Ketopimelate

DIETHYL P-KETOPIMELATE (Pimelic acid, p-oxo-, diethyl ester) 

Submitted by Maya Gdha and D. NAStPolu. Checked by William G. Dadben and RicaaAED Elus. 

Diethyl oi-acelyl-fi-ketopimelate. In a 2-1. three-necked flask equipped with a merauy-sealed Hershberg stirrer, a dropping funnel, and a reflux condenser protected with a caldum chloride tube are placed ll.S g. (0.5 g. atom) of finely powdered sodium (Note 1) and 500 ml. of dry ether. The flask is placed in an ice bath, and 65.0 g. (63.5 ml., 0.5 mole) of freshly distilled ethyl acetoacetate in 150 ml. of dry ether is slowly added from the dropping funnel with stirring (approximate time for addition is 30-40 minutes). The mixture is stirred overnight, then it is 

Clean pieces of sodium are melted under xylene and powdered by vigorous shaking. When cold, the xylene is decanted and the sodimn powder is washed by decantation with a few milliliters of dry ether and then washed into the reaction flask with dry ether. 

The distillate contains mostly C-acyl ester with a little of 0-acyl ester. Separation of these two esters by means of a carbonate solution in which only the C-acyl ester is soluble is possible. This separation is unnecessary in the present procedure for the 0-acyl derivative gives rise to ethyl acetoacetate during decomposition with ammonia. This low-boiling ester is removed during the distillation of diethyl -ketopimelate. 

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The chiral siloxycyclopropane 106 undergoes carbonylative homocoupling to form the 4-ketopimelate derivative 108 via the palladium homoenolate 107 without racemization. The reaction is catalytic in CHCI3, but stoichiometric in benzene[93]. 

Heat. When heated, succinic acid loses water and forms an internal anhydride with a stable ring stmcture. Dehydration starts at 170°C and becomes rapid at 190—210°C (25). Further heating of succinic anhydride causes decarboxylation and the formation of the dilactone of gamma ketopimelic acid (26) (eq. 1). The same reaction takes place at lower temperatures in the presence of alkaU. 

Succinic anhydride is stabilized against the deteriorative effects of heat by the addition of small amounts (0.5 wt %) of boric acid (27), the presence of which also decreases the formation of the dilactone of gamma ketopimelic acid (28). Compared with argon, CO2 has an inhibiting effect on the thermal decomposition of succinic acid, whereas air has an accelerating effect (29,30). 

The synthesis of pyrrolizidine developed by LukeS and Sorm31 and by Micheel and Flitsch32 starts with furylacrylic acid (56) which is converted by the Markwald reaction into y-ketopimelic acid (57). The carbonyl group in 57 is replaced by an amino group via the oxime or by the Leuckart-Wallach reaction this substitution results immediately in the formation of the lactam 58, which can be converted by heat into 3,5-dioxopyrrolizidine (59). The latter compound yields pyrrolizidine... 

The described method of preparing diethyl jS-ketopimelate is a modification of that described by Bouveault and is essentially the same as that reported by Bardhan and Nasipuri. This ester has also been prepared by condensation of 7-carbethoxybutyryl chloride with ethoxymagnesiummalonic ester and cleavage of the resulting acylated malonic ester by (3-naphthalenesulfonic add or by acetic or propionic acids containing a trace of concentrated sulfuric acid. ... 

The present method offers a more convenient synthesis with appreciably higher yields of diethyl /3-ketopimelate. It is reported to be useful for the preparation of dimethyl /3-hetoadipate and diethyl /3-ketosubcrate. ... 

IDegradation. Heating of succinic acid or anhydride yields y-ketopimelic dilactone, cyclohexane-1,4-dione, and a mixture of decomposition products that include acetic acid, propionic acid, acrylic acid, acetaldeide, acrolein, oxalic acid, cyclopentanone, and furane. In argon atmosphere, thermal degradation of succinic anhydride takes place at 340°C (123). Electrolysis of succinic acid produces ethylene and acetylene. 

Gardner and co-workers developed an efficient synthesis of pimelic acid (4) from furfural (1) involving conversion to furylacrylic acid (2) and esterification, which proceeds with cleavage of the ring and disproportionation to give diethyl y-ketopimelate (3). Huang-Minlon reduction by the usual procedure in diethylene... 

Recently Dhandraj and Guillet 21> reported a new photochemical synthesis of block copolymers by irradiation of poly(tetramethylene sebacate-CO-y-ketopimelate) in the presence of methyl methacrylate. The chain radicals formed from the Norrish Type I cleavage of the y-ketopimelate unit initiated polymerization of methyl methacrylate leading to blocks the length of which depend on the number of scissions. 

The reaction of a mercurio ketone and carbon monoxide in the presence of a palladium catalyst in methanol (Scheme 26) results in the formation of a 1,4-keto ester with incorporation of one molecule of carbon monoxide. Treatment of a mercurio ketone with [Ni(CO)4] results in symmetrical coupling with incorporation of one molecule of carbon monoxide to give a triketone, presumably via a 3-nickel-sub-stitut ketone (Scheme 27) Such symmetrical coupling reactions are general for alkylmercury compounds. If silyloxycyclopropane (8) is heated in CHCb in the presence of a catalytic amount of a palladium-phosphine complex under CO, symmetrical coupling with incorporation of one molecule of CO takes place to give a 4-ketopimelate (Scheme 27). ... 

The following recent examples are worth mentioning. Furfurylidene malonic ester can be converted into methyl 2-carbomethoxy-4-ketopimelate ... 

Ahpiperidine-2,6-dicarboxylate dehydrogenase (Q) N-succinyl-2-amino-6-ketopimelate synthase succinyl diaminopimelate aminotransferase succinyl diaminopimelate desuccinylase diaminopimelate epimerase diaminopimelate decarboxylase (Q threonine dehydratase (serine dehydratase) acetolactate synthase acetohydroxy acid isomeroreductase dihydroxy acid dehydratase valine aminotransferase a-isopropylmalate synthase isopropylmalate isomerase -isopropylmalate dehydrogenase leucine aminotransferase... 

Coned. H2S04 added, in very small portions at first, with manual stirring at —20 to 5° to diethyl a- (m-methoxyphenylethyl) -/ -ketopimelate, then allowed to warm to near room temp., and worked up, whereby the ester is hydrolized by refluxing 2.5 hrs. in aq. ale. KOH — y-(6-methoxy-2-carboxy-3,4-dihydro-l-naphthyl)-butyric acid. Crude Y 82%. (J. H. Hunter and J. Al Hogg, Am. Soc. 71, 1922 (1949).) s. a. 2, 795... 

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