Tandem radical cyclizations with iodoaryl azides: formal total synthesis of (+/-)-aspidospermidine.

Article abstract of DOI:10.1021/ol006477x

An iodoazide radical cascade cyclization strategy has been used as the key step in a formal synthesis of aspidospermidine. Specifically, this step generated the alkaloid's B- and E-rings in the ethylidene-functionalized tetracycle 5. In turn, this was con

Full text of DOI:10.1021/ol006477x

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3599-3601
Tandem Radical Cyclizations with
Iodoaryl Azides: Formal Total Synthesis
of (±)-Aspidospermidine
Balaram Patro and John A. Murphy*
Department of Pure and Applied Chemistry, 295 Cathedral Street,
Glasgow G1 1XL, U.K.
john.murphy@strath.ac.uk
Received August 17, 2000
ABSTRACT
An iodoazide radical cascade cyclization strategy has been used as the key step in a formal synthesis of aspidospermidine. Specifically, this
step generated the alkaloid’s B- and E-rings in the ethylidene-functionalized tetracycle 5. In turn, this was converted into pentacycle 25, a
known advanced synthetic precursor of aspidospermidine.
We recently announced a total synthesis1 of (()-aspido-
spermidine2 1 using the tetrathiafulvalene-mediated radical-
polar crossover reaction3 as the key step. In an effort to find
alternative, efficient routes to complex alkaloids such as
aspidospermidine, a second plan was devised, based on the
relative reactivity toward attack by radicals of carbon-iodine
bonds and azide groups. Kim et al. had performed4 elegant
experiments showing that alkyl iodides are selectively
attacked by organosilyl radicals in the presence of alkyl
azides. We extended this work5 to show that aryl iodides
are also selectively attacked in the presence of alkyl azides
and used the resulting radical in a tandem cyclization reaction
(2 f 3) to afford the ABCE tetracycle of Aspidosperma
alkaloids. The key challenge was to find a route, using this
tandem cyclization strategy, to allow the synthesis of
aspidospermidine.
(1) Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. J. Chem.
Soc., Perkin Trans. 1 1999, 995.
(2) (a) Camerman, A.; Camerman, N.; Kutney, J. P.; Piers, E.; Trotter,
J. Tetrahedron Lett. 1965, 637. (b) Harley-Mason, J.; Kaplan, M. J. Chem.
Soc., Chem. Commun. 1967, 915. (c) Laronze, J.-Y.; Laronze-Fontaine, J.;
Le´vy, J.; LeMen, J. Tetrahedron Lett. 1974, 491. (d) Gallagher, T.; Magnus,
P.; Huffman, J. C. J. Am. Chem. Soc. 1983, 105, 4750. (e) Ban, Y.; Yoshida,
K.; Goto, J.; Oishi, T.; Takeda, E. Tetrahedron 1983, 39, 3657. (f) Node,
M.; Nagasawa, H.; Fuji, K. J. Am. Chem. Soc. 1987, 109, 7901 (g) Mandal,
S. B.; Giri, V. S.; Sabeena, M. S.; Pakrashi, S. C. J. Org. Chem. 1988, 53,
4236. (h) Le Me´nez, P.; Kunesch, N.; Liu, S.; Wenkert, E. J. Org. Chem.
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Desmae¨le, D.; d’Angelo, J. J. Org. Chem. 1994, 59, 2292. (k) Forns, P.;
Diaz, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882. (l) Schultz, A. G.;
Pettus, L. J. Org. Chem. 1997, 62, 6855. (m) Urrutia A.; Rodriguez, J. G.
Tetrahedron Lett. 1998, 39, 4143. (n) Quinn, J. F.; Bos, M. E.; Wulff, W.
D. Org. Lett. 1999, 1, 161. (o) Urrutia, A.; Rodriguez, J. G. Tetrahedron
1999, 55, 11095. (p) Toczko M. A.; Heathcock, C. H. J. Org. Chem. 2000,
65, 2642. (q) Iyengar, R.; Schildknegt, K.; Aube´, J. Org. Lett. 2000, 2,
1625. (r) For synthesis of N-benzylaspidospermidine, see: Benchekroun-
Mounir, N.; Dugat, D.; Gramain, J.-C.; Husson, H.-P. J. Org. Chem. 1993,
58, 6457.
Diene 4 was selected as the crucial intermediate, since
cyclization of this component would afford the tetracyclic
intermediate 5, functionalized with an ethylidene group. Our
previous route to aspidospermidine1 featured this intermediate
(E isomer), and therefore its synthesis by the azide route
(4) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116,
5521.
(3) Bashir, N.; Murphy, J. A. Chem. Commun. 2000, 627-628. Bashir,
N.; Patro, B.; Murphy, J. A. In AdVances in Free Radical Chemistry, Vol.
2; Zard, S. Z., Ed.; JAI Press: 1999; pp 123-150.
(5) Callaghan, O.; Kizil, M.; Murphy, J. A.; Patro, B. J. Org. Chem.
1999, 64, 7856. Murphy, J. A.; Kizil, M. J. Chem. Soc., Chem. Commun.
1995, 1409.
10.1021/ol006477x CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/13/2000

