Stereoselective synthesis of (+)-radicamine B

Article abstract of DOI:10.1016/j.tetlet.2011.07.035

A simple and efficient stereoselective synthesis of naturally occurring pyrrolidine alkaloid, radicamine B has been accomplished in 13 steps from the commercially available starting materials with an overall yield of 9.75%. The synthesis utilizes Sharples

Full text of DOI:10.1016/j.tetlet.2011.07.035

Tetrahedron Letters 52 (2011) 4885–4887
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Tetrahedron Letters
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Stereoselective synthesis of (+)-radicamine B
⇑
G. Shankaraiah, R. Sateesh Chandra Kumar, B. Poornima, K. Suresh Babu
Natural Products Laboratory, Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient stereoselective synthesis of naturally occurring pyrrolidine alkaloid, radicamine B
has been accomplished in 13 steps from the commercially available starting materials with an overall
yield of 9.75%. The synthesis utilizes Sharpless asymmetric epoxidation and Horner–Wadsworth–
Emmons (HWE) olefination as key steps.
Received 1 June 2011
Revised 6 July 2011
Accepted 11 July 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidine alkaloids
Radicamines
Sharpless asymmetric epoxidation
HWE olefination
Nitrogen-containing heterocycles are widespread in medicinal
chemistry due to the fact that many natural, synthetic, and biolog-
ically active compounds share this common architectural fea-
ture.1Among them, polyhydroxy pyrrolidine alkaloidal (imino
sugars) framework represents one of the major classes of alkaloids,
which exhibits remarkable biological properties, such as potential
inhibition of glycosidases,2 antiviral agents,3 and acaricides.4 Rad-
icamine A and B are important groups of naturally occurring
polyhydroxylated pyrrolidine alkaloids isolated by Kusano and
co-workers from Lobelia Chinensis (Campanulaceae), which are
commonly used as a Chinese folk medicine for the treatment of a
been reported.7 In 2006, the total synthesis of radicamine B (4)
was attained by Yu et al., and revised the exact stereochemistry of
this compound through extensive studies. These reported syntheses
are almost identical and show only marginal differences, which
were relied on the same synthetic strategy with a cyclic nitrone as
a key intermediate derived from five-carbon sugar or amino acid.6,7
As continuation of our research program directed toward the
expedient synthesis of alkaloids from cheap and readily available
starting materials,8 we have initiated a program aiming for devel-
oping an efficient strategy for the stereoselective synthesis of radic-
amine B. The realization of this goal and an application to the
efficient synthesis of radicamine B (1) are presented herein. Our ap-
proach to the synthesis of radicamine B is based upon the Sharpless
asymmetric epoxidation as the key asymmetry inducing reaction,
wide range of human diseases including
a-glucosidase inhibitory
activity, antidiuretic, and anticarcinostatic properties for stomach
cancer.5 From a structural point of view, radicamine B that pos-
sesses aromatic substituent on the iminosugar ring is a rare class
of alkaloids found in nature. The structures and relative stereo-
chemistry of both these compounds (Fig. 1) were determined on
the basis of extensive NMR studies while the absolute configura-
tion of these compounds was assigned by comparing the specific
rotation with the natural codonopsinine (5).5 Because of their fas-
cinating structural features and interesting biological properties,
radicamines have solicited considerable interest among organic
chemists.
OH
OH
OH
HO
HO
HO
N
HO
OH
N
OH
N
HO
OH
H
H
H
MeO
HO
MeO
Radicamine A (1)
Radicamine A (2)
Radicamine B (3)
proposed
revised
proposed
As a consequence of the central role played by this pyrrolidine
ring system, numerous methods have been devised for the asym-
metric synthesis. There are currently three total syntheses of radic-
amine B accomplished by five groups.6 Besides, some formal
syntheses and related synthetic studies of radicamines have also
OH
HO
OH
HO
OH
HO
N
N
H
OH
N
MeO
(+) Codonopsinine (5)
HO
MeO
(-) Codonopsinine (6)
Radicamine B (4)
revised
⇑
Corresponding author. Tel.: +91 40 27191881; fax: +91 40 27160512.
E-mail address: suresh@iict.res.in (K. Suresh Babu).
Figure 1. Representative examples of pyrrolidine.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.035

4886
G. Shankaraiah et al. / Tetrahedron Letters 52 (2011) 4885–4887
OH
HO
NHBoc
OBn
NHBoc
O
O
OH
OH
N
OH
H
OH
HO
TsO
HO
7
8
(+) Radicamine B (4)
NHBoc
NHBoc
OBn
O
OH
OH
OH
OBn
TsO
TsO
HO
11
10
Scheme 1. Retrosynthetic analysis of radicamine B.
