General, regiodefined access to α-substituted butenolides through metal-halogen exchange of 3-bromo-2-silyloxyfurans. Efficient synthesis of an anti-inflammatory Gorgonian lipid

Article abstract of DOI:10.1021/jo8015924

(Chemical Equation Presented) A variety of α-substituted butenolides were efficiently prepared from 3-bromo-2-triisopropylsilyloxyfuran via lithium-bromine exchange and in situ quench with carbon or heteroatom electrophiles. The inherent flexibility of this methodology is illustrated by a short and efficient synthesis of an anti-inflammatory marine natural product.

Full text of DOI:10.1021/jo8015924

General, Regiodefined Access to r-Substituted
Butenolides through Metal-Halogen Exchange of
3-Bromo-2-silyloxyfurans. Efficient Synthesis of
an Anti-inflammatory Gorgonian Lipid
John Boukouvalas* and Richard P. Loach
De´partement de Chimie, UniVersite´ LaVal, Quebec City,
Quebec G1K 7P4, Canada
john.boukouValas@chm.ulaVal.ca
ReceiVed July 18, 2008
FIGURE 1. Naturally occurring R-substituted butenolides.
lides are valuable intermediates in the synthesis of other
important targets,5 including a host of antimicrobial6 and
herbicidal lactones.7 Consequently, a great amount of effort has
been directed at their construction8 from both acyclic9 and
oxacyclic precursors.10 Perhaps the most appealing methods are
those relying on homologation of a suitable synthon for
carbanion A,8,10e such as the lithiated Diels-Alder adduct 611
and lithiofuryl diamidophosphate 712 (Figure 2). However, these
methods have some serious limitations. For instance, the
requisite retro-Diels-Alder reaction in the synthesis of 5 from
6 is reportedly achievable only through flash vacuum pyrolysis
at 500 °C.11 Also, while lithiofuran 7 reacts with good
electrophiles (e.g., MeI and BnBr), alkylation fails with the less
reactive ethyl iodide.12b Hence, a direct and practical means
for joining the butenolide ring to a carbon chain is lacking,
thereby hampering the use of this linchpin approach (cf. Af5)
in natural product synthesis.
A variety of R-substituted butenolides were efficiently
prepared from 3-bromo-2-triisopropylsilyloxyfuran via
lithium-bromine exchange and in situ quench with carbon
or heteroatom electrophiles. The inherent flexibility of this
methodology is illustrated by a short and efficient synthesis
of an anti-inflammatory marine natural product.
The R-alkylbutenolide substructure is found in a variety of
pharmacologically active natural products, as represented by the
antileukemic/neuroprotective labdane pinusolide (1),1 the novel
antimalarial clerodane gomphostinin (2),2 a potent antitumor
acetogenin (annomolon A, 3),3 and the anti-inflammatory
gorgonian lipid 44 (Figure 1). In addition, R-substituted buteno-
(6) (a) Taber, D. F.; Nakajima, K.; Xu, M.; Rheingold, A. L. J. Org. Chem.
2002, 67, 4501–4504. (b) Shiina, J.; Obata, R.; Tomoda, H.; Nishiyama, S. Eur.
J. Org. Chem. 2006, 2362–2370. (c) Haval, K. P.; Argade, N. P. Synthesis 2007,
2198–2202.
(7) (a) Barbosa, L. C. A.; Demuner, A. J.; de Alvarenga, E. S.; Oliveira, A.;
King-Diaz, B.; Lotina-Hennsen, B. Pest Manage. Sci. 2006, 62, 214–222. (b)
Barbosa, L. C. A.; Rocha, M. E.; Teixeira, R. R.; Maltha, C. R. A.; Forlani, G.
J. Agric. Food Chem. 2007, 55, 8562–8569. (c) Teixeira, R. R.; Barbosa, L. C. A.;
Forlani, G.; Pilo´-Veloso, D.; Walkimar de Mesquita Carneiro, J. J. Agric. Food
Chem. 2008, 56, 2321–2329.
(8) Review: Knight, D. W. Contemp. Org. Synth. 1994, 1, 287–315.
(9) (a) Trost, B. M.; Mu¨ller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888–1899. (b) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem.
1997, 62, 367–371. (c) Gabriele, B.; Salerno, G.; Casta, M.; Chiusoli, G. P. I.
Tetrahedron Lett. 1999, 40, 989–990. (d) Liao, B.; Negishi, E. Heterocycles
2000, 52, 1241–1249. (e) Yoneda, E.; Zhang, S.-V.; Zhou, D.-Y.; Onitsuka, K.;
Takahashi, S. J. Org. Chem. 2003, 68, 8571–8576.
(1) (a) Shults, E. E.; Velder, J.; Schmalz, H.-G.; Chernov, S. V.; Rubalava,
T. V.; Gatilov, Y. V.; Henze, G.; Tolstikov, G. A.; Prokop, A. Bioorg. Med.
Chem. Lett. 2006, 16, 4228–4232, and references cited therein. (b) Koo, K. A.;
Lee, M. K.; Kim, S. H.; Jeong, E. J.; Oh, T. H.; Kim, Y. C. Br. J. Pharmacol.
2007, 150, 65–71.
(2) Kaushik, M. P.; Thavaselvam, D.; Nivsarkar, M.; Acharya, B. N.;
Prasanna, S.; Sekhar, K. PCT Int. Appl. (2007) WO 2007039915 (CA: 2007,
146, 408201).
(3) Son, J. K.; Kim, D. H.; Woo, M. H. J. Nat. Prod. 2003, 66, 1369–1372.
(4) Kikuchi, H.; Tsukitani, Y.; Nakanishi, H.; Shimizu, I.; Saitoh, S.; Iguchi,
K.; Yamada, Y. Chem. Pharm. Bull. 1983, 31, 1172–1176.
(5) Examples: (a) Boukouvalas, J.; Maltais, F.; Lachance, N. Tetrahedron
Lett. 1994, 48, 7897–7900. (b) De la Cruz, R. A.; Talama´s, F. X.; Va´zquez, A.;
Muchowski, J. M. Can. J. Chem. 1997, 75, 641–645. (c) Bella, M.; Piancatelli,
G.; Pigro, M. C. Tetrahedron 1999, 55, 12387–12398. (d) Monovich, L. G.; Le
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(e) Goeller, F.; Heinemann, C.; Demuth, M. Synthesis 2001, 1114–1116. (f)
Reichelt, A.; Bur, S. K.; Martin, S. F. Tetrahedron 2002, 58, 6323–6328. (g)
Boukouvalas, J.; Pouliot, M. Synlett 2005, 343–345. (h) Huang, Q.; Rawal, V. H.
Org. Lett. 2006, 8, 543–545. (i) Nagase, R.; Matsumoto, N.; Hosomi, K.; Higashi,
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7747–7750.
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2002, 58, 9117–9129, and references cited therein. (e) Hagiwara, H.; Takeuchi,
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10.1021/jo8015924 CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8109–8112 8109

