From malonic ester acid synthesis

An important example of this reaction is the malonic ester synthesis, in which both Z groups are COOEt. The product can be hydrolyzed and decarboxylated (12-38) to give a carboxylic acid. An illustration is the preparation of 2-ethyl-pentanoic acid from malonic ester ... 

The malonic ester synthesis converts a primary or secondary alkyl halide into a carboxylic acid with two more carbons (a substituted acetic acid). Identify the component that originates from malonic ester (the acid component). The rest of the molecule comes from the alkyl halide, which should be primary or methyl. 

From Malonic Ester.—The same constitution is also proven by an interesting synthesis from malonic ester. Mono-sodium di-ethyl malonate reacts with monobrom, or mono-iodo acetic acid, and yields the ester of a tri-carboxy acid which after hydrolysis to the acid loses carbon di-oxide and yields succinic acid. 

A combination of two of the reactions discussed in this chapter—alkylation of an a-carbon and decarboxylation of a j8-dicarboxylic acid—can be used to prepare carboxylic acids of any desired chain length. The procedure is called the malonic ester synthesis because the starting material for the synthesis is the diethyl ester of malonic acid. The first two carbons of the carboxylic acid come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the reaction. 

Synthesis.— The preparation of a-amino-acids from a-halogeno-acids and ammonia is often unsatisfactory owing to the occurrence of multiple alkylations etc. A way around this problem is to treat a-halogeno-esters with alkali-metal cyanates and an alcohol this gives N-alkoxycarbonyl-a-amino-esters in >90% yield. " The O-arylhydroxylamine (148) is a useful reagent for aminating enolates, especially those derived from malonic esters, which can thus be... 

We have seen that when a carboxylic acid is synthesized by a malonic ester s5mthesis, the carbonyl carbon and the a-carbon come from malonic ester. Any substituent attached to the a-carbon comes from the alkyl halide used in the second step of the synthesis. If the a-carbon has two substituents, then two successive alkylations of the a-carbon will form the desired carboxylic acid. 

In a typical example of the malonic ester synthesis 6 heptenoic acid has been pre pared from 5 bromo 1 pentene... 

The malonic ester synthesis has been adapted to the preparation of cyclo alkanecarboxyhc acids from dihaloalkanes... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

The synthetic importance of the malonic ester synthesis follows from the fact that the substituted malonic ester can easily be hydrolyzed, and subsequently decarboxylates to yield a substituted acetic acid 9. This route to substituted acetic acids is an important method in organic synthesis ... 

Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

Example Optically active acid (16) was needed (p T 107 ) for the synthesis of an ant alarm pheromone. The branch point ( in 16) is also the chiral centre so it is better to avoid disconnections there. The 1,2 C-C disconnection (16a) is ideal as it gives synthon (17), for which we use a malonate ester, and halide (18), available from optically active alcohol (19), a major by-product from fermentation. 

The malonic ester synthesis is similar to the acetoacetic ester synthesis. It begins with deprotonation of diethyl malonate (pKa = 11) to produce an enolate anion that is the synthetic equivalent of the enolate anion derived from acetic acid ... 

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

To adapt this synthesis to making amino acids, we begin with a malonic ester that contains an a-amino group. The amino group is protected as a non-nucleophilic amide to prevent it from attacking the alkylating agent (RX). 

The Gabriel-malonic ester synthesis begins with (V-phthalimidomalonic ester. Think of (V-phthalimidomalonic ester as a molecule of glycine (aminoacetic acid) with the amino group protected as an amide (a phthalimide in this case) to keep it from acting as a nucleophile. The acid is protected as an ethyl ester, and the a position is further activated by the additional (temporary) ester group of diethyl malonate. 

The chiral monodeuterated ethanols 28 and 33 were obtained by Simon s method [33] and their tosylates, 29 and 34, reacted with malonic ester anion to afford 30 and 35. The expected inversion of configuration in the malonic ester synthesis was confirmed by decarboxylating the derived acids 31 and 36 to (35)- and (3R)-[3-2H,]butanoic acids, respectively, the chiroptical properties of which were already known [34]. The chirally deuterated CoA esters 32 and 37, prepared from 31 and 36, were rearranged on methylmalonyl-CoA mutase from P. shermanii and, after hydrolysis, the methylsuccinate products were isolated. In a parallel experiment the... 

---