Secondary alcohol lipase-catalyzed resolution

The low-temperature method has been applied to some primary and secondary alcohols (Fig. 1) For example, solketal, 2,2-dimethyl-1,3-dioxolane-4-methanol (3) had been known to show low enantioselectivity in the lipase-catalyzed resolution (lipase AK, Pseudomonas fluorescens, E = 16 at 23°C, 27 at 0oc) 2ia however, the E value was successfully raised up to 55 by lowering the temperature to —40°C (Table 1). Further lowering the temperature rather decreased the E value and the rate was markedly retarded. Interestingly, the loss of the enantioselectivity below —40°C is not caused by the irreversible structural damage of lipase because the lipase once cooled below —40°C could be reused by allowing it to warm higher than -40°C, showing that the lipase does not lose conformational flexibility at such low temperatures. 

The lipase-catalyzed resolutions usually are performed with racemic secondary alcohols in the presence of an acyl donor in hydrophobic organic solvents such as toluene and tert-butyl methyl ether (Scheme 1.3). In case the enzyme is highly enantioselective E = 200 or greater), the resolution reaction in general is stopped at nearly 50% conversion to obtain both unreacted enantiomers and acylated enantiomers in enantiomerically enriched forms. With a moderately enantioselective enzyme E = 20-50), the reaction carries to well over 50% conversion to get unreacted enantiomer of high optical purity at the cost of acylated enantiomer of lower optical purity. The enantioselectivity of lipase is largely dependent on the structure of substrate as formulated by Kazlauskas [6] most lipases show... 

Scheme 1.3 Lipase-catalyzed resolution of secondary alcohols.

Secondary alcohols are by far the most frequently used targets in lipase-catalyzed resolutions. This is due to their importance in organic synthesis but also that lipases usually show much higher enantioselectivity in resolutions compared to primary and tertiary alcohols. 

Ghanem, A. Ginatta, C. Jian, Z. Schurig, V. Chirasil-/7dex with a new Cl 1-spacer for enantioselective gas chromatography application to the kinetic resolution secondary alcohols catalyzed by lipase. Chromatographia 2003, Vol. 57, S-275-281. 

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 stereochemical outcome of the lipase-catalyzed resolution of primary alcohols is somehow less predictable than the same enzymatic process carried out on secondary alcohols. For these substrates, thanks to the great number of results that have been reported, a more... 

Table 1 Lipase-Catalyzed Resolution of Secondary Alcohols...

The enzymatic resolution of racemic substrates now is a well-established approach for the synthesis of single enantiomers [1, 2]. A representative example is the kinetic resoluhon of secondary alcohols via lipase-catalyzed transesterification for the preparation of enantiomericaUy enriched alcohols and esters [3], The enzymatic resolution in general is straightforward and satisfactory in terms of optical purity, but it has an intrinsic Hmitation in that the theoretical maximum yield of a desirable enantiomer cannot exceed 50%. Accordingly, additional processes such as isolation, racemization and recycling of unwanted isomers are required to obtain the desirable isomer in a higher yield (Scheme 1.1). 

DKR of secondary alcohol is achieved by coupling enzyme-catalyzed resolution with metal-catalyzed racemization. For efficient DKR, these catalyhc reactions must be compatible with each other. In the case of DKR of secondary alcohol with the lipase-ruthenium combinahon, the use of a proper acyl donor (required for enzymatic reaction) is parhcularly crucial because metal catalyst can react with the acyl donor or its deacylated form. Popular vinyl acetate is incompatible with all the ruthenium complexes, while isopropenyl acetate can be used with most monomeric ruthenium complexes. p-Chlorophenyl acetate (PCPA) is the best acyl donor for use with dimeric ruthenium complex 1. On the other hand, reaction temperature is another crucial factor. Many enzymes lose their activities at elevated temperatures. Thus, the racemizahon catalyst should show good catalytic efficiency at room temperature to be combined with these enzymes. One representative example is subtilisin. This enzyme rapidly loses catalytic activities at elevated temperatures and gradually even at ambient temperature. It therefore is compatible with the racemization catalysts 6-9, showing good activities at ambient temperature. In case the racemization catalyst requires an elevated temperature, CALB is the best counterpart. 

As described above, the resolution of many types of secondary alcohols by hydrolase-catalyzed acylation in an organic solvent is usually possible after screening for a selective lipase and optimization of the reaction conditions. 

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-... 

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. 

Figure 7.2 The structure of the faster reacting enantiomer in lipase-catalyzed esterification in kinetic resolution of racemic secondary alcohols or hydrolysis of the corresponding esters. Small and large refer to the relative size of the groups and not to the R/S notation.

