Synthesis of the enediol isofurans, endogenous oxidation products of arachidonic acid

Article abstract of DOI:10.1021/jo051889a

Isofurans (IsoF's) are a new class of human arachidonic acid oxidation products. They are produced in vivo by a free radical mechanism, independent of the cyclooxygenase enzymes. These new compounds are available from natural sources only in microgram qua

Full text of DOI:10.1021/jo051889a

Synthesis of the Enediol Isofurans, Endogenous Oxidation Products
of Arachidonic Acid
Douglass F. Taber* and Zhe Zhang
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed September 8, 2005
Isofurans (IsoF’s) are a new class of human arachidonic acid oxidation products. They are produced in
vivo by a free radical mechanism, independent of the cyclooxygenase enzymes. These new compounds
are available from natural sources only in microgram quantities as mixtures. The enantioselective
preparation of two enediol isofurans, 15-epi-ent-SC-∆13-8-IsoF and ent-SC-∆13-8-IsoF, is described. A
key transformation in the synthesis is the selective cascade cyclization of a diol epoxide benzenesulfonate
to give the substituted tetrahydrofuran skeleton of the isofurans. This synthesis will make these metabolites
available for physiological evaluation.
Introduction
physiological role of the IsoF’s. We have previously reported5
a stereodivergent synthesis of the SC-∆13-9-IsoFs (1a and 1b).
We now report a general route to the other class of isofurans,
the enediol isofurans, represented by 15-epi-ent-SC-∆13-8-IsoF
(2a) and ent-SC-∆13-8-IsoF (2b).
Isofurans (IsoF’s) are a new class of human arachidonic acid
oxidation products.1,2 They are produced in vivo by a free radical
mechanism, independent of the cyclooxygenase enzymes.
Because these compounds are tetrahydrofuran derivatives that
are related biosynthetically to the isoprostanes, they were termed
isofurans.3 When oxygen tension is increased in vitro or in vivo
isofuran formation increases more rapidly than does isoprostane
formation.
Results and Discussion
Synthetic Approach. Our interest was to develop a flexible
route for the construction of the enediol isofurans. We sought
an advanced intermediate from which each of the enantiomeri-
cally pure diastereomers could be prepared. One such advanced
intermediate would be the substituted tetrahydrofuran 3 (Scheme
1).
We envisioned that 3 could be prepared by cascade cycliza-
tion6 of the diol epoxide 4. Although there are four different
modes of epoxide opening available to the diol 4, it seemed
likely that exo cyclization would dominate over endo cyclization
and that five-membered-ring formation would be faster than
Even though they are nonenzymatic oxidation products, the
isoprostanes have been found to have significant physiological
activity.4 It is therefore important to also investigate the
(3) For isofuran nomenclature, see: Taber, D. F.; Morrow, J. D.; Roberts,
L. J. Prostaglandins Other Lipid Mediators 2004, 73, 47.
(4) For leading references to the physiological activity of the isoprostanes,
see: Fessel, J. P.; Hulette C.; Powell S.; Roberts, L. J., II; Zhang, J. J.
Neurochem. 2003, 85, 645. Nothing is yet known about the physiological
activity of the isofurans.
(5) Taber, D. F.; Pan, Y.; Zhao, X. J. Org. Chem. 2004, 69, 7234.
(6) (a) Taber, D. F.; Bhamidipati, R. S.; Thomas, M. L. J. Org. Chem.
1994, 59, 3442. (b) Sivakumar, M.; Borhan, B. Tetrahedron Lett. 2003,
44, 5547.
(1) Fessell, J. P.; Porter, N. A.; Moore, K. P.; Sheller, J. R.; Roberts, L.
J., II Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 16713.
(2) An IsoF-type compound has been reported as a product from
enzymatic oxidation of arachidonic acid: (a) Pace-Asciak, C. Biochemistry
1971, 10, 3664. (b) Bild, G. S.; Bhat, S. G.; Ramadoss, C. S.; Axelrod, B.;
Sweeley, C. C. Biochem. Biophys. Res. Commun. 1978, 81, 486. Neither
the relative nor the absolute configuration of this product was assigned.
10.1021/jo051889a CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/31/2005
926
J. Org. Chem. 2006, 71, 926-933

