A novel and economical route to ( )-horsfiline using an aryl iodoazide
tandem radical cyclisation strategy
Dimitrios Lizos, Régis Tripoli and John A. Murphy*
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow,
UK G1 1XL. E-mail: john.murphy@strath.ac.uk; Fax: +44 141 548 4822; Tel: +44 141 548 2389
Received (in Cambridge, UK) 24th September 2001, Accepted 23rd October 2001
First published as an Advance Article on the web 29th November 2001
( )-Horsfiline has been synthesised using a tandem radical
cyclisation as the key step.
particular mention here since it also used a radical cyclisation
approach, although very different from our own. Specifically,
our approach features the aryl iodoazide10 tandem radical
cyclisation strategy, which we have recently used to prepare the
complex alkaloid, ( )-aspidospermidine.11
The spiropyrrolidinyloxindole nucleus is found in a number of
natural products of diverse origin. However, despite their
attraction as synthetic targets, the biological profile of these
compounds was not exciting—until recently. The recent
discovery of more members of this family such as spiro-
tryprostatin A (1) and spirotryprostatin B (2) caused an
increased interest, because they showed mild activity as cell-
cycle inhibitors,1 since cell-cycle inhibition frequently equates
with in vitro anti-cancer activity. However, the crucial discov-
ery was in 1999, when Danishefsky et al. showed2 that
unnatural analogues (3–5), synthesised in the laboratory, were
truly potent inhibitors of at least one human breast cancer cell
line [more than four orders of magnitude more powerful than
spirotryprostatin A itself].
With this as background, we set ourselves the task of finding
a new and flexible approach to the synthesis of the spir-
opyrrolidinyloxindole nucleus, and now present our route,
which features a tandem radical cyclisation approach as the key
step, in the synthesis of one member of the natural spir-
opyrrolidinyloxindoles, horsfiline (6). Horsfiline3 has been
synthesised by a number of research groups4–9 using diverse
methodologies; the synthesis of Jones and Wilkinson4 deserves
The starting materials for our synthesis are the commercially
available and economical compounds, itaconic acid and p-
anisidine. Double deprotonation of tBoc-protected p-anisidine 7
(prepared in 91% yield from p-anisidine) with t-BuLi and
reaction with 1,2-diiodoethane afforded the iodide 8 (86%).12
Deprotection of the t-Boc group (89%) and reductive amination
with benzaldehyde yielded the required N-benzyl derivative 10
(95%). Meanwhile, selective esterification of itaconic acid13
(82%) and then conversion to the acid chloride 11, was followed
by coupling to the amine 10, affording amide 12 in 94% yield
from the mono-acid. The plan was now to convert this
compound to the corresponding azide 18. Direct reduction of 12
with DIBAL-H yielded alcohol 13; however, this appeared to be
contaminated by, and was inseparable from, the methyl
derivative 14 that would result from conjugate addition of
DIBAL-H at the a,b-unsaturated amide group. This complica-
tion was avoided by protecting the alkene in 12 by conjugate
addition of thiophenol. The resulting sulfide 16 (96%) was then
reduced to afford the alcohol 17 (55%). [Unexpectedly, this
reaction also produced a small amount of amine 15.] Oxidation
of the sulfide and thermal elimination of the resulting sulfoxide
yielded the desired alcohol 13 (72%), which was smoothly
converted to the azide 18 (68%) with diphenylphosphoryl
azide.14 Cyclisation with tris(trimethylsilyl)silane (TTMSS)
followed by in situ methylation afforded15 the tricycle 20 (60%
over 2 steps). Finally, this was debenzylated7,9 to afford
horsfiline 6 (87%).
This simple approach to horsfiline illustrates that the aryl
iodoazide tandem radical cyclisation strategy11 is a powerful
methodology for accessing the important spiropyrrolidinylox-
indole nucleus.
We thank the EPSRC Mass Spectrometry Service Centre,
Swansea, for mass spectra, the University of Strathclyde for
University studentships (D. L. and R. T.) and the Royal Society
for a Leverhulme Senior Research Fellowship (JAM).
Notes and references
1 A. H. Osada, C.-B. Cui, R. Onose and F. Hanaoka, Bioorg. Med. Chem.,
1997, 5, 193.
2 S. Edmondson, S. J. Danishefsky, L. Sepp-Lorenzino and N. Rosen, J.
Am. Chem. Soc., 1999, 121, 2147.
3 A. Jossang, P. Jossang, H. A. Hadi, T. Sévenet and B. Bodo, J. Org.
Chem., 1991, 56, 6527.
4 K. Jones and J. Wilkinson, J. Chem. Soc., Chem. Commun., 1992,
1767.
5 C. Pellegrini, C. Strässler, M. Weber and H.-J. Borschberg, Tetra-
hedron: Asymmetry, 1994, 5, 1979.
6 S.-I. Bascop, J. Sapi, J.-Y. Laronze and J. Levy, Heterocycles, 1994, 38,
725.
7 C. Fischer, C. Meyers and E. M. Carreira, Helv. Chim. Acta, 2000, 83,
1175.
8 G. Palmisano, R. Annunziata, G. Papeo and M. Sisti, Tetrahedron:
Asymmetry, 1996, 7, 1.
Scheme 1
2732
Chem. Commun., 2001, 2732–2733
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108622g
Lizos
