Pipecolic acids, synthesis

Perhydro derivatives of pyrido[l,2-7)][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and pyrido[l,2-c][l,3]oxazines and [l,3]oxazino[3,4-u]quinolines were also used in the stereoselective syntheses of different alkaloids. Perhydropyrido[l,2-c][l,3]oxazines and their benzologs are formed form 2-(2-hydroxyethyl) piperidines and from their benzologs to justify the stereochemistry of 2-(2-hydroxyethyl) derivatives. Different optically active pipecolic acids can be prepared via 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones. 

A reaction related to alkene-aldehyde coupling is the alkene-imine coupling. A one-pot cyclization involving such a reaction (Eq. 3.27) proceeds smoothly in a mixture of water-THF. The reaction has been used in the asymmetric synthesis of pipecolic acid derivatives.114... 

TITANIUM-MEDIATED ADDITION OF SILYL DIENOL ETHERS TO ELECTROPHILIC GLYCINE A SHORT SYNTHESIS OF 4-KETOPIPECOLIC ACID HYDROCHLORIDE (Pipecolic acid, 4-oxo-, hydrochloride)... 

One of the interesting application of 12 (R= allyl, X=Br) will be the synthesis of cyclic amino acid, (S)-pipecolic acid, as its tert-butyl ester 271251 Monoalkylation of the O Donnell imine 23 with l-chloro-4-iodobutane afforded the alkylated product 26 with 99 % ee. The conversion of 26 to the tert-butyl ester of pipecolic acid 27 was achieved in high yield by the sequence imine reduction, cyclization, and hydrogenolytic removal, as shown in Scheme 8. 

Scheme 8. Asymmetric synthesis of the pipecolic acid derivative 27.

Synthesis of L-Pipecolic Acid with A -Piperidine-2-carboxyiate Reductase from Pseudomonas putida... 

The procedure can provide a higher amount of L-pipecolic acid in a shorter reaction time than the previously reported system, indicating that it is applicable in industrial production of L-pipecolic acid. A similar system was successfully employed in the enzymatic synthesis of several cyclic amino acids by our group. ... 

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. 

Scheme 2.17 Synthesis of L-pipecolic acid 42 using a lysine cyclodeaminase.

Swansonine and castanospermine synthesis starts with the a-aminoacid, y-semialadehyde and, via piperidine-6-carhoxyhc acid synthetases, L-pipecolic acid. This compound is a substrate to HSCoA and acetyl-CoA. As a result of this activity, the second ring is established. Subsequently, it changes to 1 -indolizidinone and, by oxidation reaction, produces castanospermine or swansonine (Figure 50). 

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. 

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

W-Acyliminium ions are useful intermediates for preparing heterocycles in general. This methodology was applied to the synthesis of functionalized pipecolic acids <99EJOC1127>. A -But-3-enyl-Af-styrylformamides undergo cyclization to the tetrahydropyridine when treated with 9-BBN triflate <99T4481>. 

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 ... 

The Z-protected derivative, again prepared by standard methods using benzyl chloroformate,t208 may serve in the case of racemic pipecolic acid for resolution into the pure enantiomers by fractional crystallization with L-tyrosine hydrazide/208 Acylation with N-protected pipecolic acid or of pipecolyl peptides is performed by standard procedures via the active ester methods, e.g. A-hydroxysuccinimide ester/121 by the mixed anhydride method, e.g. with isobutyl chloro-formate 95-114 or pivalic acid chloride/121 as well as by DCC/HOBt/118 In the synthesis on solid support, longer coupling times are required when compared to N-protected proline.1[235 ... 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

Further applications for the preparation of jfi-turn mimetics have also been reported by Martens et al. with the synthesis of pipecolic acid derivatives 88 (presumably proceeding via a cyclic Schiff base - not a true post-condensation modification ) [74] and Golebiowski and co-workers who have reported the solid-supported synthesis of bicyclic diketopiperazines with the generic structure 89, via the multi-step synthesis shown in Scheme 11.18 [75]. 

Reaction of an allylsilane on a chiral iminium provides the substituted pipecolic acid derivatives after oxidation and hydrolysis (Scheme 21) <1997SL799, 1997TA2975>. In an analogous reaction, BF3-Et20 can be used as the Lewis acid resulting in an asymmetric synthesis of desoxoprosopinine (Equation 44) <1997TL7469>. 

Synthesis and Application of Proline and Pipecolic Acid Derivatives Tools for Stabilization of Peptide Secondary Structures... 

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