Enantiomerically enriched acetals

When a reverse procedure was applied, i.e. enzymatic acetylation of racemic 3, formed in situ from the appropriate aldehydes and thiols, the reaction proceeded under the conditions of dynamic kinetic resolution and gave enantiomerically enriched acetates 2 with 65-90% yields and with ees up to 95% (Equation 2). It must be mentioned that the addition of silica proved crucial, as in its absence no racemization of the initially formed substrates 3 occurred and the reaction stopped at the 50% conversion. 

The acetolyses of both ero-2-norbomyl brosylate and e do-2-norbomyl brosylate produce exclusively exo-2-norbomyl acetate. The exo-brosylate is more reactive than the endo isomer by a factor of 350. Furthermore, enantiomerically enriched exo-brosylate gave completely racemic ero-acetate, and the endo-brosylate gave acetate that was at least 93% racemic. 

Searching for a method of synthesis of enantiopure lamivudine 1, the compound having a monothioacetal stereogenic centre, Rayner et al. investigated a lipase-catalysed hydrolysis of various racemic a-acetoxysulfides 2. They found out that the reaction was both chemoselective (only the acetate group was hydrolysed with no detectable hydrolysis of the other ester moieties) and stereoselective. As a result of the kinetic resolution, enantiomerically enriched unreacted starting compounds were obtained. However, the hydrolysis products 3 were lost due to decomposition." In this way, the product yields could not exceed 50% (Equation 1). The product 2 (R = CH2CH(OEt)2) was finally transformed into lamivudine 1 and its 4-epimer. ... 

There are several other examples of C-chiral hydroxy phosphorus compounds which were obtained in enantiomerically enriched forms using enzymatic methodology. Thus, a 5-l-diethylphosphonomethyl-2-hydroxycyclohexane 48 was resolved into enantiomers by enzymatic acetylation the highest enantioselectivity was achieved using lipase PS in THF or lipase AK without solvent and vinyl acetate as the acetylating agent (Equation 26). ... 

Due to the distance between the stereogenic center and the place of the nucleophilic attack, the enantioselective 1,5-substitution of chiral enyne acetates constitutes one of the rare cases of remote stereocontrol in organocopper chemistry. Moreover, the method is not limited to substrate 51, but can also be applied to the synthesis of enantiomerically enriched or pure vinylallenes 53-57 with variable substituent patterns (Scheme 2.20) [28]. 

Scheme 2.20 Enantiomerically enriched or pure vinylallenes formed by 1,5-substitution of chiral enyne acetates in the presence of tri-n-butylphosphine (53-56) or triethyl phosphite (57).

Although the separation of the diastereomeric alcohols 55 or 64 was not possible by flash chromatography we succeeded in a separation by preparative HPLC. The enantiomeric excess of the individual diastereoisomers was determined after saponification to the diol 54 or 63 by chiral GC. It turned out that the enantiomeric excess of both acetates was only 7% ee. The value was so low that we did not make an effort to continue with only marginally enantiomerically enriched material after HPLC separation. 

The second-resolution approach relied on enzymatic resolution of acetate esters 62 (Scheme 4.7) (Hayakawa et ah, 1991). The sequence opened with the alkylation of 2,3-difluoro-6-nitrophenol (59) with l-acetoxychloro-2-propane (60) to deliver ether 61. Reduction of the nitro group of 61 gave an intermediate anihne that cyclized to give racemic benzoxazine 62 in 62% yield. A variety of lipases were then examined for the resolution. The best results arose from use of LPL Amano 3, derived from P. aeruginosa, which gave a ratio of 73 23 in favor of the desired (—)-enantiomer. Benzoylation of the enantiomerically-enriched mixture followed by chromatography of the aryl amides delivered enantiomerically pure 63. 

Intramolecular cycloaddilion of kctcnc iminium salts possessing a chiral pyrrolidine auxiliary group gives bicyclic cyclobutanone 7 with good to excellent enantioselectivity. The enantiomeric enrichment was determined by conversion to the diastereomeric acetals 8 with (2R, >R)-bu-tane-2,3-diol and determination of the diastereomeric excesses.16... 

