Esters mandelate

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 enantiomeric purity of vinylsilane (S)-3a and (R)-3c are determined to be >95% ee by 1H-NMR (400 MHz) on the derived mandelate ester, obtained by a DCC-promoted coupling to (R)-O-acetylmandelic acid, and absolute stereochemical assignment is accomplished by 1H NMR analysis of the derived (R)-O-acetyl-mandelate esters. For details of this procedure see the published method of Trost.3... 

The determination of enantiomeric excess (96% ee) of the Claisen rearrangement products 4a and 4b is accomplished by a Mosher 1H NMR analysis of the (R)-O-acetylmandelate esters that are derived from the primary alcohols. For example, 4a is reduced with UAIH4 (1.0 equiv/THF/0°C) followed by esterification of the resulting primary alcohol with (R)-O-acetylmandelic acid (DCC, 1.5 equiv/cat. DMAP/CH2CI2) to afford the mandelate ester in 91% yield (two steps).3... 

Subtle yet significant refinements in the stoichiometry and reaction conditions for the base catalyzed reaction of cyanamide with a mandelate ester have been described recently in the patent literature (Scheme 6.27). The advantages include fewer impurities and avoidance of the notoriously unstable guanidine free base. In both cases, excellent yields of very pure 68 (up to 99.87A%) have... 

In solution these esters undergo a variety of transformations which are dependent on the reaction conditions. In benzene, decomposition to carbon monoxide and carbonyl compounds is observed either upon direct irradiation94 or with benzophenone sensitization.33 In cyclohexane a complex product mixture is obtained.95 Addition of solvent to the carbonyl group is observed when the reaction is carried out in cyclohexene.54 At room temperature photoreduction takes place when the reaction is carried out in a secondary alcohol.96-97 However, in the case of the phenylglyoxylates quite a different reaction is observed when the reaction is carried out at elevated temperatures. The ester is reduced to the mandelate ester of the solvent alcohol, and the alcohol moiety of the ester is oxidized to the corresponding carbonyl compound. The pyruvates have not been studied at an elevated temperature. 

Oxidation of chiral esters of phenylacetic acids. These esters can be converted into acetates of mandelic esters by oxidation with DDQ in acetic acid. The reaction is diastereoselective when carried out on esters of chiral alcohols, of which 8-phenylmenthol is the most useful. The presence of substituents on the phenyl group has slight effect on the diastereoselectivity, which depends on formation of a donor-acceptor complex between the substrate and the quinone with removal of a hydrogen atom. The acetoxy group then enters from the opposite, more bulky face. 

Corey exploited the remarkable configurational stability of cyclopropyllithiums in his synthesis of hybridalactone. The stannane 28 was made by Simmons-Smith cyclopropanation of the allylic alcohol 27 and resolved by formation of an O-methyl mandelate ester. Transmetallation of 29 with 2 equiv. BuLi gave an organolithium which retained its stereochemistry even in THF over a period of 3 h at 0 °C, finally adding to 31 to give 32. 

The keto group of a keto ester may be preferentially reduced by catalytic hydrogenation. Excellent yields of hydroxy esters are obtained. Copper-chromium oxide catalyst has been employed in the preparation of methyl p-(a-hydroxyethyl)-benzoate and several aliphatic -hydroxy esters. The last compounds have also been made by hydrogenation over nickel catalysts.Substituted mandelic esters are prepared by catalytic reduction of aromatic a-keto esters over a palladium catalyst. Similarly, platinum oxide and copper-chromium oxide have been used in the aliphatic series for the preparation of the a-hydroxy diester, diethyl... 

Alternatively, Dujardin et al. [151] prepared derivatives of 2-deoxy-L-araZ m6>-hexose via the Diels-Alder addition of achiral oxadiene 287 to 0-vinyl mandelic ester (—)-288 (Scheme 13.81). 

The Claisen rearrangement has only recently been used to provide functionalized derivatives. Thus, mandelate esters react with orthoacetates and orthopropionates to give the corresponding homophthalates. ... 

Chart L Determination of absolute configuration using mandelate esters. Con-figurations denoted refer only to carbinol carbon atom. Key A, Ref, 7 B, Ref, 8 C, Ref. 9 D, Ref. 10 and E, Ref. 5. Continued on next page. 

Chart I, Continued. Determination of absolute configuration using mandelate esters. Configurations denoted refer only to carbinol carbon atom. Key see... 

The mandelate esters serve yet an additional role in chiral synthesis - facilitation of resolution by hplc. The diastereo-mers in entries 1,2, and 4 of Chart 1 are all readily resolved on a Waters Prep 500 column utilizing 2-105S ethyl acetate in hexane (7,8,10,13). The diastereomer labelled S of entry 2,... 

