Glutaric esters synthesis

The addition of ester enolates to oi.P-unsaturated esters occurs with identical diastereoselectivity as shown for a,(3-enones this is exemplified by the diastereoselective synthesis of erythro- and threo-2,3-disubstituted glutarate esters (178 and 179). 146 -c Similarly, Yamaguchi reports a general synthesis of /ra/tJ-2-alkoxycarbonyl-l-cycloalkanepropionates (181-184) from w-halo-a,(3-unsaturated esters (180),... 

Tertiary carbons are not carboxylated, however, so the rearrangement reaction can be of advantage for the synthesis of certain symmetrical glutaric esters (equation 68). 

COOCjHs CH.—COOCjHj By using /3/3-dimetliyl glutaric ester, Kommpa obtained diketo-apocainpliorie ester which was used for the synthesis of camphoric acid 2B COOCjllj CHj.COOC.jH5 CO—CH.COOCjII6... 

Scheme 14. Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutaric ester via enzymatic hydrolysis.

From Aceto-acetic Ester.—Glutaric acid may also be made by either the aceto-acetic ester synthesis or by the malonic ester synthesis as follows,... 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Two variations of the malonic ester synthesis make use of dihaloalkanes. In the first of these, two molar equivalents of sodiomalonic ester are allowed to react with a dihaloalkane. Two consecutive alkylations occur, giving a tetraester hydrolysis and decarboxylation of the tetraester yield a dicarboxylic acid. An example is the synthesis of glutaric acid ... 

M.J. Homan, R. Vail, B. Morgan, V. Sabesan, C. Levy, D.R. Dodds, A. Zaks, Enzymatic hydrolysis of a prochiral 3-substituted glutarate ester, an intermediate in the synthesis of an NKl/ NK2 dual antagonist, Adv. Synth. Catal. 343 (6-7) (2001) 744-749. 

Similarly, glutaryl acylase was used as a biocatalyst in the synthesis of amides of glutaric acid derivatives using the acyl donor as the liquid phase in which the undissolved nucleophile was suspended [33]. In another example, immobilized lipase was used in a medium composed solely of substrate to resolve racemic ketoprofen esters via hydrolysis [36]. 

This synthesis has one rather anomalous application, when a-bromo-isobutyric acid (or its ethyl ester) is heated with silver, some tetramethyl-succinic acid is produced in the ordinary way (B., 23, 297 26, 1458). But there also appears trimethylglutaric acid (A., 292, 220). To explain the unexpected formation of this acid, it has been assumed that a portion of the a-bromoisobutyric acid gives up HBr to form methylacrylic acid. This latter then forms j3-bromoisobutyric acid, and the silver withdraws bromine from the a- and /3 acids, whereby the residues unite to tri-methyl-glutaric acid (B., 22, 48, 60). A similar explanation applies to some other syntheses in which tetramethylsuccinic and trimethylglutaric acids appear together. 

Researchers at the biotech company EntreMed, Inc., have recently prepared and tested 2-phthalimidino-glutaric acid analogs of thalidomide and found them to be potent inhibitors of tumor metastasis [28], The key to the success of their synthesis was a resolution via enantioselective ester hydrolysis catalyzed by ChiroCLEC -BL, the CLC form of the protease subtilisin. The authors were able to isolate both enantiomers of the desired product with good optical purity (95% ee) (see Fig. 7). 

Pig Liver Esterase (PLE). This is the more used car-boxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1, CAS 9016-18-6) which physiologically catalyzes the hydrolysis of carboxylic acid esters to the free acid anion and alcohol. PLE is a serine hydrolase which has been widely used for the preparation of chiral synthons and these applications have been fully reviewed. An active-site model for interpreting and predicting the specificity of the enzyme has been published. In the pioneering studies of the enzyme applications field, PLE was used for the chiral synthesis of mevalonolactone. Prochiral 3-substituted glutaric acid diesters... 

The synthesis has been reported of the D-homo-c-nor-derivative (132) from the keto-ester (129). Stobbe condensation of 2-(l-methoxycarbonylethyl)-4,5-benzindan-l-one (129) with dimethyl glutarate afforded an acid which on hydrolysis-decarboxylation and subsequent esterification provided the diester (130). Catalytic hydrogenation of (130), followed by base hydrolysis, gave the diacid (131), which on pyrolysis yielded the tetracyclic keto-derivative (132). ... 

Kompa s Synthesis of Camphoric Acid.— The synthesis of camphoric acid is accomplished by starting with di-ethyl oxalate and condensing it with the di-ethyl ester of di-methyl glutaric acid. 

A synthesis of matrine under milder conditions although in poorer yield has also been reported 106). The ester half-aldehyde of glutaric acid was condensed to the Schiff base CXLVI with aminolupinane. Dehydrogenation conditions caused cyclization with the formation of a mixture which upon reduction yielded matrine, allomatrine, and lup-anine. 

With diethyl malonate. Two different products are obtainable in moderate yield by reaction of malonic ester with formalin. With a 1 2 ratio of aldehyde to ester and diethylamine as catalyst, the product is the tetraester (1), an intermediate in one synthesis of glutaric acid. With a 2 1 ratio and potassium bicarbonate as catalyst, the product is the crystalline solid diethyl bis(hydroxymethyl)malonate (2). ... 

Figure 7.3 summarizes our synthesis of all three stereoisomers of auxin-glutaric acid (167).3 Commercially available (.S )-2-methyl-l -butanol (A) and L-isoleucine (B) were converted to (.S)-3-mclhylpcntanoic acid (C), which was previously employed by Kogl and Erxleben to synthesize auxin-glutaric acid. Then, C was converted to bromo ester E, whose intramolecular cyclization to give 5-lactone F was the key step. Chromic-acid oxidation of F furnished a stereoisomeric mixture of auxin-glutaric acid (167). 

Other derivatives from carboxylic acids can be used as substrates in Friedel-Crafts acylation reactions, including anhydrides and esters. Toluene reacted with glutaric anhydride in the presence of aluminum chloride to give 197, which was used in the Vig et al. synthesis of curcumene ether.128 Lactones are also effective substrates in this cyclization, generating ketones. 129... 

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