Skeletal and stereochemical diversification of tricyclic frameworks inspired by Ca2+-ATPaSe inhibitors, artemisinin and transtaganolide D

Article abstract of DOI:10.1021/ol802621u

(Chemical Equation Presented) Inspired by the common skeletal motifs of Ca²⁺-ATPases inhibitors involving artemisinin and transtaganolide D, small molecule collections with the three-dimensional structural diversity of tricyclic systems were designed and expeditiously synthesized (4-5 steps). A synthetic strategy featuring stereochemical diversification of ring-junctions and control of cyclizatlon modes was devised to access varied molecular architectures in a systematic fashion.

Full text of DOI:10.1021/ol802621u

ORGANIC
LETTERS
2
009
Vol. 11, No. 3
01-604
Skeletal and Stereochemical
Diversification of Tricyclic Frameworks
6
2+
Inspired by Ca -ATPase Inhibitors,
Artemisinin and Transtaganolide D
,
†,‡
†
Hiroki Oguri,* Yutaka Yamagishi, Takahisa Hiruma, and Hideaki Oikawa
†
†
DiVision of Chemistry, Graduate School of Science, and DiVision of InnoVatiVe
Research, CreatiVe Research InitiatiVe “Sousei” (CRIS), Hokkaido UniVersity, N21,
W10, Sapporo 001-0021, Japan
oguri@sci.hokudai.ac.jp
Received November 13, 2008
ABSTRACT
2+
Inspired by the common skeletal motifs of Ca -ATPases inhibitors involving artemisinin and transtaganolide D, small molecule collections
with the three-dimensional structural diversity of tricyclic systems were designed and expeditiously synthesized (4-5 steps). A synthetic
strategy featuring stereochemical diversification of ring-junctions and control of cyclization modes was devised to access varied molecular
architectures in a systematic fashion.
3
Artemisinin (1), a naturally occurring sesquiterpene endoper-
parum. In 2005, structurally related sesquiterpene lactones
oxide, and its derivatives have been clinically used to treat drug-
without peroxide bridges, designated as transtaganolides
(basiliolides), were also reported to inhibit SERCA. As
1,2
4,5
resistant malaria. The widely accepted mechanism of their
action involves iron (II)-dependent cleavage of the endop-
eroxide bridge to generate cytotoxic radical intermediates.
It has been proposed that artemisinins act by inhibiting
PfATP6, the ortholog of the sarco/endoplasmic reticulum
highlighted in Figure 1, we focused our attention on the
tricyclic system as a common structural motif of the naturally
occurring SERCA modulators despite the differences in the
stereochemical relationships of the ring junctions and
oxygenated functionalities incorporated into the cyclic
skeletons. Inspired by the common structural features of these
biologically intriguing sesquiterpenes, we sought to develop
expeditious and systematic synthetic processes to the related
tricyclic skeletons as a privileged structural motif for
2
+
Ca -ATPase (SERCA) of the parasite Plasmodium falci-
†
Graduate School of Science.
Creative Research Initiative “Sousei” (CRIS).
‡
(1) For recent reviews on artemisinin and its analogues, see: (a) O‘Neill,
P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945–2964. (b) Tang, Y. Q.;
Dong, Y. X.; Vennerstrom, J. L. Med. Res. ReV. 2004, 24, 425–448. (c)
Jefford, C. W. Drug DiscoVery Today 2007, 12, 487–495. (d) White, N. J.
6
designing natural product-inspired small molecules. Herein,
Science 2008, 320, 330–334
.
(3) Eckstein-Ludwig, U.; Webb, R. J.; van Goethem, I. D. A.; East,
J. M.; Lee, A. G.; Kimura, M.; O’Neill, P. M.; Bray, P. G.; Ward, S. A.;
Krishna, S. Nature 2003, 424, 957–961.
(
2) For selected examples of the total synthesis of artemisinin, see: (a)
Schimid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105, 624–625. (b) Xu,
X. X.; Zhu, J.; Huang, D. Z.; Zhou, W. S. Tetrahedron 1986, 42, 819–828.
(4) (a) Saouf, A.; Guerra, F. M.; Rubal, J. J.; Moreno-Dorado, F. J.;
Akssira, M.; Mellouki, F.; L o´ pez Matias, M.; Pujadas, A. J.; Jorge, Z. D.;
Massanet, G. M. Org. Lett. 2005, 7, 881–884. (b) Appendino, G.; Prosperini,
S.; Valdivia, C.; Ballero, M.; Colombano, G.; Billington, R. A.; Genazzani,
(
c) Ravindranathan, T.; Kumar, M. A.; Menon, R. B.; Hiremath, S. V.
Tetrahedron Lett. 1990, 31, 755–758. (d) Avery, M. A.; Chong, W. K. M.;
White, C. J. J. Am. Chem. Soc. 1992, 114, 974–979. (e) Liu, H. J.; Yeh,
W. L.; Chew, S. Y. Tetrahedron Lett. 1993, 34, 4435–4438. (f) Yadav,
A. A.; Sterner, O. J. Nat. Prod. 2005, 68, 1213–1217
.
J. S.; Satheesh Babu, R.; Sabitha, G. Tetrahedron Lett. 2003, 44, 387–389
.
(5) Nelson, H. M.; Stoltz, B. M. Org. Lett. 2008, 10, 25–28.
10.1021/ol802621u CCC: $40.75
Published on Web 12/31/2008
 2009 American Chemical Society

