Acetamidomalonate synthesis

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

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

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 ... 

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. 

Due to the laborious multiple steps of this synthesis and the correspondingly low yields, an alternative synthetic approach based on alkylation of the acetamidomalonate 10 with ethyl 6-bromohexanoate (9) giving the racemic a-aminosuberic acid 12 after deacetylation of the amino group in 11 and decarboxylation, as shown in Scheme 5, is significantly more efficient. ... 

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 ... 

As shown in Scheme 86, the CHIRAPHOS-Pd-catalyzed reaction of 1,1,3- or 1,3,3-triphenyl-substituted allyl acetate and sodiomalonate results in optical yields of up to 86%. A BINAP-Pd(0) complex is effective for asymmetric synthesis of a-allyl-a-acetamidomalonate esters of high enantiomeric purity (202). 

Outline the steps in the synthesis of valine from diethyl acetamidomalonate. The overall yield of valine by this method is reported to be rather low (31%). Can you think of a reason why this synthesis is not very efficient ... 

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. 

This is the difficult step in the synthesis it requires a nucleophilic substitution of the SN2 type involving a secondary alkyl halide. Competition of elimination with substitution results in only a 37% observed yield of alkylated diethyl acetamidomalonate. 

The Gabriel-malonic ester synthesis uses an aminomalonic ester with the amino group protected as a phthalimide. A variation has the amino group protected as an acetami-do group. Propose how you might use an acetamidomalonic ester synthesis to make phenylalanine. 

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

Devise a synthesis of threonine from diethyl acetamidomalonate. 

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

Methylindazole 272 was /-butoxycarbonyl (BOC)-protected followed by radical bromination with A -bromosucci-nimide to give bromoindazole 273, which then underwent nucleophilic substitution by the carbanion of diethyl acetamidomalonate followed by decarboxylation and hydrochloride salt formation to provide a synthesis of 2-azatryptophan 274 (Scheme 20) <2006T7772>. 

Compound (VIII.98), a folic acid analogue with a y-fluoro substituent in the side-chain was described first by Alekseeva e/ al. [281] and several years later by Bergmann and Chun-Hsu [282]. The synthesis of (VIII.98), as mixture of threo and erythro isomers, was achieved via the Waller method from V-(4-ami-nobenzoyl)-y-fluoroglutamic acid, 2,4,5-triamino-6(lif)-pyrimidinone, and 2,3-dibromopropionaldehyde, but the yield was low (5.6%). y-Fluoroglutamic acid, as a mixture of D- and L-enantiomers, was prepared from diethyl 2-fluoromalonate by condensation with ethyl 2-acetamidoacrylate followed by hydrolysis and decarboxylation in refluxing 12 M HCl, or from ethyl 3-chloro-2-hydroxypropanoate by a sequence consisting of (i) 0-t-butylation with CH2 = C(CH3)2, (ii) condensation with diethyl 2-acetamidomalonate, (hi)... 

---