TABLE 2. One-Pot Synthesis of r-Substituted Butenolidesa
entry
electrophile (EX)
equiv
E
% yield of 5b
1
2
3
4
5
6
7
8
n-BuI
MeI
1.3
1.3
1.3
1.5
1.3
1.3
1.5
1.2
n-Bu
Me
CH2dCHCH2
CH2dCH(CH2)2
PhCH2
m-MeO-PhCH2
I
Cl
85 (5a)
83 (5b)
84 (5c)
41 (5d)
85 (5e)
88 (5f)
80 (5g)
87 (5h)
37c (5i)
86 (5j)
72 (5k)
70 (5l)
CH2dCHCH2Br
CH2dCHCH2CH2I
PhCH2Br
m-MeO-PhCH2Br
ICH2CH2I
C2Cl6
(PhSO2)2NF (NFSi) 1.05
EtSSEt
PhSeSePh
TMSCl
FIGURE 2. Selected synthons for carbanion A.
TABLE 1. Butylation of 3-Bromo-2-triisopropylsilyloxyfurana
9
F
10
11
12
1.3
1.1
1.3
EtS
PhSe
TMS
entry
n-BuX
additive
10 (%)b
11 (%)b
a All reactions were run with 1.1 equiv of n-BuLi. b Yields refer to
chromatographically purified products. c The low yield of 5i is
attributed, in part, to its high volatility.
1
2
3
4
5
n-BuI
n-BuI
n-BuI
n-BuBr
91
81
86
9
HMPA
DMPU
19
14
60
>98
40
<2c
stituted butenolides. Thus, the initially formed 3-substituted-2-
silyloxyfurans were not isolated but hydrolyzed in situ with aq
HCl to the corresponding lactones (Table 2). Yields with carbon
electrophiles are generally high (entries 1-6) except for the
modest 41% with homoallyl iodide (entry 4), presumably due
to competing ꢀ-elimination.
Heteroatom electrophiles are equally well-behaved, allowing
a variety of R-functionalized butenolides to be efficiently
prepared from 9 in a single operation (entries 7-12). An
exception within this group is the volatile fluorobutenolide 5i,18
whose low yield is attributed to inadvertent loss during solvent
removal (37%, entry 9). Of particular interest is the high yield
of the crystalline iodobutenolide 5g (80%, entry 7), a potentially
useful cross-coupling reagent that is notoriously difficult to
prepare by existing methods.9d,10d
To further illustrate the usefulness of this chemistry, lipid 4
was chosen as a target. This compound typifies a small family
of anti-inflammatory fatty acid γ-hydroxybutenolides isolated
by Yamada and co-workers from the Japanese gorgonian
Euplexaura flaVa (Nutting).4 At the same time, 4 can be regarded
as a viable model for the right-hand portion of the antitumor
acetogenin annomolon A (3, Figure 1).3 Notwithstanding a
recent surge of interest in the construction of R-substituted
γ-hydroxybutenolides,19 there have been no reported syntheses
of 3 or 4 to date.
a All reactions were run using 1.1 equiv of n-BuLi; in entries 1-4,
1.3 equiv of n-BuX was used, and 1.0 equiv of the indicated additive in
entries 2 and 3. 10/11 ratios were determined by H NMR; the starting
material (9) was completely consumed in all cases. c See text.
b
1
We have recently reported a new synthon for A, namely
3-lithio-2-triisopropylsilyloxyfuran (8, Figure 2), which is
rapidly quenched with aldehydes at -78 °C to provide 3-(1-
hydroxyalkyl)-2-silyloxyfurans in excellent yields.13 Encouraged
by the high efficiency of this process, when compared to similar
reactions of 7,12a we decided to explore the behavior of 8 toward
less reactive electrophiles with a view to establishing a general
route to R-substituted butenolides. Reported herein is the
successful accomplishment of this goal along with an efficient
four-step synthesis of the anti-inflammatory lipid 4 from
