3- Aminoacrylates

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

Replacement of one of the ethereal oxygen atoms by a methylene group is compatible with anticoccidial activity. For example, condensation of substituted aniline 35 with dimethyl ethoxymethylenemalonate affords aminoacrylate 36. Thermal cyclization in diphenyl ether gives neguinate (37).11... 

Treatment of 2-aroyl-3-aminoacrylates 442, or their 0-acetate derivatives <1996USP5539110> with KF, or with another base, yielded 7-oxo-2,3-dihydro-7f/-pyrido[l,2,3- i ]-l,4-benzoxazine-6-carboxylates or 6-carboxylic acids (e.g., <1996GEP4428020, 1997H(45)137>). Cyclization of 2-aroyl-3-aminoacrylates 443 <1997H(45)137> or their O-acetates <1996USP5539110> led to pyrido[l,2,3- i ]-l,4-benzoxazine-6-carboxylic acids 444 (Equation 84). 

In structural terms, djenkolic has two units of L-cysteine joined through a CH2 group linked to sulfur atoms. It has also been found in seeds of Albizzia lophanta and Parkia speciosa32 and, as noted earlier, is the source of CS2 in Mimosa pudica (Section 11.1.2.2.2). An enzyme in A. lophanta seeds converted djenkolic acid to an unstable material with a leek-like odor, methylene dithiol 39.92 This was presumably an elimination of aminoacrylic acid 28 via intermediates 37 and 38 (Scheme 13). The methylene dithiol decomposed to H2S and possibly, thioformaldehyde, CH2S the latter might be a source for polysulfides. 

Isopropylidene (l-aminoalkylidene)malonates (454) were heated under reflux in ethanol in the presence of sodium ethylate overnight. After evaporation of the solvent, the residues were treated with water to give 3-aminoacrylates (1608) in 48-89% yields. If the residues were treated with water and 10% hydrochloric acid, 3-oxo esters (1609) were obtained in 22-81% yields. When isopropylidene (l-aminoalkylidene)malonates (454) were heated under reflux in concentrated hydrochloric acid, methylke-tones (1610) were prepared in 24-73% yields (81S130). 

One case where enzymatic involvement is documented is that of (R)-a-fluoro-/3-alanine (11.42), itself the major (>80%) metabolite of 5-fluoroura-cil (11.16) in humans. With rat liver homogenates, it was demonstrated that mitochondrial L-alanine-glyoxylate aminotransferase II (AlaAT-II, EC 2.6.1.44) catalyzed the defluorination of (R)- and (S)-a-fluoro-/3-alanine with catalytic efficiencies of 0.038 and 0.050 mM"1 s 1 at 37° and pH 7.0, respectively, [76], The primary product of the reaction was jS-aminoacrylate... 

The a-silyloxy alkyl radical generated by the addition of (TMS)3Si radical to the aldehyde moiety of 45 has been employed in radical cyclization of (3-aminoacrylates (Reaction 7.53) the trans-hydroxy ester and the lactone in a 2.4 1 ratio were the two products [62]. 

This enzyme [EC 4.4.1.4], also known as alliinase and cysteine sulfoxide lyase, catalyzes the conversion of an 5-alkyl-L-cysteine 5-oxide to an alkyl sulfenate and 2-aminoacrylate. The enzyme requires pyridoxal phosphate. 

Very detailed studies on the inhibition of alanine racemase by fluoroalanines have been conducted. This enzyme catalyzes the racemization of alanine to provide D-alanine, which is required for synthesis of the bacterial wall. This work has demonstrated that a more complex process than that represented in Figure 7.47 could intervene. For instance, in the case of monofluoroalanine, a second path (Figure 7.48, path b) occurs lysine-38 of the active site can also attack the Schiff base PLP-aminoacrylate that comes from the elimination of the fluorine atom. This enamine inactivation process (path b) has been confirmed by isolation and identification of the alkylation compound, after denaturation of the enzyme (Figure 7.48). ... 

In a base-catalyzed substitution reaction with benzamide, ethyl 2-cyano-3,3-bis(methylsulfanyl)acrylate 280 gave the 3-aminoacrylate derivative 281, which on thermal cyclization yielded the functionalized 6-imino-l,3-oxazine 282 (Scheme 52) <1995BML695>. 

