Succinic esters, substituted

Succinic esters condense with aldehydes and ketones in the presence of bases, eg, sodium alkoxide or piperidine, to form monoesters of alkybdenesuccinic acids, eg, condensation of diethyl succinate with acetone yields ethyl 2-isopropyhdenesuccinate (eq. 3). This reaction, known as Stobbe condensation, is specific for succinic esters and substituted succinic esters (98,99). 

The second relevant set of data is for the formation of the anhydride from substituted succinic acid derivatives. Equilibrium constants for the formation of the anhydride from the acid are available for the various methyl-substituted compounds (Table A.l) and the derived EM s are compared in Table 5 with those for intramolecular nucleophilic catalysis in the hydrolysis of half-esters... 

Erickson, L. E. Proton Magnetic Resonance Spectra of Substituted Succinic Anhydrides, Acids, Salts and Esters. J. Am. Chem. Soc. 87, 1867 (1965). 

The best compromise with respect to reactivity and availability of the starting material was the use of diisopropyl malate 107. This malic acid ester is easy to prepare and its alkylation with various benzyl bromides can be achieved with good yields (53-67%, not optimized) and high stereoselectivities (dr 95 5 for 120 and 121). An exception with respect to the stereoselectivity was the 2,4,6-trimethylbenzyl substituted succinate 122, which was obtained in a dr of only 83 17 (Fig. 6) [71]. 

Scheme 1.1.15 Enantioselective synthesis of 3-substituted 5-amino-4-oxo esters and succinic half-esters.

Substituted succinic esters are formed coincidentally with the meth-oxy esters, although in relatively smaller amounts. ds-2-Butene gives a mixture of diesters, meso and d,1-pair, while trans-2-butene yields only the d,l enantiomers. By the addition of sodium acetate, conditions which preclude prior isomerization of the olefins are obtained the diesters are the exclusive products, and the dicarbonylation is stereospecifically cis. The carbonylation of trans-2-butene, which is at least seven times faster than that of the cis isomer, gives exclusively the d,l-succinic ester while m-2-butene gives only the meso diastereomer. These results are consistent with the mechanism shown for cw-2-butene (19) (see top of next page). 

The synthesis of succinic acid derivatives, /3-alkoxy esters, and a,j3-unsaturated esters from olefins by palladium catalyzed carbonylation reactions in alcohol have been reported (24, 25, 26, 27), but full experimental details of the syntheses are incomplete and in most cases the yields of yS-alkoxy ester and diester products are low. A similar reaction employing stoichiometric amounts of palladium (II) has also been reported (28). In order to explore the scope of this reaction for the syntheses of yS-alkoxy esters and succinic acid derivatives, representative cyclic and acyclic olefins were carbonylated under these same conditions (Table I). The reactions were carried out in methanol at room temperature using catalytic amounts of palladium (II) chloride and stoichiometric amounts of copper (II) chloride under 2 atm of carbon monoxide. The methoxypalladation reaction of 1-pentene affords a good conversion (55% ) of olefin to methyl 3-methoxyhexanoate, the product of Markov-nikov addition. In the carbonylation of other 1-olefins, f3-methoxy methyl esters were obtained in high yields however, substitution of a methyl group on the double bond reduced the yield of ester markedly. For example, the carbonylation of 2-methyl-l-butene afforded < 10% yield of methyl 3-methyl-3-methoxypentanoate. This suggests that unsubstituted 1-olefins may be preferentially carbonylated in the presence of substituted 1-olefins or internal olefins. The reactivities of the olefins fall in the order RCH =CHo ]> ci -RCH=CHR > trans-RCH =CHR >... 

Organometallic reagents react with olefinic esters by both 1,2 and 1,4 addition. The latter process leads to saturated esters and is exhibited by diethyl fumarate and to a greater extent by ethylenetetracarboxylic ester, (CjH50jC)jC = C(C0jCjH5)j. These substances are starting materials for the synthesis of alkyl- and aryl-substituted succinic esters. ... 