Scheme 1
would constitute a formal total synthesis. The key questions
were whether 4 could be prepared and whether it would
undergo cyclization to the desired tetracycle.
Whereas the simpler product 13 had undergone selective
osmium-triggered dihydroxylation at the side-chain allyl
group, 12 produced a different result (Scheme 2). Dihy-
The initial target became the potentially unstable eth-
ylidene-containing trienone 10 (Scheme 1). Aldol reaction
of the enolate of 6 with acetaldehyde afforded alcohol 7,
which was transformed into the corresponding mesylate 8.
This compound was reduced with DIBAL-H,6 yielding the
enone 9, and we were pleased to see that the mesyloxy group
had remained intact. Treatment with DBU then effected
elimination of the mesylate selectively to give trienone 10
as an E/Z mixture.
Scheme 2
Despite the basic conditions, aromatization of this com-
pound was not observed. This ketone was reduced under
Luche conditions,7 and alcohol 11 was subjected to
Mitsunobu8 reaction with 2-iodophenylmethanesulfon-
amide. This reaction was not successful, and we reasoned
that this was due to the use of the large phosphine,
triphenylphosphine. However, tributylphosphine gave a
mixture of starting alcohol and coupled product after 24 h,
and trimethylphosphine gave clean conversion to coupled
product 12.
The side-chain allyl group needed to be oxidized9 selec-
tively in the presence of the other alkenes at this stage.
droxylation and subsequent separation from the osmium
residues and oxidation with periodate gave ketone 15 as the
major product, thus indicating that the regioselectivity of the
dihydroxylation was not as desired and that the dihydroxyl-
ation had afforded 14 as the major intermediate.
To overcome this problem, dihydroxylation of 9 and its
Luche reduction product 16 was investigated (Scheme 3).
In neither case was selective oxidation of the allylic group
alkene observed. Accordingly, mesylate alcohol 16 was
coupled with 2-iodophenylmethanesulfonamide to afford 17.
This was selectively oxidized to diol 18, cleaved to aldehyde
19 and reduced to alcohol 20 without affecting the mesylate
group.
(6) Ansell, M. F.; Kafka, T. M. Tetrahedron. 1969, 25, 6025. Stork, G.;
Danheiser, R. L. J. Org. Chem. 1973, 38, 1775. Fleming, I.; Goldhill, J.;
Paterson, I. Tetrahedron Lett. 1979, 35, 3209. Alexakis, A.; Commerc¸on,
A.; Coulentianos, C.; Normant, J. F. Tetrahedron 1984, 40, 715. Inhoffen,
H. H.; Kampe, D.; Milkowski, W. Liebigs Ann. Chem. 1964, 674, 28.
(7) Luche, J. L.; Hahn, L. R.; Crabbe, P. J. Chem. Soc., Chem. Commun.
1978, 601.
(8) Wovkulich, P. M.; Shankaran, K.; Kiegiel, J.; Uskokovic, M. R. J.
Org. Chem. 1993, 58, 832 For reviews, see: (a) Mitsunobu, O. Synthesis
1981, 1. (b) Hughes, D. L. Org. Prep. Proc. Intl. 1996, 28, 127-64. (c)
Jenkins, I.; Mitsunobu, O. Encyclopaedia of Reagents for Organic Syn-
theses; Paquette, L. A., Ed.; John Wiley: New York, 1995; Vol. 8,
p 5379.
(9) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993,
115, 11028.
(10) All compounds had spectroscopic data in accord with the proposed
structures and either high-resolution mass measurement or combustion
analysis in support.
Elimination afforded diene 21 selectively, which was then
converted into the crucial azide 23 in two steps. This in turn
3600
Org. Lett., Vol. 2, No. 23, 2000

Scheme 3
was cyclized to the tetracycle 5, as a mixture of E and Z
isomers. Alkylation with (Z)-3-bromo-1-iodopropene af-
forded 24, which was converted into the known1 pentacycle
25, thus completing the formal synthesis.10 This syn-
thesis complements our earlier radical-based synthesis of
aspidospermidine, allowing the construction of the B- and
E-rings in a single step. Application of the iodoazide
cyclization method to other complex products is currently
underway.
Acknowledgment. We thank the EPSRC for funding and
the EPSRC National Mass Spectrometry Service, Swansea,
for mass spectra.
OL006477X
Org. Lett., Vol. 2, No. 23, 2000
3601