Synthesis of the hypoxic signaling inhibitor furospongolide

Article abstract of DOI:10.1055/s-0030-1260329

The first synthesis of the marine HIF-1 inhibitor furospongolide has been achieved in eight linear steps from geranyl acetate. Key steps include Schlosser sp³-sp³ cross-coupling and Sonogashira alkynylation of -bromobutenolide. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260329

LETTER
2541
Synthesis of the Hypoxic Signaling Inhibitor Furospongolide
Synthesis
o
of Furospong
h
olide n Boukouvalas,* Vincent Albert
Département de Chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, QC, G1V 0A6, Canada
Fax +1(418)6567916; E-mail: john.boukouvalas@chm.ulaval.ca
Received 3 August 2011
mor cell respiration and reactive oxygen species (ROS)
Abstract: The first synthesis of the marine HIF-1 inhibitor furo-
generation.3b,4
spongolide has been achieved in eight linear steps from geranyl ac-
etate. Key steps include Schlosser sp3–sp3 cross-coupling and
Sonogashira alkynylation of b-bromobutenolide.
So far, little is known about the SAR profile of 1. It ap-
pears, however, that the intact butenolide ring is essential
Key words: alkynes, butenolides, cross-coupling, furanoterpe- for HIF-1 inhibition since both its open lactone derivative
2 and the related furanolipid 3 were found to be inactive4,6
noids, neotorreyol
(Figure 1).
The need for further chemical exploration and pharmaco-
logical optimization,3b,4 combined with an infrequently
encountered b-pentenylbutenolide motif,7 renders 1 wor-
thy of synthetic attention.
Hypoxia (oxygen deprivation) is a hallmark of solid tu-
mors. The extent of tumor hypoxia correlates with resis-
tance to radiation and chemotherapy, progression of
malignancy, and patient mortality.1 Cancer cells adapt to
the hypoxic microenvironment largely through activation
of hypoxia-inducible factor-1 (HIF-1) which orchestrates
a host of cellular responses that are important to tumor
survival.2 Therefore, HIF-1 inhibition represents an at-
tractive strategy for advanced-stage cancer therapy.1–3
To date, there has been no published work on the synthe-
sis of 1 or any other naturally occurring b-pentenyl-
butenolide.
Pursuant to our interest in developing linchpin coupling
regimens for the step-economical assembly of substituted
butenolides,8,9 we now report the first synthesis of furo-
spongolide which illustrates a potentially general ap-
proach to this class of terpenoids.
O
O
O
1
sp3–sp3 cross-coupling
alkynylation
Sonogashira
coupling
13
15
5
CO2H
OH
18
O
1
2
3
6
14
O
O
1
O
O
X
X
Y
M
Figure 1 Structure of furospongolide (1), its open lactone deriva-
tive (2), and a related marine furanolipid (3)
O
M
O
O
5
6
7
4
After screening over 10,000 marine extracts for such ac-
tivity in human breast cancer cells, Nagle and Zhou re-
cently identified furospongolide (1, Figure 1) as a
structurally unique inhibitor of HIF-1 activation with an
IC50 of 2.9 mM.4 Importantly, this unusual C21 furanoter-
pene butenolide5 also represses hypoxia-induced secre-
tion of the downstream signaling protein VEGF and
cellular oxygen consumption in a concentration-depen-
dent manner.4 Additional mechanistic studies indicated
that 1 inhibits HIF-1 activity by selectively blocking
NADH-ubiquinone oxidoreductase (complex I)-mediated
mitochondrial electron transfer, thereby suppressing tu-
13
OH
1
1
O
8
Scheme 1 Retrosynthetic analysis of furospongolide (1)
Our retrosynthetic plan for 1 hinged upon three C–C bond
disconnections leading to fragments 4–7 (Scheme 1). The
crucial b-pentenylbutenolide substructure would thus
arise by attaching the terpene and butenolide fragments
onto acetylene 6. Neotorreyol (8),
a
wood-oil
constituent10 representing the C1–13 unit, was viewed as
an initial target from which 1 would be obtained by ethy-
nylation, Sonogashira coupling with butenolide 7,11 and
chemoselective hydrogenation of the alkyne linkage.
