D-pipecolic acid

Pip = D-pipecolic acid MeAsp = A -methylaspartic acid. The amphomycin family member having (+)-3-anteisotridecenoic acid is shown not shown is... 

Dab = D-erythro-aj3-diaminobutyric acid Dab = L-threo-or,)3-diaminobutyric acid Pip = D-pipecolic acid... 

Enantiomeric excess was determined by high-performance hquid chromatography with a Chiralpak WE column (4.6 mm x 250 mm, Daicel Chemical Industries, Tokyo), 2 him CUSO4, 0.75 ruL min, 50 °C, monitored at 254 nm L-pipecolic acid r = 14.7 min, D-pipecolic acid rt= 18.0 min. 

Scheme 17.9. Asymmetric synthesis of d-threo methyiphenidate from d-pipecolic acid.

Increasingly nonpeptide substituents have been incorporated into the primary specificity pocket binding portion of the bivalent inhibitors. Higher affinity for thrombin was achieved by replacement of the (d-Phe)-Pro-Arg with either dansyl-Arg-(D-pipecolic acid) (3-17, [27]) or 4-tert-butylbenzenesulfonyl-Arg-(D-pipecolic acid) (3-18, [27]). While the arginine side chain of these and the (D-Phe)-Pro-Arg-containing inhibitors make similar interactions with the aspartic acid within the SI specificity pocket, the dansyl-Arg-(D-pipecolic acid) inhibitors bind in a nonsubstrate mode [27]. This initial result suggests that other nonpeptide thrombin inhibitors may be successfully incorporated into bivalent inhibitors. 

An EPME based on vancomycin was proposed for the assay of D-pipecolic acid [50]. The linear concentration range for the proposed enantioselective membrane electrode is 10 9-10 6mol/L with the slope of electrode function 60.2 mV/p(D-pipecolic acid). The enantioselectivity was determined over L-pipecolic acid. The proposed electrode could be reliably employed for the assay of D-pipecolic acid in serum samples. 

Another synthesis of (2R,2 71)-(+)-Z/zreo-methyl-phenidate hydrochloride (1) using an enantiomerically pure starting material, u-pipecolic acid (15), was reported by Perel et al. (Scheme Enantiomerically pure D-pipecolic acid (15) was obtained in 57% yield by recrystallization of diastereomeric tartrate salt, followed by the separation of the desired amino acid from tartaric acid by ion-exchange chromatography. D-Pipecolic acid (15) was protected with a BOC group to afford M-BOC-n-pipecoUc acid (16) in 97% yield. The key amino ketone (18 ... 

Fig. 7. Structure of one member of the amphomycin family where Dabe = D-erythro-a, /3-diaminobutyric acid Dab1 = l-threo-oc, /3-diaminobutvric acid Pip = D-pipecolic acid MeAsp = AT-methylaspartic acid. The amphomycin family member having (+)-3-anteisotridecenoic acid is shown not shown is...

After purification by counter-current distribution this peptidolipid was obtained as an amorphous powder of m.p. 230°C (dec.) and optical rotation [oi] + 9.5° (ethanol). Acid hydrolysis gave a mixture of fatty acids, the major components of which were identical with (+)-anteisotridec-3-enoic and isododec-3-enoic acids. The amino acids consisted of L-aspartic acid (3 moles), glycine (2 moles), L-tftreo-P-methyl-aspartic acid, L-proline, L-valine, D-pipecolic acid, L-tftreo-2,3-diaminobutyric acid (DAB,) and D- ryt/iro-2,3-diaminobutyric acid (DABJ (1 mole each). 

Armstrong, D.W., Zukowski, J., Ercal, N., Gasper, M.P. (1993b). Stereochemistry of pipecolic acid found in the urine and plasma of subjects with peroxisomal defieciencies. J. Pharm. Biomed. Anal. 11, 881-886. 

Muramatsu, H., Mihara, H., Yasuda, M., Ueda, M., Kurihara, T. and Esaki, N., Enzymatic synthesis of L-pipecolic acid by d -piperidine-2-carboxylate reductase from Pseudomonas putida. Biosci. Biotechnol. Biochem., 2006, 70, 2296. 

Dab1 = n-erxthro - 2.3-diaminobutanoic acid Dab = d-threo-2,3-diaminobutanoic acid Pip = pipecolic acid... 

Enantiomerically pure pipecolic acid (6) is accessible essentially by two well-established synthetic routes (i) cyclization of l- or D-lysine by reaction with disodium nitrosyl-pentacyanoferrate(II) with preservation of configuration at C2 215 216 (ii) ring closure of A ,Ae-bis(A-nitroso-A-tosyl) derivatives of l- or D-lysine, again with retention of chirality at C2. 217 Stereoselective synthesis of pipecolic acid derivatives, substituted in position 4, is achieved using the aza-Diels-Alder reaction of imines with dienes 218-220 or via an ene-iminium cyclization. 221 222 ... 

