On the intramolecular pyrone Diels-Alder approach to basiliolide B

Article abstract of DOI:10.1016/j.tetlet.2008.03.031

A unified synthetic approach to the basiliolides/transtaganolides is outlined herein, along with studies illustrating the feasibility of the strategy with respect to the total synthesis of basiliolide B. This work lays the foundation for chemical synthesis of an emerging family of Thapsia metabolites.

Full text of DOI:10.1016/j.tetlet.2008.03.031

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Tetrahedron Letters 49 (2008) 2899–2901
On the intramolecular pyrone Diels–Alder approach to basiliolide B
Mariya V. Kozytska, Gregory B. Dudley *
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Received 15 February 2008; accepted 5 March 2008
Available online 10 March 2008
Abstract
A unified synthetic approach to the basiliolides/transtaganolides is outlined herein, along with studies illustrating the feasibility of the
strategy with respect to the total synthesis of basiliolide B. This work lays the foundation for chemical synthesis of an emerging family of
Thapsia metabolites.
Ó 2008 Elsevier Ltd. All rights reserved.
1
2
9
The basiliolides and transtaganolides recently joined
The retrosynthetic analysis shown in Figure 2 calls for
3
thapsigargin (THG) as the known bioactive metabolites
from plants of the Thapsia genus, the medicinal value of
which has been appreciated as far back as Hippocrates.
Despite no obvious structural homology, both the basilio-
lides and THG are produced by Thapsia garganica L. and
inhibit SERCA-ATPase activity.
The initial report on the biological activity of the basil-
iolides highlighted similarities with THG, but subsequent
an intramolecular pyrone Diels–Alder (IMPDA) reaction
of 3, which features an ambipihilic 5-iodo-2-pyrone
diene, to construct tricycle 2. Halogen substitution on 2-
1
0
4
1
1
pyrones increases their reactivity in both normal and
inverse electron-demand Diels–Alder reactions, thereby
providing the flexibility needed to prepare other basiliolides
(Fig. 1). Installation of the O-acyl ketene acetal is deferred
until the late stages of the synthesis, at which point confor-
mational biases of the rigid framework are expected to
5
1
6
studies revealed important distinctions. THG, an irrevers-
2
+
12
ible SERCA (Ca ) pump inhibitor, induces apoptosis
stabilize this otherwise labile structural element.
7
through endoplasmic reticulum stress. In contrast, the
Nelson and Stoltz recently reported progress toward the
1
3
basiliolides appear to inhibit SERCA reversibly; reversible
inhibition of SERCA leads not to apoptosis but rather is
associated with cell homeostasis. These new data point to
potential roles for the basiliolides (transtaganolides) in
the treatment of degenerative diseases.
synthesis of the basiliolides and transtaganolides, includ-
ing an encouraging IMPDA reaction of a 3-bromo-2-pyr-
one. However, their system lacks an appropriate handle
A unified strategy that can allow access to the various
basiliolides would be most attractive. Entry into the basil-
iolides through chemical synthesis requires that several
challenges be addressed, including installation of three dis-
R
C H
7 15
O
H
O
O
O
O
H
8
O
O
O
O
C3H7
O
8
O
OH
O
OH
tinct ester/lactone linkages, six stereogenic centers, two
O
O
OCH3
quaternary carbon atoms, and an unprecedented cyclic
O-acyl ketene acetal moiety within the tetracyclic
framework.
R = Me: basiliolide A1
transtaganolide D)
C8-epi-: basiliolide A2
transtaganolide C)
(
thapsigargin
(
R = CO Me: basiliolide B (1)
2
R = CH2OAc: basiliolide C
*
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644 8281.
E-mail address: gdudley@chem.fsu.edu (G. B. Dudley).
Fig. 1. Basiliolides/transtaganolides and thapsigargin.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.031

