Kim D et al (2004) Dynamic kinetic resolution of secondary alcohols by enzyme-metal combinations in ionic liquid. Green Chem 6 471-474... 

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

K., Kaynak, E.B., and Baeckvall, ).-E. (2005) Combined mthenium(II) and lipase catalysis for efhcient dynamic kinetic resolution of secondary alcohols. Insight into the racemization mechanism. J. Am. Chem. Soc., 127 (24), 8817-8825. 

Sato, Y., Kayaki, Y., and Ikariya, T. (2012) Efficient dynamic kinetic resolution of racemic secondary alcohols by a chemoenzymatic system using bifunctional iridium complexes with C-N chelate amido ligands. Chem. Commun. (Cambridge, UK), 48 (30), 3635-3637. 

M.L, and Mueller, T.N. (2006) Lipase/aluminum-catalyzed dynamic kinetic resolution of secondary alcohols. Angew. Chem. Int. Ed., 45 (39), 6567-6570. 

Today, dynamic kinetic resolution of secondary alcohols by combination of enzymes with transition metal catalysts, originally developed by Williams and Backvall, are perhaps the best developed methods (33-36). Hitherto the most successful catalyst designs have been based on half-sandwich ruthenium complexes, of which the pentaphenylcyclopentadienyl ruthenium complex has been claimed as the currently best racemization catalyst. Racemization is then based on reversible conversion of the alcohol into the corresponding ketone (Fig. 21, A). The dynamic kinetic resolution of 1-phenylethanol with isopropenyl acetate in toluene in the presence of Novozym 435, performed in preparative scale, is a good example of the use of ruthenium complexes (35). Another thoroughly studied racemization method (Fig. 21, B) is based on the use of acidic resins or zeolites. Here the racemization takes place through prochiral sp car-benium ion by simultaneous elimination and addition of water (37). The use of... 

Zhou et al. combined the simultaneous dynamic kinetic resolution (DKR) of a secondary alcohol initiator with lipase-catalyzed ROP of s-CL. (R,5)-1-Phenyl-ethanol (PhE) was used as a model secondary alcohol and incorporated into PCL under DKR conditions using lipase CA and a Ru catalyst. A total of 75% of the PhE was incorporated as (R)-PhE-PCL with over 99% ee in 23 h at 75°C in toluene [149]. 

Scheme 19.4 Dynamic kinetic resolution of a secondary alcohol based on rhodium-catalyzed racemization and enzymatic acylation.

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

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