Kinetic resolutions with vinyl acetate

When the water-miscible ionic liquid [MMIM][MeS04] was used as a neat medium for the enzymatic transformations, however, poorer performance was observed. For the kinetic resolution of mc-l-phenylethanol by transesterification with vinyl acetate with a set of different lipases dispersed in the pure ionic liquid, it was found that [MMIM][MeS04] was among the poorest media for the enzymes (291). It has been recognized that some water-miscible ionic liquids in the pure form are denaturants (27), but, when they are used in the presence of excess water, their tendency to... 

Kinetic resolutions by means of the selective formation or hydrolysis of an ester group in enzyme-catalyzed reactions proved to be a successful strategy in the enantioseparation of 1,3-oxazine derivatives. Hydrolysis of the racemic laurate ester 275 in the presence of lipase QL resulted in formation of the enantiomerically pure alcohol derivative 276 besides the (23, 3R)-enantiomer of the unreacted ester 275 (Equation 25) <1996TA1241 >. The porcine pancreatic lipase-catalyzed acylation of 3-(tu-hydroxyalkyl)-4-substituted-3,4-dihydro-2/7-l,3-oxazines with vinyl acetate in tetrahydrofuran (THF) took place in an enantioselective fashion, despite the considerable distance of the acylated hydroxy group and the asymmetric center of the molecule <2001PAC167, 2003IJB1958>. 

Efficient kinetic resolution of chiral unsaturated secondary alcohols by irreversible enzyme-mediated acylation (with vinyl acetate as acylating agent, a crude preparation of Pseudomonas AK, and hexane as solvent) is possible, provided one relatively large and one small substituent are attached to the carbinol carbon. However, the method can be used to resolve substrates that are not amenable to asymmetric epoxidation (see examples 23, 25, 27, 29, where the double bond is either deactivated by an electron-withdrawing substituent, or is of the propargyl alcohol type). Acylation of the / -enantiomer consistently proceeds faster than that of the 5-enantiomer. An example of an allenic alcohol was also reported248. 

The kinetic resolution of racemic l-(benzofuran-2-yl)ethanol rac-33 having different substituents on the benzene was reported ring using lipase-catalyzed transesterification with vinyl acetate as acyl donor. The reaction afforded (lA)-l-acetoxy-l-(benzofuran-2-yl)ethanes (A)-34 and (16)-l-benzofuran-2-yl)ethanols (S)-33 in highly enantiopure form.65... 

Joly et al71 reported the use of Candida cylindracea lipase in the kinetic resolution of aryl-substituted /J-hydroxy ketones 44 using either the transeterification of the free /j-hydroxy ketone with vinyl acetate or the hydrolysis of its acetate. The transesterification mode afforded the alcohol with 30-70 % ee and the acetate with > 96% ee. That of hydrolysis afforded the alcohol with 64-93 % ee and the acetate with > 96% ee. 

Allenes, another class of compounds having interesting properties, have been also resolved by lipases, the kinetic resolution of a variety of racemic 1 -ethenyl and ethynyl-substituted 2,3-allenols was reported using a lipase from Candida antarctica type B (CAL-B) with vinyl acetate as acyl donors in organic solvent. The biocatalytic resolution afforded (S)-2,3-allenols (S)-98 and (i )-2,3-allenyl acetates (R)-99 in chemical yields up to 55% and an enantiomeric excess ee up to 99% for both enantiomers depending on the substituents.91... 

There are many reports of enzymatic catalysis in scC02 performing hydrolysis, oxidations, esterifications, and franr-esterification reactions. For example, the enzymatic kinetic resolution of 1-phenylethanol with vinyl acetate in scC02 using lipase from Candida antarctica B produces (R)-l-phenyethylacetate in >99% ee (i.e., enantiomeric excess, a measure of how much of one enantiomer is present as compared to the other), as shown in Figure 12.20. 

Kinetic resolution of ferrocene derivatives, mainly alcohols, had an important place during the early stage of stereochemical investigations of ferrocene derivatives. The reaction of (partially) resolved ferrocenylalkyl alcohols and amines with racemic 2-phenylbutyric acid anhydride (Korean s method) was the basis for the configurational assignment before the establishment of structures by X-ray crystallography [41]. There has been some debate on the reliability of the method [62, 63], and additional chirality information seems necessary for certainty. Recently, the kinetic resolution of 1-ferrocenylethanol by transesterification with vinyl acetate, catalyzed by a lipase from PseudomonasJluorescens, led to an enantiomeric excess of 90—96% of both enantiomers [64], opening new preparative aspects. 

Other possibilities to prepare chiral cyanohydrins are the enzyme catalysed kinetic resolution of racemic cyanohydrins or cyanohydrin esters [107 and references therein], the stereospecific enzymatic esterification with vinyl acetate [108-111] (Scheme 2) and transesterification reactions with long chain alcohols [107,112]. Many reports describe the use of fipases in this area. Although the action of whole microorganisms in cyanohydrin resolution has been described [110-116],better results can be obtained by the use of isolated enzymes. Lipases from Pseudomonas sp. [107,117-119], Bacillus coagulans [110, 111], Candida cylindracea [112,119,120] as well as lipase AY [120], Lipase PS [120] and the mammalian porcine pancreatic lipase [112, 120] are known to catalyse such resolution reactions. 