SYNLETT 2011, No. 17, pp 2541–2544
x
x
.x
x
.2
0
1
1
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260329; Art ID: S07011ST
© Georg Thieme Verlag Stuttgart · New York

2542
J. Boukouvalas, V. Albert
LETTER
MgCl
1) SeO2, t-BuOOH
PhCOOH, CH2Cl2 (49%)
O
4a
AcO
AcO
OTBS
2) TBSCl, DMAP
Et3N, CH2Cl2 (95%)
Li2CuCl4, THF
0 °C to r.t., 18 h
9
5a
ref. 14
Br
O
O
7a
n-BuLi, MsCl, THF;
OR
PdCl2(PPh3)2, CuI
i-Pr2NEt, dioxane
MgBr, CuCN
O
O
11
(94%)
10 R = TBS
8 R = H (neotorreyol)
(66%)
aq HCl, THF
(73%, 2 steps)
H2, Pd/BaSO4
EtOAc–MeOH
O
O
O
O
(89%)
O
12
furospongolide (1)
O
Scheme 2 Total synthesis of furospongolide (1)
Although several syntheses of 8 have been reported,12 Next, appendage of the butenolide moiety was swiftly re-
none were deemed particularly attractive; the best of these alized by employing our inverse-addition protocol for ef-
rely on sulfone coupling–reductive desulfonation se- fecting Sonogashira alkynylation of b-tetronic acid
quences, requiring six linear steps from commercial bromide 7a.11 In the present instance, a small excess of
chemicals.12c,d
7a22 (1.2 equiv) was successively treated with
PdCl2(PPh3)2/CuI, Hünig’s base, and 11 in 1,4-dioxane
for 18 hours at room temperature to deliver butenolide 12
in 66% yield after flash chromatography.23
To expedite matters, arrival at 8 was contemplated by
joining 4 to central linchpin 5, which we hoped to achieve
by means of Schlosser sp3–sp3 cross-coupling.13 When
considering the availability of starting materials, the opti- With the carbon skeleton in place, all that remained was
mal electrophilic partner would bear an acetate leaving to saturate the superfluous triple bond (cf. 12 to 1,
group (5, X = OAc) thus providing a superior starting Scheme 2). Initial attempts at reducing 12 with diimide,
point.
using the procedure of Carbery,24 led to complete recov-
ery of the starting alkyne. On the other hand, hydrogena-
tion under conditions recently employed by Nicolaou and
co-workers for saturation of the alkyne group of a related
enynone [H2, 10 % Pd/C, EtOAc–MeOH (3:2)]25 afforded
1, albeit with modest efficiency (ca. 50%). Pleasingly, hy-
drogenation with a milder catalyst (5 % Pd/BaSO4) using
the same solvent system provided 1 in 89% yield26 whose
spectral characteristics were identical with those reported
for the natural product.4,5
The synthesis began with the two-step transformation of
inexpensive geranyl acetate (9) to difunctional terpene 5a,
conveniently performed on a multigram scale according
to established precedent14 (Scheme 2). Schlosser cross-
coupling13 of acetate 5a with Grignard reagent 4a15,16 in
the presence of Kochi’s catalyst17 (Li2CuCl4, 10 mol%)
proceeded smoothly to furnish the desired furanoterpene
10 alongside unreacted 5a and the Wurtz homocoupling
product18 1,2-di-3-furylethane. Cleavage of the OTBS
group and ensuing purification by column chromatogra- In summary, the first synthesis of furospongolide (1) has
phy afforded neotorreyol (8) in 73% yield over two been achieved in eight linear steps and 19% overall yield
steps.19
from geranyl acetate. The brevity and high level of con-
vergence of this route should make it readily amenable to
the preparation of designed analogues of 1 as well as other
biologically important furanoterpenoids sharing the same
C1–13 subunit.27 Such studies are currently under way
and will be reported in due course.
