Glucose with ethyl acetoacetate

The reaction of D-glucose with ethyl acetoacetate was originally studied with a view to obtaining experimental information which would be useful in the interpretation of the biological phenomena of antiketogenesis. It is accepted that some kind of correlation exists between the metabolism of carbohydrates and that of /3-ketonie compounds, but views as to its nature differ. The supporters of the ketolysis theory1 contend that the oxi-... 

While a 2-(D-arabino-tetritol-l-yl)-l-methylpyrazole derivative was obtained from the condensation of 2-deoxy-2-methylamino-D-glucose with ethyl acetoacetate (c.f. Vol.l4, p.89), the 3-substituted pyrrole analogues (72) were obtained from 1-deoxy-l-raethylamino-... 

Later investigations6 have shown that its structure is actually that shown in formula II. D-Glucose also reacts with ethyl acetoacetate (with the elimination of two molar proportions of water) in dilute aqueous solutions in absence of any condensing agent. The same product II results, but it is formed at a lower rate. 

The reaction with ethyl acetoacetate has been extended to glycolaldehyde, and to carbohydrates other than n-glucose, by employing different experimental conditions it is probably applicable to aldoses in general. With d-fructose, yields are lower, but two molar proportions of water are liberated and a crystalline product results. This has a constitution similar to that of II but with the D-omhfno-tetrahydroxybutyl chain at the /3-position on the furan ring. The reaction has been applied successfully to other ketoses and... 

Other Methods of Preparation.—Ethyl 2-(D-ara6i no-tetrahydroxybutyl)-5-methyl-4-furoate has been prepared by heating D-glucose plus ethyl acetoacetate in aqueous alcohol without a catalyst,1 or from the same reagents (1 g. and 0.5 ml., respectively) in 0.5 ml. of 96% ethanol plus 1.5 ml. of water at room temperature in the presence of ferric chloride, zinc chloride (with small quantities of hydrochloric acid or of sodium hydroxide), cupric chloride, ferric sulfate, zinc sulfate, aluminum chloride, nickel chloride, or cobalt nitrate.18... 

Much more studied is the reaction of /8-dicarbonyl compounds with 2-amino-2-deoxyaldoses in particular, with 2-amino-2-deoxy-D-glu-cose (55), both in neutral and alkaline medium. In neutral methanol or aqueous acetone, 2-amino-2-deoxy-D-glucose reacts with 2,4-pen-tanedione to give52 54 3-acetyl-2-methyl-5-(D-arabino-tetrahydroxy-butyl)pyrrole (56a), and, with ethyl acetoacetate,55 the pyrrole 56b. Similar (tetrahydroxybutyl)pyrroles have been prepared from other /3-keto esters, such as ethyl 3-oxohexanoate, ethyl thiolacetoacetate, and diethyl 3-oxopentanedioate.53,56,56a... 

Synthesis of pyrrol-2-yl acyclo C-nucleosides by forming the pyrrole ring onto the alditolyl chain was reported in 1922, when Pauly and Ludwig prepared 3-ethoxycarbonyl-2-methyl-2-(D-ara6mo-tetritol-l-yl) pyrrole (211), the first example of these compounds, by reaction of 2-amino-2-deoxy-D-glucose (210) with ethyl acetoacetate (22ZPC170) (Scheme 44). Since then, Spanish chemists have pioneered the synthesis of these compounds using this route and extensively studied their properties and mecha-... 

D-Glucose condenses with ethyl acetoacetate and other /8-keto esters and with jS-diketones, in the presence of anhydrous zinc chloride, to give derivatives of furan 184), The constitution of some of the compounds has been verified by oxidation with lead tetraacetate 18S) and with periodate ion 186). The aldose would appear to react in the form of its 1,2-enediol. 

The reaction of 2-amino-2-deoxy-D-glucose (D-glucosamine) with a dicarbonyl compound was carried out for the first time by Pauly and Ludwig,91 who were trying to discover how pyrrole rings in natural products are formed. They heated free D-glucosamine and ethyl acetoacetate on a steam bath and obtained a substance in which the presence of the pyrrole ring was demonstrated by the pine-splinter test. 

If the data obtained on the dehydration of the 2-(aWo-polyhydroxy-alkyl)benzimidazoles31 is considered, it is to be expected that no inversion occurs in the configuration of the carbon atom next to the furan ring. If this is so, the anhydride should have formula XXXIV. With the object of deciding this question, researches are being carried out32 on the reaction of ethyl acetoacetate with 3,6-anhydro-n-glucose and with D-altrose. 

On heating the parent acid of ester VI (from condensation of D-glucose with diethyl 3-oxoglutarate) in aqueous solution,11 following the procedure employed to obtain the corresponding derivative of ethyl acetoacetate XXVI, a sirup results. However, its change in optical activity shows a parallelism with that in analogous cases where crystalline products are isolated, and apparently indicates anhydride formation (see the last line in Table V). 

D-Glucose or D-mannose (100 g.) is well mixed in a mortar with 50 g. of anhydrous zinc chloride,470 and the mixture is transferred to a round-bottomed flask. Ethyl acetoacetate (50 g.) plus 50 ml. of 96% ethanol are added, and the stirred suspension is heated in a boiling water bath until homogeneous.48 The hot solution is poured into 300-400 ml. of ice plus water the product separates on standing, in the form of crystalline needles. It is filtered off and recrystallized three times from hot water yield, 30 g. m. p., 148-149°.4 - ... 