2900
M. V. Kozytska, G. B. Dudley / Tetrahedron Letters 49 (2008) 2899–2901
1
6
1
2
reduced to heptyn-7-ol following the known procedure
R R
H
CO Me
and coupled with iodide 5 under Sonogashira conditions
to give alcohol 6. Homologation of alcohol 6 was achieved
using the Swern oxidation and Wittig olefination to furnish
2
H
8
O
9
O
O
O
1
7,18
O
dienyne 8. Finally, Rossi–Larock iodocyclization
O
1 (basiliolide B)
I
R'O
18
1
employing Larock’s protocol provided iodopyrone 9.
OCH3
R = Me
2
2
R = CO Me
2
CO Et
2
O
O
CO Et
2
PhCH , 100 °C
3
O
O
3 days
OR'
I
CO2Me
9
O
ð1Þ
MeO2C
O
3
9%
I
I
(46% brsm)
R'O
I
iodopyrone:
ambiphilic diene
O
10
3
3
9
O
Fig. 2. Retrosynthetic analysis on basiliolide B based on a key intramo-
lecular Diels–Alder reaction of iodopyrone 3.
5
-Iodo-2-pyrone 9 provides insight into cycloaddition
reactivity vis- a` -vis decarboxylation (Eq. 1). Heating 9 at
1
00 °C for three days provided cycloadduct 10 as a single
at the 5-position of the pyrone for further elaboration, and
the bromine atom inserted late in the sequence to activate
the key IMPDA reaction had to be removed in a subse-
quent step.
diastereomer and free from cycloreversion products. Extru-
sion of CO becomes dominant at higher temperatures,
illustrating the delicate balance of pyrone Diels–Alder
reactions.
2
Herein, we share observations on new IMPDA reactions
9
This model system (9) demonstrates the utility of 5-halo-
relevant to our approach to basiliolide B. These studies
2-pyrones in IMPDA chemistry despite the lack of
provide data specific to the challenges of the basiliolides,
and, in general terms, provide insight into the application
of IMPDA reactions in natural products synthesis. In par-
ticular, we establish that halogen substitution at the 5-posi-
tion of the pyrone (cf. 3) is suitable for the IMPDA
reaction that is central to our synthetic design.
Thorpe–Ingold conformational biases that are expected
to assist in the assembly of the basiliolides (cf. 3). A second
IMPDA substrate (13, Scheme 2) better mimics the entro-
pic biases of the key step and includes a stereogenic center
to influence the diastereoselectivity of the reaction.
1
9
To establish the feasibility of the IMPDA approach to
1
4
the basiliolides using 5-halo-2-pyrones, two main con-
cerns must be addressed: (1) reactivity with respect to
O
OMe
1
. PPh , CBr
3 4
1
1
2
0
cycloaddition versus carbon dioxide (CO ) cycloreversion
CHO 2.
n
-BuLi
4.
m-CPBA, 79%
2
and (2) diastereoselectivity. Toward this end, two model
studies were undertaken. The first addresses the feasibility
of the IMPDA reaction in simplest terms, establishing that
the desired cycloadducts of 5-iodo-2-pyrones can be
obtained free from cycloreversion products (Eq. 1). The
second study focuses on the diastereoselectivity of a strate-
gic IMPDA reaction of a readily available and chiral 5-
iodo-2-pyrone (13, Scheme 3).
5
. HIO , H O
4
2
3
. 5, PdCl (PPh )
CuI, Et3N, 87%
2
3 2
6. 7, 75%, 2 steps
11
12
2
CO Et
I
ICl, CH Cl
rt, 4 h, 61%
I
2
2
+
O
2
EtO C
O
Rossi–Larock EtO C
iodocyclization
2
1
3
O
(
2.5 : 1)
O
The first test substrate, 5-iodo-2-pyrone 9, was synthe-
sized as shown in Scheme 1. Heptynoic acid (4) was
1
5
Scheme 2. Synthesis of IMPDA substrate 13.
1
. LiAlH , THF16
4
O
O
HO
O
HO
2
.
O
4
I
CO2Me
6
CH3
O
5
cat PdCl (PPh )
cat CuI, Et N, 82%
60% EtO C
2
3 2
MeO C
2
2
EtO C
2
H
H
I
I
3
I
1
12 h
PhCH3
00 °C
CO Et
14
H
2
13
nOe
1. Swern oxid.
ICl
O
O
I
2.
PPh3
CH Cl2
2
O
H
CO Et
57%
O
2
7
not
CO2Et
1%
formed
EtO2C
CO Et
8
MeO2C
O
CH3
2
8
I
H
9
epi-14
O
A1,3 strain
15
15
Scheme 1. Synthesis of 5-iodo-2-pyrone 9.
Scheme 3. IMPDA reactivity of 13.

