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OBn
OH
a
b
14
N
COOH
N
COOH
Boc
Boc
16
17
Scheme 5. Synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxy pipecolic acid 17.
Reagents and conditions: (a) RuCl3, NaIO4, CH3CN:CCl4:H2O, rt, 64%; (b) H2, Pd(OH)2,
EtOH, rt, 48 h, 70%.
In conclusion, a simple and reliable method has been devel-
oped for the synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxy
pipecolic acid starting from D-glucose via regioselective reductive
cleavage of benzylidene acetal.26 We are confident that the func-
tionalized chiral intermediate 14 will find wide application in the
synthesis of piperidine alkaloids with diverse biological activities.
The synthetic potential of the regioselective reductive cleavage of
benzylidene acetal is being explored in our group.
19. (a) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033–7036; (b) Guilloteau-
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Acknowledgments
20. For reductive cleavage (1): (a) Aravind, A.; Baskaran, S. Tetrahedron Lett. 2005,
46, 743–745; (b) Balakumar, v.; Aravind, A.; Baskaran, S. Synlett 2004, 647–
650; For oxidative cleavage (1): (c) Aravind, A.; Mohanty, S. K.; Pratap, T. V.;
Baskaran, S. Tetrahedron Lett. 2005, 46, 2965–2968; Kumar, P. S.; Aravind, A.;
Baskaran, S. Tetrahedron Lett. 2007, 48, 1175–1178 (2).; For hydrolysis: (d)
Kumar, P. S.; Kishore, G. D. K.; Baskaran, S. Eur. J. Org. Chem. 2008, 6063–6067.
21. Jong, U. R.; Brian, I. B.; Rajanbabu, T. V. J. Am. Chem. Soc. 2003, 125,
1492–1493.
We thank CSIR, New Delhi, for the financial support and DST-
FIST, New Delhi for NMR facilities. P.S.K. thanks CSIR, New Delhi,
for a research fellowship. We thank Mr. Ram Kumar for single crys-
tal X-ray analysis.
References and notes
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DCM (30 mL) was added Et3SiH (120
lL, 0.75 mmol) followed by EtAlCl2
(417 L, 0.75 mmol) and the resultant mixture was stirred for additional 1 h.
l
The reaction mixture was slowly warmed to 0 °C and then quenched with
saturated NaHCO3 solution. The reaction mixture was extracted with ethyl
acetate and the combined organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product on purification by
column chromatography over silica gel (gradient elution with 10–35% EtOAc in
hexane) yielded the unreacted starting material (28 mg, 14%) and the pure
alcohol 14 (171 mg, 85%) as a viscous liquid. ½a D25
ꢁ
+66.7 (c 1, CHCl3); IR (Neat):
3448, 2934, 1667, 1454, 1416, 1363, 1319, 1248, 1178, 1154, 1096, 1044, 979,
698 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.37–7.28 (m, 5H), 4.58–4.55 (br s, 2H),
;
4.06–4.02 (m, 4H), 3.67–3.61 (m, 1H), 2.8 (br s, 1H), 2.2 (br s, 1H), 1.92 (br s,
1H), 1.72–1.70 (m, 2H), 1.60–1.56 (m, 2H), 1.41 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 155.1, 138.0, 128.5, 128.3, 127.8, 127.5, 80.0, 76.0, 73.1, 70.8, 66.1,
58.7, 128.3, 25.8, 23.9; HRMS (ESI) calcd for C18H27NO4Na (M+Na)+: 344.1838;
found: 344.1844.
24. X-ray crystallographic analysis for compound 15: C14H17NO3, MW = 247.29,
orthorhombic, P212121, a = 8.8214(3), b = 10.9036(3), c = 13.3824(4) Å,
V = 1287.19(7) Å3, Z = 4, Dcalcd = 1.276 Mg/m3, F(000) = 528, T = 298 K,
colorless needles, 0.39 ꢂ 0.35 ꢂ 0.32 mm, 16,670 reflections collected
(Rint = 0.0267), 3193 unique. All measurements were carried out on a Bruker
axs (Kappa Apex2) equipped with graphite monochromatic Mo Ka radiation.
Structure refinements by full-matrix least-squares methods on F2. Programs:
SHELXS and SHELXL [Bruker axs (Kappa Apex2)]. Crystallographic details have been
deposited at the Cambridge Crystallographic Data Centre (deposition number
CCDC 684130).
16. Copeland, T. D.; Wondrak, E. M.; Toszer, J.; Roberts, M. M.; Oraszan, S. Biochem.
Biophys. Res. Commun. 1990, 169, 310–314.
17. (a) Scopes, D. I. C.; Hayes, N. F.; Bays, D. E.; Belton, D.; Brain, J.; Brown, D. S.;
Judd, D. B.; McElroy, A. B.; Meerholz, C. A.; Naylor, A.; Hayes, A. G.; Sheehan, M.
J.; Birch, P. J.; Tyers, M. B. J. Med. Chem. 1992, 35, 490–501; (b) Desideri, N.;
Galli, A.; Sestili, J.; Stein, M. L. Arch. Pharm. 1992, 325, 29–34.
18. For recent examples on hydroxypipecolic acid syntheses see: (a) Liang, N.;
Datta, A. J. Org. Chem. 2005, 70, 10182–10185; (b) Kalamkar, N. B.; Kasture, V.
M.; Dhavale, D. D. J. Org. Chem. 2008, 73, 3619–3622; (c) Kim, I. S.; Ji, Y. J.; Jung,
25. During the oxidation of alcohol 14 to acid 16 using RuCl3–NaIO4 reagent
system, a small amount of 3-benzoyloxy pipecolic acid derivative was also
isolated in 10–12% yield.
26. Spectral data for selected compounds: Compound 9: ½a D25
ꢁ
ꢀ23.4 (c 1, CHCl3); 1
H
NMR (400 MHz, CDCl3) d 7.48–7.45 (m, 2H), 7.38–7.33 (m, 3H), 5.47 (s, 1H),
4.27–4.26 (m, 1H), 4.12 (dd, J = 14.4, 7.2 Hz, 2H), 3.61–3.55 (m, 3H), 2.65–2.59
(m, 1H), 2.52–2.46 (m, 1H), 2.22–2.20 (m, 1H), 2.00–1.98 (m, 1H), 1.25 (t,