Amino acids, basicity decarboxylation

Biogenic amines are derived from neutral or basic amino acids via decarboxylation (24). Some prominent examples of biogenic amines... 

Biosynthesis. Two closely related genes encode the three mammalian tachykinins. The preprotachykinin A gene encodes both substance P and substance K, while the preprotachykinin B gene encodes neuromedin K (45—47). The active sequences are flanked by the usual double-basic amino acid residues, and the carboxy-terrninal amino acid is a glycine residue which is decarboxylated to an amide. As with most neuropeptide precursors, intermediates in peptide processing can be detected, but their biological activities are not clear (ca 1994). 

An exhaustive series of reports by Grigg et al. (28) outlined two basic methods for the generation of azomethine ylides proceeding via either a 1,2-prototropic shift, or by a decarboxylative approach (29). The decarboxylative route to azomethine ylides can be exemplified by the condensation of benzaldehyde with the cyclic amino acid tetrahydroisoquinoline (108) (30), in DMF at 120 °C, to generate the intermediate awfi-dipole 109, which underwent subsequent cycloaddition with N-methyl maleimide to furnish a 1 1 endo/exo mixture of adducts 110 (R = Ph), in 82% yield (Scheme 3.30). 

NMR studies have been carried out on Schiff bases derived from pyridoxal phosphate and amino acids, since they have been proposed as intermediates in many important biological reactions such as transamination, decarboxylation, etc.90 The pK.d values of a series of Schiff bases derived from pyridoxal phosphate and a-amino adds, most of which are fluorinated (Figure 11), have been derived from H and19F titration curves.91 The imine N atom was found to be more basic and more sensitive to the electron-withdrawing effect of fluorine than the pyridine N atom. Pyridoxal and its phosphate derivative are shown in Figure 12a. The Schiff base formation by condensation of both with octopamine (Figure 12b) in water or methanol solution was studied by 13C NMR. The enolimine form is favoured in methanol, while the ketoamine form predominates in water.92... 

The two examples illustrative of the section, however, involve alternative procedures for introducing the required substituent into the a-position of the acet-amidomalonate reagent. In the first (Expt 5.183) the hydroxymethyl group is introduced by a simple base-catalysed condensation with formaldehyde subsequent hydrolysis and decarboxylation yields serine (R = CH2OH). In this case, acidic conditions are preferred for the final hydrolytic stage, and the use of a weakly basic ion exchange resin to obtain the halide-free amino acid from a solution of its hydrochloride is described. 

Dopamine is synthesized in the terminals of dopaminergic fibers originating with the amino acid tyrosine and, subsequently, L-dihydroxyphenylalanine (L-dopa or levodopa), the rate-limiting metabolic precursor of dopamine. Fortunately, L-dopa is significantly less polar than dopamine and can gain entry into the brain via an active process mediated by a carrier of aromatic amino acids. Although L-dopa is itself basically pharmacologically inert, therapeutic effects can be produced by its decarboxylation to dopamine within the CNS. 

We also studied the pyridoxal-dependent decarboxylation of an aminomalonic acid, a process providing an a-amino acid as the product. Our interest was to induce stereoselectivity in the process. Therefore, we synthesized catalysts 42 and 43, which rigidly held chirally mounted groups [42]. With the basic 42 we obtained 42% ee favoring l-phenylalanine in the decarboxylation of 2-amino-2-benzyl-malonic acid, while with non-basic 43 the ee was too low to detect. We proposed that the basic side chain delivered a proton to the decarboxylation intermediate in a stereoselective fashion. 

The vitamin is transformed into pyridoxal phosphate (PLP), which, as a pyridine, is basic at the ring nitrogen, and in the active form, is V-protonated. Enzymes containing PLP have various functions, all connected with amino acids. Amongst other activities, PLP-containing enzymes can (i) effect transfer of an amino group from an a-amino acid to an a-keto acid (ii) bring about decarboxylation of an a-amino acid or... 

The seminal report by Cotzias et al. (59) in 1967, describing dramatic symptomatic improvement of parkinsonian patients given high oral doses of racemic dopa, was followed by more clinical trials that confirmed the efficacy and safety of the levo isomer. The effectiveness of levodopa requires penetration of the drug into the CNS and its subsequent enzymatic decarboxylation to dopamine. Dopamine does not cross the blood-brain barrier, because it exists primarily in its protonated form under physiologic conditions (pKa = 10.6 [NH2]) (60). The precursor amino acid levodopa, however, is less basic (pKa = 8.72 [NH2]) and, thus, can penetrate the CNS. 

Nitro-alkenes are good Michael acceptors and the nitro group can be reduced to an amine. For the production of amino acids, this method requires that the nucleophile contain a carbonyl moiety. When nitroethene was treated with dimethyl malonate under basic conditions. 3.70 was obtained.3 As in other systems of this type, catalytic hydrogenation of 3.70 led to an amino-ester that cyclized to 2-pyrro-lidinone derivative 3.71). Acid hydrolysis (which was accompanied by decarboxylation) gave 4-aminobutanoic acid (5.48).37.29... 

Some aliphatic, aromatic and heterocyclic amines and diamines formed by decarboxylation of basic, aromatic and heterocycHc amino acids are biologically active substances called biogenic amines. Subsequent enzymatic transformations of biogenic amines... 

In addition to the fatty acids with straight (unbranched) chains and an even number of C atoms, small amounts of acids with branched methyl groups or with an odd number of C atoms are also found in nature. Their metabolic fate in jS-oxi-dation is of considerable interest and can best be studied on the examples of the methyl branched C4- and the Ce-carboxylic acids. These two acids arise from the catabolism of the amino acids leucine, isoleucine, and valine by transamination and oxidative decarboxylation, as described in Chapt. VIII-10. Basically only two situations need to be discussed one with a methyl group in the a-position, or potentially in a-position (i.e. by repeated shortening of the chain by two C atoms the methyl group eventually ends up in a-position) the other with a methyl group in the -position, or at least potentially in /3-position. 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

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