Novel synthesis of castanospermine and 1-epicastanospermine

Article abstract of DOI:10.1021/ol0508577

(Chemical Equation Presented) Polyhydroxylated indolizidines have potential for treatment of HIV, hepatitis C and HSV infection, multiple sclerosis, angiogenesis, cancer, and diabetes. A new synthetic approach to the title compounds from a 5-C-methoxypyra

Full text of DOI:10.1021/ol0508577

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2691-2693
Novel Synthesis of Castanospermine
and 1-Epicastanospermine
Linda Cronin and Paul V. Murphy*
Department of Chemistry, Centre for Synthesis and Chemical Biology, Conway
Institute of Biomolecular and Biomedical Research, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
paul.V.murphy@ucd.ie
Received April 19, 2005
ABSTRACT
Polyhydroxylated indolizidines have potential for treatment of HIV, hepatitis C and HSV infection, multiple sclerosis, angiogenesis, cancer, and
diabetes. A new synthetic approach to the title compounds from a 5-C-methoxypyranosyl azide has been developed. The route incorporates
the aldol reaction and a novel catalytic reductive amination cascade to generate the indolizidine ring.
Castanospermine 1a is a bioactive naturally occurring
polyhydroxylated indolizidine, first isolated from seeds of
Castanospermum australe.1 It and closely related congeners
have shown considerable potential as antiviral agents for the
treatment of HIV,2 hepatitis C,3 and HSV-14 infections. They
also have potential for inhibition of progression of multiple
sclerosis,5 angiogenesis, cancer,6 and diabetes.7 The develop-
ment of new synthetic routes to castanospermine enable the
production of novel analogues for biological studies, and a
number of syntheses of 1 have been developed.8 Herein we
present a novel synthesis of castanospermine 1a and 1-epi-
castanospermine 1b from methyl R-D-glucopyranoside.
We have recently reported a general synthesis of imino-
sugars from 5-C-methoxypyranosyl azides (e.g., production
of 3 from 2).9 We were interested to investigate extending
the catalytic reductive amination cascade reaction used for
(1) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce,
R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811.
(2) (a) De Clercq, E. Med. Res. ReV. 2000, 20, 323. (b) Fleet, G. W. J.;
Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
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Witty, D. R.; Jacobs, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237,
128.
(8) For selected syntheses of 1a and 1b, see: (a) Tyler, P. C.; Winchester,
B. G. In Iminosugars as Glycosidase Inhibitors; Stuetz, A., Ed.; Wiley-
VCH Verlag GmbH: Weinheim, Germany, 1999; pp 125-156. (b) Michael,
J. P. Nat. Prod. Rep. 2004, 21, 625. (c) Somfai, P.; Marchand, P.; Torsell,
S.; Lindstrom, U. M. Tetrahedron 2003, 59, 1293. (c) Zhao, H.; Mootoo,
D. R. J. Org. Chem. 1996, 61, 6762. (d) Kim, J. H.; Woo, D.; Lee, J. H.;
Lee, B. W.; Park, K. H. Synthesis 2003, 2473. (e) Denmark, S. E.; Herbert,
B. J. Org. Chem. 2000, 65, 2887. (f) Grassberger, V.; Berger, A.; Dax, K.;
Fechter, M.; Gradnig, G.; Stuetz, A. E. Liebigs Ann. Chem. 1993, 379. (g)
Mulzer, J.; Dehmlow, H.; Buschmann, J.; Luger, P. J. Org. Chem. 1992,
57, 3194. (h) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1984, 25, 165.
(i) Setoi, H.; Takeno, H.; Hashimoto, M. Tetrahedron Lett. 1985, 26, 4617.
(3) Whitby, K.; Taylor, D.; Patel, D.; Ahmed, P.; Tyms, A. S. AntiViral
Chem. Chemother. 2004, 15, 141.
(4) Bridges, C. G.; Ahmed, S. P.; Kang, M. S.; Nash, R. J.; Porter, E.
A.; Tyms, A. S. Glycobiology, 1995, 5, 249.
(5) Walter, S.; Fassbender, K.; Gulbins, E.; Liu, Y.; Rieschel, M.; Herten,
M.; Bertsch, T.; Engelhardt, B. J. Neuroimmunology 2002, 132, 1.
(6) Pili, R.; Chang, J.; Partis, R. A.; Mueller, R. A.; Chrest, F. J.;
Passaniti, A. Cancer Res. 1995, 55, 2920.
(7) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugihara, Y.; Haruno, M.; Kato,
A.; Asano, N. J. Nat. Prod. 1998, 61, 397.
10.1021/ol0508577 CCC: $30.25
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preparation of piperidine 3 to generate the indolizidine ring
system (Scheme 1). It was envisaged that the piperidine 5
were removed, and benzyl protecting groups were introduced
to give 8. Oxidation using methyl(trifluoromethyl)dioxirane
generated in situ10 gave a 1.7:1 mixture of epoxides 9.11
Treatment of the epoxides with methanol in the presence of
camphorsulfonic acid gave a mixture of 5-C-methoxy-D-
glucopyranosyl azide 10 and 5-C-methoxy-L-idopyranosyl
azide 11. This mixture was oxidized to aldehydes 12 and 13
using the method of Ley and Griffith.12 The aldehydes were
separated using chromatography,13 and the configurations
assigned to 12 and 13 were determined using 1D NOE
spectroscopy. An NOE enhancement was observed for H-3
on irradiation of the aldehyde proton for 13, with no
enhancement observed for H-4. An NOE enhancement was
observed for H-4 of 12 on irradiation of its aldehyde proton
with no enhancement observed for H-3 (Figure 1).The aldol
Scheme 1. Synthesis of 1-Deoxymannojirimycin 3 and
Retrosynthetic Analysis of 1a
generated from 5-C-methoxypyranosyl azide 6 would un-
dergo an additional cyclization and give the indolizidinone
4, which would be subsequently converted to 1a.
Figure 1. Assignment of the configuration of 12 and 13
reaction of 13 was next investigated. Reaction of ethyl acetate
at -78 °C with LDA generated the desired enolate, which
Scheme 2
Scheme 3
on reaction with 13 gave a mixture of diastereoisomeric
alcohols 14 and 15; these were separated using silica gel
(10) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
(11) (a) Enright, P. M.; O’Boyle, K. M.; Murphy, P. V. Org. Lett. 2000,
2, 3929. (b) Enright, P. M.; Tosin, M.; Nieuwenhuyzen, M.; Cronin, L.;
Murphy, P. V. J. Org. Chem. 2002, 67, 3733.
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(13) Oxidation to 12 and 13. To a mixture of 10 and 11 (1.6 g, 3.2
mmol) in dry CH2Cl2 (35 mL) were added activated 4 Å molecular sieves
(0.1 g) and N-methylmorpholine N-oxide (NMO, 0.56 g, 4.8 mmol). After
30 min of stirring at room temperature under nitrogen, tetra-n-propylam-
monium perruthenate (TPAP, 0.11 g, 0.31 mmol) was added, and the mixture
was stirred overnight and then filtered through Celite. Filtration through a
short column of silica gel, eluting with CH2Cl2 gave 13 (0.74 g, 46%).
Further elution with EtOAc gave 12 (0.33 g, 21%) as a clear oil.
The synthesis commenced from the 6-deoxyhex-5-enopy-
ranoside 7, prepared from methyl R-D-glucopyranoside in
five steps (69%) as previously described.9b The acetate groups
(9) (a) Tosin, M.; O’Brien, J.; Murphy, P. V. Org. Lett. 2001, 3, 3353.
(b) McDonnell, C.; Cronin, L.; O’Brien, J. L. J. Org. Chem. 2004, 69, 3565.
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Org. Lett., Vol. 7, No. 13, 2005

