SCHEME 1. Synthesis of Gorgonian Lipid 4
2 mL) was added. Stirring was continued for 1 h, then Et2O (5
mL) was added. After separation of the organic layer, the aqueous
phase was washed with Et2O (3 × 5 mL) and the combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(hexanes-ethyl acetate, 3:1, v:v) to give 5f as a light orange oil
(71.0 mg, 88%): Rf 0.36 (hexanes/AcOEt, 1:1); FTIR (NaCl, film)
3491, 3040, 2837, 1751, 1600, 1490 cm-1; 1H NMR (CDCl3, 400
MHz) δ 3.58 (d, J ) 1.9 Hz, 2H), 3.80 (s, 3H), 4.76 (m, 2H),
6.77-6.84 (m, 3H), 6.96 (m, 1H), 7.22-7.27 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 31.8, 55.2, 70.2, 112.0, 114.7, 121.2, 129.7,
134.1, 138.9, 145.6, 159.8, 173.9. Anal. Calcd for C12H12O3: C,
70.57; H, 5.92. Found: C, 70.81; H, 6.19.
5-Methyl-3-bromo-2(5H)-furanone (13). To 95.5 mg of ynamine
12 (0.521 mmol, 1.4 equiv) in CH2Cl2 (2.5 mL) at 0 °C were added
successively BF3 ·Et2O (66.0 µL, 1.4 equiv), propylene oxide (26.1
µL, 0.372 mmol, 1.0 equiv), and after 30 min NBS (212 mg, 3.2
equiv). The resulting dark brown mixture was kept at 0 °C for 20
min, then warmed to rt for a further 20 min and diluted with CH2Cl2
(2.5 mL), then aq HCl (1M, 2.5 mL) was added and the resulting
mixture was stirred for 30 min. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The
combined organic layers were washed with brine (5 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The resulting orange oil was dissolved in DMF (1 mL), then LiCl
(78.5 mg, 1.86 mmol, 5.0 equiv) and Li2CO3 (28.0 mg, 0.372 mmol,
1.0 equiv) were added. The mixture was heated at 70 °C for 10
min, then cooled to rt, and partitioned between pentanes-Et2O (1:
1, 15 mL) and water (15 mL). The aqueous layer was extracted
with pentanes-Et2O (1:1, 3 × 10 mL) and the combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo.
Flash chromatography on silica gel (hexanes/AcOEt, 4:1, v:v)
afforded 13 (48.2 mg, 73%) as a yellow oil: Rf 0.42 (Et2O/hexanes,
yield. Subsequent lithium-bromine exchange and quenching
with 1-iodohexadecane afforded silyloxyfuran 15, which was
subjected to our oxyfunctionalization protocol22 without prior
chromatographic purification, to deliver lipid 4 in 84% yield
over two steps.
To conclude, a general and efficient one-pot protocol for
converting 3-bromo-2-silyloxyfurans into R-substituted buteno-
lides has been developed. Furthermore, the intermediate 3-sub-
stituted 2-silyloxyfurans can be exploited for installing an
additional butenolide substituent at the γ-position,23 as dem-
onstrated by a short and efficient synthesis of the anti-
inflammatory gorgonian lipid 4 (4 steps, 57% overall yield).
Efforts to apply this methodology to the synthesis of more
complex natural products are currently underway and will be
reported in due course.
1
2:1); FTIR (NaCl, film) 2984, 1767, 1608, 1451 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.49 (d, J ) 6.8 Hz, 3H), 5.09 (qd, J ) 6.8,
2.0 Hz, 1H), 7.51 (d, J ) 2.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 18.7, 79.2, 113.0, 153.8, 168.3. Spectral data are consistent
with those reported in the literature.20c
Experimental Section
5-Methyl-3-bromo-2-triisopropylsilyloxyfuran (14). To a solu-
tion of 45.9 mg of 13 (0.259 mmol) in CH2Cl2 (2 mL) at 0 °C
were added NEt3 (90.6 µL, 1.3 equiv) and TIPSOTf (47.0 µL, 1.3
equiv). After stirring for 30 min, aq 5% NaHCO3 (5 mL) was added,
and the mixture was extracted with CH2Cl2 (3 × 2 mL). The
combined extracts were dried over MgSO4, filtered, and concen-
trated in vacuo to give a brown oil. Flash chromatography on silica
gel (hexanes/NEt3, 99:1) provided 14 (80.4 mg, 93%) as a colorless
oil: Rf 0.85 (hexanes/NEt3, 200:1); FTIR (NaCl, film) 2946, 2869,
1643, 1464, 1385, 1258, 1127, 1057, 1002 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.10 (d, J ) 7.2 Hz, 18H), 1.25 (m, 3H), 2.15 (d, J )
1.2 Hz, 3H), 5.83 (q, J ) 1.2 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 12.3, 13.6, 17.5, 72.8, 109.1, 140.9, 151.6; HRMS (ESI)
exact mass calcd for C14H25O2BrSi [M + H]+ 333.0880, found
333.0895.
