Kinetic enantioselective acylation

The infrared radiation caused by the heat of reaction of an enantioselective enzyme-catalyzed transformation can be detected by modern photovoltaic infrared (IT)-thermographic cameras equipped with focal-plane array detectors. Specifically, in the lipase-catalyzed enantioselective acylation of racemic 1-phenylethanol (20), the (K)- and (S)-substrates were allowed to react separately in the wells of microtiter plates, the (7 )-alcohol showing hot spots in the IR-thermographic images (113,114). Thus, enantioselective enzymes can be identified in kinetic resolution. However, quantification has not been achieved thus far by this method, which means that only those mutants can be identified which have E values larger than 100 (113-115). 

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. 

Yashima et al. showed an example where the polymer helicity was controlled by enzymatic enantioselective acylation of the monomers [109]. Optically active phenylacetylenes containing hydroxyl or ester groups were obtained by the kinetic resolution of the corresponding racemic hydroxy-functional phenylacetylene (see Scheme 16). Polymerization of the phenylacetylenes afforded an optically active poly(phenylacetylene) with a high molecular weight (Mn = 89kDa PDI = 2.0) and... 

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]. 

In a series of elegant studies, Miller and colleagues demonstrated that small peptides containing modified histidine residues (re-methyl-histidine) were effective catalysts for enantioselective acylation and phosphorylation reactions [12, 13]. As peptides in this family are able to transfer stereochemical information, these catalysts were also tested to carry out site- and regio-selective reactions, which take place against kinetic expectations. The screening of a small library (36 members)... 

Xu Q, Geng X, Chen P (2008) Kinetic resolution of cyanohydrins via enantioselective acylation catalyzed by lipase PS-30. Tetrahedron Lett 49 6440-6441... 

Yang, X. Liu, P. Houk, K. N. Birman, V. B. Manifestation of FeUdn-Anh control in enantioselective acyl transfer catalysis Kinetic resolution of carboxylic acids, A/igevv. Chem. Int. Ed. 2012,51, 9638-9642. 

Lou WY, Zong MH (2006) Efficient kinetic resolution of (R, S)-l-trimethylsilylethanol via lipase-mediated enantioselective acylation in ionic liquids. Chirality 18 814-821... 

The lipase-catalysed enantioselective acylation of allylic alcohols in an ionic liquid solvent was demonstrated by Itoh et al. [16] (Fig. 7.7). They found that the acylation rate was strongly dependent on the counter anion of the imidazolium salt, while the lipase-catalysed acylation proceeded with high enantioseleclivity in all ionic liquid tested. Good results were obtained when the reaction was carried out in [bmimT [PFg ] or [bmun" ][BF ]. Other examples of kinetic resolution of allylic alcohols catalysed by lipases in ionic liquids were also reported by these authors [71, 72]. The transesterification of 5-phenyl-l-penten-3-ol under reduced pressure at 27 hPa and 40°C was carried out using methyl phenylthioacetate as acyl donor in [bmim+] [PF ] and [bdmim ][BF ], for obtaining the corresponding acylated compound in optically pure form [71], The acetylation of methyl mandelate catalysed by immobilised P5L in [bdmim ][BF ] is another example reported by these authors about the successful application of ionic liquids as reaction media in racemic resolutions... 

Fig. 7 Dynamic kinetic racemate resolution via lipase-catalyzed enantioselective acylation.

This is a kinetic resolution that works by enantioselective acylation of the unwanted enantiomer of the alcohol. The reaction is therefore an ester exchange and vinyl acetate is an efficient acetate transfer agent since the other product is vinyl alcohol better known as the enol of acetaldehyde so the reaction is irreversible. 

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],... 

Kinetic resolutions. BayJis-Hillmai reactivity toward Pd(0)-catalyzed substin chiral DMAP derivative 3 and the a.xi developed as catalysts for enantiosete enantioselective acylation with the aid ol presence of a cinchona alkaloids is a good... 

Kinetic resolutions. Baylis-Hillman adducts are deracemized by exploiting their reactivity toward Pd(0)-catalyzed substitution, using chiral ligand 2. Both the planar chiral DMAP derivative 3 and the axially chiral analogue (4) ° and 5" have been developed as catalysts for enantioselective acylation. Benzylic alcohols undergo enantioselective acylation with the aid of 6. Methanolysis of meio-anhydrides in the presence of a cinchona alkaloids is a good way to desymmetrize such compounds. ... 