Synthesis of the Enediol Isofurans
SCHEME 1
SCHEME 3
SCHEME 2
pictured) was about 10:1, and the SN2′ byproduct could be easily
removed by flash chromatography. Coupling of the chloride 7
with the THP protected propargyl alcohol led to the diyne 8.
Deprotection9 followed by the reduction of the diyne 8 with
use of LAH in THF10 at reflux yields the diene 9.
Preparation of the Diol Epoxide 4 and Its Cyclization. The
diene 9 (Scheme 3) was carried on to the epoxy alcohol 10 by
the Sharpless asymmetric epoxidation.11 The derived benzene-
sulfonate 11 was subjected to the Sharpless asymmetric dihy-
droxylation12 with use of AD-mix-R to afford the desired diol
epoxide 4.
With 4 in hand, we were ready to attempt the key cyclization.6
We tried the reaction with both potassium tert-butoxide in THF13
and potassium carbonate in methanol.14 The reaction in methanol
was cleaner, but the timing was critical. The reaction was
complete after 4 h at room temperature. A shorter time gave
incomplete conversion, while longer time gave partial decom-
position of the product.
Neither the Sharpless asymmetric epoxidation nor the dihy-
droxylation proceeds with perfect enantiocontrol. We therefore
expected that 4 would be contaminated with minor amounts of
other diastereomers. We were pleased to observe that the
epoxide 3 was easily purified by flash chromatography.
Construction of the Upper Side Chain. To complete the
preparation (Scheme 4) of the upper side chain, it was necessary
to convert the epoxide 3 to the protected aldehyde 14. Since
the epoxide of 3 was already primed for SN2 opening, simple
treatment with the sulfonium ylide15 afforded the diol 12.
Protection followed by gentle oxidative cleavage16 led to the
sensitive aldehyde 14. Horner-Emmons17 condensation then
gave the enone 15.
four-membered-ring formation. Ring closure of the intermediate
alkoxide would then lead to the epoxide 3. As the diol epoxide
4 would be prepared by the Sharpless asymmetric epoxidation
and dihydroxylation reactions, the relative and absolute con-
figuration of 3 could be easily varied by using the opposite
enantiomers of the catalysts. We therefore expect that the
synthetic approach outlined here will allow the preparation of
any of the enantiomerically pure diastereomers of the different
regioisomers of the enediol isofurans.
Preparation of the Diene Alcohol 9. We projected that the
diol epoxide 4 could be prepared (Scheme 2) from the diene 9,
which would be available by deprotection and reduction of the
diyne 8. We envisioned a linchpin construction7 of 8, by
sequential Cu-mediated coupling of the commercially available
trans-1,4-dichloro-2-butene with 6, then with THP-protected
propargyl alcohol.
Starting with 5-hexyne-1-ol 5, the free alcohol was protected
first with benzyl bromide. The resulting benzyl ether 6 was
treated with CH3MgCl to form the corresponding Grignard
reagent and then reacted with trans-1,4-dichloro-2-butene to
yield the mono-alkylation product 7.7,8 Only a trace amount (less
than 1%) of the doubly alkylated product was observed. After
optimization, the ratio between SN2 and SN2′ product (not
(9) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772.
(10) Grant, B.; Djerassi, C. J. Org. Chem. 1974, 39, 968.
(11) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(13) Ho, D. K.; McKenzie, A. T.; Byrn, S. R.; Cassady, J. M. J. Org.
Chem. 1987, 52, 342.
(7) For the development of this linchpin approach to the assembly of
oxidized fatty acid metabolites, see: Taber, D. F.; Zhang, Z. J. Org. Chem.
2005, 70, 8093.
(8) (a) Gaudin, J. M.; Morel, C. Tetrahedron Lett. 1990, 31, 5749. (b)
Gaoni, Y.; Leznoff. C. C.; Sondheimer, F. J. Am. Chem. Soc. 1968, 90,
4940.
(14) Burke, S. D.; Jiang, L. Org. Lett. 2001, 2, 1953.
(15) (a) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Gall,
T. L.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449. (b) Bode,
J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410.
(16) Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Goffic, F. L. Synthesis
1989, 64.
J. Org. Chem, Vol. 71, No. 3, 2006 927