In addition to the 20 amino acids most frequently found in proteins a large group of amino acids occur in plants, bacteria, and animals that are not found in proteins. Some are found in peptide linkages in compounds that are important as cell wall or capsular structures in bacteria or as antibiotic substances produced by bacteria and fungi. Others are found as free amino acids in seeds and other plant structures. Some amino acids are never found in proteins. These nonprotein amino acids, numbering in the hundreds, include precursors of normal amino acids, such as homoserine and diaminopimelate intermediates in catabolic pathways, such as pipecolic acid d enantiomers of normal amino acids and amino acid analogs, such as azetidine-2-carboxylic acid and canavanine, that might be formed by unique pathways or by modification of normal amino acid biosynthetic pathways. 

The authors reported the chiral separation of proline and thereonine amino acid up to 20 and 6g, respectively, in a single run. Micropreparative resolution of lecucine was presented. The resolution was discussed with respect to the degree of sorbent saturation with copper(II), elution rate, eluent concentration, temperature, and column loading condition [16]. Weinstein [74] reported the micropreparative separation of alkylated amino acids on a Chiral ProCu column. In another article, a preparative chiral resolution of 3-methylene-7-benzylidene-bicyclo[3.3.1]nonane was achieved on 7.5% silver(I)-d-camphor- 10-sulfonate CSP [75]. Later, Shieh et al. [71] used L-proline-loaded silica gel for the chiral resolution of (ft,5 )-phcnylcthanolaminc as the Schiff base of 2-hydroxy-4-methoxyacetophenone. Gris et al. [76] presented the preparative separations of amino acids on Chirosolve L-proline and Chirosolve L-pipecolic acid CSPs. 

Nemak, K., Acs M., Jaszay M.Zs., Kozma, D., and Fogassy, E. Study of die diastereoisomers formed between pipecolic acid N-alkylanilides and 2R,3R-tartaric acid or 0,0 -dibenzoyl-2R,3R-tartaric acid. Do the tartaric acids form molecular complexes instead of salts during optical resolutions , Tetrahedron 1996, 52, 1637-1642. 

The chirality of a precursor product relationship was determined by the use of doubly labeled lysine, in which one enantiomer was labeled only with tritium and the other with tritium and 14C (55). Comparison of the 3H/14C ratios of substrate and products demonstrated that decodine and decinine were derived from L-lysine, whereas pipecolic acid (186) was derived from D-lysine. Thus, pipecolic acid does not serve as a precursor of Lythraceae alkaloids (57). 

Lysine.—Lysine is a common precursor of piperidine alkaloids. Of the two enantiomers of this amino-acid, the L-isomer is the more direct precursor, in plants, for piperidine alkaloids, e.g. anabasine, whereas D-lysine is more directly implicated in the biosynthesis of pipecolic acid (24)1,2,23 (cf Vol. 7, p. 7). It has now been shown that a pathway exists in the plant Nicotiana glauca,24 and also in the micro-organism Neurospora crassa2S which transforms D-lysine into L-lysine by way of L-pipecolic acid (24). 

In accord with a general body of evidence on the biosynthesis of alkaloids as against that of pipecolic acid (see above), L-lysine has been shown to be the preferred precursor for lupanine (27) and D-lysine the preferred precursor for l-pipecolic acid (24) in Lupinus angustifolia,36 A high retention of tritium, present at C-4 and C-5 in the lysine, on formation of (27) is to be noted. 

In a similar way, D,L-pipecoUc add was converted to L-pipecolic acid [49]. However, the use of sodium borohydride, which slowly decomposes in aqueous solution, causes a significant rise in the pH value, which has to be controlled and which interferes with the necessary repeated cycles. Turner and Fotheringham expanded the applicability of the method, using milder and water stable reducing agents [50] and applying amino acid oxidases with either D- or L-spedficity. 

D2. Danks, D. M., Tippett, P., Adams, C., and Campbell, P., Cerebro-hepato-renal syndrome of Zellweger A report of eight cases with comments upon the incidence, the liver lesion, and a fault in pipecolic acid metabolism. J. Pediatr. 86, 382-387 (1975). 

Figure 16.7-9. One-pot chemo-enzymatic deracemisation of D,L-pipecolic acid catalyzed by D-amino acid oxidase (d-AAO). Utilization of catalase was not reported.

Synthesis from o-mannose Syntheses of a-homonojirimycin (1), 6-cp/-a-homo-mannojirimycin (39) and the pipecolic acid derivative 36 from D-mannose have been reported (Scheme 5). The azidolactone 31, ° prepared from diacetone mannose (30), nnderwent selective removal of the terminal isopropylidene gronp, followed by selective protection of the resnlting primary hydroxyl gronp with fcrt-butyldimethylsilyl chloride to... 

Synthesis of pipecolic acid 1 and its epimer 14 from D-glncose has been achieved from the carbamate 10 (Scheme Oxidation of the C-5-OH in 10 with pyridininm chlorochro-... 

D-penicillamine, streptolidine, 3-aminosalicylic acid D-a-pipecolic acid, 4-oxopipecolic acid, 2-(]-amino-2-rnethylpropyl) thiazole-4-carboxylic acid Thiostreptoic acid, thiostreptine... 

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