Aminomalonic acid esters

Lactams from aminomalonic acid esters and y-Lactams... 

Reactions of this type provide one of the major routes to the commercially important l,4-benzodiazepin-2-one system (156) via the reaction of substituted o-aminobenzoph-enones (155) with amino acid esters (68CRV747, p. 756). This synthesis allows the easy preparation of 3-substituted products by the use of readily available a-substituted amino acids, e.g. the CNS active Tranxene (156 Y = C1, Ar = Ph, R1 = CC>2H) by using aminomalonic ester. Similar reactions have been carried out using other three-atom components, e.g. 2-bromoethylamine (77MIP51800) and ketenimines (77JHC99). 

In Ama-L-Phe-OMe (47) (14, 15), it is also not known whether the sweet-tasting isomer has the L-L(or S-S) or the D-L(or R-S) configuration. In the case of aspartyl dipeptide esters, the L-L isomer was sweet. By analogy, other researchers deduced that the L-L(or S-S) isomer ((47b) in Figure 4) would be sweet. However, it seemed to us that the D(or i )-configuration would be preferred for the aminomalonic acid because the D-L(or R-S) isomer ((47a) in Figure 4) was compatible with the sweet formula and could also fit the spatial barrier model (13), whereas the L-L(or S-S) isomer could neither fit the receptor model nor meet the sweet formula. 

A -Acylated amino acids are anodically oxidized in methanol or acetic acid solution under decarboxylative methoxylation or acetoxylation via the intermediate A-acyliminium ion in the course of a Non-Kolbe reaction (Hofer-Moest reaction) according to Scheme 8, path b. This type of reaction has been used intensively for amidoalkylation reactions by Mori, Seebach, and Steckhan. These reactions were based on the results of Iwasaki applying N-acyl aminomalonic acid half esters [Eq. (46)] [239]. 

Formation of chiral a-amino acids from aminomalonic acids via decarboxylative protonation is readily accomplished in the presence of thiourea 1 (ex quinidine)/ The diaster-eomeric 2 (ex quinine) has been employed to generate monomethyl esters in chiral form by methanolysis meso-cydic anhydrides ... 

Shaprio described a nonoxidative method for preparing 2-substituted 4-ox-azolecarboxylic acid esters 591 (Scheme 1.161). He prepared the key intermediate, dimethyl amino[(phenylthio)methyl]malonate 588, in three straightforward steps from diethyl aminomalonate hydrochloride. Acylation of 588 gave the A-acyl derivative 589 in excellent yield, which was sequentially chlorinated and cyclized in one pot to afford the 2,4,4,5-tetrasubstituted oxazoline 590. The author noted that anhydrous conditions were required to minimize sulfoxide formation. This was the only product isolated if the chlorination cyclization sequence was carried out in a hydroxylic solvent. 

The sweet taste of aspartic acid dipeptide esters (I) was discovered by chance in 1969 for a-L-aspartyl-L-phenylalanine methyl ester ( Aspartame , NutraSweet ). The corresponding peptide ester of L-aminomalonic acid (II) is also sweet. 

Peptides, Kke amino acids, can taste bitter, sweet, salty or indifferent. Most natural and synthetic oligopeptides have a bitter taste (see Section 2.3.3.2). A sweet taste indicates dipeptides derived from L-aspartic acid (2-91) and others derived from its lower homologue L-aminomalonic acid (2-92). is always a hydrogen atom or a methyl group, substituents are alkyls or aryls and substituents are esterified carboxyl groups (usually methyl esters, but some ethyl, propyl, isopropyl and other esters are also sweet). The best... 

The enantioselective decarboxylative protonation of aminomalonic acid derivatives has been also extensively investigated by Rouden et al. [17]. Their first contribution in this area aimed at preparing enantioenriched pipecoUc esters by decarboxylation of A7-acetyl piperidinohemimalonate 24 [17]. Among the different cinchona alkaloids investigated, the best result was obtained by means of 9-ep/-cinchonine-benzamide 19b, previously developed by Brunner [14, 16]. Pipecolic ester 25 was obtained in up to 52% ee when conducting the reaction in THF at room temperature for 24 h. Various bis-cinchona alkaloids such as (DHQDj AQN 26 or (DHQDj Pyr 27 were also evaluated providing modest enantiomeric excesses not exceeding 24% ee. Most of the results outlined in this study were obtained in the presence of a stoichiometric amount of the chiral base. The few attempts to carry out experiments under catalytic conditions seem to... 

DIETHYL AMINOMALONATE HYDROCHLORIDE (Malonic acid, amino-, diethyl ester, hydrochloride)... 

The formic acid Is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This Is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. 

B) Preparation of 7-Chloro-3-Methoxycarbony/-5-Phenyl-2-0xo-2,3-Dihydro-iH-Benzo [fl-1,4-Diazepine (4347 CB) A solution of 9.2 g (0.04 mol) of compound 4356 CB in 20 ml of methanol is added dropwise, in the course of one hour and 30 minutes, to a boiling solution of 9.2 g (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml of methanol. When this is completed, heating under reflux is continued for 30 minutes and the product then concentrated to dryness under reduced pressure. The residue is taken up in water and ether, the ethereal layer separated, the product washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue, which consists of the methyl ester, could not be obtained in the crystalline state. It is dissolved in 25 ml of acetic acid, heated under reflux for 15 minutes, the product evaporated to dryness and the residual oil taken up in ether. A colorless solid separates which... 

The low percentage of obtaining products belonging to the a-kainic acid series (at best 50%) was attributed to unfavorable transition states with repulsion between one of the aminomalonate ester groups and the isoprenyl chain. These difficulties were circumvented by using a simple a-amino ester (131) in lieu of the aminomalonate group this has led to a simple synthesis of a-kainic acid (Scheme 33) (178). 

This sequence was obviously not amenable to a synthesis of optically active a-allokainic acid given the fact that an aminomalonate group was necessary. After unfruitful assays with menthyl esters, the Swiss group was rewarded by the discovery that the phenylmenthyl group (180) brings sufficient asymmetry to the reaction intermediate to afford products with a high percentage of favorable diastereoisomer (Scheme 35) (181). 

In 2008, Gong and coworkers introduced a new chiral bisphosphoric acid 19 (Fig. 4) that consists of two BINOL phosphates linked by an oxygen atom for a three-component 1,3-dipolar cycloaddition (Scheme 42) [66]. Aldehydes 40 reacted with a-amino esters 105 and maleates 106 in the presence of Brpnsted acid 19 (10 mol%) to afford pyrrolidines 107 as endo-diastereomers in high yields (67-97%) and enantioselectivities (76-99% ee). This protocol tolerated aromatic, a,P-unsaturated, and aliphatic aldehydes. Aminomalonates as well as phenylglycine esters could be employed as dipolarophiles. 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

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. 

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