Hydroxy esters, formation

Fluormation of tertiary benzylic hydroxy esters with the Ishikawa reagent gives somewhat lower yields of fluorides because of the formation of dehydrated products, 2-aryl acrylates [87] (equation 54)... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Since 1,4-butanediol (BD) undergoes dehydration side reaction in the presence of acid resulting in THF formation, the hydroxy-ester interchange reaction is the preferred method for the preparation of PBT. The first stage of reaction is carried out at 150-200°C and consists of a hydroxy-ester interchange between DMT and excess butanediol with elimination of methanol. In the second stage, temperature is raised to 250°C and BD excess is eliminated under vacuum. Tetraisopropoxy-and tetrabutoxytitanium are efficient catalysts for bodi stages (Scheme 2.20). 

The dimethyl ester of a carboxy-terminated diamide is reacted with 1,2-ethanediol in the conditions of PBT synthesis. The amide functions are unaffected while the hydroxy-ester interchange reaction proceeds to the formation of an alternating copolyesteramide (Scheme 2.60). The procedures given below are reproduced from ref. 430. (Copyright 1997 Elsevier Science Ltd, with permission of the copyright owner.)... 

Studies on Trifluoroacetic Acid. Part I. Trifluoroacetic Anhydride as a Promotor of Ester Formation between Hydroxy-Compounds and Carboxylic Acids, E. J. Bourne, M. Stacey, J. C. Tatlow, and J. M. Tedder, J. Chem. Soc., (1949) 2976-2979. 

The DKRs of a-, (3-, y- and 8-hydroxy esters were also accomplished with PCL and 1 at 60-70°C. In the DKRs, the enantioselectivities were good in most cases though the yields were moderate. The use of H2 was necessary in the DKR of 7- and 8-hydroxy esters to suppress the formation of ketones (Tables 8-10). 

A further example of highly diastereoseleetive and enantioseleetive C-H insertions performed in similar eonditions to those deseribed above was the reaetion between aryldiazoacetates and allylsilyl ethers, yielding p-hydroxy ester derivatives that are equivalents to aldol products. " An illustrative reaction between an aryldiazoacetate and trani-2-butenylsilyl ether is shown in Scheme 10.78. This reaction led to the diastereoseleetive formation of the equivalent of a syn-a do product in both high yield and enantioselectivity. 

In a study aim to develop biocatalytic process for the synthesis of Kaneka alcohol, apotential intermediate for the synthesis of HMG-CoA reductase inhibitors, cell suspensions of Acine-tobacter sp. SC 13 874 was found to reduce diketo ethyl ester to give the desired syn-(AR,5S)-dihydroxy ester with an ee of 99% and a de of 63% (Figure 7.4). When the tert-butyl ester was used as the starting material, a mixture of mono- and di-hydroxy esters was obtained with the dihydroxy ester showing an ee of 87% and de of 51% for the desired, sy -(3/t,5,Sr)-dihydroxy ester [16]. Three different ketoreductases were purified from this strain. Reductase I only catalyzes the reduction of diketo ester to its monohydroxy products, whereas reductase II catalyzes the formation of dihydroxy products from monohydroxy substrates. A third reductase (III) catalyzes the reduction of diketo ester to, vv -(3/t,55)-dihydroxy ester. 

B. Borhan, A. D. Jones, F. Knot, D. F. Grant, M. J. Kurth, B. D. Hammock, Mechanism of Soluble Epoxide Hydrolase. Formation of an a-Hydroxy Ester-Enzyme Intermediate through Asp-333 , J. Biol. Chem. 1995, 270, 26923 - 26930. 

A demonstration of the utility of the electroreductive cyclization reaction is provided by the formal total synthesis of the antitumor agent quadrone (16, Scheme 4) [17]. The first stage of the synthesis involved a controlled potential reduction of (9) in the presence of dimethyl malonate as the proton donor. An efficient cyclization ensued, leading to the formation of the y-hydroxy ester (10)... 

The methanesulfonates (481) of a-hydroxy esters can be converted to the deoxygenated esters (482) in 70 88% yields by indirect electrolysis with PhSeSePh as a recyclable reagent in a divided cell (Scheme 166). The procedure involves the formation of a-phenylselenoester by substitution of the a-methylsulfonyloxyl group with the PhSe followed by displacement of the CK-phenylseleno group with PhSe . The electrolysis is performed in a DMF-NaCl04-(Pt/C) system in the presence of PhSeSePh and ethyl malonate at 50 °C [567]. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

Sharpless and his group have also studied a series of selective transformations of r/jreo-2,3-dihydroxy esters (6) -prepared by catalytic ADH of a,P-unsaturated esters 5- which lead to very useful and highly elaborated synthetic intermediates [36], such as a-(sulfonyloxy)-P-hydroxyesters (2), P-acetoxy-a-bromo esters or a-acetoxy-p-bromo esters (8 and 9), threo- and erythro-glycidxc. esters QO and U.) and P-hydroxy esters (12). The substituent at the p-position plays an important role in determining the regiochemistry of the bromination of the 2,3-dihydroxy esters whereas a P-alkyl substituent leads to p-acetoxy-a-bromo esters, a phenyl group directs formation of the a-acetoxy-P-bromo esters (Scheme 10.5). 

Lemer and Benkovic examined the possibility of performing an intramolecular cyclisation reaction [30]. They chose the formation of a six-membered lactone ring from a hydroxy ester (12) and observed that only one single enantiomer of the 5-lactone (14) in 94% ee was formed from the corresponding 5-hydroxy ester. Moreover, the stereospecific ring closure reaction was accelerated by the antibody -elicited from the transition-state analog 15- by about a factor of 170. 

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

Scheme 28 Proposed mechanism for the formation of (l-hydroxy esters...

The data clearly indicate that the only primary product was phenylbenzoate, while all the other compounds formed by consecutive reactions upon the ester. Therefore, the scheme of reaction is that one summarized in Figure 3. The formation of the ester as the only primary product represents one important difference with respect to the Friedel-Crafts benzoylation of phenol with benzoylchloride or benzyltrichloride, catalyzed by AICI3. In the latter case, in fact, the product of para-C-acylation (p-hydroxybenzophenone) is the main product of reaction this is due to the fact that AICI3 coordinates with the 0 atom of the hydroxy group in phenol, and makes it less available for the ester formation, due to both electronic and steric reasons. 

Other reagents have also been used to effect carbon-carbon bond formation. For example, chiral monosubstituted epoxides (93) can be regioselectively carbomethoxylated under relatively mild conditions with CO/H, in the presence of the salen complex 69. The reaction proceeds with retention of chirality about the secondary epoxide carbon and represents a new route to chiral hydroxy esters 94 <99JOC2164>. 

Table 3. a-Alkylation of -Hydroxy Esters the Formation of Quaternary Carbon Centers13,16,42-48... 

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