Kinetic Resolution by Transesterification. Asymmetric transformation involving acylation of chiral alcohols is by far the most common example of kinetic resolution by lipase-catalyzed transesterification, most commonly with irreversible vinyl esters. This field is now becoming the most widely applied technique involving lipases. Recent reports of the numerous secondary alcohol substrates include various monocyclic (eq 6) andacyclic compounds, cyanohydrins, sulfones, and glycals, to name a few. 

Examples of kinetic resolutions with lipases are numerous [9], Impressive enantioselectivities are often obtainable with secondary alcohols, e.g., in acetylations with vinyl acetate, or in hydrolysis of the racemic ester. Likewise, the corresponding amines can be resolved, e.g. by enantioselective acetylation with EtOAc as both acyl donor and solvent. This has been demonstrated by Gotor and coworkers using Novozym 435 [50]. The reaction (Scheme 13.3) follows Kazlauskas selectivity. In fact an impressive range of CALB (Novozym 435) catalyzed transformations on nitrogenated compounds have been collected in a recent review article [51]. 

The most widely used enzymes are the hydrolytic enzymes lipases, proteases, and nitrilases, probably because these enzymes do not require cofactors and are available commercially. They are particularly useful for resolution of esters, 5,7 and for organic synthesis." 9 Esterases can also catalyze esterification if the water concentration is low. Enzyme-catalyzed transcstcrification can be used for resolution of secondary alcohols and diols.10... 

Dynamic Resolution. Lipase-catalyzed acyl transfer has become a well-established and popular method for the kinetic resolution of primary and secondary alcohols. In order to circumvent the limitations of kinetic resolution (i.e., a 50% theoretical yield of both enantiomers), several strategies have been developed, which achieve a more economic dynamic resolution process and allow the formation of a single stereoisomer as the sole product (for the theoretical background see Sect. 2.1.1). In contrast to compounds bearing a chiral center adjacent to an electron-withdrawing... 

Jing, Q. and Kazlauskas, R.J. (2008) Determination of absolute configuration of secondary alcohols using lipase-catalyzed kinetic resolutions. Chirality, 20 (5), 724-735. 

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

The Mitsunobu esterification was the first inversion of configuration applied together with the lipase-catalyzed acylation of secondary alcohols (38). Another possibility is shown in Figure 23. The CAL-B-catalyzed kinetic resolution of ethyl-3-hydroxybutanoate by acylation with vinyl acetate has been discussed already in Figure 4 (9). Normal kinetic resolution under the solvent-free conditions by... 

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]. 

A third reason to use organic solvents is that other features of the reaction require it to be an acylation and not a hydrolysis. For example, some dynamic kinetic resolutions require an alcohol substrate because organometal-lic complexes racemize secondary alcohols, but not esters. The substrate must be an alcohol for the dynamic kinetic resolution to proceed. In another example, lipase- and esterase-catalyzed hydrolysis of amides to amines is too slow for practical use. However, the lipase-catalyzed acylation of amines in... 

KINETIC RESOLUTION OF A SECONDARY ALCOHOL (4-TRIMETHYLSILYL-3-BUTYN-2-0L) BY LIPASE-CATALYZED ACETYLATION WITH VINYL ACETATE... 

Special attention should be devoted to less conventional applications of the enzymatic transesterification methodology such as resolution of unstable substrates as racemic secondary hydroperoxides [291]. The development of new reactions in the presence of enzymes should pursued, as, for example, the simultaneous formation of a hemithioac-etal and die irreversible transesterification in the presence of a lipase [292]. Also, for synthetic applications, the combination of enzymatic and chemical asymmetrical methods could lead to interesting results, such as the one-pot lipase-catalyzed acylation and the Mitsonobu inversion of the configuration of the unreacted alcohol, which should lead to only one enantiomeric ester [293]. 

Numerous examples exist on the kinetic resolution of chiral acyl acceptors. Among other compounds primary and secondary alcohols, various amines, and peroxides have been resolved. Representative examples are shown in Scheme 7. The secondary alcohol 2-octanol was resolved using S-ethyl octanethioate as acyl donor and C. antarctica lipase B [12]. The alkyl peroxide was acylated with isopropenyl acetate using P. cepacia lipase [87]. The primary amine was resolved by C. antarctica lipase B-catalyzed acylation of ethyl octanoate at reduced pressure [88]. The primary alcohol was successfully resolved by acylation of vinyl acetate at — 40 C [89]. 

ScheniB 7 Examples of lipase-catalyzed kinetic resolution by deacylation of an acyl enzyme (RiCOO-Enz). The chiral acyl acceptors are a secondary alcohol [12], a j roxide [87], a primary amine [88], and a primary alcohol [89]. The fast-reacting enantiomers are shown. 

Scheme 2.30 Kinetic resolution of aromatic secondary alcohols catalyzed by lipase PS catalysts.

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