Scheme 1
.
Schematic Illustration of Synthetic Strategies for
Sesquiterpene-Like Small Molecules
a
Figure 1. Naturally occurring sesquiterpenes, artemisinin (1) and
transtaganolide D (2). The common skeleton is highlighted in bold.
we describe the development of a synthetic process entailing
7
generation of skeletal and stereochemical diversity of the
tricyclic systems.
To access varied molecular architectures in a systematic
fashion, we envisioned stereochemical diversification of ring-
junctions of the tricyclic system into three types involving
cis-cis, trans-cis, and trans-trans fused skeletons (Scheme
1). The collections of precursors having distinct functional
groups at three sites (A-C) with requisite stereochemical
variations (syn-syn, anti-syn, and anti-anti) would be syn-
thesized by assembly of three building blocks into consecutive
carbon centers of a six-membered ring. Reliable and robust
cyclization reactions must be employed for the paring of the
functionalities at the three sites to override the stereochemical
bias of the substrates. To this end, we planned tandem ring-
a
Systematic stereochemical alterations of ring-junctions were devised
to generate three-dimensional structural diversity.
10
group by adapting Fleming’s protocol. Subsequent alkylation
of the resulting C-magnesiated nitrile would proceed with
8
retention of configuration to afford a product having R
groups installed with high levels of stereoselectivities. Either
alkylation of the secondary alcohol or introduction of a R group
having a terminal olefin as a Grignard reagent at site A would
construct syn or anti stereochemical relationships with the
acetylene group at site B. Likewise, introduction of an olefin
1
-R
3
closing olefin metathesis reactions of dienynes leading to
tricyclic systems with concomitant incorporation of diene
functionalities into the skeletons. The collection of the resultant
tricycles would be a useful platform for incorporation of
heteroatom functionalities leading to small molecule collections
reminiscent of naturally occurring sesquiterpenes with high
oxidation levels.
1
3
group as the R group or manipulation of the nitrile group would
establish requisite stereochemical relationships between sites
B and C. In addition to stereochemical diversification, we
planned to generate skeletal diversity by controlling the modes
of dienyne cyclizations leading to products with distinct cyclic
arrays. Since olefin substitution can alter the site of initial
With our goal toward the rapid and stereocontrolled assembly
of building blocks, six-membered oxonitrile 3 was designed as
a versatile scaffold for installing the dienynes on the three sites
9
(
A-C) (Scheme 2). Addition of a R
1
group to the carbonyl
group would produce a hydroxylalkenenitrile that allows
chelation-controlled conjugate additions of acetylides as the R
11
ruthenium carbene complex formation, the tandem ring-
2
closure of dienyne with sterically differentiated olefins would
proceed via cyclization from sites A to B followed by B to C
leading to a tricyclic diene, whereas a reversed substitution
(
6) (a) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281–286. (b)
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res.
008, 41, 40–49. (c) H u¨ bel, K.; Lebmann, T.; Waldmann, H. Chem. Soc.
ReV. 2008, 37, 1361–1374.
7) Recent reviews for diversity-oriented synthesis, see: (a) Burke, M. D.;
2
(10) Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. J. Org. Chem.
2006, 71, 1430–1435.
(
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58. (b) Arya, P.;
Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163–180. (c) Tan,
D. S. Nat. Chem. Biol. 2005, 1, 74–84. (d) Nielsen, T. E.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2008, 47, 48–56. (e) Spandl, R. J.; Bender, A.;
Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149–1158.
(11) For selected examples of synthesis of polycyclic systems by tandem
metathesis of dienynes, see: (a) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073–1081. (b) Codesido, E. M.;
Castedo, L.; Granja, J. R. Org. Lett. 2001, 3, 1483–1486. (c) Shimizu, K.;
Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323–2325. (d) Honda, T.;
Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004, 6, 87–89. (e) Boyer,
F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820. (f) Garcia-
Fandino, R.; Codesido, E. M.; Sobarzo-Sanchez, E.; Castedo, L.; Granja,
J. R. Org. Lett. 2004, 6, 193–196. (g) Gonzalez, A.; Dominguez, G.; Castells,
J. P. Tetrahedron Lett. 2005, 46, 7267–7270.
(
8) For recent reviews, see: (a) Mori, M. AdV. Synth. Catal. 2007, 349,
1
(
21–135. (b) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509–519.
c) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317–1382.
9) Generation of skeletal diversity employing a scaffold with three
reactive sites, see: Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50.
(
602
Org. Lett., Vol. 11, No. 3, 2009