9
starting from commercially and cheaply available p-hydroxybenz-
aldehyde (12) in 13 steps with an overall yield of 9.75%.
Reduction of azide functionality in 14 using PPh3 in THF, water
(1:1 ratio) to amine,12 followed by addition of Boc anhydride affor-
ded Boc-protected amine in good yield, in which diol functionality
was protected with benzaldehyde dimethylacetal to using the cat-
alytic amount of p-TSA in DCM13 to give 15. Ring opening of hemi
acetal in 15 with DIBAL-H (4 equiv) yielded primary alcohol 10.
The resultant benzyl ether 10 was subjected to IBX oxidation fol-
As shown retrosynthetically in Scheme 1, synthesis of radic-
amine B (4) was envisaged based on the construction of key inter-
mediate 8 by Sharpless asymmetric epoxidation of 9, which could
be obtained through two carbon Wittig olefination reaction of
aldehyde generated from 10. The preparation of 10 was proposed
from 11 by performing regioselective SN2 opening of epoxide with
NaN3. The chiral synthon 11 could be prepared from p-hydroxy-
benzaldhyde from the reported procedure. This short and versatile
synthetic approach should also provide access to potentially active
substituted pyrrolidine derivatives at the C-2 position. More
importantly, we have successfully implemented a strategy that
minimizes protecting group manipulation in a unique fashion, a
common and unavoidable practice in synthesis of alkaloids.
Based on the above mentioned plan, synthesis of (+) radicamine
B(4) was initiated with commercially available p-hydroxybenzal-
dehyde 12, which was converted into its p-tosyl cinnamyl alcohol
13 in three steps by following the literature procedure.9 Sharpless
asymmetric epoxidation of 13 with (+)-DET furnished 11 in 98%
yield9 with excellent enantioselectivity of 99.5% ee (determined
by chiral HPLC).10 Regioselective ring opening of epoxide 11 at
benzylic position with NaN3 (1.6 equiv) in the presence of NH4Cl
(0.3 equiv) overnight stirring at 55 °C in THF, water (2:1 ratio) to
yield azido diol 14 (77%)11 and this was further confirmed by chop-
ping reaction with NaIO4.
lowed by Horner–Wadsworth–Emmons olefination to yield
a,b-
unsaturated ester 1614 with excellent E-selectivity. Further, E-selec-
tivity of 16 was confirmed by the large coupling constant (J = 16 Hz)
in the 1H NMR spectrum. Upon reduction of
a,b-unsaturated ester
16 with DIBAL-H in DCM at 0 °C for 1 h yielded corresponding allyl-
alcohol 9 in 90% yield. Finally, Sharpless asymmetric epoxidation of
resultant allyl alcohol 9 with (+)-DIPT in the presence of cumene
hydrogen peroxide acquired key intermediate 8 in excellent yield
(90%) with 99.2% ee (Scheme 2).15,16
With the successful synthesis of key fragment 8 in hand, we
turned our attention to the synthesis of radicamine B. Thus, depro-
tection of tosyl group in compound 8 using K2CO3 in refluxing
methanol yielded 17, which was further treated with Pd/C, under
H2 atmosphere in methanol to get 7 in good yield.17 Finally, re-
moval of Boc-group with TFA in DCM at 0 °C followed by treatment
with satd NaHCO3 smoothly yielded alkaloid (+) radicamine B in
good yield (Scheme 3).18,19 Spectroscopic data and optical rotation
½
a 2D5
+70.6 (c, 0.2, H2O)] of (+) radicamine B(4) were in full
ꢀ
agreement with reported literature5a and all the intermediate
O
O
OH
OH
H
d
e
a, b, c
TsO
TsO
HO
13
11
12
NHBoc
O
NHBoc
OBn
N3
O
f
OH
g
OH
h
TsO
OH
TsO
TsO
TsO
15
10
14
NHBoc
OBn
NHBoc
OBn
O
NHBoc
OBn
O
OH
i
OH
j
O
TsO
TsO
8
9
16
OEt
Ph3P
Scheme 2. Synthesis of key intermediate 8. Reagents and conditions: (a) TsCl, Et3N, DCM, 0 °C to rt, 1 h, 98%; (b)
benzene, rt, 6 h, 96%; (c) DIBAL-H, DCM, 0 °C to
O
0
rt, 1.5 h, 90%; (d) (+)-DET, Ti(i-prO)4, TBHP, 4 ÅA molecular sieves, DCM, ꢁ20 °C, 3 h, 98%; (e) NaN3, NH4Cl, THF–water (2:1), 55 °C, overnight, 77%; (f) (i) PPh3, THF–water (1:1),
rt, 1 h, then (Boc)2O, satd NaHCO3, 6 h, 97%; (ii) benzaldehyde dimethyl acetal, DCM, cat. PTSA, 4 h, 75%; (g) DIBAL-H, DCM, 0 °C to rt, 3 h, 80%; (h) (i) IBX, DMSO, THF, rt, 3 h;
0
(ii) (OEt)2PO(CH2COOEt), NaH, THF, 0 °C to rt, 6 h, 90% (over two steps); (i) DIBAL-H, DCM, 0 °C to rt, 1.5 h, 90%; (j) (+)-DIPT, Ti(i-pro)4, CHP, 4 ÅA molecular sieves, DCM, ꢁ20 °C,
12 h, 90%.

