Amino acrylates

Mechanistic studies (6,26,27,67) have shown that the acyl enzyme species is the ring opened compound (13), which can tautomerize to the transientiy inhibited amino acrylate (14), and both of these species can react further to give irreversibly inactivated enzyme. Three inactivated forms of the enzyme have been detected. Two, according to labeling studies, retain the complete clavulanate skeleton and the other retains only the carbon chain of the P-lactam ring. Stmcture (15) has been suggested as one possible inactivated form. 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

C-alkylated material 119. The cyclization of a 3-aminopyridino-methylene malonate has been shown. The formation of amino-acrylate 121 was nearly quantitative and subsequent cyclization afforded a 50% yield of the 1,5-napthyridine. Saponification and decarboxylation gave the desired 1,5-napthyridine 124 in good yield. 

Formation of the amino-acrylate of aminopyrimidine intermediates was reported. In the absence of base, alkylation occurred on the carbon and not the nitrogen, followed by cyclization to give 125. In the presence of base (EtONa), condensation occurred on the nitrogen. Cyclization under thermal conditions afforded 128. °... 

With pyrimidine systems, another anomaly occurred with which group underwent cyclization in the case of a-cyano-P-(pyrimidino)amino-acrylate. For example, cyclization of 129 occurred on the CN group providing the 5-amino-pyridopyrimidine 130. 

Cyclization of methyl 2-[2-benzoyl-2-ethoxycarbonyl-l-vinyl)amino]-3-[(4-methyl-2-pyridyl)amino]acrylate (311) afforded the 3-amino-8-methyl-4//-pyrido[l,2-n]pyrimidin-4-one derivative 312 (97JHC1511). 

Dihydropyrazoles were prepared by reaction of a monosubstituted hydrazine with benzimidazole amino acrylates 120. The reaction was carried... 

Pyridines 158 have been also prepared by cyclocondensation of alkynyl ketones 157 and amino acrylates in DMSO as the solvent at 170 °C for 20 min (Scheme 56 and Sect. 5.2 for more details) [102,103]. 

Other cyclic tetrapeptides have also been isolated by Japanese workers and AM toxins I, II, and III, isolated from Alternaria mail., are extremely toxic to certain plant species (9.10). These are constructed of L- i-hydroxyisovaleric acid, L-alanine, c-amino-acrylic acid and, in AM toxin I, L-6(-amino- -( .-methoxyphenyl)-valeric acid. The phenyl residue in AM toxin II is L-t(-amino-S-phenylvaleric acid, while in AM toxin III, it is L-ol-amino-( .-hydroxyphenyl)valeric acid (Figure 2), All the AM toxins produce leaf spot, or necrosis, in apple but as might he expected slight change in substitution (R-group) on the phenyl ring radically alters the specific activity of the molecule. Both AM toxin I and III induce interveinal necrosis in the "Indo" apple cultivar, which is also highly susceptible to A. mail. at concentrations as low as 0.1 pph within 18 h after treatment. In contrast, the resistant apple cultivar "Jonathan" is only affected by 1 ppm of AM toxin I and 10 ppm of AM toxin III. 

Kim and co-workers described an efficient and high-yielding sequence to the penultimate intermediate of LVX (Kang et al., 1997). Their strategy involved synthesizing a chiral amino acrylate as a 4 1 mixture of Z to olefin isomers. The reaction sequence... 

Scheme 4.15) began with a Michael addition between (5)-2-amino-l-propanol (94) and ethyl propiolate (95) to afford chiral amino acrylate (96) in 99% yield. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

The different reactivity of 1,2- and 1,1-acceptor/donor-substituted alkenes is paralleled by the readiness with which these compounds can be prepared. Thus, /3-amino acrylates are often spontaneously formed by mixing amines with /3-keto esters, and these derivatives have been used as protective groups for amines because of their low reactivity. a-Amino acrylates can, similarly, be prepared from a-keto esters [40], but this condensation reaction does not proceed spontaneously and requires chemical or azeotropic removal of water [41—43]. a-Amino acrylates are unstable compounds which must be stored at low temperatures [41] or N-acylated immediately after their generation [43]. 

Achiwa s procedure has been utilized by several authors toward the synthesis of cucurbitine, an aminoacid extracted from pumpkin seeds which share structural features with arginine. Different precursors have been used in chiral and achiral synthetic pathways. First, cucurbitine methyl ester was obtained from an a-amino acrylate.424 Other substituted acrylates were tested and 3,3-dimethyl-2-aminocarboxylate did not react at all. 

The initially formed rhodium/substrate (B) complex of the hydrogenation of Z-OC-(acyl-amino)acrylic acid in Figure 17.77 possesses structure C (Figure 17.78). The reaction starts with the reversible dissociation of two MeOH ligands from the central atom Rh(I). The two now... 

Fig. 17.78. Key intermediates in the enantioselective hydrogenations of the Z-configu-rated stereoiso meric a-(acyl-amino)acrylic acids in Fig.

Fig. 7.6 Mechanism of -replacement and /3-elimination reactions with L-serine (X =OH-) or /S-chloro-L-alanine (X- = Cl-). Formation of the Schiff base intermediate with the amino acid ES 1 is followed by removal of the a-proton (H ) and of the leaving group (X-) to form the Schiff base of amino acrylate ES III, the key intermediate in both types of reaction. ES III can be hydrolyzed to pyruvate and NH3 (/3-elimination) or can add the indole cosubstrate (RH) to form the Schiff base of the quinonoid of L-tryptophan ES IV (/3-replacement). Protonation of ES IV leads to release of L-tryptophan. ES IV can also be formed in the reverse direction from L-tryptophan.

An important intermediate step in the reaction of L-serine and indole to form l-tryptophan is the nucleophilic attack of indole on the Schiff base of amino acrylate (ES III... 

Fig. 7.10 Cartoon depicting the a/3 reaction. L-serine is converted to the Schiff base of amino acrylate at the j8-site. Indole, which is produced by cleavage of indole-3-glycerol phosphate at the o-site, diffuses through the tunnel and reacts with the Schiff base of amino acrylate at the /3-site to form L-tryptophan. (Reproduced with permission from Brzovic et a .. J. Biol. Chem., 267, 13028 (1992)).

Although this mechanism was widely accepted, later work by Metzler and coworkers167 and by Walsh and coworkers168,169 revealed that, whereas the eneamino aldimine complex is formed in the inhibition process, subsequent elimination produces amino acrylate. Nucleophilic addition of amino acrylate to the Schiff base formed between the enzyme lysine residue and PLP results in irreversible inhibition (Figure 15). Support for this mechanism includes the isolation of the pyruvate derivative 103 (the Schnackerz adduct) upon denaturization. The significance of the reversed polarity pathway as an alternative mechanism is discussed effectively in a review by Walsh170. 

Alkali treatment of proteins is becoming more common in the food industry and may result in several undesirable reactions. When cystine is treated with calcium hydroxide, it is transformed into amino-acrylic acid, hydrogen sulfide, free sulfur, and 2-methyl thia-zoIidine-2,4-dicarboxyIic acid as follows ... 

Amino-acrylic acid (dehydroalanine) is very reactive and can combine with the e-amino... 

Enamines can be deprotonated with n-BuLi or f-BuLi if some stabilizing groups are present at the nitrogen or on the alkene. Some examples are /3-amino acrylic acid derivatives 68 2987,988, which have also been employed as /S-acyl vinyl anion equivalents858. 

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