Enantioselective acetylation

The resolution of optically active compounds by gas chromatography with chiral phases is a well-established procedure, and the separation of Al-perfluoto-acetylated ammo acid ester enantiomers m 1967 was the first successful application of enantioselective gas-liquid chromatography [39] Ammo acids have been resolved as their A -trifluoroacetyl esters on chiral diamide phases such as N-lauroyl-L-valineferf-butylamideorAl-docosanoyl-L-valme /ez-r-butylamide [40,41,... 

Interestingly, phase-transfer catalysts including crown ethers have been used to promote enantioselective variations of Darzens condensation. Toke and coworkers showed that the novel 15-crown-5 catalyst derived from d-glucose 33 could promote the condensation between acetyl chloride 31 and benzaldehyde to give the epoxide in 49% yield and 71% A modified cinchoninium bromide was shown to act as an effective phase transfer catalyst for the transformation as well. ... 

It was our delight that the reactions catalyzed were activated even at -40 °C in the presence of a catalytic amount of achiral titanium catalysts (10 mol%) to afford the desilylacetylated 2-pyrazoline cycloadduct Na, l-acetyl-4-methyl-5-(2-oxo-3-oxazolidinylcarbonyl)-2-pyrazoline, in high yields as the far major product (Scheme 7.35). Although some chiral titanium TADDOlate catalysts were successfully applied to activate these reactions leading to the moderate enantioselectivities (up to 55% ee), the chemical yields were not satisfactory. 

In a first report [24], the enantioselectivities of various proteases were evaluated by comparing the biocatalyzedhydrolysis of2-chloroethyl esters of N-acetyl-i- and D-amino acids in water and their transesterification with w-propanol in butyl ether. By comparing the ratio of the kc t/Ku values for the l- and D-enantiomers in the two reactions, a remarkable relation of the proteases enantioselectivity was observed apparently, in this case, the organic solvents destroyed the selectivity of the tested enzymes. This finding... 

The research group of Backvall employed the Shvo s ruthenium complex (1) [21] for the racemization. This complex is activated by heat. For the KR they used p-chlorophenyl acetate as the acyl donor in combination with thermostable enzymes, such as CALB [20] (Figure 4.7). This was the first practical chemoenzymatic DKR affording acetylated sec-alcohols in high yields and excellent enantioselectivities. In the best case 100% conversion (92% isolated yield) with 99% ee was obtained. This method was subsequently applied to a variety of different substrates and it is employed (with a different ruthenium complex) by the Dutch company DSM for the large-scale production of (R)-phenylethanol [22]. 

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). ... 

In turn, an attempt at the resolution of phosphothreonine diester using both the acetylation and hydrolysis approaches proved that the reactions were chemo-and diastereoselective, hut completely non-enantioselective. Another approach to the synthesis of phosphoisoserine was reported by Hammerschmidt et al. In the first step, they resolved diisopropyl 2-azido-l-hydroxyethanephosphonate 64... 

Layh N, A Stolz, S Eorster, E Effenberger, H-J Knackmuss (1992) Enantioselective hydrolysis of O-acetyl-mandelonitrile to O-acetylmandelic acid by bacterial nitrilases. Arch Microbiol 158 405-411. 

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. 

Several hundred tons of L-methionine per year are produced by enzymatic conversion in an enzyme membrane reactor. An alternative approach is dynamic resolution, where the unconverted enantiomer is racemized in situ. Starting from racemic /V-acetyl-amino acid, the enantioselective L-acylase is used in combination with an TV-acyl-amino acid racemase to enable nearly total conversion of the substrate. 

In the studies conducted by Reetz, rhodium catalysts based on mixtures of monodentate phosphites, monodentate phosphonites and combinations of the two were screened in the enantioselective hydrogenation of a- and /9-N-acetyl-de-hydroamino acid esters, enamides and dimethyl itaconate [40], and a number of the more striking positive results are listed in Table 36.3. An enhanced ee-value was found mostly with combinations of two phosphonites, or one phosphonite and one phosphite, in particular when one of the ligands carries a bulky substituent and the other a small one. 

There is little doubt that the hydrogenation of dehydro a-amino acids is the best-studied enantioselective catalytic reaction. This was initiated by the successful development of the L-dopa process by Knowles (see below) and for many years, acetylated aminocinnamic acid derivatives were the model substrates to test most newly developed ligands. As can be seen below, this is the transformation most often used for the stereoselective synthesis of a variety of pharma and... 

Brunner et al. [26] synthesized and applied so-called dendrizymes in enan-tioselective catalysis. These catalysts are based on dendrimers which have a functionalized periphery that carries chiral subunits, (e.g. dendrons functionalized with chiral menthol or borneol ligands). The core phosphine donor atoms can be complexed to (transition) metal salts. The resultant dendron-enlarged 1,2-diphosphino-ethane (e.g. 16, see Scheme 17) Rh1 complexes were used as catalysts in the hydrogenation of acetamidocinnamic acid to yield iV-acetyl-phenylalanine (Scheme 17) [26]. A small retardation of the hydrogenation of the substrate was encountered, pointing to an effect of the meta-positioned dendron substituents. No significantly enantiomerically enriched products were isolated. However, a somewhat improved enantioselectivity (up to 10-11% e.e.) was... 

Jin and Weinreb reported the enantioselective total synthesis of 5,11-methano-morphanthridine Amaryllidaceae alkaloids via ethynylation of a chiral aldehyde followed by allenylsilane cyclization (Scheme 4.6) [10]. Addition of ethynylmagnesium bromide to 27 produced a 2 1 mixture of (S)- and (R)-propargyl alcohols 28. Both of these isomers were separately converted into the desired same acetate 28 by acetylation or Mitsunobu inversion reaction. After the reaction of 28 with a silyl cuprate, the resulting allene 29 was then converted into (-)-coccinine 31 via an allenylsilane cyclization. 

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. 

FIGURE 1.3 Enantiomer separation of the chiral acid iV-acetyl-a-allyl-glycine on CHIR-ALPAK QN-AX (a) and CHIRALPAK QD-AX (b) by an enantioselective anion-exchange retention process. Chromatographic conditions Column dimension, 150 x 4 mm ID eluent, 1 % (v/v) glacial acetic acid in methanol flow rate, 1 mLmin temperature, 25°C detection, UV 230 nm. (Reproduced from M. Lammerhofer, et ah, Nachrichten aus der Chemie, 50 1037 (2002). With permission.)... 

Yu, Y-R and Wu, W-H., Simultaneous analysis of enantiomeric composition of amino acids and A -acetyl-amino acids by enantioselective chromatography. Chirality, 13, 231, 2001. 

Lundgren, S. Wingstrand, E. Penhoat, M. Moberg, C. Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources. J. Am. Chem. Soc. 2005,127, 11592-11593. 

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