G. Shankaraiah et al. / Tetrahedron Letters 52 (2011) 4885–4887
4887
OH
HO
NHBoc
NHBoc
OBn
O
O
m
l
k
OH
N
OH
OH
8
H
OH
HO
HO
HO
(+) Radicamine B (4)
7
17
Scheme 3. Synthesis of (+) radicamine B (4). Reagents and conditions: (k) K2CO3, MeOH, reflux, 1 h, 95%; (l) Pd/C, H2 balloon, MeOH, overnight, 90%; (m) TFA, DCM, 0 °C,
30 min then solid NaHCO3, 30 h, 40%.
compounds were well characterized by the 1H NMR, 13C NMR,
8. (a) Kumar, R. S. C.; Reddy, G. V.; Shankaraiah, G.; Babu, K. S.; Rao, J. M.
Tetrahedron Lett. 2010, 51, 1114; Kumar, R. S. C.; Sreedhar, E.; Reddy, G. V.;
Mass and IR spectroscopic techniques.20
Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 1160.
In conclusion, we have developed an efficient, linear synthetic
protocol for synthesis of polyhydroxy pyrrolidine alkaloid, (+)-rad-
icamine B (4) using Sharpless epoxidation and HWE olefination as
key steps. This general synthetic route demonstrates its versatility
toward the synthesis of highly functionalized pyrrolidine and also
paves the way for the structurally related analogues. On the basis
of the route described herein, further work toward preparation of
the library of polyhydroxy pyrrolidine alkaloids for biological anal-
ysis is in progress in our laboratory.
9. Clive, D. L. J.; Stoffman, E. J. L. Org. Biomol. Chem. 2008, 6, 1831.
10. The enantioselectivity was determined by HPLC [Waters Atlantis dC18,
150 ꢂ 4.6 mm, 5
l, 210 nm, eluent, acetonitrile–water (1:1), 10 lL injection
volume, flow rate 1 mL/min, retention time 5.525 min].
11. Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 5756.
12. Liu, G.; Romo, D. Org. Lett. 2009, 11, 1143.
13. Crich, D.; Banerjee, A. J. Am. Chem. So. 2006, 128, 8078.
14. Cui, M.; Song, H.; Feng, A.; Wang, Z.; Wang, Q. J. Org. Chem. 2010, 75,
7018.
15. Fu, R.; Ye, J. L.; Dai, X. J.; Ruan, Y. P.; Huang, P. Q. J. Org. Chem. 2010, 75,
4230.
16. The diastereoselectivity was determined by HPLC [Waters HR C18,
300 ꢂ 3.9 mm, 6
l, 210 nm, eluent, acetonitrile–water (6:4), 20 lL injection
volume, flow rate 1 mL/min, retention time 9.067 min].
Acknowledgments
17. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4,
3919.
18. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734; (b) Hevko, J. M.; Dua,
S.; Taylor, M. S.; Bowie, J. H. J. Chem. Soc., Perkin Trans. 2 1998, 1629; (c)
Chandrasekhar, S.; Vijaykumar, B. V. D.; Pratap, T. V. Tetrahedron: Asymmetry
2008, 19, 746.
The authors gratefully acknowledge the keen interest shown by
Dr. J. S. Yadav, Director, IICT, Hyderabad. R.S.C.K. and B.P. thank
CSIR and UGC, New Delhi for financial support.
19. Experimental procedure for the synthesis (+)- radicamine B (4): To a stirred
solution of the compound 7 (0.2 g, 0.61 mmol) in 2 mL DCM at 0 °C was added
TFA (1 mL) drop wise and allowed to stir at the same temparature for 30 min.