commercially available starting materials.
Our work began with an investigation of the butylation of 8,
generated in situ by metal-halogen exchange of the easily
prepared 3-bromo-2-triisopropylsilyloxyfuran 914 (Table 1).
Gratifyingly, alkylation proceeded smoothly in THF by using
a small excess of n-BuI (1.3 equiv), to give 3-n-butyl-2-
silyloxyfuran 10 in high yield (entry 1). Although additives such
as HMPA or DMPU are known to be beneficial to the alkylation
of the parent 3-lithiofuran,15 their use had a slightly negative
impact on the yield of 10 (entries 2 and 3).16 Replacement of
n-butyl iodide with the less reactive n-BuBr, which is also
produced by Li-Br exchange,17 led to a substantially reduced
yield of 10 (entry 4). In the absence of added n-BuBr, however,
no alkylation product was detected (entry 5).
Our route to 4 commenced with the conversion of com-
mercially available ynamine 12 and propylene oxide to bro-
mobutenolide 1320 using the method of Jacobsen21 (Scheme 1).
Silylation of 13 provided the key building block 14 in excellent
The scope and preparative value of this reaction were then
explored by application to the synthesis of a range of R-sub-
(18) For alternative syntheses of 5i see: (a) Kv´ıe`ala, J.; Plocar, J.; Vlasa´kova´,
R.; Paleta, O.; Pelter, A. Synlett 1997, 986–988. (b) Paleta, O.; Volkov, A.;
Hetflejsˇ, J. J. Fluorine Chem. 2000, 102, 147–157. (c) Motherwell, W. B.;
Greaney, M. F.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 2002, 2809–
2815.
(19) (a) Aquino, M.; Bruno, I.; Riccio, R.; Gomez-Paloma, L. Org. Lett.
2006, 8, 4831–4834. (b) Patil, S. N.; Liu, F. J. Org. Chem. 2007, 72, 6305–
6308. (c) Li, C.; Xue, J.; Xu, B.; Xie, Z.; Li, Y. Chem. Lett. 2007, 36, 1058–
1059. (d) Margaros, I.; Vassilikogiannakis, G. J. Org. Chem. 2008, 73, 2021–
2023. (e) Patil, S. N.; Liu, F. J. Org. Chem. 2008, 73, 4476–4483.
(20) Previously, 13 has been prepared from R-angelica lactone by isomer-
ization and ensuing bromination-dehydrobromination in 20-52% yield over 2
steps: (a) Sorg, A.; Blank, F.; Bru¨ckner, R. Synlett 2005, 1286–1290. (b)
Mathews, C. J.; Taylor, J.; Tyte, M. J.; Worthington, P. A. Synlett 2005, 538–
540. See also: (c) Ochoa de Echagu¨en, C.; Ortuño, R. M. Tetrahedron 1994,
50, 12457–12462.
(13) (a) Boukouvalas, J.; Marion, O. Synlett 2006, 1511–1514. (b) Boukou-
valas, J.; Wang, J.-X.; Marion, O.; Ndzi, B. J. Org. Chem. 2006, 71, 6670–
6673.
(14) Prepared in two steps from the parent butenolide (82% overall yield);
see the Supporting Information of ref 13b for experimental details.
(15) Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron 1990, 46,
1199–1210.
(16) For a similar observation on the use of DMPU in a related reaction,
see: Xin, Z.; Zheng, G. Z.; Stewart, A. O. Synlett 2000, 1324–1326.
(17) The precise mechanism of metal-halogen exchange reactions has yet
to be settled; for recent studies see: ( a) Jedlicka, B.; Crabtree, R. H.; Siegbahn,
P. E. M. Organometallics 1997, 16, 6021–6023. (b) Hoffmann, R. W.; Bro¨nstrup,
M.; Mu¨ller, M, Org. Lett. 2003, 5, 313-316, and references cited therein.
8110 J. Org. Chem. Vol. 73, No. 20, 2008