Ethynylation of 8 was best accomplished by adaptation of
a procedure developed by Lee and Corey during their syn-
thesis of eunicenone A.20 Thus, mesylation (n-BuLi,
MsCl, THF, –78 °C) followed by reaction of the crude
mesylate with ethynylmagnesium bromide and copper(I)
cyanide, gave acetylene 11 in excellent yield (94%, 2
steps).21
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 17, 2541–2544 © Thieme Stuttgart · New York

LETTER
Synthesis of Furospongolide
2543
(14) (a) Dauben, W. G.; Saugier, R. K.; Fleischhauer, I. J. Org.
Chem. 1985, 50, 3767. (b) Marshall, J. A.; Lebreton, J.;
DeHoff, B. S.; Jenson, T. M. J. Org. Chem. 1987, 52, 3883.
(15) (a) Tanis, S. P. Tetrahedron Lett. 1982, 23, 3115.
(b) Snider, B. B.; O’Hare, S. M. Synth. Commun. 2001, 31,
3753.
Acknowledgment
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC) and the FQRNT-Québec Centre in Green Che-
mistry and Catalysis (CGCC) for financial support.
(16) A 0.3 M solution of Grignard reagent 4a in THF was
prepared as follows: Magnesium powder (1.04 g, 42.65
mmol) was flame heated, allowed to cool to r.t., and
activated by successively adding a crystal of iodine and a
solution of 1,2-dibromoethane (0.1 mL) in THF (7 mL)
under argon. The mixture was refluxed for 25 min (until
bubbling of acetylene gas ceased), and then cooled to 0 °C.
A solution of 3-chloromethylfuran15a (497 mg, 4.27 mmol)
in THF (3 mL) was then added at once. Vigorous stirring
was continued for 4 h at –3 to 0 °C (salt-water bath). The
mixture was decanted over 15 min without stirring. The
resulting THF solution of 4a (0.3 M) could be kept for 1–3 h
at –3 to 0 °C without any signs of decomposition.
References and Notes
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Nash, Z. M.; DeYoung, M. P.; Sgroi, D.; Ellisen, L. W. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 4675.
(3) (a) Denko, N. C. Nat. Rev. Cancer 2008, 8, 705. (b) Nagle,
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Biochimie 2009, 91, 1347.
(4) Liu, Y.; Liu, R.; Mao, S.-C.; Morgan, J. B.; Jekabsons, M.
B.; Zhou, Y.-D.; Nagle, D. G. J. Nat. Prod. 2008, 71, 1854.
(5) Furospongolide was first isolated from the marine sponge
Dysidea herbacea: Kashman, Y.; Zviely, M. Experientia
1980, 36, 1279.
(17) Tamura, M.; Kochi, J. Synthesis 1971, 303.
(18) Baker, R.; Ekanayake, N. J.; Simon, A. J. Chem. Res.,
Synop. 1983, 74.
(19) Synthesis of Neotorreyol (8)
To a stirred solution of acetate 5a (434 mg, 1.33 mmol) in
THF (3 mL) was added Li2CuCl4 in THF (0.1 M, 1.33 mL,
0.133 mmol). After cooling to 0 °C, a freshly prepared
solution of Grignard reagent 4a in THF16 (0.3 M, 8.5 mL,
2.55 mmol) was added over 10 min at 0 °C. After 10 min the
reaction mixture was allowed to warm to r.t. and stirring
continued for 18 h before quenching with brine (3 mL). The
mixture was poured to EtOAc (15 mL), the organic layer was
separated, washed with brine (2 × 10 mL), dried over
MgSO4, and concentrated under reduced pressure. The
residue was subjected to column chromatography on silica
gel (2% EtOAc in hexanes) to give 361 mg of a mixture
consisting of cross-coupled product 10 and 1,2-di-3-
furylethane. Due to difficulties in separating the Wurtz
homocoupling product at this stage, crude 10 was used as is
for the subsequent reaction; it was dissolved in THF (3 mL)
and aq HCl (1 M, 1.25 mL) was added with stirring at r.t.