The reactions of D-glucose with 2,4-pentanedione (acetylacetone), diethyl 3-oxoglutarate, ethyl benzoylacetate, ethyl propionylacetate, ethyl butyrylacetate, ethyl isovalerylacetate, and methyl acetoacetate have been effected, with formation of crystalline products. 

Monosaccharides react with a variety of 1,3-dicarbonyl compounds in the presence of zinc chloride in ethanolic or aqueous solution to yield substituted furans (Scheme 69) (56MI31200). The reaction of ethyl acetoacetate with D-glucose and D-mannose yielded the trisubstituted furan (252) in 20% yield, while D-fructose under similar conditions yielded (253 7%). These products have been used for the synthesis of dehydromuscarones (63HCA1259). Oxidation of the tetrahydroxybutyl side chains with lead tetraacetate gives the aldehyde, which can be converted to the corresponding acid with alkaline silver oxide. 

In this section we discuss the model predictions for the ketone ethyl acetoacetate (1). With the ketone absent ([Ket]x = 0 mM), the extended model reproduces all previous results with oscillations of all system variables above [Glc]xo > 18.5 mM [53]. Figure 3.6 shows the system s response to a fixed glucose concentration [Glc]xo at 30 mM and an increase of [Ket]x to 1 mM. The oscillations vanish at [Ket]x = 0.23 mM in a supercritical Hopf bifurcation and the steady state is stable for [Ket]x > 0.23 mM. Figure 3.6a shows the minimum and maximum concentrations of NADH as two thick curves, while in all other panels the time averages of the plotted variables are shown, not the minimum and maximum values. Since the addition of ketone provides an alternative mode of oxidation of NADH, the concentration of NADH is decreasing in Fig. 3.6a whereas the fluxes of carbinol production are increasing in Fig. 3.6b. 

In the experiments first described, 2-amino-2-deoxy-D-glucose was heated with an excess of the /3-dicarbonyl compound in the absence of solvent. The product so obtained from ethyl acetoacetate, m.p. 142°, [a]n 49.7°, had an analysis corresponding to that for ethyl 2-methyl-5-(D-ara6mo-tetrahydroxybutyl)pyrrole-3-carboxylate and was considered to have this structure (1). In the reaction with 2,4-pentanedione, a material (m.p. 98°, Md — 25.1°) was obtained which was described as 3-acetyl-2-methyl-5-(D-ara5fno-tetrahydroxybutyl)pyrrole (2). Boyer and Furth" repeated the latter reaction, but in methanol solution, and obtained a product, m.p. 133°, whose analytical data were in agreement with those for structure (2). 

The reactions of amino glycoses with a variety of jS-dicarbonyl compounds have been studied systematically in aqueous acetone solution at neutral pH and room temperature. Under these conditions, well defined products are obtained, sometimes in yields as high as 90-100%. Using this technique, 2-amino-2-deoxy-D-glucose hydrochloride, plus the equivalent amounts of sodium carbonate and ethyl acetoacetate, gives a product (m.p. 142-143°, [a]D —25°) different from that obtained by Pauly and... 

The reaction of amino sugars with (8-dicarbonyl compounds in alkaline solution produces (tetrahydroxybutyl) pyrroles together with simpler pyrrole compounds lacking the tetrahydroxybutyl side-chain. 2-Amino-2-deoxy-D-glucose hydrochloride and ethyl acetoacetate, heated in aqueous solution at pH 9.7, give a mixture of ethyl 2-methyl-5-(D-ara )mo-tetra-hydroxybutyl)pyrrole-3-carboxylate (1) and ethyl 2-methylpyrrole-3-carboxylate. The yields of these compounds are in the approximate ratio... 

In the reactions of 2-amino-2-deoxy-D-glucose with some /3-dicarbonyl compounds (such as ethyl acetoacetate, 2,4-pentanedione, or pyruvic acid) in alkaline solution, pyrroles lacking the tetrahydroxybutyl chain are obtained. The loss of this group cannot occur with the already formed (tetrahydroxybutyl)pyrroles, because these compounds, as exemplified by 3-acetyl-2-methyl-5-(D-ora wo-tetrahydroxybutyl)pyrrole (2), remain unchanged at the pH (9-10) of the reaction. The fission of the sugar chain most probably occurs for one of the intermediates of the reaction, for instance (79), and it may be formulated as a concerted-elimination reaction catalyzed by the hydroxyl ion, as indicated in Scheme C. The... 

The study of the reactions of amino sugars with /3-keto thiolesters was undertaken in order to obtain data on the way in which simple models of (S-acetoacetyl-Coenzyme A may react. There is no difference between the modes of reaction of ethyl thiolacetoacetate and ethyl acetoacetate with 2-amino-2-deoxy-D-glucose. In the reaction with l-amino-l-deoxy-o-fructose, the product (18) of the thiolester liberates ethanethiol very readily and forms the lactone (27). amino sugar interact, giving lactone (27). No compound similar to the pyrrole thiolester (18) was found. In this context, the investigation of similar reactions with acetamido sugars will be of interest. 

Cyclic acetals of L-ascorbic acid have been prepared in good yield by the transacetalation of L-ascorbic acid with various ketone dimethylacetals, and a furanyl analogue of dehydro-L-ascorbic acid 45 has been synthesized by condensation of ethyl acetoacetate with D-glucose followed by periodate oxidation. ... 

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