Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis of pumiliotoxin-251D

Article abstract of DOI:10.1016/j.tetlet.2012.08.061

A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8- trihydroxyindolizidine (1-deoxy-7,8a-di-epi-castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermediate 9 and is used effectively in constructing indol

Full text of DOI:10.1016/j.tetlet.2012.08.061

Tetrahedron Letters 53 (2012) 5856–5858
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Tetrahedron Letters
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Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis
of pumiliotoxin-251D
⇑
Prakash R. Sultane, Amar R. Mohite, Ramakrishna G. Bhat
Department of Chemistry, Mendeleev Block, Indian Institute of Science Education and Research (IISER), Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-
castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermedi-
ate 9 and is used effectively in constructing indolizidine skeleton for the total synthesis of 1-deoxy-7,
8a-di-epi-castanospermine and also for the bicyclic framework of pumiliotoxin 251D 12, 13. The indolizi-
dine skeleton is achieved in one pot sequence of transformations such as deprotection of Cbz group,
reduction of double bond, and cyclization. The configurational and conformational structures of com-
pound 10 are unambiguously confirmed by X-ray analysis.
Received 29 June 2012
Revised 11 August 2012
Accepted 15 August 2012
Available online 25 August 2012
Keywords:
Dihydroxylation
Cross-metathesis
Wittig reaction
Cyclization
Ó 2012 Elsevier Ltd. All rights reserved.
Castanospermine
Pumiliotoxin
Aza fused indolizidine bicyclic alkaloids are widely distributed
in microorganisms, vertebrates, higher invertebrates, and plants.1,2
These bicyclic core structures being biologically active have drawn
attention of synthetic organic chemists to develop a concise and
efficient strategy.1,3 The naturally occurring polyhydroxylated
indolizidine alkaloids such as (+)-castanospermine 1 and their ana-
logues 2, 3 have been reported to exhibit glycosidase inhibition
activity,4 and they are also known to display potential antitumor,
antiviral, and immunomodulating activities (Fig. 1). Similarly, the
structurally related alkaloids of pumiliotoxin 4 (Fig. 1) have been
isolated and characterized from the neotropical frogs of family
‘Dendrobadidae’.5 These alkaloids are known to act as chemical de-
fense agents against predators and have a high pharmacological
activity on nerve and muscle.6 Though several reports of racemic
and enantioselective syntheses of 1-deoxy-8a-epi-castanosper-
mine stereoisomers exist,7 there are discrepancies in the reported
assignments and characterization. This prompted us to synthesize
1-deoxy-7,8a-di-epi-castanospermine diastereomer 2. Herein, we
wish to report a short and practical synthesis as a general synthetic
N,O-dimethylhydroxylamine hydrochloride to give the correspond-
ing Weinreb amide 6 in 92% yield, which on reduction with lithium
aluminium hydride (LAH) led to the formation of the corresponding
aldehyde 7 in 90% yield. The addition of vinyl magnesium bromide
to aldehyde 7 afforded an inseparable mixture of diastereomeric
alcohol 8 in 70% yield (Scheme 1).
Olefin metathesis of acyclic or cyclic olefins using alkylidene
ruthenium and molybdenum catalysts8 plays a pivotal role in the
synthesis of heterocyclic framework. Thus olefin 8 was subjected
to cross metathesis approach to arrive at the key intermediate 9
(Scheme 1).
The cross metathesis of 8 and methyl acrylate was performed
with Grubbs’ second generation catalyst (G-II) in toluene at room
temperature and gave the expected E-isomer 9 predominantly (E/
Z 20:1) in an excellent yield of 92%. Then compound 9 upon
dihydroxylation9 using OsO4 and NMO resulted in the formation
of a mixture of lactones owing to the alkaline condition of the
route to 1-deoxy-7,8a-di-epi-castanospermine
2 and bicyclic
OH
OH
frameworks of pumiliotoxin 251D (12, 13). Compound 9 was effec-
tively used as a common key intermediate for the syntheses of 2,
12, and 13 in this approach.
(2S)-N-Cbz-pyrrolidine-2-carboxaldehyde 7 was prepared in
two steps from N-Cbz-L-proline 5. Compound 5 was coupled with
OH
HO
H
H
N
1
OH
OH
H
N
OH
OH
8
7
6
N
α−ΟΗ−6; β−ΟΗ−7
β−ΟΗ−6; α−ΟΗ−7
2
3
4
Pumiliotoxin 251D
⇑
Corresponding author. Fax: +91 20 25898022
E-mail address: rgb@iiserpune.ac.in (R.G. Bhat).
Figure 1. Polyhydroxylated indolizidine alkaloids and pumiliotoxin 251 D.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.061