M. V. Kozytska, G. B. Dudley / Tetrahedron Letters 49 (2008) 2899–2901
2901
Scheme 2 illustrates the synthesis of IMPDA substrate
3. Corey–Fuchs homologation of citronellal (6), Sono-
Akssira, M.; Mellouki, F.; Romero-Garrida, R.; Massanet, G. M.
Phytochemistry 2007, 68, 2480–2486.
2
0
1
3
. For the chemical synthesis of thapsigargin and leading references into
its isolation and activity, see: Andrews, S. P.; Ball, M.; Wierschem, F.;
Cleator, E.; Oliver, S.; H o¨ genauer, K.; Simic, O.; Antonello, A.;
H u¨ nger, U.; Smith, M. D.; Ley, S. V. Chem. Eur. J. 2007, 13, 5688–
5712.
. For discussion and leading references, see: (a) Christensen, S. B.;
Ramussen, U. Tetrahedron Lett. 1980, 21, 3829–3830; (b) Christensen,
S. B.; Andersen, A.; Smitt, U. W. Prog. Chem. Org. Nat. Prod. 1997,
gashira coupling with iodide 5, chemoselective epoxidation,
hydration to the diol, cleavage with periodic acid, and
Wittig olefination provided enyne 12 (15% yield from 11).
Iodocyclization provided iodopyrone 13 along with the
iodobutenolide product of 5-exo cyclization in a 2.5:1 ratio.
The IMPDA reaction of pyrone 13 (13?14, Scheme 3)
was much faster than that of pyrone 9 with the four-meth-
ylene tether and no Thorpe–Ingold assistance (9?10, Eq.
4
7
1, 130–167.
5. The molecular connectivity for the basiliolides was established largely
through NMR spectroscopy. The absolute stereochemistry is
unknown.
. Navarrete, C.; Sancho, R.; Caballero, F. J.; Pollastro, F.; Fiebich, B.
L.; Sterner, O.; Appendino, G.; Mu n˜ oz, E. J. Pharmacol. Exp. Ther.
1
1
): complete conversion of 13 occurred within 12 h at
00 °C. Furthermore, the desired cycloadduct formed as a
6
single diastereomer along with a minor by-product (69%)
1
5
arising from decarboxylation.
2
006, 319, 422–430.
The cycloaddition reactions of 9 and 13 illustrate the
utility of 5-iodo-2-pyrones in intramolecular Diels–Alder
reactions, building on promising initial data from related
7. (a) Yamaguchi, H.; Bhalla, K.; Wang, H.-G. Cancer Res. 2003, 63,
1483–1489; (b) Futami, T.; Miyagishi, M.; Taira, K. J. Biol. Chem.
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005, 280, 826–831.
1
0d
8. The stereogenic centers are at adjoining carbons. The contiguous
nature of the stereocenters simplifies rather than confounds the
problem.
9. (a) Portions of this work have been presented: (a) Kozytska, M. V.;
Dudley, G. B. Abstracts of Papers 58th Southeast Regional Meeting
of the American Chemical Society, Augusta, GA, November 1–4,
inter molecular processes. It is worth noting that similar
IMPDA reactions are completely intractable in the absence
1
3
of halogen activation.
These initial studies provide a solid foundation for the
synthesis of the basiliolides and transtaganolides. Impor-
tantly, this work afforded preliminary experimental
support—in the form of a diastereoselective IMPDA
reaction (13?14, Scheme 3) controlled by a stereogenic
center on the tether—for the hypothesis that the C9 stereo-
chemistry can be used to impart diastereocontrol over the
construction of the basiliolides and transtaganolides
2
0
006; American Chemical Society; Washington, DC, 2006; SRM06
11; (b) Kozytska, M. V.; Dudley, G. B. Abstracts of Papers 234th
National Meeting of the American Chemical Society, Boston, MA,
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1
0. Relevant applications of 5-halo-2-pyrones in Diels–Alder reactions:
(
7
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(
Fig. 2). What remains is to prepare, following the general
approach outlined in Scheme 1, an IMPDA substrate (cf.
) with appropriate functional group handles for further
Koo, S. J. Org. Chem. 2002, 67, 290–293; (c) Shin, J.-T.; Shin, S.;
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1
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2
73–274.
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Supplementary data
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of 5-halo-2-pyrones, Nelson and Stoltz also highlighted their potential
utility for the synthesis of basiliolide B (Ref. 13).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
1
1
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