A concise synthesis of R-(-)-cicutoxin, a natural 17-carbon polyenyne

Article abstract of DOI:10.1002/ejoc.200801172

A concise synthesis of the natural polyenyne R-(-)-cicutoxin (1) is described. After several trials, the successful synthesis commenced with three key fragments, R-(-)-1-hexyn-3-ol (8), 1,4-diiodo-1,3-butadiene (9), and THP-protected 4,6-heptadiyn-1-ol (6

Full text of DOI:10.1002/ejoc.200801172

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801172
A Concise Synthesis of R-(–)-Cicutoxin, a Natural 17-Carbon Polyenyne
[a]
[a]
Benjamin W. Gung* and Ann O. Omollo
Keywords: Total synthesis / Biological activity / Natural products / Enynes / Conjugation
A concise synthesis of the natural polyenyne R-(–)-cicutoxin
1) is described. After several trials, the successful synthesis
commenced with three key fragments, R-(–)-1-hexyn-3-ol (8),
,4-diiodo-1,3-butadiene (9), and THP-protected 4,6-hep-
regioselective reduction of a triple bond with Red-Al and re-
(
moval of the THP protecting group afforded the natural prod-
uct in four linear steps. The triply convergent synthesis gave
R-(–)-cicutoxin in 18% overall yield.
1
tadiyn-1-ol (6). Sonogashira coupling of compound 9 with
acetylenes 6 and 8 gave the 17-carbon frame, which upon
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
cicutoxin, but also for its potent antileukemic activity.[2,3]
Introduction
These interesting biological properties have prompted
Cicutoxin (1, Figure 1), a major toxic component of
water hemlock (Cicuta virosa and Cicuta maculate),
longs to the class of C -polyacetylenes bearing a long π-
bond conjugation system. Cicutoxin is known to have lethal
toxicity to the central nervous system, causing respiratory
paralysis and death. The most recent report of fatal poison-
ing was in 2001, when a native North American boy died
[7–10]
several total syntheses of virols A (2) and C (3).
How-
[
1–3]
be-
ever, the only synthetic study on cicutoxin (1) itself was re-
1
7
[11]
ported in 1955 by Trippett and coworkers.
As a result
of its extended unsaturation conjugation and a smaller end
capping group, cicutoxin is considerably more labile than
its congeners. Despite the low yield in the final step (≈4%),
it was a significant accomplishment that the group of Trip-
[
4]
after ingesting a carrot-like plant containing cicutoxin.
pett was able to synthesize the racemic cicutoxin without
[5]
The natural poison was isolated in 1915 and its structure
was first reported in 1953;[ its absolute configuration was
identified in 1999 along with its congeners virol A (2) and
[11]
the benefit of modern coupling reactions.
The more re-
6]
cent syntheses of virols took advantage of either Cadiot–
[12]
[13]
Chodkiewicz
or Sonogashira coupling reactions.
De-
[
1]
C (3).
spite being equipped with these modern techniques, no
enantioselective synthesis of cicutoxin has been reported.
[
14,15]
As previously reported,
polyacetylenic compounds are
sensitive to light and air and in general are very reactive in
nature. It is reasonable to assume that the reactive charac-
teristics of cicutoxin have prevented a stereoselective total
synthesis of this astonishing natural toxin.
Results and Discussion
Our interest in the total synthesis of biologically active
acetylenic alcohols prompted us to tackle this challenging
problem. Recently, we completed the total syntheses of sev-
eral polyacetylenic natural products including adociace-
Figure 1. The structure of R-(–)-cicutoxin (1) and its congeners tylene, minquartynoic acids, bidensyneosides, duryne, and
virol A (2) and C (3) from Cicuta virosa and Cicuta maculate.
[16–21]
dideoxypetrosynol.
On the basis of our experience in
this area, we planned our first attempt by using known
compounds 4 and 6 to construct the extended conjugation
system as shown in Scheme 1.
Cicutoxin (1, Figure 1) and its congeners virol A (2) and
C (3) are chemically and biologically interesting polyacetyl-
enic alcohols not only for the acute toxicity displayed by
[
22]
Known trienol 4,
which was first synthesized by the
[
a] Department of Chemistry & Biochemistry, Miami University,
group of Linstrumelle from the commercially available
starting materials propargyl alcohol and 1,2-trans-dichloro-
ethene, was subjected to a one-pot Swern oxidation–Grig-
nard addition reaction to produce the left half of target
Oxford, OH 45056, USA
Fax: +1-513-529-5715
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
1136
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1136–1138

