Diethyl acetamidomalonate, amino acid

Diethyl acetamidomalonate is useful in the synthesis of ce-amino acids by alkylation, as, for example, histidine and tryptophan. 

The most widely used method for the laboratory synthesis of a-amino acids is a modification of the malonic ester synthesis (Section 21.7). The key reagent is diethyl acetamidomalonate, a derivative of malonic ester that aheady has the critical nitrogen substituent in place at the a-caibon atom. The side chain is introduced by alkylating diethyl acetamidomalonate in the same way as diethyl malonate itself is alkylated. 

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 ... 

From diethyl acetamidomalonate and 2-(4-fluorophenoxy)ethyl bromide a spiro-benzopyranyl amino acid 101 could be prepared (88TL5493). 

The multistep synthesis shown in Figures 16-39 and 16-40 leads to the synthesis of an amino acid. (Note that the diethyl acetamidomalonate shown in Figure 16-40 is the product of the reaction in Figure 16-39.) The example in the figures is a natural amino acid however, you can synthesize other (not natural) amino acids with this procedure. 

The lipo-amino acids are generally synthesized as racemic mixtures which are resolved into optically pure a-amino acids by chemical or enzymatic methods.113" 137 133 The synthesis is based on the alkylation of diethyl acetamidomalonate followed by hydrolysis and decarboxylation. 129 138 140 Also, 20% DMF has been used in the hydrolysis step, as it is suitable for industrial scale preparation. 138] Alternatively, lipidated a-amino acids are synthesized by reacting a-bromoalkanoic acid with ammonium hydroxide. 141 ... 

American workers needed to prepare the bis-amino acid 1 and adopted a literature procedure in which two equivalents of diethyl acetamidomalonate were to be alkylated with one equivalent of l,4-dichloro-2-butyne using two equivalents of sodium ethoxide in hot ethanol. Hydrolysis and decarboxylation of the dialkylated malonate would then give 1. This alkylation reaction was carried out, but ten equivalents of sodium ethoxide were used rather than two. This resulted in formation of ethyl 5-methylpyrrole-2-carboxylate in ca. 40% yield. Further study showed that the reaction to produce the pyrrole required equimolar amounts of the acetamidomalonate and the dichlorobutyne, excess of sodium ethoxide, and heating. No pyrrole was formed at room temperature. 

Acylaminomalonic esters and related reagents are widely used for the synthesis of a-amino acids. The method differs from those syntheses already discussed in that the amino group is incorporated into the system from the outset. A popular reagent is diethyl acetamidomalonate (35). The acetamido group can readily be introduced into the reactive methylene position in diethyl malonate by first converting the latter into the hydroxy-imino derivative (33) by reaction with nitrous acid or an alkyl nitrite (cf. Section 4.2.7, p. 413). This derivative is then reduced catalytically to diethyl aminomalonate (34) which is acetylated using acetic anhydride. 

Diethyl acetamidomalonate, CH3C0NHCH(C02Et)2 Reacts with alkyl halides in a common method of a-amino acid synthesis (Section 26.3). 

What alkyl halide is needed to synthesize each amino acid from diethyl acetamidomalonate (a) Asn (b) His (c) Trp ... 

B Alkylation of diethyl acetamidomalonate to form an amino acid 28.2C Strecker synthesis of an amino acid... 

Amino acids can be synthesized by several methods, including ainmonoly-sis of an cr-bromo acid, Strecker reaction of an aldehyde with KCN/NH3 followed by hydrolysis, alkylation of diethyl acetamidomalonate, and reductive amination of an a-keto acid. Resolution of the synthetic racemate is necessary to obtain an optically active amino acid. 

Amino acids can be prepared by reaction of alkyl halides with diethyl acetamidomalonate, followed by heating the initial alkylation product with aqueous HCl. Show how you would prepare alanine, CH3CH(NH2)C02H, one of the twenty amino adds found in proteins, and propose a mechanism for acid-catalyzed conversion of the initial alkylation product to the amino acid. 

Using the enolate of the glycine equivalent methyl diphenylmethyleneaminoacetate 46 or of diethyl acetamidomalonate 49 as nucleophiles, novel amino acid derivatives have been prepared from allenes (Scheme 19).[24],[25],[37]... 

The use of (acylamino)malonate as a nucleophilic reagent toward 1,3-dienes is an efficient route for the synthesis of a-amino acid derivatives. The reaction of diethyl acetamidomalonate 15 with butadiene in the presence of Pd(OAc)2-PPh3-NaOPh as a catalyst produces diethyl l-octa-2,7-dienylacetamidomalonate 16 in 91% yield as a major product. Subsequent hydrogenation followed by hydrolysis gave octyl glycine 17 in 47% yield (Scheme 4). 

Problem 28.5 The enolate derived from diethyl acetamidomalonate is treated with each of the following alkyl halides. After hydrolysis and decarboxylation, what amino acid is formed (a) CH3I (b) (CHj aCHCHaCI (c) CH3CH2CH(CH3)Br ... 

Alkylation of diethyl acetamidomalonate to form an amino acid... 

One of the best methods for synthesizing amino acids is based on the chemistry of malonate esters (Section 22.17) and a modification of the Gabriel synthesis of amines (Section 23.7). Diethyl acetamidomalonate has a nitrogen atom bonded to the a-carbon of the malonate ester. This nitrogen eventually becomes the nitrogen of the final amino acid product. 

The a carbon atom, the (X amino group, and the carboxyl group are derived from diethyl acetamidomalonate. The side chain of the amino acid, the R group, is derived from an alkyl halide. In this case, the side chain contains a thiomethyl group. 

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