Hydrolase-catalyzed acylation can be used to purify a diastereo- and enantiomerically enriched product. For example dimethylzinc addition to the racemic aldehyde 77 furnishes the racemic phenylsulfanylbutanol 78 (Scheme 4.29) in a 95/5 (2R, 3R )/(2R, 3S )-mtio. When this is treated with Chirazyme L2 (CALB) and vinyl acetate in heptane it is resolved with a high E-value (>400) [91]. However the diastereomeric ratio in the remaining substrate and produced ester is virtually unchanged. To circumvent the problematic contamination with the undesired diastereomers, enantiomerically enriched aldehyde 77 was reacted with dimethyl-zinc to furnish one major stereoisomer of 78 contaminated with a small amount of a mixture of the other three (Scheme 4.29). Because the two major contaminants had the opposite configuration at position 2 relative to the major product, these contaminants were efficiently removed from the major product and the trace byproduct by treatment with the 2R-selective Chirazyme L2 (CALB) and vinyl acetate in heptane to furnish virtually diastereo- and enantiomerically pure acetate (2R,3R)-79 or the alcohol (2S,3S)-78 (Scheme 4.29) [91]. 

An additional interesting example is the conjugate addition of 1 to activated allylic acetates 18 under the chiral phase-transfer catalysis of 4d, and subsequent elimination reaction, as reported by Ramachandran and coworkers, as this enables the synthesis of various enantiomerically enriched glutamic add derivatives [39]. The utility of this process has been demonstrated by the transformation of (S)-19 (R = Ph) into 4-substituted pyroglutamate (2S,4S)-20, as illustrated in Scheme 2.17. 

Interestingly, the use of optically active alcohol 51 in this protocol leads, after cleavage of the benzylic ether in the initial adduct 52, to the enantiomerically enriched homoallylic alcohol 26. This approach appears to be the first asymmetric preparation of homoallylic alcohols via open-chain acetal derivatives (Scheme 13.19). 

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. 

Arylpropionic acids are important class of non-steroidal anti-inflammatory drugs (NSAID). Their pharmacological activity is mainly in one of both enantiomers. Thus, efforts had been made to access to the enantiomerically pure substance. The kinetic resolution of racemic 2-(2-fluoro-4-biphenyl) propanoic acid 56 and 2(4-isobutylphenyl) propanoic acid 59 (Ibuprofen) was performed via enzymatic esterification and transesterification using an alcohol and vinyl acetate, respectively in a membrane reactor. The unreacted acid is obtained in highly enantiomerically enriched form. A consecutive approach consisting of the enzymatic hydrolysis of the resulted esters is needed to achieve the alcohol in optically pure form.77... 

Enantiomerically enriched a-hydroxy acetals are interesting synthons and can be transformed to a variety of chiral building blocks such as 1,2-diols, a-hydroxy acids, or 1,2-amino alcohols (Scheme 18.4). Whereas the oxidation to (f )-ethyl lactate was rather difficult and required the protection of the OH group, the reduction could be easily accomplished after hydrolysis of the acetal. No significant racemization was observed. With a boronic acid derivative and a secondary amine as described by Petasis and Zavialov,24 it was also possible to synthesize an amino alcohol with high diastereoselectivity. 

Several enantiomerically-enriched templates have also been employed in the preparation of chiral, non-racemic piperidines. The RCM of N, O- and O, O-acetals have been developed by Rutjes and co-workers into a powerful method for the preparation of a wide-variety of heterocycles <02MI736> (Scheme 17). Here the reaction of an enantiopure Ts-protected allyl glycine is employed to prepare a chiral, non-racemic, cyclic amino acid derivative. These N,0-acetals can be readily transformed into synthetically useful iV-sulfonyliminium ions by treatment with BF3 OEt2 <00CC699>. 

The structural core of (-)-adaline was prepared by a lithium-activated SN2-type alkynylation of an enantiomerically-enriched tricyclic N, O-acetal followed by reduction, Ar-formylation (80, R = CHO), and RCM using the MC2 <02OL2469> (Scheme 61). Yields were only slightly lower with the GMC. RCM fails with the HC1 salt of 80 (R =H2C1), presumably because of a diequatorial arrangement of the 2,6-dialkenyl substituents in that derivative. 

Treatment of chiral, nonracemic vinyl sulfoxides (214) with O-silylated ketene acetal (215) in the presence of a catalytic amount of zinc chloride resulted in an enantioselective additive Pummerer-type reaction, affording the corresponding enantiomerically enriched methyl-4-siloxy-4-sulfenylbuyrate (216) (Scheme 55).122 This is the overall addition of the enolate equivalent to the vinyl sulfoxide. 

Instead of applying enantioselective hydrolysis of meso diacetates monoacetylation of meso-diols can generate enantiomerically enriched monoesters. The catalyst can be an esterase in vinyl acetate (e. g. 44 — (S)-42) or a short peptide derivative (e. g. 45 — 46 catalyzed by 48) as shown in O Scheme 36. Transition state 49 has been proposed for the asymmetric monoacetylation of diol 45 with acetic anhydride catalyzed by peptide 48 [189]. 

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