P. R. Sultane et al. / Tetrahedron Letters 53 (2012) 5856–5858
5857
MeNHOMe.HCl
O
H
H
H
N
DCC, HOBt, Et3N
LAH, THF, 0 °C
30 min, 90%
COOH
CHO
N
N
N
0 °C - rt, 6 h, 92%
Cbz
Cbz
Cbz
O
7
5
6
Methyl acrylate
G-II (3 mol%)
O
MgBr, THF
H
H
OMe
N
Toluene, rt, 2 h, 92%
(E:Z 20:1)
N
0 °C, 3 h, 70%
Cbz
Cbz
OH
OH
9
8
Scheme 1. Synthesis of key intermediate 9.
O
OH
O
H
H
N
OsO4, NMO
OMe
Mixture
of
N
OH
H2O-Acetone
rt, 3 h,
+
Cbz
Cbz
OH
Isomers
O
10
9
(Major) 61%
Pd/C, H2
MeOH, rt
85%
.
OH
OH
BH3 SMe2
THF, reflux
H
H
OH
OH
OH
OH
N
then EtOH, reflux
82%
N
O
2
11
Scheme 2. Synthesis of 1-deoxy-7,8a-di-epi-castanospermine.
complex7f,11 in THF gave the desired final compound 1-deoxy-
7,8a-di-epi-castanospermine 2 in 82% yield (Scheme 2).
It is important to note that in contrast to the usual practice,11 we
successfully reduced the amide bond without protecting any of the
hydroxyl groups thus minimizing the extra two steps in the route.
After completion of reaction it was refluxed with EtOH to avoid
the formation of amine-borane complex. Thus, the synthesis of
(6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-
castanospermine) 2 was accomplished in a total of 7 steps with an
overall yield of 23%. 1H and 13C NMR data for compound 2 do not
match with the spectral data reported by Chan et al.7a However,
the data of its enantiomer reported by Martin et al.7c and Pandey
et al.7d were in close agreement with the spectral data of 2. Specific
rotation of compound 2 was in close agreement with that of its
enantiomer (for 2, obs: ½a D25
ꢁ
ꢂ30 c 0.5, MeOH; its enantiomer ½a D27
ꢁ
+26.1 c 0.45, MeOH).7d Our assignment is further supported by the
X-ray crystal structure of compound 10.
Earlier Gallagher12d and Nubbemyer12i,j have reported the syn-
thesis of pumiliotoxin 251D 4 using indolizidine bicyclic frame-
works (12–14) as key intermediates (Fig 3).
Figure 2. Molecular structure of lactone 10 by X-ray analysis (ORTEP diagram;
ellipsoids are drawn at 50% probability).
reaction. The mixture was purified by column chromatography and
lactone 10 was isolated in major amount (61% yield) as a white so-
lid (Scheme 2). The molecular structure of 10 was confirmed by
single-crystal X-ray analysis.10 This gave the exclusive evidence
for the stereochemistry of hydroxyl groups (Fig. 2).
OH
O
H
N
H
N
H
N
Compound 10 under hydrogenolysis condition with Pd/C, H2
deprotected the benzyloxycarbonyl (Cbz) group followed by the
facile and rapid cyclization in one pot to give aza fused lactam:
indolizidinone 11 in 85% yield. This on reduction with BH3ꢀDMS
O
O
O
12
13
14
Figure 3. Key intermediates of pumiliotoxin 251D