Concise Synthesis of R-(–)-Cicutoxin, a Natural 17-Carbon Polyenyne
Scheme 1. Initial attempt at kinetic resolution for access to enantio-
enriched cicutoxin.
5
.[23] This procedure usually tolerates reactive carbonyl
[
23]
compounds,
but only gave an average of 20% yield in
Scheme 2. Triply convergent synthesis of R-(–)-cicutoxin.
this case. Trienol compound 4 cannot be stored for long
periods of time, as it is not even stable when stored in a
freezer. With limited supply of compound 5, a cross-coup-
ling reaction was performed with the known tetrahydro-
pyranyl (THP) ether protected diynol 6, first reported by
the group of Oshima.[ This afforded the racemic 17-car-
bon frame of cicutoxin with the primary alcohol protected
as tetrahydropyran ether 7. Attempted kinetic resolution of
racemic secondary alcohol 7 by using lipase AK[ resulted
only in decomposition of the starting material. The three
reactions shown in Scheme 1 suffered from either low yields
or complete decomposition. On the basis of our experience
in the synthesis of polyyne natural products, we felt that an
alternate route to enantioenriched cicutoxin would be to
assemble the extended conjugation system at a later stage.
Although the first attempt failed to yield the enantiomeri-
cally enriched cicutoxin, valuable lessons were learned. This
led to the decision that all difficult reactions should be done
before the assembly of the conjugation system. Therefore,
the stereocenter should be prepared in a fragment before
the final assembly. The improved plan is shown in
Scheme 2.
bond in compound 11 to the corresponding double bond
[(R)-7] was accomplished by using Red-Al. Removal of the
THP protecting group then gave enantioenriched (R)-(–)-
cicutoxin (1). Nonregioselective reduction was observed
when the THP protecting group was removed before Red-
Al reduction. The optical rotation of the synthetic sample
7]
[3]
is [α]D = –12.5 (c = 0.02, EtOH) {ref. [α]D = –11.8 (c =
24]
[1]
0
.55, EtOH) and ref. [α]D = –14.9 (c = 1.12, MeOH)}.
1
13
The IR and H and C NMR spectra, in addition to the
MS data, are consistent with reported data, although sam-
ples sent for HRMS analysis suffered decomposition.
Conclusions
In summary, we have completed a concise synthesis of
the natural product (R)-(–)-cicutoxin by adopting a strategy
to manage the lability of the target compound. This synthe-
sis took only four linear steps from the known starting ma-
terials and was triply convergent. (R)-(–)-Cicutoxin was
synthesized in 18% overall yield. Currently we are planning
to use this general strategy for the total synthesis of more
challenging natural products.
Enantiomerically pure (R)-1-hexyn-3-ol (8, [α]D = +16.9,
c = 0.32) is a known compound and was obtained by
[
25,26]
Supporting Information (see footnote on the first page of this arti-
Corey–Bakshi–Shibata reduction of 1-hexyn-3-one.
1
13
cle): Experimental details, H and C NMR and IR spectra for
Known 1,4-diiodo-1,3-butadiene (9) is a very useful com-
compounds 1, (R)-7, 10, and 11.
[
27]
pound for Suzuki coupling to unsaturated systems, yet it
has received little attention. Compound 9 is readily avail-
able by dimerization of acetylene accompanied by addition Acknowledgments
of iodine in the presence of a platinum(IV) catalyst and
[
28]
Financial support from the National Institutes of Health
(GM069441) is gratefully acknowledged.
sodium iodide.
Sonogashira coupling between 8 and 9
afforded dienynol 10 in 63% yield.[ A second palladium-
13]
catalyzed coupling reaction under slightly different condi-
tions provided 17-carbon frame 11 with the stereocenter al-
ready in place. The only structural changes needed were re-
duction of the triple bond at C5 and removal of the THP
protecting group. Regioselective reduction of the C5 triple
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www.eurjoc.org
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Received: November 25, 2008
Published Online: January 28, 2009
4
1138
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Eur. J. Org. Chem. 2009, 1136–1138