Taber and Zhang
SCHEME 4
SCHEME 6
Diastereoselective Reduction of Enone 15. Continuing with
the synthesis (Scheme 6), the next step was the reduction of
the enone 15. We were pleased to observe that the mixture of
diastereomeric alcohols 20 and 21 from NaBH4 and CeCl3‚7H2O
reduction19 was easily separable by TLC. Excellent diastereo-
control in favor of 20 or 21 could be achieved by using the
appropriate enantiomer of DIP-Cl in the reduction.20
SCHEME 5
Construction of the Lower Chain and Synthesis of the
Isofurans. With each of the alcohols 20 and 21 in hand, the
next step (Scheme 7) was silyl protection, followed by partial
hydrogenation with P-2 Ni catalyst21 to afford the dienes 24
and 25. We found that the P-2 Ni catalyst did not require
protection from air. The resulting catalyst is efficient for the
partial hydrogenation for the alkynes. Even after stirring under
an H2 atmosphere for 24 h, we did not observe even trace
amounts of over-hydrogenation products. Debenzylation of diene
24 and 25 with lithium and naphthalene22 affords the desired
alcohols 26 and 27, respectively.
The final steps in the synthesis (Scheme 8) were the oxidation
of the primary alcohol of 26 and 27 to the corresponding acids,
and deprotection to yield the final isofurans. While PDC in wet
DMF served to convert the alcohol 26 to the acid 29, this
protocol worked poorly with the alcohol 27. Happily, a two-
step protocol of Dess-Martin oxidation followed by the NaClO2
oxidation24 delivered the desired acid 29 in good yield.
Desilylation with TBAF then afforded the desired epi-ent-SC-
∆13-8-IsoF (2a) and ent-SC-∆13-8- IsoF (2b).
Conclusion
We have established what we expect will be a general route
to the enediol isofurans. The key steps include the cascade
cyclization of the diol 4 to the epoxide 3 and the diastereo-
selective DIP-Cl reduction of enone 15. This approach will make
Inversion of the Second Alcohols. To ensure stereodiver-
gence, it was necessary (Scheme 5) to invert the alcohols at
C-9 and C-12. The inversion to prepare 16 was a particularly
delicate transformation, as 3 was prone to further cyclization
by intramolecular addition of the secondary alcohol to the
epoxide. Nevertheless, the secondary alcohols at both C-9 and
C-12 participated efficiently in Mitsunobu inversion18 to give,
after methanolysis, the inverted alcohols 16 and 19.
(19) Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(20) (a) Beardley, D. A.; Fisher, G. B.; Goralski, C. T.; Nicholson, W.
L.; Singaram, B. Tetrahedron Lett. 1994, 35, 1151. (b) Ramachandran, P.
V.; Gong, B.; Brown, H. C. Tetrahedron Lett. 1994, 35, 2141.
(21) (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226. (b)
Taber, D. F.; Hoerrner, R. S. J. Org. Chem. 1992, 57, 441. (c) Magatti, C.
V.; Kaminski, J. J.; Rothberg, I. J. Org. Chem. 1991, 56, 3102.
(22) Liu, H. J.; Yip, J.; Shia, K. S. Tetrahedron Lett. 1997, 38, 2252.
(23) (a) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1978, 5, 399. (b)
Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765.
(24) Nicolaou, K. C.; Sasmal, P. K.; Xu, H.; Namoto, K.; Ritzen, A.
Angew. Chem., Int. Ed. 2003, 42, 4225.
(17) (a) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem. Ber.
1958, 91, 61. (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem.
Soc. 1961, 83, 1733.
(18) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge, J.
A. Tetrahedron Lett. 1991, 32, 3017.
928 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of the Enediol Isofurans
SCHEME 7
N2. After addition, the reaction mixture was stirred at 50 to 60 °C
for 2 h and then cannula transferred to a solution of trans-1,4-
dichloro-2-butene (6.65 g, 53.3 mmol) and CuCl (264 mg, 2.66
mmol) in THF (20 mL) at 50 to 60 °C under N2. The resulting
mixture was heated to reflux for 4 h. After being cooled to room
temperature, the reaction mixture was partitioned between saturated
aqueous NH4Cl and ether. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
give chlorobenzyl ether 7 as a colorless oil (4.78 g, 17.3 mmol,
1
65% yield): TLC Rf(MTBE/petroleum ether ) 1:30) ) 0.45; H
NMR δ 1.59-1.72 (m, 4H), 2.19-2.22 (m, 2H), 2.94 (br s, 2H),