5-Hydroxy-5-methyl-3-(n-hexadecyl)-2(5H)-furanone (4). To
99.1 mg of 14 (0.297 mmol) in 3 mL of THF at -78 °C was added
n-BuLi (130 µL, 2.5 M in hexanes, 1.1 equiv) then the solution
was stirred for 2 h. After slowly warming to -10 °C, 1-iodohexa-
decane (186.7 µL, 2.0 equiv) was added and the mixture was stirred
for 2 h at -10 °C, then slowly warmed to rt. Water (5 mL) and
Et2O (8 mL) were added, the aqueous layer was separated and
extracted with Et2O (3 × 5 mL), and the combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The yellow
residue was dissolved in hexane (3 mL) and filtered through a plug
of NEt3-neutralized silica gel. The hexane was evaporated and the
resulting colorless oil was dissolved in 5 mL of anhydrous Et2O
and cooled to 5 °C. Dimethyldioxirane (8.1 mL, ca. 0.06–0.11 M
in acetone)24 was added and the mixture was warmed to rt over
General Procedure for the Preparation of r-Substituted
Butenolides: Synthesis of 3-(3-Methoxybenzyl)-2(5H)-fura-
none (5f). To 125.9 mg of 9 (0.394 mmol) in 4 mL of THF under
nitrogen at -78 °C was added n-BuLi (174 µL, 2.5 M in hexanes,
1.1 equiv). After stirring for 2 h then warming to -25 °C,
3-methoxybenzyl bromide (71.8 µL, 0.512 mmol, 1.3 equiv) was
added. The temperature was kept at -25 °C for 30 min, then at
-10 °C for 2 h. The mixture was warmed to rt and aq HCl (1 M,
(21) Movassaghi, M.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2456–
2457.
(22) For the oxyfunctionalization of 2-silyloxyfurans and related compounds,
see: (a) Boukouvalas, J.; Lachance, N. Synlett 1998, 31–32. (b) Boukouvalas,
J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem. 1998, 63, 228–229. (c)
Boukouvalas, J.; Cheng, Y.-X. Tetrahedron Lett. 1998, 39, 7025–7026. (d)
Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Diez, D.; Garc´ıa, N.; Escola,
M. A.; Basabe, P.; Conde, A.; Moro, R. F.; Urones, J. G. Synthesis 2005, 3301–
3310. (e) Boukouvalas, J.; Robichaud, J.; Maltais, F. Synlett 2006, 2480–2482.
(f) Boukouvalas, J.; Xiao, Y.; Cheng, Y.-X.; Loach, R. P. Synlett 2007, 3198–
3200.
(23) For some recent synthetic applications of vinylogous reactions of
2-silyloxyfurans with carbon electrophiles, see: (a) Martin, S. F. Acc. Chem. Res.
2002, 35, 895–904. (b) Hanessian, S.; Giroux, S.; Buffat, M. Org. Lett. 2005, 7,
3989–3992. (c) Vaz, B.; Alvarez, R.; Bru¨ckner, R.; de Lera, A. R. Org. Lett.
2005, 7, 545–548. (d) Rosso, G. B.; Pilli, R. A. Tetrahedron Lett. 2006, 47,
185–188. (e) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2006, 45, 7230–7233. (f) Robichaud, J.; Tremblay, F. Org. Lett. 2006,
8, 597–600. (g) Maulide, N.; Marko´, I. E. Org. Lett. 2006, 8, 3705–3707. (h)
Catino, A. J.; Nicols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc.
2006, 128, 5648–5649. (i) Boeckman, R. K., Jr.; Pero, J. E.; Boehmler, D. J.
J. Am. Chem. Soc. 2006, 128, 11032–11033. (j) Boukouvalas, J.; Beltra´n, P. P.;
Lachance, N.; Coˆte´, S.; Maltais, F.; Pouliot, M. Synlett 2007, 219–222. (k) Evans,
D. A.; Dunn, T. B.; Kvœrnø, L.; Beauchemin, A.; Raymer, B.; Olhava, E. J.;
Mulder, J. A.; Juhl, M.; Kagechika, K.; Favor, D. A. Angew. Chem., Int. Ed.
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