In place of simple alkyl halides, certain other halogen-containing compounds may be used, in particular the readily available a-bromo esters (why can a-bromo-acids not be used ), which yield substituted succinic acids by the malonic ester synthesis. For example ... 

The first enzymatic reaction investigated in the whole project concerned the introduction of chirality in route B (Fig. 2) by generation of succinic acid mononitrile (R)-12 from its racemic precursor. Since in a broad sense the nitrile ester substrate 10 can be interpreted as an amino acid analogue, proteases recommended themselves as catalysts to be tested. From the literature, 2-substituted succinic and butyric acid esters were known to be resolved by proteases [6, 7]. Proteases are... 

Route C (Fig. 2) starts from the extremely cheap bulk agents isobutylene and maleic anhydride 4 and provides diester 9 in two steps. When in the course of process development this attractive access to the potential enzyme substrate 9 could be established, work concentrated immediately on its enantio- and regioselective monohydrolysis. Thus, the sterically more hindered ester group had to be hydrolyzed to the target monoacid (R)-2 a. Protease-catalyzed reactions with the stated specificity had already been described for several 2-substituted succinate diesters, such as 2-... 

Piperidazine derivative (491) treated with substituted succinic acid ester chloride (490) provides (492). The intermediate after deprotection with hydrogen bromide in acetic acid is cyclized into (493) by a sequential treatment with phosphorus pentachloride and pyridine (Scheme 104) <84JCS(Pl)l55>. 

Substituted succinate esters (130) have been prepared by dimerization of silyl-ated enolates (129) using titanium tetrachloride yields are about 80%. Phthalic... 

Martin et al. observed modest to excellent diastereoselectivily for substituted succinate esters (Scheme 4.27) [30]. A similar Cieplak-type effect as in the Yamazaki report (cf Scheme 4.25) could be argued in these cases as well. Allylic strain would orient the Cl stereocenter as shown with the C—H bond eclipsed with the ether oxygen. Attack of the allyhc ether would then occur anti to the more electron rich cyclopenlyl C-C bond. Alternatively, a simple aUyUc strain argument could account for the observed results [27]. Attack of the allyUc alkene would occur syn to the smaller COjBn group. 

Esters of mono- and diacylglycerols with acetic acid (E472a) are used as substances preventing crystallisation of fats, esters of succinic acid have found use as flour conditioners (enhancers), esters of citric acid as emulsifiers, solvents for antioxidants and fat substitutes in some foods. They also enhance the baking properties of flour. 

It is also known that a malonic ester substituted in the j5-position with cobalt can rearrange into the corresponding succinic ester. To test the possible role of the metal and to better simulate the situation of the enzyme, the group of J. Retey (266) synthesized the following cobalt complex in which the substrate is anchored covalently by two methylene bridges to planar cobaloxime. 

The preparation of succinic esters by anion coupling with polyhalides has been described/ The scope of the Wurtz coupling of a-halogenoesters to give alkyl-substituted succinic esters has been investigated optimum conditions utilize a-bromoesters and zinc in THF, the presence of copper(n) salts being mandatory to avoid Dieckmann-type condensation to form p-ketoesters. 

Wurzburg, O. B., Crosslinked Starches, p. 41 Jarawenko, W., Acetylated Starch and Miscellaneous Organic Esters, p. 55 Moser, K. B., Hydroxyethy-lated Starches, p. 79 TuschhofF, J. V., Hydroxypro-pylated Starches, p. 89 Solarek, D. B., Phosphorylated Starches and Miscellaneous Inorganic Esters, p. 113 Trubiano, P. C., Succinate and Substituted Succinate Derivatives of Starch, p. 131 Fanta, G. F., and Doane, W. M., Grafted Starches, p. 149 Hofreiter, B. T., Miscellaneous Modifications, p. 179 all in Ref. 8. 

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