Enantioselectivity transesterification

Lipase-catalyzed enantioselective transesterification of 0-substituted-l,2-diols is another practical route for the synthesis of P-blockers. Lipase PS suspended in toluene catalyzes the transesterification of (63) with vinyl acetate to give the (5)-ester in 43% yield and >98% ee (78). The desired product, optically pure (R)-ttitylglycidol, is then easily obtained by treating the ester with alcohoHc alkaU. Moreover, Pseudomonas Hpase catalyzes the acylation of oxazohdinone (64) with acetic anhydride in very good yield and selectivity (74). PPL-catalyzed transesterification of a number of /n j -norbomene derivatives proceeds in about 30% yield and 92% ee (79,80). 

Figure 6.16 Enantioselective transesterification of N-Cbz-amino acid 2,2,2-trifluoroethyl esters.

In contrast to Mori s synthesis, Pawar and Chattapadhyay used enzymatically controlled enantiomeric separation as the final step [300]. Butanone H was converted into 3-methylpent-l-en-3-ol I. Reaction with trimethyl orthoacetate and subsequent Claisen-orthoester rearrangement yielded ethyl (E)-5-methyl-hept-4-enoate K. Transformation of K into the aldehyde L, followed by reaction with ethylmagnesium bromide furnished racemic ( )-7-methylnon-6-ene-3-ol M. Its enzyme-catalysed enantioselective transesterification using vinylacetate and lipase from Penicillium or Pseudomonas directly afforded 157, while its enantiomer was obtained from the separated alcohol by standard acetylation. 

In a succeeding publication, the same authors reported on an enantiose-lective approach to diquinane enones 6 and ent-6 by combining the above-described synthesis with an enzymatic kinetic resolution (Scheme 4) [12]. After lipase-catalyzed enantioselective transesterification of diol rac-12. 

Suzuki and co-workers first published on the topic of enantioselective transesterification in 2004 [140, 141]. This process exploits C -symmetric imidazolium salts with various substitutions. When vinyl propionate 281 acts as the acyl donor, ester 282 is isolated in 68% ee at 19% conversion, corresponding to an s value of 6.1 (Eq. 27). 

Although [BMIM]BF4 has been evaluated as an isolation medium for lipase-catalyzed biotransformations, the general experience with it has not been favorable, relative to that with other ionic liquids, such as [BMIM]PF6. However, excellent performance was recently reported for [BDMIM]BF4 when it was used to host Candida antarctica (Novozym 435) for the enantioselective transesterification of 5-phenyl-l-penten-3-ol (+ and -) with vinyl acetate. The working hypothesis was that the oligomerization of acetaldehyde may be caused by the C2 proton of the [BMIM] ion because of the unfavorable acidity of this group (226). In contrast, the cation in [BDMIM]BF4 lacks this acidity. 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

In order to reduce the time needed to perform a complete kinetic resolution Lindner et al53 reported the use of the allylic alcohol 30 in enantiomerically enriched form rather than a racemic mixture in kinetic resolution. Thus, the kinetic resolution of 30 was performed starting from the enantiomerically enriched alcohol (R) or (S)-30 (45%) ee obtained by the ruthenium-catalyzed asymmetric reduction of 32 with the aim to reach 100 % ee in a consecutive approach. Several lipases were screened in resolving the enantiomerically enriched 30 either in the enantioselective transesterification of (<5)-30 (45% ee) using isopropenyl acetate as an acyl donor in toluene in non-aqueous medium or in the enantioselective hydrolysis of the corresponding acetate (R)-31, (45% ee) using a phosphate buffer (pH = 6) in aqueous medium. An E value of 300 was observed and the reaction was terminated after 3 h yielding (<5)-30 > 99% ee and the ester (R)-31 was recovered with 86% ee determined by capillary GC after 50 % conversion. 

Figure 24 Lipase-catalyzed enantioselective transesterification of 4-hydroxy-2-methyl-2-/>tolyl-cyclopentane-...

A set of -methylene-/ -hydroxy esters 42 were resolved via enzymatic enantioselective transesterification with Pseudomonas sp. lipase (PCL), free and immobilized one using either vinyl or isopropenyl acetate as acyl donors under different conditions. The corresponding (R)-(+)-acetates (R)-43 and the unreacted (S)-(-)-substrates (S)-42 were obtained with an ee up to >99%.70... 

Figure 26 Lipase-catalysed enantioselective transesterification of <2 -methylene-/ -hydroxy esters 42.

Krishna et al73 reported the enantioselective transesterification of a tertiary alcohol 51 using lipase A from Candida antarctica (CAL-A) and vinyl acetate as acyl donor in organic solvent. 

Figure 29 Lipase-catalyzed enantioselective transesterification of 2-phenylbut-3-yn-2-ol 51.

