Carboxylic acids enantioselective

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids [4]. Scientists at Diversa expanded the collection of nitrilases by metagenome panning [56]. Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity, limited activity (substrate acceptance), and/or product inhibition. Diversa also reported the first example of the directed evolution of an enantioselective nitrilase [20]. An additional limitation had to be overcome, which is sometimes ignored, when enzymes are used as catalysts in synthetic organic chemistry product inhibition and/or decreased enantioselectivity at high substrate concentrations [20]. 

Burk and coworkers have used a variety of nitrilases for the DKR of cyanohydrins [48]. Nitrilases catalyze the hydrolytic conversion of cyanohydrins directly to the corresponding carboxylic acids. Racemization was performed under basic conditions (phosphate buffer, pH 8) through reversible loss of HCN. (R)-Mandelic acid was obtained in high yield (86% yield) and high enantioselectivity (98% ee) after 3 hours (Figure 4.23). 

Enantioselective Biotran ormations of Carboxylic Acid Derivatives 147 Racemase (in situ) ... 

Although the aminolysis of esters to amides is auseful synthetic operation, usually it presents some disadvantages in terms of drastic reaction conditions, long reaction times or strong alkali metal as catalyst, which are usually not compatible with other functional groups in the molecule [6]. For this reason, enzymatic aminolysis of carboxylic acid derivatives offers a clean and ecological way for the preparation of different kind of amines and amides in a regio-, chemo-, and enantioselective manner. 

It is worthy of note that a-sulfanyl phosphonic acids, which can now be obtained enantioselectively from corresponding a-hydroxyphosphonates, are analogues of the a-sulfanyl carboxylic acids, which, for some of them, are metallo- -lactamases inhibitors [ 112]. To our knowledge, it does not seem that biological activities of a-sulfanyl phosphonic acids have been examined so far. 

By an alternative approach, the enantioselective reduction of 1,2-diketimines was achieved by using hydride reagents in the presence of stoichiometric amounts or an excess of enantiopure carboxylic acids. An... 

A different type of catalysis is observed using proline as a catalyst.166 Proline promotes addition of acetone to aromatic aldehydes with 65-77% enantioselectivity. It has been suggested that the carboxylic acid functions as an intramolecular proton donor and promotes reaction through an enamine intermediate. 

Ruthenium complexes containing this ligand are able to reduce a variety of double bonds with e.e. above 95%. In order to achieve high enantioselectivity, the reactant must show a strong preference for a specific orientation when complexed with the catalyst. This ordinarily requires the presence of a functional group that can coordinate with the metal. The ruthenium-BINAP catalyst has been used successfully with unsaturated amides,23 allylic and homoallylic alcohols,24 and unsaturated carboxylic acids.25... 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

The use of ethanol as an achiral auxiliary gave the adduct 53 with 55% ee, while neopentyl alcohol and methanol gave 96 and 87% ee, respectively. These results suggested that the achiral alcohol might exert a steric effect on the stereoselectivity. However, the increase in enantioselectivity from 55% to about 96% when 2,2,2-trifluoroethanol (TFE) was used instead of ethanol indicates a possible significant inductive effect also. Good enantioselectivities were also obtained with carboxylic acids and phenols. 

Adam, W., Lazarus, M., Boss, B. et al. (1997) Enzymic resolution of chiral 2-hydroxy carboxylic acids by enantioselective oxidation with molecular oxygen catalyzed by the glycolate oxidase from spinach (Spinacia oleracea). The Journal of Organic Chemistry, 62 (22), 7841-7843. 

By screening 53 Rhodococcus and Pseudomonas strains, an NHase-amidase biocatalyst system was identified for the production of the 2,2-dimethylcyclopropane carboxylic acid precursor of the dehydropeptidase inhibitor Cilastatin, which is used to prolong the antibacterial effect of Imipenem. A systematic study of the most selective of these strains, Rhodococcus erythropolis ATCC25 544, revealed that maximal product formation occurs at pH 8.0 but that ee decreased above pH 7.0. In addition, significant enantioselectivity decreases were observed above 20 °C. A survey of organic solvent effects identified methanol (10% v/v) as the... 

The nitrilase from cyanobacterium Synechocystis sp. PCC6803 was found to effect the stereoselective hydrolysis of phenyl-substituted /3-hydroxy nitriles to (S)-enriched /3-hydroxy carboxylic acids. The enzyme also effected the conversion of y-hydroxynitrile, albeit with lesser enantioselectivity (Table 8.10). Interestingly, this enzyme was also was found to hydrolyze aliphatic dinitriles, such that for 1,2-dicyanoethane and 1,3-dicyanopropane the... 

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