Scheme 2. Synthetic Strategy for Six Distinct Tricyclic Dienes:
Generation of Stereochemical Diversity Based on
Scheme 3
.
Synthesis of Tricyclic Dienes with Cis-Cis
Ring-Junctions in 5 Steps
Chelation-Controlled Conjugate Addition-Alkylations Leading to
Dienynes and Functional Group Manipulations at Sites A and C
pattern of olefins at sites A and C could invert the cyclization
mode to produce a distinct tricycle.
With this strategic plan in mind, we commenced synthesis
of the six distinct tricycles incorporating internal dienes starting
from the common scaffold 3 (Scheme 2). First, we developed
synthetic pathways 1 and 2 to produce cis-cis fused tricyclic
dienes 15 and 16 (Scheme 3). The C1 position of the scaffold
successfully controlled by exploiting the group-selective
ruthenium carbene complex formation of monosubstituted
olefins in the presence of disubstituted olefins.
3
was reduced with NaBH
4
-CeCl
3
to provide hydroxylalk-
We then investigated pathways 3 and 4 affording trans-cis
fused tricyclic dienes 23 and 24 (Scheme 4). Addition of
Grignard reagent 17 to 3 gave alcohol 19 in 55% yield.
enenitrile 4. The chelation-controlled conjugate addition of
acetylide 5 and subsequent steteroselective alkylation of the
resulting anion with 6 produced 8 in 61% yield. Since allylation
of the alcohol 8 under basic conditions caused isomerization
of the acetylene into an allene, we applied acid-catalyzed
conditions using trichloroacetimidate 10. Subsequent removal
of the trimethylsilyl group furnished the dienyne 12 in 75%
yield (2 steps). Similarly, the precursor 13 with a 2-methylallyl
ether at site A and a 3-butenyl group at site C was synthesized.
Upon treatment of 12 with 10 mol % Grubbs second generation
catalyst 14 in benzene under reflux for 3.5 h, tandem ring-
closing metathesis (RCM) of the dienyne system proceeded
smoothly to afford the desired tricyclic diene 15 in 90%
14
Chelation-controlled conjugate addition-alkylation and subse-
quent removal of the silyl group produced 21 in 71% yield (2
15
steps) as the major product. Similar stepwise transformations
produced 22, in which the substitution pattern of terminal olefins
at sites A and C was exchanged compared to that of 21 by the
use of Grignard reagent 18 and alkyliodide 7 in place of 17
and 6, respectively. Tandem cyclization of 21 required a high
catalyst loading (14: 66 mol %) and resulted in a modest yield
(52%) of the desired 23 with trans-cis ring junctions. On the
other hand, ring closure of 22 with 20 mol % catalyst produced
24 in satisfactory yield (75%). The structure of 24 was
12,13
13
yield.
Accordingly, ring-closure of 13 produced tricyclic
confirmed based on X-ray analysis.
diene 16 in excellent yield (90%). Thus, pathways 1 and 2
generated skeletal diversity in tricyclic dienes having cis-cis
fused ring-junctions, in which the modes of ring closure were
Next, tricyclic dienes, 31-34, with trans-trans ring-junctions
were synthesized via pathways 5 and 6 (Scheme 5). Three-
component assembly of 3, 17, and 5 followed by protonation
of the resulting carbanion in one pot stereoselectively produced
25 in 46% yield. Reduction of the nitrile 25 gave an aldehyde
in 88% yield, which was treated with 2-methylallyl Grignard
(
12) The stereochemistry of 15 with cis-cis fused ring junction was
unambiguously determined based on X-ray analysis of a crystalline
derivative (see, the Supporting Infromation and ref 13)
13) CCDC-699155 (derivative of 15), CCDC-699152 (24), CCDC-
99153 (silylated derivative of 27), and CCDC-699151 (mono p-bromoben-
.
(
6
(14) The four-component assembly of 3, 5, 6, and 17 in one pot turned
out to be impracticable (21 <15% yield).
(15) The undesired diastereomer (7% yield) formed by the alkylation
was separated by silica gel chromatography.
zoate of 34) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 11, No. 3, 2009
603

