Total synthesis of (-)-radicamine B

Article abstract of DOI:10.1016/j.tetlet.2006.07.120

The synthesis of a chiral cyclic nitrone with l-arabino configuration and its application in the total synthesis of radicamine B is reported. An agreement in the spectral data with natural radicamine B but specific rotation with an opposite sign warranted

Full text of DOI:10.1016/j.tetlet.2006.07.120

Tetrahedron Letters 47 (2006) 6979–6981
Total synthesis of (ꢀ)-radicamine B
Mukund K. Gurjar,* Ramdas G. Borhade, Vedavati G. Puranik and C. V. Ramana*
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411 008, India
Received 13 June 2006; revised 18 July 2006; accepted 25 July 2006
Abstract—The synthesis of a chiral cyclic nitrone with L-arabino configuration and its application in the total synthesis of
radicamine B is reported. An agreement in the spectral data with natural radicamine B but specific rotation with an opposite sign
warranted a revision of the absolute configuration of radicamine B.
Ó 2006 Elsevier Ltd. All rights reserved.
Radicamines A 1 and B 2,1 two new pyrrolidine alka-
loids were isolated as inhibitors of a-glucosidase2 from
the plant Lobelia chinensis Lour., a herb that is used
as a diuretic, an antidote, a hemostat and as a carcino-
static agent for stomach cancer in Chinese folk medi-
cine. The structures and relative stereochemistry of
both these compounds (Fig. 1) were determined on the
basis of extensive NMR studies. However, the absolute
configuration of these compounds was assigned by
comparing the specific rotation with the natural
codonopsinine 3 and with its antipode 4. Due to its
remarkable biological properties we have undertaken
the synthesis of radicamine B. Herein, we describe the
total synthesis of radicamine B with the proposed abso-
lute configuration.
The facial selective addition of a suitable aryl Grignard
to the L-arabino configured cyclic nitrone 5 (Fig. 1)
forms the key approach of our intended synthesis of
2.3 Synthesis of the key nitrone 5 was envisaged from
L-arabinose.4 Very recently, Yu et al. reported (5 was
made from D-xylose) a similar strategy for the synthesis
of radicamines A and B and revised the absolute config-
uration of both.5
Our initial efforts on the synthesis of 2 were focused on
the preparation of cyclic nitrone 5 with control of the
relative configuration of the three contiguous stereo-
centers, as shown in Scheme 1, based on the reported
synthesis of ent-5 from D-arabinose by Vogel and
co-workers.4b
OMe
H3C
OMe
CH3
N
CH3
N
OH
OMe
OH
OH
H
N
H
N
H
N
HO
HO
HO
H3C
HO
(+)-codonopsinine 3
O−
OH
HO
OH
HO
radicamine B
(revised)
OH
OH
OH
radicamine B 2
HO
HO
(-)-codonopsinine 4
radicamine A 1
BnO
HO
O
O−
N
nucleophile adds
opposite to the
2-alkoxy group
+
N
OH
+
1/2
R
OBn
BnO
nitrone 5
OH
HO
L-arabinose
OR
Figure 1. Radicamines and their retrosynthetic analysis.
Keywords: Polyhydroxy pyrrolidine alkaloids; Radicamine B; Codonopsinine; Cyclic nitrone; Grignard addition.
*
Corresponding authors. Tel.: +91 20 25902627; fax: +91 20 25902629; e-mail addresses: mk.gurjar@ncl.res.in; vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.120