After 16 h, the mixture was poured into EtOAc (15 mL), the
organic layer was separated, washed with brine (1 × 10 mL),
dried over MgSO4, and concentrated under reduced pressure.
The product was purified by flash chromatography on silica
gel (8% EtOAc in hexanes) to give neotorreyol (8) as a
colorless oil (227 mg, 73% over 2 steps); Rf = 0.35 (20%
EtOAc–hexanes). IR (NaCl, film): 3341, 2920, 2855, 1501,
1446, 1383, 1164, 1065, 1025, 874, 778 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.34 (s, 1 H), 7.21 (s, 1 H), 6.28 (s, 1 H),
5.37 (t, J = 5.8 Hz, 1 H), 5.17 (t, J = 5.8 Hz, 1 H), 3.99 (s, 2
H), 2.45 (t, J = 7.4 Hz, 2 H), 2.25 (q, J = 7.4 Hz, 2 H), 2.13
(q, J = 7.4 Hz, 2 H), 2.03 (t, J = 7.4 Hz, 2 H), 1.67 (s, 3 H),
1.60 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 142.8, 139.1,
135.6, 135.0, 126.2, 125.2, 124.3, 111.3, 69.2, 39.5, 28.6,
26.3, 25.2, 16.3, 13.9. ESI-HRMS: m/z calcd for C15H22O2:
234.1627; found: 234.1620.
(6) Dai, J.; Liu, Y.; Zhou, Y.-D.; Nagle, D. G. J. Nat. Prod.
2007, 70, 1824.
(7) Only a few other naturally occurring b-pentenylbutenolides
are known: (a) Bohlmann, F.; Grenz, M. Chem. Ber. 1975,
108, 357. (b) Liu, Y.; Mansoor, T. A.; Hong, J.; Lee, C.-O.;
Sim, C. J.; Im, K. S.; Kim, N. D.; Jung, J. H. J. Nat. Prod.
2003, 66, 1451. (c) Wang, N.; Song, J.; Jang, K. H.; Lee,
H.-S.; Li, X.; Oh, K.-B.; Shin, J. J. Nat. Prod. 2008, 71, 551.
(8) (a) Boukouvalas, J.; Pouliot, M. Synlett 2005, 343.
(b) Boukouvalas, J.; Wang, J.-X.; Marion, O.; Ndzi, B.
J. Org. Chem. 2006, 71, 6670. (c) Boukouvalas, J.; Marion,
O. Synlett 2006, 1511. (d) Boukouvalas, J.; Beltrán, P. P.;
Lachance, N.; Côté, S.; Maltais, F.; Pouliot, M. Synlett 2007,
219. (e) Boukouvalas, J.; Wang, J.-X.; Marion, O.
Tetrahedron Lett. 2007, 48, 7747. (f) Boukouvalas, J.;
Loach, R. P. J. Org. Chem. 2008, 73, 8109.
(g) Boukouvalas, J.; McCann, L. C. Tetrahedron Lett. 2010,
51, 4636. (h) Boukouvalas, J.; McCann, L. C. Tetrahedron
Lett. 2011, 52, 1202.
(9) Synthesis of b-homoallylbutenolides: (a) Boukouvalas, J.;
Robichaud, J.; Maltais, F. Synlett 2006, 2480.
(b) Boukouvalas, J.; Lachance, N. Synlett 1998, 31.