After completion of the reaction (by TLC analysis), solvent and excess TFA were
removed in high vacuum. 10 mL of dry DCM was added to the reaction mixture
at 0 °C under nitrogen atmosphere. Reaction was quenched with solid NaHCO3
and stirred at room temperature for 30 h. The reaction mixture was filtered
and washed with DCM (10 ꢂ 2 mL), the organic layer was separated and
evaporated under reduced pressure to afford the crude product which was
purified by column chromatography on neutral alumina using chloroform–
MeOH (6:4) as a eluent to afford target compound 4 in 40% (0.05 g) yield.
20. Spectral data of selected compounds; Compound 7: pale yellow sticky liquid;
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.035.
References and notes
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Eur. J. Org. Chem. 2008, 2929; (f) Ribes, C.; Falomir, E.; Carda, M.; Marco, A. J. J.
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½ ꢀ
a 2D5 +40.4 (c 1, CH3OH); 1H NMR (300 MHz CDCl3 + CD3OD): d 7.13–7.03 (d,
2H, J = 8.4 Hz), 6.77–6.72(d, 2H, J = 8.3 Hz), 4.93–4.83 (br s, 1H), 4.34–3.98 (m,
1H), 3.77–3.34 (m, 4H), 2.90–2.72 (m, 1H), 1.41–1.38 (s, 9H); 13C NMR
(300 MHz CDCl3 + CD3OD): d 156.5, 156.3, 130.5, 128.4, 115.8, 80.0, 77.2, 66.8,
60.8, 60.2, 59.2, 28.3; FABMS: m/z 348 [M+Na]+; IR (KBr): cmꢁ1. 3345, 2925,
2854, 1689, 1614, 1514, 1368, 1248, 1167, 1043. Compound 8: pale yellow
sticky liquid; ½a D25
ꢀ
ꢁ15.8 (c 1, CHCl3); 1H NMR (300 MHz CDCl3): d 7.77–7.57 (d,
2H, J = 8.3 Hz), 7.41–6.99 (m, 9H), 6.99–6.74 (d, 2H, J = 8.3 Hz), 5.68–5.40 (br d,
1H), 4.87–4.60 (br s, 1H), 4.51–4.39 (s, 2H), 3.82–3.46 (m, 3H), 3.27–3.19 (d,
1H, J = 10.5 Hz), 3.03–2.77 (m, 1H), 2.47–2.41 (s, 3H), 1.46–1.37 (s, 9H); 13C
NMR (75 MHz, CDCl3):
d 154.9, 149.2, 144.9, 137.1, 236.5, 132.8, 129.7,
128.7,128.6, 128.4, 128.1, 127.9, 122.4, 77.4, 73.9, 68.4, 62.7, 61.2, 60.6, 28.4,
21.7; FABMS: m/z 592 [M+Na]+; IR (KBr): cmꢁ1; 3407, 2925, 2853, 1702, 1598,
1501, 1370, 1177, 1155, 866, 749. Compound 10: pale yellow liquid; ½a D25
ꢀ
ꢁ12.5 (c 1, CHCl3); 1H NMR (300 MHz CDCl3): d 7.69–7.65 (d, 2H, J = 8.12 Hz),
7.32–7.13 (m, 9H), 6.90–6.86 (d, 2H, J = 8.12 Hz), 5.79–5.72 (br d, 1H), 4.77–
4.70 (br s, 1H), 4.43–4.41 (s, 2H), 4.01–3.93 (m, 1H), 3.36–3.28 (m, 1H), 3.19–
3.10 (m, 1H), 2.45–2.42 (s, 3H), 1.41–1.37 (s, 9H); 13C NMR (75 MHz, CDCl3): d
155.2, 148.2, 144.9, 138.1, 137.2, 132.7, 129.6, 128.5, 127.9, 127.6, 122.2, 79.6,
76.9, 73.5, 71.0, 56.6, 28.4, 21.7; FABMS:m/z 550 [M+Na]+; IR (KBr): cmꢁ1
;
3409, 2923, 2853, 1700, 1598, 1501, 1370, 1198, 1177, 867,750; Compound 14:
Pale yellow oily liquid; ½a D25
ꢀ
ꢁ32.8 (c1, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.71–7.67 (d, 2H, J = 8.3 Hz), 7.32–7.23 (m, 4H), 7.01–6.97 (d, 2H, J = 8.4 Hz),
4.52–4.48 (m, 1H), 3.77–3.46 (m, 3H), 2.47–2.44 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 149.5, 145.4, 135.4, 132.7, 129.9, 129.2, 128.5, 122.2, 74.0, 66.1, 62.7,
21.8; FABMS: m/z 386 [M+Na]+; IR (KBr): cmꢁ1; 3360, 2921, 2851, 2105, 1598,
1502, 1373, 1198, 1178, 867.
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16(24), 10198.