Nonaqueous procedures for oxidation of mandelic esters and the cleavage of p-nitro-phenylhydrazones and semicarbazones involves treatment with ammonium chlorochromate adsorbed on alumina. ... 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Structure XII was favored by Merling, for like Fischer s triacetonealka-mine, XIV (the mandelic ester possesses mydriatic properties (86)), the hydroxyl is gamma with respect to the nitrogen. Tropidine would then have an unsaturated iSmns-bridge while tropinic acid would be iV-methyl-... 

Scopolamine produces the same effects in the eye as atropine, but is more powerful. It is usually administered as its hydrobromide, and a 0.2 % solution of this salt can be used instead of 1 % atropine. sulfate. The semisynthetic mandelic ester of tropine, homatropine, is useful as a transitory mydriatic. Both its mydriatic and cycloplegic effects are weaker than those of atropine and much shorter in duration. It is used as its hydrochloride or hydrobromide in 1-2 % solution. 

More far-reaching modifications of the tropane nucleus must now be considered. The tropic ester of homotropine (III) is said to act qualitatively like atropine on the eye and the heart, but to stimulate intestinal muscle and to antagonize atropine in that tissue. Its mandelic ester was said to be devoid of mydriatic activity (34). 

Eucatropine (Euphthalmin) was the first successful mydriatic not containing the tropane nucleus it is the mandelic ester (VI) of the /3-form of 4-hydroxy-l, 2,2,6-tetramethylpiperidine. It is a relatively weak mydriatic and does not paralyze accommodation. The benzilic esters of both the a- and /3-forms of the same 4-hydroxypiperidine derivative, and their methochlorides, were prepared by Ford-Moore and Ing (36). The metho-salts were about 50 % more active than atropine in the mouse, but the more active /3-metho-salt proved to be a very weak mydriatic in man like eucatropine it was not cycloplegic. 

Most of the efforts within this area have been directed towards the achievement of enantioselectivety in the Abramov process. Thus, in the reactions between ArCHO and diethyl hydrogen phosphonate, the presence of 20% of a catalyst derived from LaCl3.7H20 and dilithium (/f)-binaphthoxide, in THF at temperatures lower than -20°, results in the formation of (5)-(-)-( -hydroxybenzyl)phosphonic diesters (110) in >90% yields at -40° - the most effective temperature. However, the enantioselectivity does depend on the individual aromatic substituent, being 82% when Ar is 4-methoxyphenyl, but <50% for Ar = Ph or 4-chlorophenyl. Similar results were later reported for reactions which involved dnnamaldehyde the enantioselectivity, described as modest, was also dependent on temperature, timing, and ratio of reactants the enantiomeric forms of the product were separated by HPLC of the ( )-mandelate esters, and the minor, but crystalline, diastereoisomer was shown by X-ray analysis to have the (/ ,/ ) configuration... 

Sarhan (112) used a copolymer (with 4-vinylpyridine as one comonomer) imprinted with the D-mandelic ester monomer 6 for deprotonation and selective protonation of the racemate of mandelic acid. An enantiomeric excess of several per cent for one enantiomer was observed. 

Hou reported (23) that Flavobacterium sp. DS5 converted oleic acid to 10-KSA in 85% yield. Optimum time, pH, and temperature for the production of 10-KSA are as follows 36 h, 7.5, and 30°C. Asmall amount of 10-HSA( 10% ofthe main product 10-KSA) is also produced during the bioconversion. 10-KSA is not further metabolized by strain DS5 and accumulates in the medium. In contrast to growing cells, a resting cell suspension of strain DS5 produces 10-HSA and 10-KSA in a ratio of 1 3. The cell-free crude extract obtained from ultrasonic disruption of the cells converts oleic acid mainly to 10-HSA (10-HSA 10-KSA = 97 3). This result strongly suggested that oleic acid is converted to 10-KSA via 10-HSA. Stereochemistry of 10-HSA from strain DS5, determined by H NMR ofthe mandelate esters, showed 66% enantiomeric excess in 10(7 ) form. 

The use of subtilisin (a protease which is widely used in detergent formulations) as a biocatalyst for the stereospecific hydrolysis of esters is well established [271-273]. Along the same lines, a protease derived from Aspergillus oryzae, which has hitherto mainly been used for cheese processing, has been shown to be particularly useful for the resolution of sterically hindered substrates such as a,a,a-trisubstituted carboxylates [274] (Scheme 2.42). While traditionaT proteases such as subtilisin were plagued by slow reaction rates and low selectivities, the a-tri-fluoromethyl mandelic ester (which constitutes a precursor of a widely used chiral derivatization agent, Mosher s acid [275]) was successfully resolved by Aspergillus oryzae protease [276]. 

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