(10) Sakai, T.; Nishimura, K.; Hirose, Y. Bull. Chem. Soc. Jpn.
1965, 38, 381.
(11) Boukouvalas, J.; Côté, S.; Ndzi, B. Tetrahedron Lett. 2007,
48, 105.
(20) Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 1872.
(21) Data for Acetylene 11
(12) (a) Thomas, A. F. Chem. Commun. 1968, 1657. (b) Kondo,
K.; Matsumoto, M. Tetrahedron Lett. 1976, 17, 391.
(c) Masaki, Y.; Hashimoto, K.; Sakuma, K.; Kaji, K.
J. Chem. Soc., Perkin Trans. 1 1984, 1289. (d) Takabe, K.;
Hashimoto, H.; Sugimoto, H.; Nomoto, M.; Yoda, H.
Tetrahedron: Asymmetry 2004, 15, 909.
(13) (a) Fouquet, G.; Schlosser, M. Angew. Chem., Int. Ed. Engl.
1974, 13, 82. See also: (b) Bäckvall, J.-E.; Sellén, M.;
Grant, B. J. Am. Chem. Soc. 1990, 112, 6615. (c) Carpita,
A.; Bonaccorsi, F.; Rossi, R. Gazz. Chim. Ital. 1984, 114,
443. (d) Kolympadi, M.; Liapis, M.; Ragoussis, V.
Tetrahedron 2005, 61, 2003.
Colorless oil; Rf = 0.20 (hexanes). IR (NaCl, film): 3302,
2921, 2855, 1501, 1444, 1384, 1164, 1065, 1025, 874, 779,
634 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.34 (s, 1 H),
7.21 (s, 1 H), 6.28 (s, 1 H), 5.39 (t, J = 5.8 Hz, 1 H), 5.17 (t,
J = 5.8 Hz, 1 H), 2.88 (s, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.25
(q, J = 7.4 Hz, 2 H), 2.13 (q, J = 7.4 Hz, 2 H), 2.09 (s, 1 H),
2.03 (t, J = 7.4 Hz, 2 H), 1.69 (s, 3 H), 1.59 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 142.8, 139.1, 135.7, 129.6,
126.3, 125.2, 124.2, 111.3, 82.4, 70.3, 39.6, 28.8, 28.7, 26.8,
Synlett 2011, No. 17, 2541–2544 © Thieme Stuttgart · New York

2544
J. Boukouvalas, V. Albert
LETTER
25.2, 16.3, 16.2. ESI-HRMS: m/z calcd for C17H22O:
242.1673; found: 242.1671.
(24) Marsh, B. J.; Carbery, D. R. J. Org. Chem. 2009, 74, 3186.
(25) Nicolaou, K. C.; Peng, X.-S.; Sun, Y.-P.; Polet, D.; Zou, B.;
Lim, C. S.; Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131,
10587.
(22) (a) Bromide 7a (mp 77 °C) was prepared by Vilsmeier
bromination of b-tetronic acid (86%, 30 g scale) using the
procedure of Jas: Jas, G. Synthesis 1991, 965. (b) See also:
Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M.
Tetrahedron Lett. 1998, 39, 7665.
