Pipecolinic acid

CjHiiNOj 3105-95-1) see Ropivacaine hydrochloride pipecolinic acid 2,6-xylidide... 

C(,Hi2N20 39546-32-2) see Metopimazine Pipamazine piperidine-2-carboxylic acid (2,6-dimetbylanilide) see under pipecolinic acid 2,6-xylidide... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The key feature of the first total synthesis of (+)-homopumiliotoxin 223G 418 was a Lewis acid-induced, chelation-controlled propargylation of the trifluoroacetate salt of (. )-2-acetyl pi peri dine 415, derived from iV-Cbz-L-pipecolinic acid. Alkyne 416 thus formed was transformed after several steps into 417, which was cyclized by activation of the primary hydroxyl with the carbon tetrabromide-triphenylphosphine system to give the natural product (Scheme 98) <1998TL2149>. 

Ugi five-center three-component reaction of pipecolinic acid and glycol aldehyde dimer with isocyanides gave a 1 1.7-2.1 diastereomeric mixture of l-oxoperhydropyrido[2,Tc][l,4]oxazine-9-carboxamides 397 (Scheme 35) <20010L4149>. Using CF3CH2OH as solvent is critical for the reaction. When 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was employed, 1,3,4,6,11,11 a-hexahydro-[ l,4]oxazino[4,3+]isoquinoline-4-carboxarnide was formed. 

Optically active and deuterated pipecolinic acids were prepared via 4-phenyl-l,3,4,6,7,9a-hexahydro <2002JOC2424>, -perhydropyrido[2,l-f][l,4]oxazin-l-ones <1995TL1657, 1996JOC5736, 1996TL4001,... 

Reaction of the aldehyde-tethered furanone 244 with pipecolinic acid results in the formation of the oxazolopyr-idine derivative 245, which undergoes spontaneous decarboxylation to give the ylide 246. This in turn undergoes an intramolecular cycloaddition with the tethered exomethylene group to give 247, or with the endocyclic alkene to give the furoindolizine 248 <1997T10633> (Scheme 66). 

As in the case of the formation of an azepine (Scheme 43), Pro afforded a pyrrolo[l,2-fl]azepine 88, and pipecolinic acid afforded a pyrido[l,2-a]aze-pine 89 (80JHC1593). 

The resulting 2,6-xylidide a-pipecolinic acid (2.2.5) is methylated to mepivacaine using formaldehyde with simultaneous reduction by hydrogen in the presence of platinum on carbon catalyst [15]. 

Enaminone 128 (Scheme 33) is obtained, together with an isomeric indo-lizine derivative, by flash vacuum thermolysis of aminomethylene Meldrum s acid derivative through intermediate ketene and delocalized azomethine ylide (85TL833). The thermally induced cyclization of semi-cyclic dienamines to afford, for instance, tricyclic 129 is also believed to start with an azomethine ylide (97JOC7744) the p-chlorophenyl substituent is essential for the reaction. Unstabilized ylide 130, on the other hand, is generated from pipecolinic acid and /1-phenylcinnamaldehyde by the decarboxylation method target base 131 is formed by 1,7-electrocycliza-tion and [l,5]-hydrogen shift (99J(P1)2605). 

Fig. 11.3 Reaction mechanism of photocatalytic synthesis of pipecolinic acid (PCA) from L-lysine.

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

Formamides derived from L-pipecolinic acid act as Lewis base organocatalysts for reduction of A-arylimines with trichlorosilane, giving yields and ees in the high 90s for a wide range of imine substrates.54... 

L-Pipecolinic acid-derived formamides have been developed as highly efficient and enantioselective Lewis basic organo-catalysts for the reduction of IV-arylimines with trichlorosilane. High isolated yields and enantioselectivities up to 96% are obtained under mild conditions with a large substrate spectrum.365... 

A dual catalyst combination of pipecolinic acid and (V-methylimidazole gives 84% ee in a Morita-BH cyclization.178... 

Methods were developed for the preparation of thienoindolizines 254 and thienoquinolizines 255 from derivatives of proline and pipecolinic acid (1993H2303, 1994JHC495, 1996JHC873, 1996PS169, 1999H445). Polyphosphoric acid (PPA) can be used as a cyclizing agent. The reaction can also be performed by the transformation of pipecolinic acids into acid chlorides followed by the intramolecular Friedel-Crafts reaction without isolation of the intermediate. 

Employing a flow rate of 1 (il min 1 and a residence time of 0.86 min, the authors obtained 87% conversion of L-lysine (191), exhibiting 22% selectivity for pipecolinic acid and 14% yield of L-pipecolinic acid 190. To demonstrate the TCM s efficiency, the authors also performed the reaction in batch employing 2wt% Pt-loaded Ti02 particles, which afforded the same surface to volume ratio of catalyst as calculated to be within the TCM, whereby a reaction time of 60 min afforded analogous results. The authors concluded that the increased reaction efficiency observed within the TCM was attributed to the efficient irradiation of the reaction mixture however, for a true comparison they noted that measurement of the quantum yield of each system would be required. 

Scheme 55 Photocatalytic synthesis of L-pipecolinic acid 190 and D-pipecolinic acid 192.

Scheme 5.14 The aldol cycloisomerization by pipecolinic acid and NMI-catalyzed asymmetric intramolecular MBH reaction followed by a kinetic resolution quench .

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Replacing the rigid proline core with a more flexible pipecolinic acid, as in 83, led to an increased selectivity (Table 7.7, entry 3) [79]. However, a real improvement was attained with catalysts 84a,b, where 1,2-diphenylamino ethanol derivatives were used instead of aniline to form the amide (entries 4 and 5). Configuration at the a-carbon of the amino alcohol moiety proved to be critical in forming the matched pair (compare entries 4 and 6), while configuration at the /Tcarbon bore no influence on the enantioselectivity (compare entries 4 and 5). 

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