Piperideine-6-carboxylic acid

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

Rumbero, A., Martin, J.C., Lumbreras, M.A., Liras, P., and Es-mahan, C. (1995) Chemical Synthesis of AUysine Ethylene Acetal and Conversion In Situ into l-Piperideine-6-carboxylic Acid Key Intermediate of the a-Aminoadipic Acid for p-Lactam Antibiotics Biosynthesis, Bioorg. Med. Chem. 3,1237-1240. 

Rumbero A, Martin JF, Lumbreras MA, Liras P, Esmahan C. Chemical synthesis of allysine ethylene acetal and conversion in situ into l-piperideine-6-carboxylic acid-key intermediate of the alpha-aminoadipic acid for beta-lactam antibiotics biosynthesis. Bioorg. Med. Chem. 1995 3 1237-1240. 

By use of potassium phthalimide we can isolate the intermediate. a-Oxo-S-aminovaleric (9, = 1) and a-oxo-e-aminocaproic acids (9, = 2) readily yield 2l -pyrroline-2-carboxylic acid (10, =1) and. d -piperideine-2-carboxylic acids (10, n = 2), respectively (7-10). The equilibria of the acids with their cyclic forms was observed in water solutions (11,12). 

The reactivity of the methylene group adjacent to the lactam group affords the possibility of a Claisen condensation. Thus, treatment of 2-pyrrolidone or 2-piperidone with ethyl oxalate leads to the J -pyrroline-carboxylic (70) and, d -piperideine-2-carboxylic acids (71), respectively. N-methyl lactams furnish N-methyl derivatives (72,73) (Scheme 3). 

Condensation of -pyrroline with pyrrole readily affords 2-(2-pyrro-lidyl)pyrrole (82). The dimerizations of some derivatives of A -piperideine, e.g., zl -pyrroiine and -piperideine-2-carboxylic acids, take a similar course (301). 

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

Pyrrolidone (22) and piperidone themselves afford J1-pyrroline-2-carboxylic acid161 (23) and J 1-piperideine-2-carboxylic acid.162... 

A -piperideine-2-carboxylic acid which is subsequently converted into pipecolic acid, the molecule that is entirely incorporated. The other lysine unit provides the C5N (N-8, C-9 to C-13) through cadaverine, which is generated by stereospecific decarboxylation of the amino acid catalyzed by lysine decarboxylase. Intramolecular cyclization of cadaverine affords 2,3,4,5-tetrahydropyridiniuni, which undergoes nucleophilic attach by pipecolic acid to generate l,2-biperidine-2-carboxylic acid. A further intramolecular cyclization generates imidazo-dipyridin-one which upon reduction, dehydration, and subsequent oxidation produces anosmine (Figure 5.88) [333, 334]. 

In rat liver, Lys degradation (Fig.l) occurs primarily in the mitochondria. Some features of the degradation pathway appear to be a reversal of the reactions of Lys synthesis (Figs. 4 5). Saccharopine is formed, offering a direct route to 2-aminoadipic-6-semialdehyde, and bypassing the cyclic piperideine and piperidine intermediates. The semialdehyde is also produced by a second pathway, initiated by L-amino acid oxidase. The resulting oxoacid cyclizes spontaneously to A -piperideine 2-carboxylic acid. 

Imino-aclds.—The transformation of DL-[6- H,6- C]lysine into pipecolic add with retention of tritium has been demonstrated in rats, in Neurospora crassa, in kidney beans, and in Sedum acre, and into the piperidine alkaloid sedamine with retention of tritium in S. acre. Correspondingly, [2- H,6- C]lysine is incorporated into pipecolic acid in kidney beans and S. acre with loss of tritium, indicating that the transformation takes place via 6-amino-2-keto-hexanoic acid and A -piperideine-2-carboxylic acid. In S. acre, however. 

The reactivity of the a-methylene group in lactams allows Claisen condensation with esters of formic, oxalic, and arylcarboxylic acids. Treatment of ethyl formate with A-methylpiperidone, followed by acidification, yields a salt of 1 -methyl- J2-piperideine, whereas in an alkaline medium its dimer was isolated.34- 158 With oxalic acid ester as the condensing reagent, 1-methyl-J2-pyrroline-2-carboxylic acid159 and l-methyl-d2-piperideine-2-carboxylic acid160 were obtained (Scheme 4). 

ATP-dependent adenylation domain in the loading module of the PKS, transferred to the ACP domain of this module, and then reduced in situ by an adjacent enoylreductase domain [248], Some years later, the heterologous overexpression and purification of RapL and validation of its ability to convert L-lysine to L-pipecolic acid by a cyclodeamination reaction that involves redox catalysis (NAD+ZNADH) were reported. Turnover is presumed to go through a reversible oxidation of the a-amine to imine, internal cyclization, and subsequent re-reduction of the cyclic A -piperideine-2-carboxylate intermediate. RapL also accepts L-ornithine as a substrate, although with a significantly reduced catalytic efficiency [249]. 

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