Total synthesis of pyrrolidine alkaloid, Radicamine-B via Stille coupling

Article abstract of DOI:10.1016/j.tetlet.2011.09.034

Total synthesis of (-) Radicamine-B is achieved in eight steps from (R)-(+)-Garner aldehyde in a stereoflexible manner involving Stille coupling and one-pot domino epoxidation-pyrrolidine formation as key steps.

Full text of DOI:10.1016/j.tetlet.2011.09.034

Tetrahedron Letters 52 (2011) 6145–6147
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of pyrrolidine alkaloid, Radicamine-B via Stille coupling
P. Mallesham a, B. V .D. Vijaykumar a, Dong-Soo Shin b, , S. Chandrasekhar a,
⇑
⇑
a Organic Chemistry Division-I, Indian Institute of Chemical Technology-CSIR, Hyderabad 500 007, India
b Department of Chemistry, Changwon National University, Changwan 641-713, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2011
Revised 6 September 2011
Accepted 7 September 2011
Available online 10 September 2011
Total synthesis of (ꢀ) Radicamine-B is achieved in eight steps from (R)-(+)-Garner aldehyde in a stereo-
flexible manner involving Stille coupling and one-pot domino epoxidation-pyrrolidine formation as key
steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Radicamine B
Garner aldehyde
Stille coupling
One-pot reaction
Iminosugars have been extensively studied for their applica-
tions in pharmaceuticals.1 Polyhydroxylated alkaloids fall under
this class and exist as pyrrolidine, piperidine, and bicyclic frame-
works (Fig. 1).2
Radicamine B (1, Fig. 2) is one such iminosugar isolated from
Lobelia chinensis Lour (Campanulaceae),3 and encompasses a pyr-
rolidine skeleton functionalized on the entire carbon framework.
perfect (E)-geometry was achieved by treating 4 with nBu3SnH
and AIBN in refluxing benzene to isolate vinyl stannane 5 in
90% yield. The hydroxyl group in vinyl stannane 5 was protected
as TBDMS ether 6 in 85% isolated yield which was ready for Stille
coupling with 4-acetoxy bromobenzene 7 catalyzed by Pd(0).
Thus, vinyl stannane
6 and bromide 7 were coupled using
Pd(PPh3)4 in toluene to furnish the styrene derivative 8 in moder-
ate yields (60%).7 The acid labile silyl and ketal protections were
removed by stirring 8 in CHCl3 in the presence of TFA to yield diol
9 in 80% yield. Compound 9 was subjected to the domino process
of one-pot epoxidation-pyrrolidine construction by reacting it
with m-CPBA in CH2Cl2. This operation provided a mixture of pyr-
rolidine 10 contaminated with ꢁ20% of intermediate epoxide 10a
which was not isolated. Instead, CHCl3 was removed from the
reaction mixture, MeOH was added as the solvent and NaHCO3
as a base to force the reaction to ensure the complete formation
of 10 (60% yield, 2 steps). The stereochemistry of 10 was homo-
geneous with the formation of a single diastereomer as exempli-
fied by HPLC studies. The target, (ꢀ) Radicamine B (1), was
realized by treating compound 10 with TFA:CH2Cl2 in 80% yield.
The product thus obtained was identical in all respects including
Radicamines have shown potent inhibitory activity against a-glu-
cosidase. This natural product has attracted our attention owing
to the continued interest in the synthesis of iminosugars with var-
ious frameworks, in our group.4 Also we were interested in devel-
oping a general strategy to synthesize pyrrolidines with complete
stereocontrol and Radicamine B incidentally, became a target of
choice. Our concise synthesis relied on Stille coupling as a handle
for incorporating the aryl group. Total synthesis of Radicamine B
has been achieved few times earlier,3a,5 and the absolute stereo
chemistry has been revised based on the optical rotation of the
synthetic sample by Yu et al.5a
We envisaged easily available Garner aldehyde, in both stereo
forms with ease, to be an apt starting material for the target
synthesis (Scheme 1). Thus (R)-Garner aldehyde (3), was con-
verted to propargylic alcohol 4, as reported,6 in multiples of
grams, with ease. Stannylation of acetylenic functionality with
optical rotation {½a D32
ꢂ
ꢀ72 (c 0.1, H2O)}, lit. {½a D30
ꢀ72.7 (c 0.17,
ꢂ
H2O)}5a and spectral data (1H, 13C, HRMS).8
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail addresses: dsshin@changwon.ac.kr (D.-S. Shin), srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.034

