A formal synthesis of swainsonine by gold-catalyzed allene cyclization

Article abstract of DOI:10.1021/ol901094h

Image Presented A formal synthesis of swainsonine has been achieved using a highly efficient and diastereoselective gold(III)-catalyzed allene cyclization.

Full text of DOI:10.1021/ol901094h

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3706-3708
A Formal Synthesis of Swainsonine by
Gold-Catalyzed Allene Cyclization
Roderick W. Bates* and Mark R. Dewey
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link, Singapore 637371
roderick@ntu.edu.sg
Received May 19, 2009
ABSTRACT
A formal synthesis of swainsonine has been achieved using a highly efficient and diastereoselective gold(III)-catalyzed allene cyclization.
Swainsonine 1, isolated from the fungus Rhizoctonia legu-
minicola and later the Australian plant Swainsona canesens,
the North American spotted locoweed plant Astragalous
lentiginosus, and the fungus Metarhizium anisopline, is a
potent mannosidase inhibitor and has attracted attention due
to its potential in the treatment of a range of conditions.
Numerous synthetic studies have been reported.1 In
particular, we were interested in the approach of Pyne,2
involving the use of dihydroxylation of an unsaturated
indolizidine 2 to introduce the cis-diol moiety (Figure 1).
For some years, originally inspired by the work of
Hegedus,5 we have been interested in organometallic nu-
cleophilic cyclization reactions of allenes.6 Such reactions
using either a silver(I),7 a gold(I), or a gold(III) catalyst,8
when carried out in an exo-sense, can yield R-vinyl hetero-
cycles in an overall cycloisomerization process. Combined
with ring-closing metathesis, this could produce a short route
to Pyne’s swainsonine intermediate 2 depending on the
diastereoselectivity on cyclization.
The allene precursor for cyclization was synthesized from
THF (Scheme 1). Ring opening of THF with sodium iodide
in the presence of benzoyl chloride yielded 4-iodobutyl
benzoate.9 Displacement of the iodide with azide, followed
by saponification, easily gave 4-azidobutanol 3 on a multi-
gram scale. IBX oxidation gave 4-azidobutanal 4 which
underwent efficient addition of (trimethylsilyl)ethynyllithium
(3) Buschmann, N.; Ru¨ckert, A.; Blechert, S. J. Org. Chem. 2002, 67,
4325.
Figure 1. Swainsonine and Pyne’s intermediate.
(4) de Vicente, J.; Arraya´s, R. G.; Can˜ada, J.; Carretero, J. C. Synlett
2000, 53.
(5) Hegedus, L. S.; Inoue, Y. J. Am. Chem. Soc. 1982, 104, 4917.
(6) Bates, R. W.; Satchareon, V. Chem. Soc. ReV. 2002, 12.
(7) Originally reported by Claesson: Claesson, A.; Sahlberg, C.;
Luthman, K. Acta Chem. Scand. B 1979, 309. For additional examples, see
ref 6.
Blechert also employed this step.3 Carretero employed the
corresponding TIPS ether.4
(8) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. For reviews of the use of gold, see: Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766. Li, Z.; Brouwer,
C.; He, C. Chem. ReV. 2008, 108, 3239. Patil, N. T.; Yamamoto, Y. Chem.
ReV. 2008, 108, 3395. Arcadi, A. Chem. ReV. 2009, 108, 3266. Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180. Hoffmann-Ro¨der, A.; Krause, N.
Org. Biomol. Chem. 2005, 3, 387. Arcadi, A.; Di Giuseppe, S. Curr. Org.
Chem. 2004, 8, 795.
(1) For reviews, see: El Nemr, A. Tetrahedron 2000, 56, 8579. Pyne,
S. G. Curr. Org. Synth. 2005, 2, 39. For some recent syntheses, see: Shi,
G.-F.; Li, J.-Q.; Jiang, X.-P.; Cheng, Y. Tetrahedron 2008, 64, 5005. Guo,
H.; O’Doherty, G. A. Tetrahedron 2008, 64, 304. De´champs, I.; Pardo,
D. G.; Cossy, J. Tetrahedron 2007, 63, 9082. Mart´ın, R.; Murruzzu, C.;
Pericas, M. A.; Riera, A. J. Org. Chem. 2005, 70, 2325.
(2) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097. Lindsay,
K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774.
(9) Oku, A.; Harada, T.; Kita, K. Tetrahedron Lett. 1982, 23, 681.
10.1021/ol901094h CCC: $40.75
Published on Web 07/29/2009
 2009 American Chemical Society