6980
M. K. Gurjar et al. / Tetrahedron Letters 47 (2006) 6979–6981
OTBS
OH
N
BnO
BnO
BnO
HO
I
O
OH
O
N
OH
OH
a)
b)
ref 6
4
+ 8
Z
95%
63%
BnO
OBn
c)
BnO
OBn
BnO
OBn
OH
HO
L-arabinose
6
7
8E
89%
O
OH
N
BnO
H
N
+
OBn
OBn
BnO
BnO
N
f)
e)
d)
2
62%
98%
78%
ORTEP structure of 5
BnO
OBn
BnO
OBn
BnO
OBn
5
10
9
Scheme 1. Reagents and conditions: (a) NH2OHÆHCl, NaHCO3, EtOH, reflux, 2 h; (b) i. TBDMSCl, pyridine, rt, 36 h; ii. I2, TPP, imidazole,
toluene, reflux, 3 h; (c) TBAF, toluene, reflux, 3 h; (d) 4-benzyloxyphenyl MgBr, Et2O–THF (1:2), ꢀ78 °C, 2 h; (e) Zn, aq NH4Cl, reflux, 3 h; (f) H2,
PdCl2, EtOH, rt, 20 h.
The 2,3,5-tri-O-benzyl-L-arabinose 6 was prepared from
L-arabinose (48% overall yield) using the reported pro-
cedure.6 The reaction of lactol 6 with hydroxylamine
hydrochloride afforded an inseparable mixture (7:3) of
E/Z-oximes 7. Selective O-silylation with TBDMSCl in
dry pyridine, followed by iodination with inversion of
the configuration at C(4) led to the isolation of a mix-
ture of E/Z-oxime derivatives 8. After chromatographic
separation, desilylation of the major isomer 8E with
concomitant intramolecular nucleophilic displacement
was attempted with anhydrous TBAF in toluene under
reflux and the required nitrone 5 was obtained as a crys-
talline solid. The spectral and analytical data of 5 were
in agreement with the reported data of ent-5. A single
crystal X-ray structural analysis of 5 confirmed the
structure (Scheme 1).7
Acknowledgements
Financial support by CSIR (New Delhi) in the form
of a research fellowship to R.G.B. is gratefully
acknowledged.
Supplementary data
NMR spectra of compounds 2, 5, and 9, and crystallo-
graphic data for 5 are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.07.120.
References and notes
1. Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.;
Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362–1365.
2. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265–295.
The reaction of cyclic nitrone 5 with p-benzyloxyphenyl-
magnesium bromide was executed in Et2O–THF at
ꢀ78 °C.3b The reaction was highly diastereo-selective
and afforded N-hydroxypyrrolidine derivative 9 in 78%
yield. The spectral and analytical data of 9 were in
agreement with the proposed structure. Reductive
N–O bond cleavage using Zn in aq NH4Cl gave the
pyrrolidine derivative 10. Finally, hydrogenolysis of 10
with H2 over PdCl2 in ethanol gave 2 in 62%
yield. The relative stereochemistry of 2 was confirmed
from 1H–1H coupling constants, COSY and NOESY
spectra. Although, the spectral data of synthetic 2 had
minor deviations (chemical shifts) from the reported
data of the natural product, which was expected due
to the exceptional chelating ability of these polyhy-
3. (a) Lombardo, M.; Trombini, C. Synthesis 2000, 759–774;
For references related to Grignard additions to sugar
derived cyclic nitrones see: (b) Holzapfel, C. W.; Crous, R.
Heterocycles 1998, 48, 1337–1342; (c) Peer, A.; Vasella, A.
Helv. Chim. Acta 1999, 82, 1044–1065; (d) Tamura, O.;
Toyao, A.; Ishibashi, H. Synlett 2002, 1344–1346; (e) Goti,
A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.;
Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235–4238; (f)
Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett
2003, 35–38.
4. (a) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.;
Goti, A. Tetrahedron Lett. 2003, 44, 2315–2318; (b)
Carmona, A. T.; Whigtman, R. H.; Robina, I.; Vogel, P.
Helv. Chim. Acta 2003, 86, 3066–3073; (c) Desvergnes, S.;
droxy pyrrolidine compounds with
a
metal or
25
proton,8 the optical rotation however, of 2 (½aꢁD ꢀ69
Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459–1462.
´
25
(c 0.2, H2O) {lit.1 ½aꢁD +72 (c 0.1, H2O)}),9 was similar
5. During the preparation of this manuscript Yu et al.
reported a similar strategy for the synthesis of radicamines
A and B and revised the absolute configuration of both. Yu,
C.-Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021–3024.
6. (a) Tejima, S.; Fletcher, G. F., Jr. J. Org. Chem. 1963, 28,
2999–3004; (b) Barker, R.; Fletcher, G. F., Jr. J. Org.
Chem. 1961, 26, 4605–4609.
7. The crystallographic data of compound 5 have been
deposited with the Cambridge Crystallographic Data
Centre as deposition No. CCDC 611018. Copies of the
data can be obtained, free of charge, on application to the
in magnitude but opposite in sign. This confirmed
the revision5 in the absolute configuration of radicamine
B.
In conclusion, a concise synthesis of unnatural (ꢀ)-radic-
amine B is described herein from L-arabinose (10 steps,
in an overall yield of 12%) which confirms the revised
absolute configuration of naturally occurring radic-
amine B as (2R,3R,4R,5R).

M. K. Gurjar et al. / Tetrahedron Letters 47 (2006) 6979–6981
6981
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
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J = 12.5, 3.9 Hz, 1H), 4.23 (t, J = 7.8 Hz, 1H), 4.43 (d,
J = 10.1 Hz, 1H), 4.51 (dd, J = 10.1, 7.8 Hz, 1H), 7.05 (d,
J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H). 13C NMR
(125 MHz): 58.5 (t), 61.4 (d), 62.7 (d), 73.9 (d), 77.6 (d),
115.9 (d), 123.8 (s), 129.8 (d), 156.7 (s). ESI-MS m/z: 226.53
([M+1]+). Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71;
N, 6.22%. Found C, 58.40; H, 7.02; N, 6.32%.
25
9. Spectral data of compound 2: ½aꢁD ꢀ69 (c 0.2, H2O); lit.1
25
½aꢁD +72 (c 0.1, H2O); 1H NMR (500 MHz, CDCl3): d
3.68–3.70 (m, 1H), 3.96 (dd, J = 12.5, 5.8 Hz, 1H), 4.01 (dd,