Pipecolate formation

Cyclization of the (E)- and (Z)-A-hexenylglycine derivatives ( )-l and (Z)-l with formic acid leads to pipecolic acid derivatives, in which formation of the new C-C bond occurs with high stereoselectivity, but subsequent formylation of the intermediary carboeation proceeds with low stereoselectivity89. 

The five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

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. 

Why are there so many pathways of lysine breakdown The answer is probably related to the ease of spontaneous formation of cyclic intermediates as occurs in the pipecolate pathway (pathway C, Fig. 24-15). These intermediates may be too stable for efficient... 

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 ... 

Figure 4 Modular PKS gene organization. The 6-deoxyerythronolide B (DEBS) and rapamycin (RAPS) PKSs are composed of 6 and 14 modules, respectively. DEBS catalyzes the formation of 6-deoxyerythronolide B (6-dEB) from a propionyl-CoA primer unit and six methylmalonyl-CoA extender units. Rapamycin is formed from a cyclohexenoyl starter unit, seven malonyl-CoA (modules 2, 5, 8, 9, 11, 12, and 14), and seven methylmalonyl-CoA (modules 1, 3, 4, 6, 7, 10, and 13) extender units, and pipecolic acid. For RAPS, only the domains which are believed to be functional in the PKS are shown.

Substituted pipecolic acid derivatives can be accessed from a suitably protected allylglycine derivative by first use of a palladium-catalyzed N, O-acetal formation followed by RCM.43 Treatment of 19 with boron trifluoride etherate followed by a variety of nucleophiles formed the corresponding substituted products 20 and 21 (Scheme 28.12). 

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. 

The processes are based on whole bacterial cells. In the case of the pipecolic acid, an important building block for pharmaceutical chemistry, an S-selective amidase in Pseudomonas fluorescens cells, catalyses the reaction with high selectivity and the acid is obtained with an ee >99% (Scheme 6.27A). For the preparation of piperazine-2-carboxylic acid from the racemic amide a R- and a S-selective amidase are available. Utilising Klebsiella terrigena cells the S-enantiomer is prepared with 42% isolated yield and ee > 99%, while Burkholderia sp. cells catalyse the formation of the -enantiomer (ee=99%, Scheme 6.27 B). 

Although some product from ( )-12a was formed by NlT-106, pipecolic acid 12c could not be synthesized in a preparatively satisfying way, in particular because the amide formation is twice as high as the acid formation. A structural comparison of heterocycUc amino nitriles ( )-10a-( )-12a with carbocydic P-amino nitriles... 

Not surprisingly, some nitrilase reactions were accompanied by the formation of the corresponding amides, such as pipecolic amide 12b (up to 10%) and pyrrolidine-3-carbo3amide 10b (for a discussion of nitrile hydratase activity of nitrilases see Section 15.3.3). 

Gatto et al m characterized the mechanism of L-pipecolic acid formation by cyclodeaminase RapL from L-lysine within rapamycin biosynthesis, which is a hybrid NRP—polyketide antibiotic (Figure 25(a)). RapL was characterized by biochemical assays to require cofactor nicotinamide adenine dinucleotide (NAD+) and an oxidative cyclodeamination reaction mechanism corresponding to ornithine cyclodeamination was proposed based on ESI-FTMS analysis of RapL reaction products (Figure 25(b)). 

Figure 25 L-Pipecolic acid formation by cyclodeaminase RapL in rapamycin biosynthesis, (a) Rapamycin and incorporated pipecolic acid moiety, (b) Proposed oxidative cyclodeamination mechanism of pipecolic acid formation from L-lysine. (c) RapL activity assays and exact ESI-FTMS analysis of derivatized reaction products revealing mechanistic insights such as a-H retainment and loss of e-N.

The first total synthesis of rapamycin (2) was accomplished by Nicolaou et al. in 1993. The synthetic feature includes esterification of the C34 hydroxyl group of the C21-C42 segment with pipecolic acid, amide formation with the C8-C18 segment, and extremely novel macrocyclization by double Stille coupling using vinyl stannane at the Cl8 and C21 positions (Fig. 6). 

The elimination of the 6-amino group could occur via the action of an amine oxidase as has been suggested orPisum sativum (Mann and Smithies, 1955) or via the formation of saccharopine (Nabeta et al., 1973). Labeled pipecolic acid was found to serve as a precursor for the hydroxypipecolic acids of Umonium (Larher, 1976) and this conversion could proceed via the hydroxylation of 4,5-dehydropipecolic acid (baikiain). 

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]. 

Homoserine (13), threonine (14), isoleucine (15), methionine (16), and cysteine (12) are all derived from aspartic acid (22). Lysine (23) (Fig. 13.1) is derived via 3-aspar-tylsemialdehyde and is, in turn, involved in formation of many nonprotein amino acids such as pipecolic acid (17) and mimosine (18) (Figs. 13.5 and 13.6) (Rosenthal, 1982). D-Lysine is a precursor of L-pipecolic acid in many plants... 

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