(26) Synthesis of Furospongolide (1)
To a solution of butenolide 12 (48.7 mg, 0.1501 mmol) in
EtOAc–MeOH (3:2, 1 mL) was added 5% Pd(0) on BaSO4
(127.8 mg). The reaction mixture was stirred for 5.25 h
under a balloon of hydrogen at r.t., filtered through a Celite
pad, and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (40% Et2O in pentane) to furnish furo-
spongolide (1, 29.4 mg, 60%). Some of the remaining
fractions containing 12 and partially hydrogenated product
were combined, concentrated under reduced pressure, and
the residue was dissolved in EtOAc–MeOH (3:2, 1 mL) and
rehydrogenated using 30.2 mg of 5% Pd(0) on BaSO4 for 30
min at r.t. The solution was filtered through Celite and silica
gel and concentrated to afford an additional 14.5 mg (29%)
of pure 1, thereby making the total yield 89%; colorless oil,
Rf = 0.23 (30% Et2O–pentane). IR (NaCl, film): 2929, 2857,
1781, 1749, 1638, 1501, 1446, 1384, 1168, 1130, 1064,
1025, 886, 874, 854, 780 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.34 (s, 1 H), 7.21 (s, 1 H), 6.28 (s, 1 H), 5.84 (s, 1 H),
5.16 (t, J = 6.8 Hz, 1 H), 5.11 (t, J = 6.8 Hz, 1 H), 4.73 (s, 1
H), 2.45 (t, J = 7.5 Hz, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 2.26
(q, J = 7.5 Hz, 2 H), 2.11–1.98 (m, J = 7.5 Hz, 6 H), 1.69
(quin, J = 7.5 Hz, 2 H), 1.60 (s, 6 H). 13C NMR (100 MHz,
CDCl3): d = 174.4, 170.7, 142.8, 139.0, 135.8, 133.6, 125.9,
125.1, 124.1, 115.6, 111.3, 73.3, 39.8, 39.1, 28.6, 28.1, 26.7,
25.5, 25.3, 16.3, 16.0. ESI-HRMS: m/z calcd for C21H28O3:
328.2050; found: 328.2038.
(23) Synthesis of Butenolide 12
A vial charged with PdCl2(PPh3)2 (18.0 mg, 0.024 mmol),
CuI (3.5 mg, 0.018 mmol), and 7a (50.0 mg, 0.291 mmol)
was placed on a vacuum pump for 30 min and then purged
with argon. Degassed 1,4-dioxane (0.5 mL) was added, and
the mixture was stirred for 30 min at r.t. To this mixture was
added (using a cannula) a solution of Hünig’s base (64 mg,
0.485 mmol) and alkyne 11 (58.8 mg, 0.243 mmol) in 1,4-
dioxane (0.8 mL, purged with Ar). The mixture was stirred
for 18 h at r.t. and then quenched with brine (2 mL). EtOAc
(5 mL) was added and the aqueous layer was separated and
extracted with EtOAc (2 × 10 mL). The combined organic
layers were dried over MgSO4, concentrated under reduced
pressure, and the residue was subjected to flash chromatog-
raphy on silica gel (15% Et2O in pentane) to give butenolide
12 as a yellow oil (51.6 mg, 66%); Rf = 0.23 (10% EtOAc–
hexanes). IR (NaCl, film): 2920, 2856, 2225, 1779, 1750,
1611, 1446, 1301, 1145, 1043, 1025, 881, 874, 855, 780 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34 (s, 1 H), 7.20 (s, 1 H),
6.27 (s, 1 H), 6.12 (s, 1 H), 5.35 (t, J = 5.8 Hz, 1 H), 5.17 (t,
J = 5.8 Hz, 1 H), 4.78 (s, 1 H), 3.13 (s, 2 H), 2.45 (t, J = 7.4
Hz, 2 H), 2.25 (q, J = 7.4 Hz, 2 H), 2.13 (q, J = 7.4 Hz, 2 H),
2.02 (t, J = 7.4 Hz, 2 H), 1.70 (s, 3 H), 1.60 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 173.8, 148.2, 142.8, 139.1,
135.5, 128.4, 127.5, 125.1, 124.4, 121.9, 111.3, 105.8, 73.4,
73.3, 39.4, 30.2, 28.6, 26.8, 25.2, 16.4, 16.3. ESI-HRMS:
m/z calcd for C21H24O3: 324.1742; found: 324.1725.
(27) Liu, Y.; Zhang, S.; Abreu, P. J. M. Nat. Prod. Rep. 2006, 23,
630.
Synlett 2011, No. 17, 2541–2544 © Thieme Stuttgart · New York

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