Dynamic Kinetic Resolution of Racemic Alcohols

Structures of suitable acyl donors in hydrolase-catalyzed dynamic kinetic resolution of racemic alcohols. 

Satisfyingly a broad number of hydrolase-catalyzed DKR processes have been reported, mainly using lipases as described in previous comprehensive bibliographic revisions [99-103]. Prior to the description of selected examples for the DKR resolution of racemic alcohols via hydrolase-catalyzed acylation, three issues must be highlighted and explained in detail. These are (i) the use of an adequate acyl donor, (ii) the role of the solvent in the reaction, and (iii) the nature of the racemization agent and its compatibility with the hydrolase. 

The solvent is also a critical parameter as it must be compatible with both catalysts avoiding their deactivation and must be inert with the acyl donor. The requirement of an initial activation of metal catalyst for the racemization step has led to the common selection of THF and toluene as ideal solvents, the latter having the advantage of its higher boiling point where a high temperature is required in the system although temperatures over 100 °C are not recommendable due to enzyme denaturation. 

Other green solvents, such as 2-methyltetrahydrofuran [104] or ionic liquids [105] also have additional advantages for safety reasons. 

DKR of racemic 1-phenylethanol and other families of alcohols using a ruthenium dimeric catalyst as racemization agent. 

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Scheme 7.8 Dynamic kinetic resolution of racemic alcohols by the combination of transition metal catalysis with enzymatic acylation.

Egi, M., Sugiyama, K., Saneto, M., Hanada, R., et d. (2013). A mesoporous-siUca-immobi-lized oxovanadium cocatalyst for the lipase-catalyzed dynamic kinetic resolution of racemic alcohols. Angew. Chem. Int. Ed., 52,3654 -3658. 

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. 

Fu and co-workers have also applied their planar chiral catalyst 9 to dynamic kinetic resolution of racemic azalactones [50], Azalactones 54 racemize under the reaction conditions, allowing all material to be funneled to optically pure product. Protected (S)-amino acids 55 are formed in excellent yields with moderate enantioselectivities (83-98% yield, 44-61% ee, see Scheme 11). Use of more sterically encumbered alcohols as nucleophiles increases enantioselectivities but reaction rates become slower. 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

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. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions.29 For example, baker s yeast reduction of (/ /5)-2-(4-methoxyphenyl)-l,5-benzothiazepin-3,4(2H,5H)-dione gave only (25, 35)-alcohol as a product out of four possible isomers as shown in Figure 28 (a).29a Only (5)-ketone was recognized by the enzyme as a substrate and reduction of the ketone proceeded enantioselectively. The resulting product was used for the synthesis of (25, 35)-Diltiazem, a coronary vasodilator. 

Another ruthenium catalyst was used for the dynamic kinetic resolution of allylic alcohols [reaction (24)] by acylation yielding allylic acetates. Again a redox process should be responsible for the racemization. 

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. 

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... 

Alternatively, they were also found to be good racemization catalysts. Iridium complexes, but also rhodium compounds, catalyzed the racemization step in the enzymatic dynamic kinetic resolution of secondary alcohols, and excellent results were reported for alkyl-aryl as well as dialkyl secondary alcohols. Finally, picolyl and pyridine functionalized N-heterocyclic carbene iridium complexes [(C N)Ir(Cp )Cl]Cl were moderately active catalysts for the polymerization of norbomene in the presence of methylaluminoxane as cocatalyst. ... 

Dynamic kinetic resolution (DKR) of a racemic alcohol with lipase and metal catalysts is often conducted in organic solvents. Since the maximum yield of kinetic resolution of racemic alcohol by lipase is only 50% with 100% ee, metal catalysts to racemize the unreactive enantiomer substrate is necessary to achieve 100% yield and 100% ee [22]. For example, mthenium catalysts have been widely used for this process as shown in Figure 3.12a [22b]. Vanadium has also been used, and to improve both catalytic activity and compatibility of the oxovanadium catalysts with the lipases, a novel oxovanadium catalyst (V-MPS) immobilized inside mesoporous silica (MPS) with pores of approximately 3 nm in diameter was prepared. With this immobilization preparation, a complete division of the racemization site and the enzymatic reaction site was achieved. 

Akai, S. (2014). Dynamic kinetic resolution of racemic allylic alcohols via hydrolase-metal combo catalysis An effective method for the synthesis of optically active compounds. Chem. Lett., 43,746-754. 

The enantioselective acylation of alcohols, and amine reactions by lipases and esterases in organic synthesis with examples of classical and dynamic kinetic resolutions of racemates, are shown, giving attention to the desymmetrization of meso-compoxmds. 

Maviynsky D, Paivio M, LundeU K, Sillanpaa R, Kanerva LT, Leino R. Dicarbonylchloro(pentabenzylcyclopentadienyl) ruthenium as racemization catalyst in the dynamic kinetic resolution of secondary alcohols. Eur. J. Org. Chem. 2009 1317-1320. 

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

Scheme 20.31 The dynamic kinetic resolution of a racemic alcohol.

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

Figure 5.15 a Generic scheme of dynamic kinetic resolution of alcohols b example of the resolution of a racemic 8-aminotetrahydroquinoline, where the racemization iscatalyzed by the organic ketone 8-aza-l-tetralone (the racemization cycle is highlighted in gray). 

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]. 

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,... 

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]. 

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