6146
P. Mallesham et al. / Tetrahedron Letters 52 (2011) 6145–6147
OH
O
OH
ref.6
O
O
HSnBu3, AIBN
SnBu3
N
O
N
benzene, reflux
3h, 90%
Boc
Boc
NBoc
(R)-Garner aldehyde (3)
4
5
Br
OTBS
O
Pd(PPh3)4
TBSCl, Imidazole
N
toluene, reflux
6h, 60%
CH2Cl2, rt, 5h
85%
Boc
AcO
SnBu3
6
7
OTBS
O
OH
a.
m
CPBA, CH2Cl2
TFA:CH2Cl2 (9:1)
4h, 80%
N
b.NaHCO3, MeOH
4h, 60% (2 steps)
OAc
HO
Boc
NHBoc
8
9
OAc
OH
HO
TFA, rt, 12h
1
OAc
HO
80%
N
Radicamine B
Boc
10
OH
HO
BocHN
OAc
O
10a
Scheme 1. Synthesis of Radicamine B.
OH
HO
OH
OH
H
N
HO
HOH2C
OH
CH2OH
OH
H
HO
HO
OH
CH2OH
HO
HO
HO
OH
N
N
H
N
H
OH
2,5-Dihydroxymethyl-
3,4-dihydroxypyrrolidine
(DMDP)
castanospermine
Nojirimycin
hyacinthacine C1
(bicyclic)
(piperidine)
(bicyclic)
(Pyrrolidine)
Figure 1. Representative natural polyhydroxylated alkaloids.
References and notes
OH
OH
OH
OMe
HO
HO
HO
HO
1. (a) Asano, N. Glycobiology 2003, 13, 93R; (b) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. Rev. 2006, 106, 4484; (c) Murruzzu, C.; Riera, A. Tetrahedron: Asymmetry
2007, 18, 149; (d) Håkansson, A. E.; van Ameijde, J.; Guglielmini, L.; Horne, G.;
Nash, R. J.; Evinson, E. L.; Kato, A.; Fleet, G. W. J. Tetrahedron: Asymmetry 2007,
18, 282; (e) Martin, O. Ann. Pharm. Fr. 2007, 65, 5; (f) Ak, A.; Prudent, S.; LeNouen,
D.; Defoin, A.; Tarnus, C. Bioorg. Med. Chem. Lett. 2010, 20, 7410.
2. (a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265; (b) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.;
Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929; (c)
Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. J. Org. Chem. 2010, 75, 815; (d)
Kotland, A.; Accadbled, F.; Robeyns, K.; Behr, J. B. J. Org. Chem. 2011, 76, 4094; (e)
Delso, I.; Tejero, T.; Goti, A.; Merino, P. J. Org. Chem. 2011, 76, 4139.
3. (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G. Chem. Pharm.
Bull. 2001, 49, 1362; (b) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles
2002, 57, 1539.
OH
N
N
H
H
Radicamine A (2)
Radicamine B (1)
Figure 2. Structure of Radicamine B and A.
In conclusion, the total synthesis of pyrrolidine alkaloid, (ꢀ)
Radicamine B, is achieved through a strategy which allows one to
synthesize analogues with ease.
Acknowledgments
4. (a) Chandrasekhar, S.; Ramchander, T.; Reddy, M. V. Synthesis 2002, 13, 1867; (b)
Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46,
3127; (c) Chandrasekhar, S.; Vijaykumar, B. V. D.; Pratap, T. V. Tetrahedron:
Asymmetry 2008, 19, 746; (d) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org.
Chem. 2008, 73, 7826.
5. (a) Yu, C.-Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021; (b) Gurjar, M. K.; Borhade, R.
G.; Puranik, V. G.; Ramana, C. V. Tetrahedron Lett. 2006, 47, 6979; (c) Merino, P.;
Delso, I.; Tejero, T.; Cardona, F.; Goti, A. Synlett 2007, 2651; (d) Liu, C.; Gao, J.;
Yang, G.; Wightman, R. H.; Jiang, S. Lett. Org. Chem. 2007, 4, 556; (e) Ribes, C.;
Falomir, E.; Carda, M.; Marco, A. J. J. Org. Chem. 2008, 73, 7779; (f) Merino, P.;
Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A.
Eur. J. Org. Chem. 2008, 2929–2947.
P.M. and B.V.D.V. are grateful to the CSIR, New Delhi for re-
search fellowship. Research grant from the Sancheong Oriental
Medicinal Herb Institute (SOMHI), South Korea is also gratefully
acknowledged.
Supplementary data
Supplementary data (1H and 13C NMR spectra) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.09.034.
6. Herold, P. Helv. Chim. Acta 1988, 71, 354.

