Alkylmalonic acid

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

This chapter focuses on the synthetic aspects unique to the preparation of PMRI-peptides, including those with non-amino acid residues (e.g., 2-5, 7, 9-11 Scheme 1). These residues, gem-diaminoalkyl, and sometimes 2-alkylmalonic acid derivatives, are introduced as an integral part of the PMRI modification. 

Large cycloalkanes have been prepared by C-alkylation of resin-bound 2-alkylmalonic acid esters [18]. 

Alkaline hydrolysis of an alkylmalonic ester followed by careful acidification at 0°C gives the alkylmalonic acid (e.g. Expt 5.133). The alkylmalonic acids... 

When it is required to prepare an a-bromo acid from a carboxylic acid which is not particularly readily available commercially, but which can be synthesised by the malonic acid route (Section 5.11.6, p. 680), advantage may be taken of the ease of bromination in the a-position of the intermediate alkylmalonic acid. The substituted bromomalonic acid undergoes ready decarboxylation on heating to yield the a-bromo acid (e.g. 2-bromo-3-methylpentanoic acid, Expt 5.166). 

Chloroacetic acid is readily converted into glycine by treatment with concentrated aqueous ammonia solution, but in general an a-bromocarboxylic acid is preferred. This can usually be prepared in good yield by a Hell-Volhard-Zelinsky bromination (Section 5.14.1, p. 720) of the corresponding carboxylic acid if the carboxylic acid is not readily available it can usually be obtained by the synthesis and bromination of the appropriate alkylmalonic, acid (see Expt 5.166). 

Any carboxylic acid with a carbonyl group in the jS position is prone to decarboxylate. At the temperature of the hydrolysis, the alkylmalonic acid loses CO2 to give a substituted derivative of acetic acid. Decarboxylation takes place through a cyclic transition state, initially giving an enol that quickly tautomerizes to the product, a substituted acetic acid. 

The /3-keto acid decarboxylates by the same mechanism as the alkylmalonic acid in the malonic ester synthesis. A six-membered cyclic transition state splits out carbon dioxide to give the enol form of the substituted acetone. This decarboxylation usually takes place spontaneously at the temperature of the hydrolysis. 

Olefinic halides may be used as alkylating agents in the malonic ester synthesis. The olefinic malonic acids are decatboxylated to olefinic acids at lower temperatures (140-160°) than those employed for alkylmalonic acids. Examples include the conversion of 4-pentenylmalonic acid to 6-heptenoic acid (67%), allylmalonic acid to allylacetic acid (70%), and 2-cyclopentenylmalonic acid to 2-cyclopentenylacetic acid (99%)- ... 

Aliphatic carboxylic acids may be sulfonated directly to sulfocar-boxylic acids in which the sulfonic acid group is on the a-carbon atom. Better results are sometimes obtained by sulfonation of the corresponding alkylmalonic acid followed by decarboxylation. Sulfonation of propionic anhydride with pyrosulfuric acid gives a-sulfopropionic acid (75%). Several simple olefinic acids containing a sulfonic acid group in the a-position have been made by direct sulfonation of a.,/3-olefinic acids or /3-halo acids. In the latter case, dehydrohalogenation accompanies sulfonation. 

Hydrolysis of alkylmalonic esters leads to alkylmalonic acids and is invariably carried out with aqueous or alcoholic potassium hydroxide. 

Esters of diacids are also useful in asymmetric synthesis. Alkylations of the dianions of 2-alkylmalonic acid half-esters 1.20 lead to products bearing a quaternary carbon with high diastereoselectivity. These products are precursors of chiral diols and aminoacids [166], The corresponding half-esters of 1.4 (R = H) or 1.7... 

The a>bromo carboxylic acid required for preparation of the a>alkoxy acid is often obtained by a malonic ester synthesis the malonic ester is treated with an alkyl halide, the alkylmalonic acid obtained by hydrolysis of the product is brominated by elemental bromine at a low temperature, and the resulting a>bromo dicarboxylic acid is decarboxylated.54 This has led to a particularly important synthesis of aldehydes which utilizes the decarbonylation of -hydroxy or a-alkoxy acids for conversion of an alkyl halide RX into the aldehyde RCHO containing one more carbon atom ... 

Syntheses based on the strongly activated methylene group of malonic esters which on reaction with sodium ethoxide form a resonance-stabilized ion that can be alkylated or acylated. After hydrolysis, the free alkylmalonic acids readily decarboxylate to mono- or disubstituted monocarboxyl ic acids ... 

To explain this observation, Wakil and Ganguly suggested a mechanism of fatty acid synthesis in which dicarboxylic acid intermediates were postulated [equation (6)], which, after reduction to alkylmalonic acid derivatives, are decarboxylated [equation (7)]. The saturated acyl-CoA thus formed condenses, in turn, with the next molecule of malonyl CoA. 

Michael reaction to fumarates, 65 Michael reaction to maleates, 65 Alkylmalonic acids, Michael addition to maleates, 63-66... 

A. MONO-CARBOXYLIC ACIDS Alkylmalonic acid (continued)... 

---