5858
P. R. Sultane et al. / Tetrahedron Letters 53 (2012) 5856–5858
OH
Acknowledgements
O
H
N
H2, Pd/C, MeOH
then K2CO3
H
OMe
P.R.S. thanks CSIR, New Delhi for Senior Research Fellowship.
Authors greatly acknowledge the IISER Pune for the financial sup-
port to carry out this research work.
N
50 °C, 4 h, 80%
Cbz
OH
O
15
9
Supplementary data
O
H
H
COCl2, DMSO
CH2Cl2, -78 °C
PPh3CH3I
n-BuLi
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
061.
N
N
0 °C-rt, 70%
99%
O
O
12
13
References and notes
Ref.12i,j
Ref.12d
1. Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
OH
2. (a) Michael, J. P. Beilstein J. Org. Chem. 2007, 3, 27; (b) Pyne, S. G. Curr. Org. Synth.
2005, 2, 39–57; (c) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471–484; (d)
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265–295; (e) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (f) Elbein, A. D.;
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Interscience: New York, 1987; Vol. 5, p 1. Chapter 1.
H
N
4
Pumiliotoxin 251D
3. (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729; (b) Maryanoff, B. E.;
Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104,
1431–1628.
Scheme 3. Formal synthesis of pumiliotoxin 251D.
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Chem. Rev. 1990, 90, 1171–1202.
Encouraged by this we planned to utilize effectively olefin 9 for
the synthesis of the compounds 12 and 13 (Scheme 3). Compound
9 on treatment with Pd/C, H2 in MeOH, followed by the addition of
K2CO3 gave the corresponding alcohol 15 in 80% yield. It is striking
to note that the sequence of transformations viz. deprotection of
benzyloxycarbonyl (Cbz) group, reduction of double bond, and
facile cyclization takes place in one pot. Subsequently, alcohol 15
upon Swern oxidation, gave indolizidinedione 12 in almost quanti-
tative yield of 99%. Thus compound 12 was obtained in an overall
yield of 42% in 6 steps. Spectral data for compound 12 were in close
5. (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1993; Vol. 43, p 185; (b) Daly, J. W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; John Wiley
and Sons: New York, 1986; Vol. 4, p 1; (c) Tokuyama, T.; Nishimori, N.;
Shimada, A.; Edwards, M. W.; Daly, J. W. Tetrahedron 1987, 43, 643–652.
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Sudaub, A.; Nubbemeyer, U.; Mebsc, D.; Tytgata, J. Toxicon 2008, 51, 334–344.
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H.-J.; Lynch, V. M. J. Org. Chem. 1995, 60, 276–278; (d) Pandey, G.; Dumbre, S.
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H.; Ni, Y. K.; Zhao, G.; Ding, Y. Eur. J. Org. Chem. 2003, 1918–1922; (f) Zambrano,
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Colombo, A.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 590–596; (d)
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agreement with the reported values (obs: ½a D20
ꢂ243, c 1.56, CHCl3
ꢁ
lit.12i,j
½
a 2D0
ꢁ
ꢂ245, c 1.56, CHCl3).
Finally when compound 12 was subjected to Wittig olefination
afforded bicyclic lactam 13 in 70% yield. Spectral data for com-
pound 13 were in close agreement with the reported values
(Obs: ½a 2D0
ꢁ
ꢂ99.6, c 1.2, CHCl3; lit.12d
½
a 2D0
ꢁ
ꢂ98.3 c 1.2, CHCl3). While
both the compounds 12 and 13 have been explored earlier as key
intermediates for the synthesis of pumiliotoxin 251D,12d,i,j it is
evident that 13 is a more viable and an efficient precursor of pumi-
liotoxin 251D than 12, as the conversion of 12 to the corresponding
tertiary alcohol 14 was diastereoselectively poor (1:1.9).12i,j But the
conversion of bicyclic lactam 13 to the corresponding tertiary alco-
hol 14 was highly diastereoselective (10:1).12d Also in comparison
with the reported procedures,12 synthesis routes to 12 and 13 de-
scribed in this Letter are shorter and better yielding.
9. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973–1976.
10. CCDC numbers of 10: CCDC 866794. These numbers contain all crystallographic
details of this publication and are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html.
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Eur. J. Org. Chem. 1999, 1395–1400.
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In summary, we have developed a concise and convenient total
synthesis of (6R,7S,8R, 8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-
7,8a-di-epi-castanospermine) 2. This procedure requires a total of 7
steps starting from N-Cbz-L-Proline 5 and proceeded in overall 23%
yield. X-ray analysis of 10 established its unambiguous structural
determination, which in turn confirmed the configurational struc-
ture of 2. In addition, the formal synthesis of pumiliotoxin 251D
was accomplished in a total of 6 or 7 steps starting from 5 in an
overall 30% yield. Olefin 9 resulting from cross metathesis was
used as a common key intermediate for both the syntheses.