gold(III) chloride in dichloromethane resulted in formation
of dihydrofuran 12, isomeric with the desired piperidine 11
(Table 1). A similar result was obtained using acetonitrile
Scheme 1. Allene Synthesis and Cyclization
Table 1. Allene Cyclization
entry
conditions
product (yield %)
1
2
3
4
5
6
AgNO3, aq acetone
Ph3PAuCl, AgOTf, CH2Cl2
AuCl3, CH2Cl2
AuCl3, CH3CN
AuCl3, CH3CN, CaCO3
AuCl3, CH2Cl2, CH3CN, CaCO3
NR
NR
12 (ca. 10%a)
12 (ca. 10%a)
11 (13%a)
11 (99%)
a Significant amounts of starting material recovered.
as the solvent. We attribute the formation of dihydrofuran
12 to cleavage of the O-Si bond due to traces of hydrogen
chloride in the mixture due to adventitious moisture, followed
by facile 5-endo cyclization. Dihydrofuran formation could
be prevented by inclusion of calcium carbonate, leading to
formation of piperidine 11 in modest yield. However, an
excellent yield of piperidine 11 could only be obtained by
inclusion of both calcium carbonate and acetonitrile14 to
solubilize and stabilize the gold(III). Under these conditions,
the desired piperidine 11 was obtained as a single diastere-
oisomer in 99% yield.15
To construct the five-membered ring, it was necessary at this
stage to achieve selective deprotection of the nitrogen. Attempts
to do this by the method of Cavelier and Enjalbal proved
fruitless,16 but to our surprise, simple treatment of 11 with
trifluoroacetic acid in anhydrous dichloromethane yielded the
desired piperidine 13 with the silyl ether intact. We attribute
this to the absence of any nucleophile in the reaction mixture
capable of nucleophilic attack on the silicon atom.
Allylation of the nitrogen atom under standard conditions
(allyl bromide, sodium hydroxide) gave only a modest yield
(28%) of the desired diene 15. On the other hand, a sequence
of allyl carbamate (alloc) formation,17 followed by palladium(0)-
catalyzed “alloc contraction”18 proved to be highly satisfactory,
delivering diene 15 in 83% yield from the piperidine. The formal
synthesis was completed by ring-closing metathesis using
Grubbs second-generation catalyst in the presence of 1 equiv
of tosic acid, followed by a basic workup (NaOH), to give
indolizidine 2 in good yield (Scheme 2). The synthetic material19
to give azidoalkyne 5. This azido alkyne, as expected, proved
to be highly unstable, presumably due to intramolecular 1,3-
dipolar cycloaddition. This material was either used im-
mediately or stored at -80 °C.
The racemic alkyne rac-5 was converted to its (R)-isomer
by an oxidation-reduction sequence. The Dess-Martin
periodinane was employed for the oxidation to ketone 6 to
ensure a rapid conversion. Asymmetric reduction was
originally attempted using borane-dimethyl sulfide in the
presence of the CBS catalyst.10 On a small scale, this worked
well, delivering (R)-5 in 67% yield and an ee of 99%. On a
larger scale, however, the formation of byproduct, including
from alkyne hydroboration and possibly attack on the azide,
resulted in a low yield. The use of catechol borane gave a
more reliable result, delivering the alkyne (R)-5 in a reliable
86% yield, but an ee of only 75%.
At this stage, the azide group was subjected to reduction-
protection to give the t-Boc derivative 7. To complete the
synthesis of the precursor for cyclization, the trimethylsilyl
group was removed, the alkyne 8 was homologated to an
allene 9 using the Searles-Crabbe´ procedure,11 and the
alcohol was protected as its TBS ether 10.
(13) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658.
Gold(I) complexes with other ligands have also been employed: Zhang,
Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2006, 128, 9066. Zhang, Z.; Bender, C. F.; Widenhoefer, R. A.
Org. Lett. 2007, 9, 2887. Kinder, R. E.; Zhang, Z.; Widenhoefer, R. A.
Org. Lett. 2008, 10, 3157.
A number of catalysts and conditions were tested for
cyclization. Both silver(I) nitrate12 and the combination of
(triphenylphospine)gold(I) chloride-silver triflate13 proved
ineffective, returning unreacted starting material. The use of
(14) Krause, N.; Morita, N. Org. Lett. 2004, 6, 4121.
(15) The corresponding alloc protected material also underwent cycliza-
tion with excellent diastereoselectivity, but in low yield.
(16) Cavelier, F.; Enjalbal, C. Tetrahedron Lett. 1996, 37, 5131.
(17) The allyl carbamate derivative did not undergo ring-closing
metathesis with either the Grubbs I or II catalysts.
(10) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
Corey, E. J.; Magriotis, P. A.; Helal, C. J. J. Am. Chem. Soc. 1996, 118,
10938. Ledeboer, M. W.; Parker, K. A. J. Org. Chem. 1996, 61, 3214.
(11) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe´,
P. J. Chem. Soc., Perkin I 1984, 747.
(18) For examples, see: Torque, C.; Sueur, B.; Cabou, J.; Bricout, H.;
Hapiot, F.; Monflier, E. Tetrahedron 2005, 61, 4811. Gomez-Martinez, P.;
Dessolin, M.; Guibe´, F.; Albericio, F. J. Chem. Soc., Perkin Trans. 1999,
1, 2871.
(12) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. B 1979,
309.
Org. Lett., Vol. 11, No. 16, 2009
3707

Acknowledgment. We thank Nanyang Technological
University and the Singapore Ministry of Education Aca-
demic Research Fund Tier 1 (grant RG33/05) for support of
this work. We also thank Professors Stephen Hashmi
(University of Heidelberg), Louis Hegedus (Colorado State
University), and Christopher Hyland (California State Uni-
versity, Fullerton) for helpful discussions.
Scheme 2. Completion of the Formal Synthesis
Supporting Information Available: Complete experi-
mental procedures and spectroscopic data for compounds
2-15, 4-iodobutyl benzoate, and 4-azidobutyl benzoate. This
material is available free of charge via the Internet at
http://pubs.acs.org.
was spectroscopically identical to that reported by Pyne2 and
by Blechert.3
OL901094H
In conclusion, a formal synthesis of swainsonine has
been achieved employing a highly stereoselective, gold-
catalyzed allene cyclization which uses a simple catalyst
system.
(19) For material prepared via the catechol borane reduction, RD23
)
-59.6, c ) 1, CH2Cl2 (ref 2, -72, c ) 0.65, benzene), is consistent with
an ee of ca. 75%.
3708
Org. Lett., Vol. 11, No. 16, 2009