S. P. Chavan et al. / Tetrahedron Letters 52 (2011) 404–406
405
OH
ref- 9a
c
b
OEt
BnO
BnO
11
HO
O
HO
O
OH
OH
10
12
9
O
O
O
N3
BnO
e
f
O
d
g
MsO
HO
BnO
O
7
8
13
BnO
HO
HO
R1O
HO
BnO
h
i
k
BnO
N
N
N
H
14
O
Boc
16
H
15
j
R1= Bn; 17 R1= H
TBSO
BnO
TBSO
HO
TBSO
HO
m
n
l
N
N
N
Boc
Boc
18
Boc
O
6
19
HO
HO
N
H
1
.
O
HCl
Scheme 2. Reagents and conditions: (a) HgSO4, H2SO4 (cat), H2O, 100 °C, 3 h, 65%; (b) KOH (1.1 equiv), BnCl (1.1 equiv), benzene, reflux, 8 h, 60%; (c) CH3C(OEt)3, propanoic
acid (cat.), 140 °C, 3 h, 85%; (d) K3Fe(CN)6, K2CO3, (DHQ)2PHAL, OsO4, MeSO2NH2, 0 °C, 24 h, 94%; (e) MsCl, Et3N, DMAP (cat.), DCM, 5 h, 91%; (f) NaN3, DMF, 90 °C, 18 h, 87%;
(g) Pd/(OH)2, H2, MeOH, 30 psi, rt, 3 h, 90%; (h) LAH, THF, 0 °C to rt, 3 h, 74%; (i) Boc anhydride, Et3N, DMAP (cat.), dioxane/H2O, 0 °C, 3 h, 90%; (j) Pd/C, H2, MeOH, 70 psi, rt, 3 h,
93%; (k) TBSCl, imidazole, DMF, rt, 6 h, 90%; (l) Pd/C, H2, 70 psi, rt, 3 h, 95%; (m) RuCl3, NaIO4, CH3CN/CCl4/H2O (1:1:3), rt, 30 min, 58%; (n) 6 N HCl, reflux, 2 h.
the desired six membered lactam 1412 in 90% yield. Lactam 14 was
reduced using LiAlH4 in anhydrous THF to afford the corresponding
W., Ed.; Pergamon: Oxford, 1996; pp 155–299; (b) Fodor, G. B.; Colasanti, B. The
Pyridine and Piperidine Alkaloids: Chemistry and Pharmacology In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley-Interscience:
amine 15 in 74% yield. To avoid further functional group complica-
tion, amine group was protected as carbamate using Boc-anhy-
dride, triethyl amine in dioxane/H2O (1:1) to furnish urethane 16
in 90% yield. Compound 16 was subjected to hydrogenation using
Pd/C in methanol at 70 psi to afford dihydroxy compound 17 in
93% yield (ee >99%).13 Using the same strategy we prepared race-
mic intermediate of 1712 which was an important precursor of 3-
hydroxy pipecolic acid.6h,j The hydroxy group of 16 was protected
by using TBSCl, imidazole, DMAP cat. in anhydrous DMF which fur-
nished TBS protected compound 6 in 90% yield. Compound 6 was
subjected to hydrogenation by using Pd/C in methanol at 70 psi
to furnish compound 18 into 95% yield. Oxidation of the primary
hydroxyl group was achieved by using RuCl3, NaIO4 as an oxidant
to afford acid 1911 in 58% yield. Finally, removal of both protecting
groups under acidic condition using 6 N HCl completed the synthe-
sis of (2S,3S)-3-hydroxypipecolic acid hydrochloride 1. Spectral
data of 112 were in complete agreement with the ones reported
in the literature.6g
New York, 1985; Vol. 3, pp 1–90.
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In conclusion we have achieved the enantioselective total syn-
thesis of (2S,3S)-3-hydroxypipecolic acid 1 based on Sharpless
asymmetric dihydroxylation of olefinic ester 12. Intramolecular
lactone ring opening was employed as one of the key steps for
the construction of piperidine core.
Acknowledgements
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N.B.D. thanks CSIR, New Delhi, India. We thank Mrs. Kunte for
HPLC analysis.
References and notes
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Pharmacology. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.