pubs.acs.org/joc
are derived from amino acid 1 or contain it as a key stuctural
Stereoselective Syntheses of L-Pipecolic Acid and
(2S,3S)-3-Hydroxypipecolic Acid from a Chiral
N-Imino-2-phenyl-1,2-dihydropyridine Intermediate
unit (e.g., amyloglucosidase inhibitor lentiginosine,3 antic-
onvulsant pipradol,4 immunosuppressants FK506,5 and
rapamycin6). L-Pipecolic acid and derivatives have been
prepared7 by resolution of the racemates,1c,8 by synthesis
from L-lysine,9 by diastereoselective10 and enantioselective
syntheses,11 as well as by deracemization.12 It has also been
recently employed as a catalyst for asymmetric Mannich
reactions.13 (2S,3S)-3-Hydroxypipecolic acid (2) is also of
current interest as a synthetic target.14 The structure of 2 is
found in febrifugine,15 a potential antimalarial agent, and
the enantiomer of 2 is found in the structure of the phytotox-
in swainsonine.16 In addition, 1 and 2 are also conforma-
tionally constrained amino acids relevant to the study of
peptide structure and drug design.17
ꢀ
Alexandre Lemire and Andre B. Charette*
Deꢀpartement de chimie, Universiteꢀ de Montreꢀal, P.O. Box
ꢀ ꢀ
6128, Station Downtown, Montreal, Quebec, Canada,
H3C 3J7
Received November 27, 2009
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(b) Aketa, K.-i.; Terashima, S.; Yamada, S.-i. Chem. Pharm. Bull. 1976,
ꢀ
ꢀ
24, 621. (c) Kisfaludy, L.; Korenczki, F.; Katho, A. Synthesis 1982, 163.
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2000, 30, 2565. (d) Hou, D.-R.; Hung, S.-Y.; Hu, C.-C. Tetrahedron:
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Stereoselective syntheses of L-pipecolic acid and (2S,3S)-
3-hydroxypipecolic acid were achieved from a chiral
N-imino-2-phenyl-1,2-dihydropyridine intermediate. The
3-hydroxy substituent of the latter amino acid was intro-
duced by hetero-Diels-Alder reaction of singlet oxygen
with the 1,2-dihydropyridine.
ꢀ
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´
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A metabolite of L-lysine, L-pipecolic acid (1, Figure 1) is a
naturally occurring nonproteinogenic R-amino acid.1,2 Nu-
merous natural and synthetic biologically active alkaloids
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DOI: 10.1021/jo902527s
r
Published on Web 02/25/2010
J. Org. Chem. 2010, 75, 2077–2080 2077
2010 American Chemical Society