4-hydroxypipecolic acid

Several methods were described for the preparation of pipecolic acid (hexahydropyridine-2-carboxylic acid) from Lys [57ZPC(308)179 59CCC2318 75BCJ1341 81JCS(P1)1769 82S163 83CC1169]. In a similar manner, 4-hydroxypipecolic acid was prepared from 5-hydroxy-L-Lys (65JA2030). 

In addition, stereoselective syntheses of pipecolic acid derivatives, such as the stereoisomers of 4-hydroxypipecolic acid, 223-225 3-hydroxypipecolic acid, 2261 and variously ring-substituted analogues, 227-234 have been reported. 

Perhydropyrido[l,2-fl]pyrazin-l-one N-oxide 167 was formed from 1-hydroxypipecolic acid amide 261 by reverse Cope elimination by heating in CHCI3. Similar reaction of 1-hydroxypipecolinate 262 resulted an 1 5 30 equilibrium mixture of 262, 263, and 264 (07TL1683). 

Dihydroxylation of olefins followed by oxidation with periodate leads to cyclization and the corresponding carbinolamine. This can then be reduced to the piperidine <2005JOC10182> (Scheme 12). The strategy was used in the synthesis of both the (2A,3i )-3-hydroxypipecolic acid 13 and (2 5, 3A)-3-hydroxypipecolic acid 14 from D-serine. Variations in this strategy toward both trans-isomers of the 3-hydroxypipecolic acid moiety are shown in Schemes 13 and 14. The initial stereochemistry was introduced using Sharpless method <2005JOC360>. 

Further acid-catalyzed reactions include the use of />-toluene sulfonic acid-DMF in a cyclization of the protected amino acid 17 (DMF = dimethylformamide Scheme 15) <20040L4941>. This was the key step in the stereoselective synthesis of 5-hydroxypipecolic acid. A similar acid-catalyzed ring closure of a hemiacetal yielded the fused piperidine 18 <2004JOC1872> (Equation 32). The indolizidine alkaloid can be accessed by a Barton-Ester method utilizing a polyphosphoric acid (PPA) cyclization (Scheme 16) <1994T19157>. 

This protocol was used in the synthesis of both (2S, 3R)-3-hydroxypipecolic acid 281 and (2S, 3S)-3-hydroxypipecolic acid 282 from D-serine <05JOC10182>... 

Hydroxypipecolic acid is a structural moiety found in many compounds of medicinal interest. Using Sharpless asymmetric oxidation techniques both enantiomers of the tram-form (283 and 284) of this compound were synthesized from 1,4-butanediol. The piperidine ring-forming steps used (285 to 286 and 287 to 288) are shown in Scheme 87 <05JOC360>. 

Rings have fewer conformations than open chains. This is as important in transmitting asymmetry as it was in chapters 20-29 in creating asymmetry. A simple illustration is Bailey s synthesis of m-5-hydroxypipecolic acid 15 by a chiral pool strategy from natural (S) -glutamic acid 13. Bailey s original idea was to cyclise the a-chloroketone 14 but this was not successful, even when NH2 and C02H were protected.2... 

Methods considered for development and tried experimentally but rejected A successful large scale asymmetric synthesis by resolution Part II - (2S,4/ )-4-Hydroxypipecolic Acid... 

S,47 ) -Hydroxypipecolic acid [(-)-a3 -4-hydroxy-2-piperidine carboxylic acid, 3] was isolated from the leaves of Calliandra piuieri and Strophantus scandeus and it was identified as a constituent of cyclopeptide antibiotics, such as virginiamycin S2. It was also employed as a precursor in the preparation of selective N-methyl-D-aspartate receptor antagonists. Furthermore, (-)-3 has served as a building block in a recent synthesis of palinavir, a potent peptidomimetic-based HIV protease inhibitor. ... 

S,4S)-4-hydroxypipecolic acid) and d5-4-hydroxy-2-piperine carboxylic acid], 177... 

A key step in the synthesis of optically pure 5-hydroxypipecolic acid derivatives was effected by PTSA-DMF in refluxing toluene to give 148 <04OL4941>. A similar acid-catalyzed ring closure of a hemiacetal gave 149 <04JOC1872>. 

Ketones and aldehydes are reduced in acidic media, but not at neutral pH. Sodium cyanoborohydride is stable at pH 3-4 and in this acid medium, a carbonyl is converted to the protonated form (C=OH+) which is susceptible to reduction. At pH 3-A, ketones and aldehydes are rapidly reduced,as illustrated by the reduction of the aldehyde unit in 163 to give 164 in 89% yield (at pH 4 in this case), in Varela s asymmetric synthesis of 4-hydroxypipecolic acid. Note that neither the lactone moiety or the benzyl carbamate were reduced under these conditions. 

In a synthesis of 4-hydroxypipecolic acid, Varela and co-workers protected the primary amine unit in 147 as the benzyl carbamate (148).Manipulation of the protected diol led to the primary mesylate in 149, and catalytic hydrogenation removed the Cbz group to give the primary amine in 150. 

Three isolates, hyperin, pipecolic acid (45) and 5-hydroxypipecolic acid (46) elicited noncompetitive antagonism against serotonin on the same preparation "Fig. (14)." The plant extracts did not antagonize muscarinic and nicotinic cholinergic receptors on rat jejunum and frog rectus abdominis [71], which had been previously reported for extracts of B. sericea. 

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). 

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