Aspartate scheme

Lotrafiban, a nonpeptidic glycoprotein llb/llla receptor anagonist that was under development as a treatment for the prevention of platelet aggregation and thrombus formation, was initially prepared using an 11-step linear sequence starting from methyl Cbz-L-aspartate (Scheme 1.35). An overall yield of 9 % and issues with obtaining the product in sufficient enantiopurity led the group to look for an alternative route via the enzymatic... 

The aminotransferase, or transaminase class of enzymes, are ubiquitous, PLP-requiring enzymes that have been used extensively to prepare natural L-amino acids [84,85]. They catalyze the general reaction shown in Scheme 15, where an amino group from one L-amino acid is transferred to an a-keto acid to produce a new L-amino acid and the respective a-keto acid. Those enzymes most commonly used have been cloned, overexpressed, and generally used as whole cell or immobilized preparations. These include the following branched chain aminotransferase (SCAT) (EC 2.6.1.42), aspartate aminotransferase (AAT) (EC 2.6.1.1), and tyrosine aminotransferase (TAT) (EC 2.6.1.5). A transaminase patented by Celgene Corporation (Warren. NJ), called an co-aminotransferase, does not require an a-amino acid as amino donor and hence is used to produce chiral amines [86,87]. Another useful transaminase, n-amino acid transaminase (DAT) (EC 2.6.1.21), has been the subject of much study [37,88,89]. This enzyme catalyzes the reaction using a n-amino acid donor, either alanine or aspartate (Scheme 16). 

Thermolysin, which is another protease, will also catalyse peptide synthesis, and a new plant will shortly use this enzyme for the manufacture of the artificial sweetener Aspartame, at a scale of2,000 tonnes per year. In this reaction the L-enantiomer of racemic phenylalanine methyl ester reacts specifically with the a-carboxyl group of JV-protected L-aspartate (Scheme 6.26). Thus both the separation of the enantiomers of the phenylalanine and the protection of the y-carboxyl group of the L-aspartate are unnecessary, which simplifies the synthesis. Although the equilibrium favours hydrolysis rather than synthesis, the peptide product, which is the JV-protected precursor ester of Aspartame, forms an insoluble salt with the... 

The improvements in resolution achieved in each deconvolution step are shown in Figure 3-3. While the initial library could only afford a modest separation of DNB-glutamic acid, the library with proline in position 4 also separated DNP derivatives of alanine and aspartic acid, and further improvement in both resolution and the number of separable racemates was observed for peptides with hydrophobic amino acid residues in position 3. However, the most dramatic improvement and best selectivity were found for c(Arg-Lys-Tyr-Pro-Tyr-(3-Ala) (Scheme 3-2a) with the tyrosine residue at position 5 with a resolution factor as high as 28 observed for the separation of DNP-glutamic acid enantiomers. 

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

The noteworthy successes of a relevant model study12 provided the foundation for Merck s thienamycin syntheses. In the first approach (see Schemes 2 and 3), the journey to the natural product commences from a readily available derivative of aspartic acid this route furnishes thienamycin in its naturally occurring enantiomeric form, and is noted for its convergency. During the course of this elegant synthesis, an equally impressive path to thienamycin was under parallel development (see Schemes 4 and 5). This operationally simple route is very efficient (>10% overall yield), and is well suited for the production of racemic thienamycin on a commercial scale.. x... 

Much less is known about the participation of sugars in the biosynthesis of pyramine in yeasts, and although it has been proven that sugars can provide some carbon atoms, the exact nature of the more advanced intermediates of sugar origin is not yet clear. Some features of the biosynthesis in S. cerevisiae are summarized in Scheme 33. Two l5N atoms from DL-(l,3-,5N2)histidine were incorporated into the N-3 and amino nitrogen atoms of pyramine. The nitrogen atom of (,5N)aspartate, a known precursor of N-l of histidine, was incorporated into pyramine without dilution.58-70 It was also found that N-l and C-2 of pyramine came respectively from N-l and C-2 of pyridoxol.71-73... 

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

In a comparable approach, Roques and coworkers [15] converted the aspartic acid derivative 7-23, which bears a protected thiol in the 3-position, into unsaturated compounds 7-27 and 7-28, respectively (Scheme 7.9). 

Scheme 7.9. Domino reduction/Wittig-Horner olefination process of aspartates.

Moser et al. (1968) (one of the co-authors was Clifford Matthews) reported a peptide synthesis using the HCN trimer aminomalonitrile, after pre-treatment in the form of a mild hydrolysis. IR spectra showed the typical nitrile bands (2,200 cm ) and imino-keto bands (1,650 cm ). Acid hydrolysis gave only glycine, while alkaline cleavage of the polymer afforded other amino acids, such as arginine, aspartic acid, threonine etc. The formation of the polymer could have occurred according to the scheme shown in Fig. 4.9. 

A number of P-chirogenic diaminophosphine oxides (DIAPHOXs) 275 derived from aspartic acid were prepared via hydrolysis of triaminophosphine intermediate 274, generated in a fully diastereoselective reaction of triamines 273 with phosphorus trichloride (Scheme 65) [102, 103],... 

Scheme 6-28. Statine 65, part of aspartic proteinase inhibitor.

A tetracarboxylated derivative was prepared recently by reaction of a commercial reactive dye with two molar equivalents of aspartic acid. This novel derivative was evaluated by pad-dry-bake and pad-batch-bake methods under slightly acidic conditions in the presence of cyanamide as activator [49]. An interesting disperse dye containing a novel reactive anhydride system (7.54) was prepared from the parent dye carboxylate (7.53) by reaction with ethyl chloroformate in the presence of a tertiary base (Scheme 7.32). Such dyes will... 

A potent and selective N-methyl-D-aspartate (NMDA) antagonist, AP5112, was synthesized from 111, which was a pseudo-Claisen [2,3] rearrangement product of 110 (Scheme 4.29) [47]. 

For example, coupling alanine transamination (via ALT) with GLDH is shown in Figure 6.6b. A similar scheme can be drawn using, for example, aspartate transaminase in place of alanine transaminase. 

Numerous groups have described the use of d-AAO in a variety of combinations with other agents and in a variety of processes. Cheng and Wu, in the context of a biotransformation of DL-aspartic acid to L-alanine, in which the key reaction works only with L-Asp, removed residual D-Asp with d-AAO and converted the resulting oxaloacetate into L-Asp by including L-aspartate aminotransferase (r-AspAT) in the reaction mixture (Scheme 1). 

The same group have used the enzyme combination employed in the aspartate deracemization cited above to deracemize 2-naphthylalanine, hut have made use of an interesting innovation introduced by Helaine et al to pull over the poised equilibrium of the transamination reaction. Cysteine sulphinic acid was used as the amino donor in the transamination. The oxoacid product spontaneously decomposes in to pyruvic acid and SO2 (Scheme 3). 

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