Scheme 2. Kinetic resolution of racemic cyanohydrins by lipase catalysed hydrolysis and by lipase catalysed irreversible esterification with vinyl acetate...

Different groups have studied the kinetic resolution of rac-l-phenylethanol by transesterification with vinyl acetate using lipases in ionic liquids as the reaction media [6,17,46] (Fig. 7.8). Schofer et al. [17] screened a set of nine lipases and two esterases for activity in ten different ionic liquids and compared the results with the reaction performed in methyl tert-butyl eter (MTBE) as the solvent. The lipases showed good activity and, in some cases, improved enantioseleclivity in these new reaction media. For example, the enantiomeric excess with PiL and AsL in [bmim ]... 

Fipases and esterases are often used for kinetic resolution of racemates, variously by hydrolysis, esterification, or transesterification of suitable precursors. Scheme 8.3-3 illustrates the principal for the resolution of a secondary alcohol by esterification with vinyl acetate. 

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]. 

Aliphatic secondary diols were also employed as the substrate, but DKRP of these diols did not lead to enantiopure polymers. At most, an ee of 46% was obtained with low molecular weights in the range of 3.3-3.7 kg mol-1. The latter was attributed to the low of selectivity of Novozym 435 for these secondary diols as revealed by kinetic resolution experiments of 2,9-decandiol with vinyl acetate and Novozym 435. Apparently, the S-alcohol showed significant reactivity, decreasing the ee of the polymer. 

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... 

Enantioselective enzymatic transesterification has also been used for a kinetic racemate resolution. Starting from the racemic (hydroxymethyl)silane rac-92 (analytical scale), transesterification with vinyl acetate in water-saturated 2,2,4-trimethylpentane, catalyzed by a commercial crude papain preparation (E.C. 3.4.22.2), yielded the corresponding optically active (acetoxymethyl)silane 93 (sign of optical rotation and absolute configuration not reported) (Scheme 21). The enantiomeric purity of the remaining dextrorotatory (hydroxymethyl)silane (-l-)-92 was moderate (49% ee). 

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

TABLE 9.1 Lipase-Catalyzed Kinetic Resolution of Racemic Alcohols with Vinyl Acetate in Organic Solvent... 

Double kinetic resolution of 2-phenylpropan-1-ol with vinyl acetate using PPL as biocatalyst for the synthesis of (S)-turmenorol B. 

Consequently, in a stereoselective reaction, one stereoisomer is formed preferentially over other possible stereoisomers, as illustrated in Fig. 2.24, or enantiomers can be separated as shown in Fig. 2.25 for acylation of 1-phenyl-ethanol with vinyl acetate using lipase as enzyme in the so-called kinetic resolution approach. 

The lipase PS from Burkholderia cepacia was supported on a Kynol ACC 507-15 active carbon cloth with and without modification by IL phase for the kinetic resolution (KR) of aromatic secondary alcohols with vinyl acetate. Scheme 2.30 [124]. For the asymmetric acylation of 1-phenylethanol, the conversion was about 50% using the ACC-supported [EMIm][NTf2] containing the enzyme. If other supports such as active carbon and alumina were used, the conversion of 1-phenylethanol was <10% even when a higher catalyst loading was employed. By applying optimized reaction conditions, the conversions of l-(furan-2-yl) ethanol and N-(2-hydroxy-2-phenylethyl) propionamide in the acylation reactions were 30-50% with 86-99% ee, respectively. 

A novel continuous-flow SCCO2 process for the kinetic resolution of 1-phenyethanol enantiomers (Figure 30) using Novozym 435 immobilized enzyme from Candida antarctica was described by Matsuda et al. [51], The lipase enzyme, selectively acetylated the R)-alcohol component. A mixture of starting material and vinyl acetate was passed through the enzyme with supercritical carbon-dioxide (Figure 31). The reaction zone was pressurized and heated, so the reaction could be performed imder supercritical conditions, synthesizing the desired (i )-acetate with 99.7% ee. and 47% yield. 

Finally, Sanfilippo and coworkers describe the enzymatic kinetic resolution of atropisomeric ( )-3,3 -bis(hydroxymethyl)-2,2 -bipyridine N,N-dioxide by enantioselective esterifcation in an unusual medium of 2-propanol/vinyl acetate (20 80) [139]. Lipase from Mucor miehei (immobilized lipase preparation, Lipozyme ) was found to give good enantioselectivity with an (aS)-enantiopreference in the axial recognition and allowed efficient preparation of both enantioforms with > 98%. Despite the fact that the propanol reacts with the acyl donor, this did not diminish its positive effects on the solubility of the bipyridyl substrate. 

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-... 

Biphenyls are recognised as stable analogues of BINOL. They are found in numerous natural products. Sanfilippo et al85 reported the Pseudomonas cepacia lipase-catalysed kinetic resolution of 2,2 -dihydroxy-6,6 -dimethoxy-l,l -biphenyl 74 using vinyl acetate as acyl donor in tert-butyl methyl ether as organic solvent. (R)-15 is obtained with an ee up to 98% while i.S)-74 is recovered with an ee up to 96%. 

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