P. Mallesham et al. / Tetrahedron Letters 52 (2011) 6145–6147
6147
7. This step allows one to synthesize analogues. See: Tsou, E.-L.; Chen, S.-Y.; Yang,
M.-H.; Wang, S.-C.; Cheng, T.-R. R.; Cheng, W.-C. Bioorg. Med. Chem. 2008, 16,
10198.
1371 cmꢀ1; ½a 2D0
ꢂ
+0.75 (c 1, CHCl3); HRMS (ESI): calculated for C27H43NO6SiNa
528.2757 found: 528.2774.
Compound 9: 1H NMR (CDCl3, 300 MHz) d 7.36 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H,
J = 8.4 Hz), 6.65 (d, 1H, J = 16.0 Hz), 6.23, 6.18 (dd, 1H, J = 16.0, 5.6 Hz), 5.38 (d,
1H, J = 5.6 Hz), 4.47 (br s, 1H), 3.98–3.90 (m, 1H), 3.73–3.59 (m, 2H), 3.37 (t,
1.5H, J = 6.9 Hz), 2.28 (s, 3H), 1.42 (s, 9H); 13C NMR (CDCl3, 75 MHz): d 169.6,
156.3, 150.0, 131.5, 128.9, 127.8, 127.4, 121.6, 79.9, 74.3, 62.4, 55.3, 28.3, 21.0;
8. Spectral data of representative compounds:
Compound 5: 1H NMR (CDCl3, 300 MHz): d 6.28 (d, 1H, J = 18.8 Hz), 5.96 (d, 1H,
J = 18.8 Hz), 4.26–3.78 (br m, 5H), 1.52–1.45 (m, 20H), 1.37–1.23 (m, 6H), 0.92–
0.84 (m, 16H); 13C NMR (CHCl3, 75 MHz): d 153.7, 146.2, 129.3, 94.2, 80.6, 75.6,
64.5, 62.1, 29.0, 28.3, 27.2, 26.1, 13.6, 9.3; IR (CHCl3): mmax 3421, 2956, 2926,
IR (CHCl3): mmax 3477, 2924, 2855, 1647, 1073, 767 cmꢀ1; ½a D20
ꢀ97.1 (c 0.21,
ꢂ
2872, 1698, 1382 cmꢀ1; ½a D25
ꢂ
+25.5 (c 1, CHCl3); HRMS (ESI): calculated for
26H49NO4SnNa 570.2581, found: 570.2574.
MeOH); HRMS (ESI): calculated for C18H25NO6Na 374.1579, found: 374.1582.
Compound 1: 1H NMR (MeOH-d4 500 MHz): d 7.19 (d, 2H, J = 8.3 Hz), 6.70 (d,
2H, J = 8.3 Hz), 3.92 (m, 1H), 3.85–3.81 (m, 2H), 3.67–3.62 (m, 1H) 3.61–3.56 (m,
1H), 3.18–3.13 (m, 1H), 3.27–3.22 (m, 1H); 13C NMR (MeOH-d4, 75 MHz): d
158.5, 131.6, 129.9, 116.4, 83.9, 78.7, 66.1, 64.5, 62.9; IR (CHCl3): mmax 3485,
C
Compound 8: 1H NMR(CDCl3, 300 MHz): d 7.33 (d, 2H, J = 8.4 Hz) 6.99 (d, 2H,
J = 8.4 Hz), 6.47 (dd, 1H, J = 15.8, 7.1 Hz), 6.15–6.04 (m, 1H), 4.53 (br, 1H), 4.04
(br, 1H), 3.89 (br, 2H), 2.29 (s, 3H), 1.52 (s, 3H), 1.46 (s, 3H), 1.36 (s, 6H), 1.30 (s,
3H), 0.91 (s, 9H), 08 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 168.9,
152.5, 150.0, 134.6, 131.0, 129.6, 127.4, 121.6, 93.8, 79.9, 73.3, 63.9, 61.9, 28.4,
27.2, 26.0, 25.0, 21.1, ꢀ4.4, ꢀ3.9; IR (CHCl3): mmax 3367(br), 2930, 2858, 1696,
2925, 2854, 1743, 1465, 722 cmꢀ1; ½a D32
ꢀ72 (c 0.1, H2O); HRMS (ESI): calculated
ꢂ
for C11H15NO4 226.1074 found: 226.1075.