Pipecolic acid esters

D-Glucono-5-lactone has been transformed in several steps to the protected pipecolic acid ester derivative 31 which, on reduction with lithium aluminium hydride, then hydrolysis, gives 1-deoxymannojirimycin. Hydrolysis only of 31 provided the iduronidase inhibitor 2,6-imino-D-mannonic acid. ... 

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. 

A-Phenylthiomethylpipecolic acid methyl ester afforded with methyl cin-namate and a mixture of two regioisomers 65 and 66 (84TL1579). Pipecolic acid and diethyl fumarate or maleinate gave three isomers (85TL2775). 

Another possible mechanism for the racemization of amino acid esters involves the in situ, transient, formation of Schiff s bases by reaction of the amine group of an amino acid ester with an aldehyde. Using this approach, DKR of the methyl esters of proline 5 and pipecolic acid 6 was achieved using lipase A from C. ant-arclica as the enantioselective hydrolytic enzyme and acetaldehyde as the racemiz-ing agent (Scheme 2.4). Interestingly, the acetaldehyde was released in situ from vinyl butanoate, which acted as the acyl donor, in the presence of triethylamine. The use of other reaction additives was also investigated. Yields of up to 97% and up to 97% e.e. were obtained [6]. 

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. 

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]. 

The 3,4,5-trimethoxyphenyl group is also an excellent replacement for the pyran moiety of FK506, as reported by workers at Vertex Pharmaceuticals.189 Compound 7 is a very potent FKBP inhibitor, and the branched ester semaphore compound 8 is equipotent with FK506 as an FKBP 12 inhibitor and ligand. Replacement of the pipecolic acid ring... 

Pipecolic acid derivatives. Under conventional hydroformylation conditions, 2-allylglycine esters undergo cyclohydrocarbonylation. However, the biphenyl phosphite ligand plays a unique role In the reaction, as PhjP and CyjP are totally ineffective, and in the presence of a bidentate phosphine ligand (dppb), a mixture of pyrrolidine and piperidine products results. 

Formation of azetidines and tetrahydropyridines is expected by the reaction of 3,4-pentadienylamines with alkenyl halides. The ratio of the two products was found to change depending on the substrates. The reaction of the amino acid ester 412 with the triflate 413 afforded the azetidine 414 with high selectivity and the six-membered ring 415 as tlie minor product. On the other hand, the pipecolic ester 416 was obtained as the sole product of the reaction of 412 with iodobenzene [159]. 

The reactivity of the compounds to be derivatized clearly plays an equally important part. Thus, for example, ephedrine, pseudoephedrine and analogues were acylated with TFAA for 5 minutes at 60 "C [57], tricyclic antidepressants with HFBA for 10 minutes at 60 °C [58], the methyl esters of pipecolic acid, proline, glutamic acid and y-aminobutyric acid with HFBA for 20 minutes at 150 °C [59], and catecholamines (after methylation of the j8-hydroxyl) with PFPA for 15 minutes at 80 °C [60]. 

Very recently, the direct y-carbon functionalisation of a,p-unsaturated esters 221 via NHC catalysis was developed by Chi and coworkers.In the presence of NHC precatalyst D7, the cx,(3-unsaturated esters reacted with hydrazones 222 to provide p-lactams 223 with excellent stereoselectivities. The p-lactams 223 served as precursors for a four-step synthesis of the corresponding pipecolic acid derivatives (Scheme 20.90). 

Another example of DKR of amines was reported by Kanerva s group in 2004. In this case, the DKR of the methyl esters of proline and pipecolic acid was based on the acylation of the secondary amino group of the amino esters with vinyl butanoate by Candida antarctica lipase A. Acetaldehyde, used as a racemising agent, was released in situ from vinyl butanoate in the presence of TEA, allowing proline and pipecolic add methyl esters to be acylated in the forms of highly enantiopure butanamides (Scheme 3.51). 

Scheme 3.51 DKR of proline and pipecolic acid methyl esters.

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