Acylation. The Cj-symmetric phosphine 2 is useful for enantioselective acylation of alcohols." Chiral mixed carbonates are prepared from 3 and secondary alcohols, allowing a kinetic resolution of the alcohols. ... 

Amidines catalyse the Baylis-Hillman reaction [52]. A novel one-pot synthesis-kinetic resolution process involving a DBU (l)-catalysed Baylis-Hillman reaction and a subsequent pyridine catalyst/DBU (l)-mediated enantioselective acylation has been developed [52a] (Scheme 3.32). 

In addition to kinetic resolution processes, the previously described peptide-catalysed acylation reaction of alcohols can be applied to desymmetrisation of meso compounds. In 2005, Miller and coworkers published the desymmetrisation of prochiral glycerol derivatives via enantioselective acylation of one primaiy alcohol function. A (3-tum histidine-based pentapeptide was identified as the most promising catalyst from a peptide libraiy and afforded the monoacylated product with up to 97% enantiomeric excess. One year later Miller and Hansen successfully demonstrated the desymmetrisation of a meso bis-phenol compound, which was found to be challenging because of the large distance between the two OH groups as well as between the desired site of functionalisation and the prochiral stereogenic centre of the substrate. The nucleophilic N-methylhistidine containing peptide 9 was identified as a powerful tool for monoacylation via extensive libraiy... 

Copeland GT, Miller SJ (2001) Selection of enantioselective acyl transfer catalysts fimn a pooled peptide library through a fluorescence-based activity assay an approach to kinetic resolution of secondary alcohols of broad structural scope. J Am Chem Soc 123 6496-6502... 

The kinetic resolution of cyanohydrins via enantioselective acylation may be converted into a dynamic process by making use of the chemical instability of cyanohydrins (Scheme 3.15) [235], Thus, racemic cyanohydrins were generated from an aldehyde and acetone cyanohydrin (as a relatively safe source of hydrogen cyanide) under catalysis by an anion exchange resin. The latter also served as catalytic base for the in-situ racemization. Enantioselective acylation using PSL and tsopropenyl acetate led to the exclusive formation of the corresponding (S)-cyanohydrin acetates in 47-91% optical purity. 

In another context, Cao and Qu showed that an enantioselective acylation catalysed by a chiral thioamide modified 1-methylhistidine methyl ester (Scheme 2.19) in combination with a DABCO-mediated racemisation of the substrate led to the efficient dynamic kinetic resolution (DKR) of meso-1,2-diol monodichloroacetates. As shown in Scheme 2.19, both cyclic and acyclic meso-l,2-diol monodichloroacetates could be transformed to the corresponding enantiomerically enriched (15, 2R)-heterosubstituted diol esters in good yields and moderate enantioselectivities of up to 74% ee. 

For example Vedejs, E., Daugulis, O., and Diver, S. T., 1996, Enantioselective Acylations Catalyzed by Chiral Phosphines. J. Org. Chem. 61 430-431 Vedejs, E., and Rozners, E., 2001, Parallel Kinetic Resolution under Catalytic Conditions A Three-Phase System Allows Selective Reagent Activation Using Two Catalysts. J. Am. Chem. Soc. 123 2428-2429 Qiao, S., and Fu, G. C, 1998, The First Application of a Planar-Chiral Phosphorus Heterocycle in Asymmetric Catalysis Enantioselective Hydrogenation of Dehydroamino Acids, y. Org. Chem. 63 4168-4169. 

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. 

In the previous chapters, achiral substrates or substrates with a chiral acid moiety have been considered. But the kinetic resolution of racemic alcohols and the desymmetrization of meyo-diols are equally important for the synthesis of pharmaceutical and natural substances [87], Enantioselective acylation of racemic... 

Table 12. Enantioselectivities in the acylation and deacylation steps in the burst kinetics of the reaction of (Z)-Phe-PNP(52)...

Table 1.3 Influence ofthe organic solvent on the enantioselectivity of the protease subtilisin in the kinetic resolution ofthe racemic amine (9) (expressed as the ratio ofthe initial rate of acylation of the pure enatiomers, Vs/vr).

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. 

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