Fumaric acid derivatives

Pyrroles react at free a- or -positions with acetylenedicarboxylic acid or the methyl ester yielding mixtures of the corresponding maleic and fumaric acid derivatives. Protons are readily available to satisfy... 

Another issue important to the success of this chiral titanium reagent 31 was the discovery of a marked solvent effect. When the fumaric acid derivative is reacted with isoprene in the presence of 10 mol% of the titanium reagent 31 in toluene, poor optical purity results (36-68% ee). Interestingly the optical purity of the adduct greatly increased in the order benzene, toluene, xylenes, and mesitylene, with 92% ee obtained in the last. Mesitylene is difficult to remove, because of its high boiling point, and other solvents were screened in detail. As a result, the mixed solvent system toluene petroleum ether (1 1) was discovered to be very effective. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

The hydrogen transfer photosensitization has been applied to the diastereo-selective alkylation of chiral fumaric acid derivatives, where again the mild conditions of the photochemical method are advantageous (Figure 3.8). ... 

Figure 3.8 Diastereoselective alkylation of chiral fumaric acid derivatives.

An attempted synthesis of biotin using thiocarbonyl ylide cycloaddition was carried out (131,133,134). The crucial step involves the formation of the tetrahydrothiophene ring by [3 + 2] cycloaddition of a properly substituted thiocarbonyl ylide with a maleic or fumaric acid derivative (Scheme 5.27). As precursors of the thiocarbonyl ylides, compounds 25a, 72, and 73 were used. Further conversion of cycloadducts 74 into biotin (75) required several additional steps including a Curtius rearrangement to replace the carboxylic groups at C(3) and C(4) by amino moieties. 

Pyrrolidines and pyrrolidinones can be synthesized on insoluble supports by intramolecular carbometallation of alkenes (Entry 1, Table 15.4) and by Ugi reaction of support-bound isonitriles with amines and 4-oxo acids (Entry 4, Table 15.4). In Entry 5 in Table 15.4, the pyrrolidinone ring is formed by intramolecular Diels-Alder reaction of a furan with a fumaric acid derivative. 2-Pyrrolidinones have also been prepared by treatment of resin-bound O-mesitylenesulfonyl cyclobutanone oximes with... 

Narasaka reported a highly enantioselective Diels-Alder reaction between isoprene and a fumaric acid derivative 17 using a catalytic amount of a chiral titanium reagent prepared from tartrate-derived chiral 1,4-diol 18 and TiCI2(0-/-Pr)2 [27]. When a stoichiometric amount of the partially resolved chiral diol (25% ee) was used, the corresponding cycloadduct 19 with 83% ee was obtained (Scheme 9.12). In this reaction, white precipitate was formed, which proved to... 

Griffin, G. W., A. F. Vellturo, and K. Furukawa The chemistry of photodimers of maleic and fumaric acid derivatives. I. Dimethyl fumarate dimer. J. Amer. chem. Soc. 83, 2725 (1961). 

Fig. 9a4) between cyclopentadiene and a C=C bond of the dumbbell-shaped part of the rotaxane. The dumbbell-shaped part contains two dicarbonyl stations (Fig. 9a3), one derived from fumaric acid (tram -CO-C H=CH-CO-. station 1), the other derived from succinic acid (—CO-CH2-CH2-CO-, station 2). The two diamide sites of the macrocycle can form four H-bonds with the two carbonyl groups of a given station (Fig. 9al for the interaction of the two carbonyl groups of fumaric-acid-derived station 1 with the four NH groups of the macrocycle through four H-bonds, see Fig. 9a2). Station 1 (derived from fumaric acid) has a tram C=C double bond due to its preorganization, this station interacts with the macrocycle better than the station 2. Consequently, the macrocycle is initially located at station 1 (Fig. 9a5). The Diels-Alder cycloaddition (80° C, 90% yield) of cyclopentadiene to the double bond of station 1 results in a mixture of diastereomers (Fig. 9a4) and causes displacement of the macrocycle from station 1 to station 2 (Fig. 9a6). The cycloaddition is reversible and the retro-Diels-Alder reaction occurs quantitatively (250°C, reduced pressure) when cyclopentadiene dissociates from the axle of the rotaxane this produces a displacement of the macrocycle from station 2 back to station 1. 

Fumaric acid is used in oral pharmaceutical formulations and food products and is generally regarded as a relatively nontoxic and nonirritant material. However, acute renal failure and other adverse reactions have occurred following the topical and systemic therapeutic use of fumaric acid and fumaric acid derivatives in the treatment of psoriasis or other skin disorders. Other adverse effects of oral therapy have included disturbances of liver function, gastrointestinal effects, and flushing. ... 

Two developments in the syntheses involving addition of a Me2C group (with isopropylidenetriphenylphosphorane, Vol. 4, p. 486, Ref. 242) to fumaric acid derivatives have been published, with the idea of synthesizing chiral compounds. De Vos and Krief (whose names were originally attached to the route ) have used the dimenthyl ester 258, and obtained 74% diastereoisomeric excess (optically pure after one crystallization) of the traru-substituted cyclopropane... 

To a suspension of 150 mg of 4 A molecular sieves in 3 mL of toluene, 10 mL of a toluene solution of about 0.07 mmol of the chiral titanium catalyst (prepared by the procedure above) are added and the mixture is cooled to OX. 0.7 mmol of the fumaric acid derivative 1 in 4mL of toluene is added to the mixture, and then 5 mL of hexane and 1 mL of isoprene (3, R1 = CH3) are added. The mixture is stirred overnight at 0 X. pH 7 phosphate buffer is added, and the mixture is worked up as above. 

Menzer and Dauterman (1970) studied extensively the substrate specificity of malathionase and established that carboxy esters with longer carbon chains can be hydrolysed more easily by the enzyme than those with short carbon chains. The stereospecific character of the enzymatic action is shown by the fact that /-isomers are hydrolysed more easily than /-isomers, and fumaric acid derivatives more easily than maleic acid derivatives. 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Heating benzoyl azide with ethanol or benzoylhydrazine gave the corresponding urethane (5) or benzoylphenyl semicarbazide (6), respectively. The explosive diacyl azide 8, prepared from fumaric acid-derived 7, underwent double rearrangement in ethanol to the dicarbamate 9. ... 

Although no geometries have been indicated in most of these synthetic works, it is known that amines isomerize maleic acid derivatives to the thermodynamically more stable fumaric acid derivatives. Furthermore, cycliz-ation to imides is much more easily obtained with succinic acid and phthalic acid/ It may be concluded, therefore, that low yields of cyclization in maleamic acid is not so much due to lack of reactivity as to the formation of less reactive fumaramic derivative by isomerization. 

The situation improves considerably when the bis-substituted fumaric acid derivative 4.24 is used as the chiral dienophile (Table 1.8) ... 

Chapuis and Jurczak et al. reported a diastereoselective Diels-Alder reaction of the symmetrical fumaric acid derivatives including a chiral sultam part [15] promoted by Lewis acids, such as SnCU, TiCU(O Pr)4 n, ZrCU, RnAlCU-n, or ZnBr2 [16]. The best result (99% de) was obtained when SnCU or Me2AlCl was used (Scheme 10.2), whereas others except for AlMe3 gave more than 80% de. 

Campari, G., MeUa, M., Fagnoni, M., and Albini, A., Diastereoselective photosensitized radical addition to fumaric acid derivatives bearing oxazoKdine chiral auxiliaries. Tetrahedron Assym., 11, 1891, 2000. 

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