Peptides that contain 2-aminoacrylic acid and 2-aminocrotonic acid groups absorb in the ultraviolet region, the former at a wavelength maximum of 240 nm, and the latter with a more generalized absorption. At 240 nm, the molar absorptivity is the same (4,200) for the two... 

The 2-aminoacrylic and 2-aminocrotonic acid residues initially produced by alkali are reduced to L-alanine and 2-aminobutyric acid (But) residues, respectively. Use of a further reducing agent is indicated. The results are expressed as decrease or increase in moles of amino acid for the glycopeptides, and as jumoles per g for the glycoproteins. 

While investigating the biomimetic formation of cysteine, Schmidt et al. 2331 added thiolates to N-protected chiral a-aminoacrylic acid derivatives (dehydropeptides). (235) was obtained in optical yields up to 90 %. 

MECHANISM FIGURE 22-18 Tryptophan synthase reaction. This enzyme catalyzes a multistep reaction with several types of chemical rearrangements. An aldol cleavage produces indole and glyceraldehyde 3-phosphate this reaction does not require PLP. Dehydration of serine forms a PLP-aminoacrylate intermediate. In steps and this condenses with indole, and the product is hydrolyzed to release tryptophan. These PLP-facilitated transformations occur at the /3 carbon (C-3) of the amino acid, as opposed to the a-carbon reactions described in Figure 18-6. The /3 carbon of serine is attached to the indole ring system. Tryptophan Synthase Mechanism... 

Several 3-vinyl- and 1,3-divinyl-hydantoin derivatives have been prepared and converted to polymers having pendant hydantoin groups, e.g. (66) (B-74MI11100). Interesting spiro hydantoin polymers (67) are readily prepared from the very reactive 5-methylenehydantoin, hydrolysis of which cleanly produces polymers containing a-aminoacrylic acid units and having corresponding polyampholytic properties. 

Two general syntheses of 3-pyrrolinones which utilize easily available starting materials are known. One involves acylation and cyclization of /3-aminoacrylates by reaction with chloroacetyl chloride, as shown in reaction (198). The condensation of /3-keto esters with ethyl glycinate (reaction 199) also appears to be a reasonably general route to 3-pyrrolinones. Other methods, which are summarized by Jones and Bean (B-77MI0610), lead to specialized products or require unusual starting materials. 

Beta-chloroalanine and serine O-sulfate can undergo (3 elimination (as in Eq. 14-29) in active sites of glutamate decarboxylase or aspartate aminotransferase. The enzymes then form free aminoacrylate, a reactive molecule that can undergo an aldol-type condensation with the external aldimine to give the following product.1... 

Nucleophilic groups from enzymes can add to double bonds, e.g., in an aminoacrylate Schiff base, or to multiple bonds present in die inhibitor. An example is y-vinyl y-aminobutyrate (4-amino-5-hexenoic acid), another inhibitor of brain y-aminobutyrate aminotransferase which is a useful anticonvulsant drug. 

Beta replacement is catalyzed by such enzymes of amino acid biosynthesis as tryptophan synthase (Chapter 25),184 O-acetylserine sulfhydrylase (cysteine synthase),185 186a and cystathionine (3-synthase (Chapter 24).187 188c In both elimination and (3 replacement an unsaturated Schiff base, usually of aminoacrylate or aminocrotonate, is a probable intermediate (Eq. 14-29). Conversion to the final products is usually assumed to be via hydrolysis to free aminoacrylate, tautomerization to an imino acid, and hydrolysis of the latter, e.g., to pyruvate and ammonium ion (Eq. 14-29). However, the observed stereospecific addition of a... 

A (3 replacement reaction catalyzed by the PLP-dependent tryptophan synthase converts indoleglycerol phosphate and serine to tryptophan. Tryptophan synthase from E. coli consists of two subunits associated as an a2P2 tetramer (Fig. 25-3). The a subunit catalyzes the cleavage (essentially a reverse aldol) of indoleglycerol phosphate to glyceraldehyde 3-phosphate and free indole (Fig. 25-2, step s).67 The P subunit contains PLP. It presumably generates, from serine, the Schiff base of aminoacrylate, as indicated in Fig. 25-2 (step f). The enzyme catalyzes the addition of the free indole to the Schiff base to form tryptophan. The indole must diffuse for a distance of 2.5 ran... 

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