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.;
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J. Org. Chem. Vol. 73, No. 20, 2008 8111

1 h. Evaporation of the volatiles gave a white waxy solid, which
was dissolved in 5 mL of Et2O. Water (3 drops) and Amberlyst-15
(50 mg) were added, the mixture was stirred for 90 min, and then
water (5 mL) was added and the ether layer was separated. The
aqueous layer was extracted with Et2O (2 × 5 mL), and the
combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuo. Flash chromatography of the resulting white
solid (SiO2, hexanes/AcOEt, 40:1 to 20:1 v:v) furnished lipid 4
(84.9 mg, 84%) as colorless crystals: mp 68-69 °C (lit.4 mp 67
°C); Rf 0.28 (hexanes/AcOEt, 3:1); FTIR (NaCl, film) 3430 (br),
3089, 2917, 2850, 1756, 1725, 1657, 1471 cm-1; 1H NMR (CDCl3,
400 MHz) δ 0.88 (t, J ) 6.8 Hz, 3H), 1.24-1.37 (m, 26H), 1.54
(m, 2H), 1.69 (s, 3H), 2.25 (td, J ) 8.0, 1.2 Hz, 2H), 6.80 (t, J )
1.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 22.7, 24.8, 24.9,
27.2, 29.2, 29.3, 29.4, 29.5, 29.6, 29.65 (2C), 29.7 (4C), 31.9, 104.2,
136.4, 146.5, 171.3. Anal. Calcd for C21H38O3: C, 74.51; H, 11.31.
Found: C, 74.45; H, 11.56. The NMR data of 4 are in excellent
agreement with those of the natural product.4
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council (NSERC) of Canada for
financial support. We also thank HydroQue´bec for a postgradu-
ate scholarship to R.P.L.
Supporting Information Available: Experimental details,
characterization data, and copies of NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
2377. (b) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91–100.
JO8015924
8112 J. Org. Chem. Vol. 73, No. 20, 2008