Krishna, S., H. Persson, M. Bomscheuer, U., T. Enantioselective transesterification of a tertiary alcohol by lipase A from Candida antarctica. Tetrahedron Asymmetry 2002, 13, 2693-2696. 

Ema T, Jittani M, Furuie K, Utaka M, Sakai T (2002) 5-[4-(l-Hydroxyethyl)phenyl]-10,15,20-triphenylporphyrin as a probe of the transition-state conformation in hydrolase-catalyzed enantioselective transesterifications. J Org Chem 67 2144-2151... 

There are also several reports of enantioselective transesterification involving primary alcohols possessing stereogenic centers by similar acylation procedures, such as 2,3-epoxy alcohols (eq 7), norbomene-derived iodolactones, and 1,3-propanediols. ... 

Resolution might have been possible either by asymmetric reduction at the penultimate step, or by classical methods on the final product. However, the overall yield for the eight-step synthesis was still only 2%. Nevertheless, resolution was indeed accomplished at the penultimate stage using enantioselective transesterification and hydrolysis, both catalyzed by Pseudomonas fluorescens lipase, as shown in Scheme 7. 

Scheme 9.2 Synthesis of homochiral MOCP 1 and its catalytic application in the enantioselective transesterification of racemic l-phenyl-2-propanol.

The synthetic compounds are obviously esters of a cyclopropane carboxylic acid and a cyanohydrin 202. Enantioselective transesterification of butanol and the acetate 201 of the cyanohydrin using immobilised lipases gives the required (S)-alcohol 202 and the unreacted enantiomer of the acetate (R) -201 easily racemised with Et3N. Reports using different lipases appeared at the same time CHIRAZYME L-6, the lipase from Pseudomonas immobilised on sephadex DEAE was used in i-Pr20 and the racemisation carried out with Et3N under reflux in the same solvent.55... 

Resolution by transesterification. Using vinylic acetates to esterify allyl alcohols, propargyl alcohols, 2-phenylthiocycloalkanols, a-hydroxy esters," methyl 5-hydroxy-2-hexenoates, and 2-substituted 1,3-propanediols, the enantioselective esterification provides a means of separation of optical isomers. Vinyl carbonates are also resolved by lipase-mediated enantioselective conversion to benzyl carbonates. Other esters that have also been used in the kinetic resolution include 2,2,2-tri-fluoroethyl propionate. There is a report on a double enantioselective transesterification" of racemic trifluoroethyl esters and cyclic meso-diols by lipase catalysis. 

The enzymatic reaction is promoted by microwave. Significant effects of acyl groups on the enantioselective transesterification have been observed. ... 

KR of Alcohols. KR of alcohols has traditionally relied on enzyme-catalyzed enantioselective transesterification and hydrolysis. BTM and the closely related (27 -7-chloro-l,2-dihydro-2-phenyl-imidazo[ l,2-a]quinoline (Cl-PIQ) are among the most easily obtainable and effective nonenzymatic enantioselective acylation catalysts reported to date and thus represent a... 

As reported by Kanca and co-workers, the enantioselective transesterification polycondensation of racemic AB-type monomers containing a secondary hydroxy group and a methyl ester moiety led to chiral polyesters by iterative tandem catalysis. The concurrent actions of an enantioselective acylation catalyst (such as CALB) and a racemisation catalyst (Ru(Shvo)) resulted in the high conversion of the racemic monomers to enantioenriched polymers. AB-type monomers used were typically methyl 6-hydroxyheptanoate, methyl 8-hydroxynonanoate and methyl 13-hydroxytetradecanoate. The polycondensation at 70 "C in toluene gave a polyester of high yield with a M of around several thousand and an enantiomeric excess higher than 74% [18]. 

We will consider as an example the fipase-catalyzed kinetic resolution of an alcohol by enantioselective transesterification (Fig. 6.64)... 

Fig. 6.64 Enantioselective transesterification of (R,S)-2-methyl-1-pentanol with vinylacetate.

Figure 48 Synthesis of chiral intermediates for (-)-carbovir Enantioselective transesterification of 2-hydroxymethyl-2-azabicyclo[2.2.1]hept-5-ene-3-one 135.

Scheme 14 Ethyl acetate as reagent and solvent of an enantioselective transesterification.

Scheme 16 Enantioselective transesterification of esters with 1-butanol.

Methyl-1-alkanols are excellent substrates for the lipase-catalyzed enantioselective transesterification with vinyl esters, mainly acetate or isopropenyl, and the best results have been obtained in organic solvents such as chloroform or dichloromethane [la], as shown in Scheme 26.. Many other examples of resolution of 2-methyl-1-alkanols have been, reported (Scheme 27) and the results confirmed the enantioselectivity of the reaction and a constant stereochemical outcome that may lead to the unreacted (/ )-alcohol and (5)-acetate [138-140]. 

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