Scheme 4
.
Synthesis of Tricyclic Dienes with Trans-Cis
Scheme 5
.
Synthesis of Tricyclic Dienes with Trans-Trans
Ring-Junctions in 4 Steps
Ring-Junctions in 5 Steps
reagent to yield a diastereomeric mixture of diols in an
approximately 1:1 ratio. Separation of the diastereomers and
removal of the silyl group produced the dieneynes 27 and 28.
The dieneynes 29 and 30 with the substitution patterns of
terminal olefins at sites A and C exchanged were synthesized
in a similar fashion except for stepwise additions of the Grignard
reagents (3 f 20 f 26). While tandem ring-closures of 27
and 28 to afford the tricyclic dienes 31 and 32 resulted in
moderate yields (39-49%), cyclizations of 29 and 30 proceeded
smoothly to produce 33 and 34 in good yields (80-86%).
Structures of 27 and 34 were unambiguously determined based
mations would be readily applicable for the synthesis of
terpenoid-like fused skeletons. Further synthetic investigations
and preliminary screenings of biological activities are currently
underway and will be reported in due course.
13
on X-ray analysis of their derivatives. Thus, we have
successfully constructed the six types of tricyclic systems
incorporating internal dienes in a systemic fashion.
Acknowledgement. This work was supported by Grants-
in-Aid for Young Scientists (A) 19681022 to H.Oguri and also
in part by the Takeda Science Foundation, and Northern
Advancement Center for Science and Technology. We thank
Prof. Takanori Suzuki (Hokkaido University) and Prof. Kiyoshi
Tsuge (Osaka University) for performing the X-ray analysis.
In conclusion, we have developed an expeditious and
programmable synthetic process that controls not only the
stereochemical relationships of ring-junctions but also the modes
of cyclization, and entails the formation of six types of
sesquiterpene-like skeletons in 4-5 steps from 3. In this
synthetic process, functional groups including conjugated dienes,
hydroxyl groups and nitrile were incorporated in the skeletons
to allow further manipulations to produce natural product-
inspired small molecule collections. In addition, since this
synthetic process employs eneynes as precursors for cycliza-
tions, a variety of metal-catalyzed or radical-initiated transfor-
Supporting Information Available: Exprimental proce-
1
13
dures and H and C NMR sprctra of compounds 8, 9, 12,
3, 15, 16, 19-34, as well as CIF files for 24, and crystalline
1
derivatives of 15, 27 and 34. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL802621U
604
Org. Lett., Vol. 11, No. 3, 2009