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DOI: 10.1055/s-0030-1260329
Synthesis of the Hypoxic Signaling Inhibitor Furospongolide
Publikationsverlauf
Publikationsdatum:
27. September 2011 (online)
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Abstract
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 β-bromobutenolide.
Key words
alkynes - butenolides - cross-coupling - furanoterpenoids - neotorreyol
- Supporting Information for this article is available online:
- Supporting Information
-
1a
Semenza GL. Drug Discovery Today 2007, 12: 853 -
1b
Semenza GL. Oncogene 2010, 29: 625 -
1c
Mooring SR.Wang BH. Sci. China Chem. 2011, 54: 24 -
1d
Wilson WR.Hay MP. Nat. Rev. Cancer 2011, 11: 393 -
2a
Pouysségur J.Dayan F.Mazure NM. Nature (London) 2006, 441: 437 -
2b
Cairns RA.Papandreou I.Sutphin PD.Denko NC. Proc. Natl. Acad. Sci. U.S.A. 2007, 104: 9445 -
2c
Sendoel A.Kohler I.Fellmann C.Lowe SE.Hengartner MO. Nature (London) 2010, 465: 577 -
2d
Horak P.Crawford AR.Vadysirisack DD.Nash ZM.DeYoung MP.Sgroi D.Ellisen LW. Proc. Natl. Acad. Sci. U.S.A. 2010, 107: 4675 -
3a
Denko NC. Nat. Rev. Cancer 2008, 8: 705 -
3b
Nagle DG.Zhou Y.-D. Phytochem. Rev. 2009, 8: 415 -
3c
Manolescu B.Oprea E.Busu C.Cercasov C. Biochimie 2009, 91: 1347 - 4
Liu Y.Liu R.Mao S.-C.Morgan JB.Jekabsons MB.Zhou Y.-D.Nagle DG. 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 - 6
Dai J.Liu Y.Zhou Y.-D.Nagle DG. J. Nat. Prod. 2007, 70: 1824 - Only a few other naturally occurring β-pentenylbutenolides are known:
-
7a
Bohlmann F.Grenz M. Chem. Ber. 1975, 108: 357 -
7b
Liu Y.Mansoor TA.Hong J.Lee C.-O.Sim CJ.Im KS.Kim ND.Jung JH. J. Nat. Prod. 2003, 66: 1451 -
7c
Wang N.Song J.Jang KH.Lee H.-S.Li X.Oh K.-B.Shin J. J. Nat. Prod. 2008, 71: 551 -
8a
Boukouvalas J.Pouliot M. Synlett 2005, 343 -
8b
Boukouvalas J.Wang J.-X.Marion O.Ndzi B.
J. Org. Chem. 2006, 71: 6670 -
8c
Boukouvalas J.Marion O. Synlett 2006, 1511 -
8d
Boukouvalas J.Beltrán PP.Lachance N.Côté S.Maltais F.Pouliot M. Synlett 2007, 219 -
8e
Boukouvalas J.Wang J.-X.Marion O. Tetrahedron Lett. 2007, 48: 7747 -
8f
Boukouvalas J.Loach RP. J. Org. Chem. 2008, 73: 8109 -
8g
Boukouvalas J.McCann LC. Tetrahedron Lett. 2010, 51: 4636 -
8h
Boukouvalas J.McCann LC. Tetrahedron Lett. 2011, 52: 1202 - Synthesis of β-homoallylbutenolides:
-
9a
Boukouvalas J.Robichaud J.Maltais F. Synlett 2006, 2480 -
9b
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 -
12a
Thomas AF. Chem. Commun. 1968, 1657 -
12b
Kondo K.Matsumoto M. Tetrahedron Lett. 1976, 17: 391 -
12c
Masaki Y.Hashimoto K.Sakuma K.Kaji K.
J. Chem. Soc., Perkin Trans. 1 1984, 1289 -
12d
Takabe K.Hashimoto H.Sugimoto H.Nomoto M.Yoda H. Tetrahedron: Asymmetry 2004, 15: 909 -
13a
Fouquet G.Schlosser M. Angew. Chem., Int. Ed. Engl. 1974, 13: 82 - See also:
-
13b
Bäckvall J.-E.Sellén M.Grant B. J. Am. Chem. Soc. 1990, 112: 6615 -
13c
Carpita A.Bonaccorsi F.Rossi R. Gazz. Chim. Ital. 1984, 114: 443 -
13d
Kolympadi M.Liapis M.Ragoussis V. Tetrahedron 2005, 61: 2003 -
14a
Dauben WG.Saugier RK.Fleischhauer I. J. Org. Chem. 1985, 50: 3767 -
14b
Marshall JA.Lebreton J.DeHoff BS.Jenson TM. J. Org. Chem. 1987, 52: 3883 -
15a
Tanis SP. Tetrahedron Lett. 1982, 23: 3115 -
15b
Snider BB.O’Hare SM. Synth. Commun. 2001, 31: 3753 - 17
Tamura M.Kochi J. Synthesis 1971, 303 - 18
Baker R.Ekanayake NJ.Simon A. J. Chem. Res., Synop. 1983, 74 - 20
Lee TW.Corey EJ. J. Am. Chem. Soc. 2001, 123: 1872 -
22a Bromide 7a (mp 77 ˚C) was prepared
by Vilsmeier bromination of β-tetronic acid (86%,
30 g scale) using the procedure of Jas:
Jas G. Synthesis 1991, 965 -
22b See also:
Boukouvalas J.Lachance N.Ouellet M.Trudeau M. Tetrahedron Lett. 1998, 39: 7665 - 24
Marsh BJ.Carbery DR. J. Org. Chem. 2009, 74: 3186 - 25
Nicolaou KC.Peng X.-S.Sun Y.-P.Polet D.Zou B.Lim CS.Chen DY.-K. J. Am. Chem. Soc. 2009, 131: 10587 - 27
Liu Y.Zhang S.Abreu PJM. Nat. Prod. Rep. 2006, 23: 630
References and Notes
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.
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); R
f
= 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): δ = 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): δ = 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.
Data for Acetylene
11
Colorless oil; R
f
= 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): δ = 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). ¹³C NMR
(100 MHz, CDCl3): δ = 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, 25.2, 16.3, 16.2. ESI-HRMS: m/z calcd
for C17H22O: 242.1673; found: 242.1671.
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%); R
f
= 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): δ = 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). ¹³C NMR
(100 MHz, CDCl3): δ = 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.
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, R
f
= 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): δ = 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): δ = 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.