Alcohol enantioselective esterification

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

Burgess, K. Jennings, L. D. Enantioselective esterifications of unsaturated alcohols mediated by a lipase prepared from Pseudomonas sp. J. Am. Chem. Soc. 1991,113, 6129-6139. 

The enantioselective esterification of 2-arylpropionic acids catalysed by a lipase was discussed earlier.26 Steady-state kinetics of the Pseudomonas cepacia lipase-catalysed hydrolysis of five analogous chiral and achiral esters (R)- and (.S )-(235 R1 = Me, R2 = H), (R)- and (reaction mixtures of water-insoluble substrates.212 The Km values were all die same and the apparent kcat values reflected the binding abilities of the alcoholate ions for the fast-reacting enantiomers. All the substrates are believed to be... 

Various lipases and esterases have been used for the enantioselective esterification of alcohols and hydrolysis of esters. For example, Burkholderia cepacia lipases (PS, Amano Enzyme Inc.) and Candida antarctica lipase (CAL, Novozymes) have been widely used for its wide substrate specificities, high activities and chemo, regio and enantioselectivities. Fundamentals and some selected applications are shown in this section. The origins and abbreviations of lipases introduced here are as follows. 

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. 

An enzyme-catalyzed enantioselective esterification of racemic LA 3 with -alcohols containing one to eight carbon atoms in hexane as a solvent, using Candida rugosa lipase <1997TA337>, has been described (Scheme 24). The best selectivity at 30% conversion was obtained with -hexanol, yielding the (3)-ester 176 with 72% ee, along with (K)-lipoic acid (20% ee) this decreased with -octanol (58% ee for an ester and 24% for acid) and there was a drastic drop... 

Lipases have been used to effect the enantioselective esterification of cyanohydrins or the enantioselective hydrolysis of cyanohydrin esters. This works for aldehyde cyanohydrins. Selective (S)-cyanohydrin esterification is effected by the enzyme from Pseudomonas sp. [11], There is also an example of selective (R)-cyanohydrin esterification by Candida cylindracea lipase [12]. Effenberger has shown the feasibility of this approach in principle to produce a number of enantiopure cyanohydrins derived from aldehydes. In situ derivatization with racemization as shown in Fig. 7 is possible, resulting in theoretically 100% yield of the desired enantiomer [13]. Ketone cyanohydrins, which are tertiary alcohols, do not easily undergo this reaction. 

Resolutions. The following types of substrates have been resolved via lipase-mediated enantioselective esterification malic and aspartic esters, 3-hydroxyalken-l-yl p-tolyl sulfoxides, P-hydroxy sulfoxides." A practical method involves sequential transacetylation and sulfation, followed by extraction and treatment of the aqueous layer with methanolic HCl to recover the alcohol (the organic layer yields the acetate). The use of 1-ethoxyvinyl acetate as acetyl donor in these reactions has been proposed."... 

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 enantiomers of 274 (R = H) were also independently obtained by a rare example of enzymatic enantioselective esterification in alcohol/vinyl acetate (06TA12). 

From Achiral Non-carbohydrates. — 3-Deoxy-3-guanidino-D-threose 48 equilibrates with 49. a transition state inhibitor for galactosidase. It was synthesized as shown in Scheme 12 from epoxide 47, which was obtained by porcine pancreatic lipase catalysed enantioselective esterification of the racemic epoxy-alcohol precursor. 6-Deoxy-L-talonolactone 50 was synthesized by an asymmetric aldol condensation - dihydroxylation sequence (Vol.24, p.lS2) in improved diastereoselectivity and was converted into 2-acetamido-2,6-dideoxy-L-fucose (shown as its furanose isomer 51 in Scheme 13), 3-acetamido-3,6Hlideoxy-L-idose and 5-acetamido-S,6-dideoxy-D-allose by S 2 displacements of triflate with azide ion. 4-Amino-4-deoxy-DL-erthrose 53 was obtained from the hetero-Diels-Alder adduct 52 by a sequence of reactions including cis-dihydroxylation (OSO4, NMNO) of the alkene moiety (Scheme 14). The synthesis of a racemic branched-chain lactam is covered in Chapter 16. 

The unusual chlorinated stannane 125 was used by Keck for the preparation of pyrans. The BINOL/Ti(0/-Pr)4 catalyzed reaction of (2-chloromethyl)allylstannane 125 provided the homoallylic alcohol 126 in high yields and excellent enantioselectivities. Esterification and treatment with Nal gave the iodinated ester 127, poised for cyclization. Sml2 promoted the cyclization to hemiketal 128, which was derivatized to ketal 129 to simplify its chromatographic purification. 

Naproxen, (S)-2-(6-methoxy-2-naphthyl)propanoic acid 126 is a nonsteroidal anti-inflammatory and analgesic agent first developed by Syntex [220,221]. Biologically active desired S-naproxen has been prepared by enantioselective hydrolysis of the methyl ester of naproxen by esterase derived from Bacillus subtilis Thai 1-8 [222]. The esterase was subsequently clone in Escherichia coli with over 800-fold ipcrease in activity of enzyme. The resolution of racemic naproxen amide and ketoprofen amides has been demonstrated by amidases from Rhodococcus erythropolis MP50 and Rhodococcus sp. C311 (223-226). 5-Naproxen 126 and 5-ketoprofen 127 (Fig. 44) were obtained in 40% yields (theoretical maximum yield is 50%) and 97% e.e. Recently, the enantioselective esterification of naproxen has been demonstrated using lipase from Candida cylindraceae in isooctane as solvent and trimethylsilyl as alcohol. The undesired isomer of naproxen was esterified leaving desired S isomer unreacted [227]. 

The enantioselective esterification of unsaturated secondary alcohols has been extensively studied [182] and has found several successful additional applications with substrates containing double bonds [183-188]. The results have been collected in Table 2 and Scheme 40, whereas Scheme 41 shows interesting examples of the resolution of hydroxy compounds that contain a triple bond in the molecule [189,190]. 

Lipase P. Jragi Activated PEG2 Synthesis of teipene alcohol ester and gefamate, enantioselective esterification Benzene 60, 80, 86, 114... 

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. 

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

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