Dimethylglutarate,

When acetone is condensed with ethyl cyanoacetate in the presence of a solution of anhydrous ammonia in absolute alcohol at —5°, the ammonium salt of the dicyano-imlde (I) is precipitated. Upon dissolving this salt in water and adding excess of concentrated hydrochloric acid, the crystalline dicyano-imide (II) is obtained. Hydrolysis of the last-named with strong sulphuric acid affords p p dimethylglutaric acid (III). 

Elution 0.05 M GTA buffer, pH 7.0 (G, 3,3-dimethylglutaric acid T, trishydroxyaminomethane A, 2-amino-2-methyl-l,3-propanediol) plus indicated salt. 

The syntheses in Schemes 13.36 to 13.40 are conceptually related. They begin with symmetric achiral derivatives of meso2,4-dimethylglutaric acid and utilize various approaches to the desymmetrization of the meso starting material. In Scheme 13.36... 

The synthesis in Scheme 13.37 also used a me,ro-3,4-dimethylglutaric acid as the starting material. Both the resolved aldehyde employed in Scheme 13.36 and a resolved half-amide were successfully used as intermediates. The configuration at C(2) and C(3) was controlled by addition of a butenylborane to an aldehyde (see Section 9.1.5). The boronate was used in enantiomerically pure form so that stereoselectivity was enhanced by double stereodifferentiation. The allylic additions carried out by the butenylboronates do not appear to have been quite as highly stereoselective as the aldol condensations used in Scheme 13.37, since a minor diastereoisomer was formed in the boronate addition reactions. 

The synthesis in Scheme 13.38 is based on an interesting kinetic differentiation in the reactivity of two centers that are structurally identical, but diastereomeric. A bis-amide of we.w-2,4-dimethylglutaric acid and a chiral thiazoline was formed in Step A. The thiazoline is derived from the amino acid cysteine. The two amide carbonyls in this to-amide are nonequivalent by virtue of the diastereomeric relationship established... 

The synthesis in Scheme 13.40 features a catalytic asymmetric epoxidation (see Section 12.2.1.2). By use of me30-2,4-dimethylglutaric anhydride as the starting material, the proper relative configuration at C(4) and C(6) is ensured. The epoxidation directed by the (+)-tartrate catalyst controls the configuration established at C(2) and C(3) by the epoxidation. Although the epoxidation is highly selective in... 

In order to better understand the reaction of CIRh(PPh3)3 and PMMA model compound studies were begun. The model of choice is dimethylglutarate, DMG, since this provides a similar structure and a suitable boiling point for sealed tube reactions. 

Synthetic methods. / / -Dimethylglutaric acid (prepared from mesityl oxide) was converted into the di-silver salt, which, by an improvement of the method of Windaus and Klanhardt, was converted into / / -dimethyl-y-butyrolactone. The latter on treatment with constant-boiling hydrobromic and sulphuric acid gave y bromo /i/ dimethylbutyric acid which readily gave its ethyl ester. The pure fluoro ester was obtained from this by heating with silver fluoride, although the yield was low. 

The reactions were carried out in dilute homogeneous solution in dipolar aprotic solvents ([ester]g=0.2-0.4 mole.l- ) using stereoregular (pure I or S) or predominantly syndiotactic radical (R) PMMA, polymethylacrylate (PMA) and radical azeotropic styrene-MMA copolymer (PSMMA, MMA mole.fraction = 0.47) as well as model monomeric (methylpivalate) and dimeric (dimethylglutarate) compounds. The overall reaction is outlined in the simplified scheme ... 

These results may be compared with those of the experiments of Schwartz and Carter (64) and Cohen (65a) with fl-phenylglutaric anhydride. [See also the more recent results of Fujita and co-workers with meso-2,4-dimethylglutaric acid (65b).] The former group showed that a chiral amine could discriminate between attack at the pro-(/J) and pro-(S) carbonyl groups of the anhydride. The two diastereomers were formed in a ratio of 3 2, with optical purities of about 20%. 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

The syntheses in Schemes 13.30 and 13.31 are conceptually related. The starting material is prepared by reduction of the half-ester of meso-2,4-dimethylglutaric acid. The use of the //zt. vo-diacid ensures the correct relative configuration of the C-4 and C-6 methyl substituents. The half-acid is resolved, and the correct enantiomer is reduced to the aldehyde. 

The reduction of acrylic acid was attempted at elevated temperatures. Surprisingly, the reaction was found to yield not only propionic acid, but also the dimer, a-methylglutaric acid. When the reaction was conducted in the absence of hydrogen, the product obtained was 3-methylglutaconic acid, which apparently is the precursor of the saturated dimer formed in a hydrogen atmosphere. Similarly, methacrylic acid yielded a-methylene-y,y-dimethylglutaric acid when heated with cyanocobaltate (II) in the absence of hydrogen. Its structure was established via ozonolysis. Similar dimerizations have been reported for acrylic acid (I, 14), methacrylate ester (7, 11), crotonic acid (13), and its diethylamide (15). 

Dimethylglutaric acid [2121-67-7J M 160.2, m 144-145°. Distd in steam and crystd from ether/pet ether. 

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