gave a sample of 1a of higher purity. This sample was found
1
to have H and 13C NMR spectroscopic data17 identical to
Scheme 4
those previously reported18 and to those of an authentic
sample. Similarly 1b was found to have spectroscopic data
identical to those reported in the literature.19 A possible
sequence of intermediates explaining the formation of the
lactam 17 is shown in Scheme 5. This involves reduction of
Scheme 5
azide group to give a pyranosylamine, which ring opens to
an acyclic imine. Further reductive cyclization gives a cyclic
imine, which is reduced in situ to give 5, and subsequent
cyclization gives lactam 17.
In summary, a new strategy for the synthesis of polyhy-
droxylated indolizidines and related lactams has been
demonstrated and should be amenable to the synthesis of
further analogues. A wider investigation of the aldol reaction
from the view of generating analogues for biological evalu-
ation as well as improving stereoselectivity would seem
appropriate next studies. In addition aldehydes such as 13
could have more wide application as synthetic intermediates
to novel iminosugars and indolizidines.
chromatography with 14 being eluted first. The one-pot
reductive indolizidine ring generating cascade reaction was
then investigated and, gratifyingly, succeeded in a highly
stereoselective manner for both substrates 14 and 15, giving
lactams 16 (70%) and 1714 (62%), respectively.15 Reduction
of 16 and 17 was achieved by protection of the hydroxyl
groups as trimethylsilyl ethers and subsequent reaction using
LiAlH4 in THF, giving 1-epicastanospermine 1b and (+)-
castanospermine 1a, respectively.16 Indolizidine 1a was
converted to its per-O-acetate, which was subjected to
chromatographic purification, and subsequent deacetylation
Acknowledgment. The authors thank Science Foundation
Ireland for Programme Grant funding and Dr. Stan Tyms of
Oneida Theradiagnostics for the generous gift of castano-
spermine.
Supporting Information Available: Full experimental
(14) We repeated the previously reported synthesis of 17 from castano-
spermine and the NMR spectroscopic data of the two samples were identical.
See: Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C.
Carbohydr. Res. 2004, 339, 1747.
1
details and H and 13C spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Preparation of 17. Azide 15 (110 mg, 0.186 mmol), Pd(OH)2 (30
mg), and formic acid (0.82 mL) were added to MeOH (60 mL), and the
mixture was stirred in a Parr reactor in an atmosphere of hydrogen (500
psi) for 48 h. The suspension was then filtered through Celite, washing
first with MeOH and then water; the combined filtrate was evaporated to
dryness in vacuo; and the residue was purified using silica gel chromatog-
raphy (4:1 EtOAc/MeOH) to give 17 (23 mg, 62%).
OL0508577
(17) 1H NMR data for 1a: δ (300 MHz, D2O) 4.41 (ddd, 1H, J 6.8, J
4.6, J 1.5), 3.61 (m, 1H, H-6), 3.60 (t, 1H, J 9.6), 3.32 (t, 1H, J 9.1), 3.18
(dd, 1H, J 10.8, J 5.1), 3.08 (dt, 1H, J 9.1, J 2.1), 2.33 (dddd, 1H, J 14.8,
J 8.1, J 7.3, J 2.2), 2.21 (q, 1H, J 9.2), 2.06 (t, 1H, J 10.7), 2.02 (dd, 1H,
J 9.8, J 4.4), 1.17 (dddd, 1H, J 14.2, J 8.7, J 8.7, J 1.8).
(16) The removal of the TMS protecting groups is facile and occurs
during the workup after reduction.
(18) Miller, S. A.; Chamberlain, R. J. Am. Chem. Soc. 1990, 112, 8100.
(19) Ina, H.; Kibayashi, C. J. Org. Chem. 1993, 58, 52.
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