3.49 (t, J ) 5.4 Hz, 2H), 4.05 (d, J ) 7.5 Hz, 2H), 4.49 (s, 2H),
5.77-5.88 (m, 2H), 7.33 (br s, 5H); 13C NMR δ u 138.5, 82.7,
76.2, 72.8, 69.8, 44.6, 28.9, 25.6, 21.6, 18.5, d 130.2, 128.3, 127.6,
127.5, 127.1; IR (cm-1) 2940, 1717, 1453; MS m/z (%) 275 (15),
167 (100), 149 (45); HRMS calcd for C17H20OCl (M) 275.1204,
obsd 275.1203.
Diyne 8. To a solution of tetrahydro-2-(2-propynyloxyl)-2H-
pyran (7.3 g, 52.1 mmol) in THF (30 mL) was added a solution of
CH3MgCl (2.0 M solution in THF, 14.3 mL, 28.6 mmol) at 50 to
60 °C under N2. After addition, the reaction mixture was stirred at
50 to 60 °C for 3 h and then cannula transferred to a solution of
chlorobenzyl ether 7 (7.2 g, 26.0 mmol) and CuCl (258 mg, 2.6
mmol) in THF (30 mL) at 50 to 60 °C under N2. The resulting
mixture was heated to reflux for 3 h. After being cooled to room
temperature, the reaction mixture was partitioned between saturated
aqueous NH4Cl and ether. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
give diyne 8 as a colorless oil (8.50 g, 22.4 mmol, 86% yield):
TLC Rf(MTBE/petroleum ether ) 1:10) ) 0.35; 1H NMR δ 1.56-
1.72 (m, 10H), 2.17-2.22 (m, 2H), 2.89 (br s, 2H), 2.97 (br s,
2H), 3.47 (t, J ) 6.4 Hz, 2H), 3.50-3.53 (m, 1H), 3.79-3.85 (m,
1H), 4.20 (dt, J ) 17.4, 2.1 Hz, 1H), 4.30 (dt, J ) 17.4, 2.1 Hz,
1H), 4.48 (s, 2H), 4.79 (t, J ) 3.4 Hz, 1H), 5.65 (br s, 2H), 7.30
(br s, 5H); 13C NMR δ u 138.6, 83.5, 82.1, 77.7, 77.1, 72.8, 69.9,
62.0, 54.6, 30.2, 28.9, 25.7, 25.3, 21.8, 21.7, 19.1, 18.6, d 128.3,
127.6, 127.5, 126.8, 125.2, 96.7; IR (cm-1) 2942, 1453, 1023; MS
m/z (%) 380 (10), 167 (55); HRMS calcd for C25H32O3Na (M +
Na) 403.2249, obsd 403.2248.
SCHEME 8
Diene 9. To a solution of diyne 8 (9.0 g, 23.7 mmol) in EtOH
(180 mL) was added PPTS (595 mg, 2.37 mmol) at room
temperature. After addition, the reaction mixture was stirred at 55
°C for 6 h, then concentrated. The residue was chromatographed
to give the free alcohol as a colorless oil (6.45 g, 21.8 mmol, 92%
yield): TLC Rf(MTBE/petroleum ether ) 1:4) ) 0.25; 1H NMR δ
1.55-1.73 (m, 4H), 2.18-2.21 (m, 2H), 2.89 (br s, 2H), 2.94-
2.96 (m, 2H), 3.47 (t, J ) 6.4 Hz, 2H), 4.24 (br s, 2H), 4.49 (s,
2H), 5.66-5.67 (m, 2H), 7.33 (br s, 5H); 13C NMR δ u 138.5,
82.5, 82.2, 80.2, 77.1, 72.9, 69.9, 51.3, 28.9, 25.6, 21.7, 21.6, 18.6,
d 128.4, 127.6, 127.5, 126.9, 125.2; IR (cm-1) 3300, 2862, 1104;
MS m/z (%) 319 (M + Na, 100), 199 (12), 128 (20); HRMS calcd
for C20H24O2Na (M + Na) 319.1674, obsd 319.1669.
To a suspension of LiAlH4 (2.59 g, 68.1 mmol) in THF (220
mL) was added a solution of the alcohol (10.1 g, 34.1 mmol) in
THF (20 mL) at 0 °C under N2. After addition, the reaction mixture
was heated to reflux for 24 h. The reaction mixture was cooled in
an ice bath, and cold water (2.6 mL) was added dropwise over 5
min. After 30 min of vigorous stirring, aq NaOH (15% w/v, 2.6
mL) was added, and the mixture was stirred for an additional 30
min. Then water (7.8 mL) was added, and the mixture was stirred
for another 30 min. The solid was filtered and then rinsed with
diethyl ether. The combined filtrate was concentrated, and the
resulting residue was chromatographed to give diene 9 as a colorless
oil (6.10 g, 20.5 mmol, 60% yield): TLC Rf(MTBE/petroleum ether
each of the enediol isofurans, previously known only in
microgram quantities as mixtures, available in sufficient quantity
to assess their individual physiological activity.
Experimental Section
Chlorobenzyl Ether 7. To a solution of benzyl ether 625 (5.0 g,
26.6 mmol) in THF (20 mL) was added a solution of CH3MgCl
(2.0 M solution in THF, 17.3 mL, 34.6 mmol) at 50 to 60 °C under
1
) 1:2) ) 0.25; H NMR δ 1.55-1.72 (m, 5H), 2.18-2.20 (m,
2H), 2.75 (br s, 2H), 2.86-2.88 (m, 2H), 3.47 (t, J ) 6.4 Hz, 2H),
4.06 (br s, 2H), 4.48 (s, 2H), 5.45-5.68 (m, 4H), 7.33 (br s, 5H);
13C NMR δ u 138.5, 81.9, 77.5, 72.8, 69.9, 63.6, 34.8, 28.9, 25.7,
21.9, 18.6, d 130.8, 129.9, 129.0, 128.3, 127.6, 127.5, 126.1; IR
(25) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima,
K. J. Org. Chem. 2003, 68, 6627.
J. Org. Chem, Vol. 71, No. 3, 2006 929

Taber and Zhang
(cm-1) 3300, 2861, 1101; MS m/z (%) 281 (M - H, 100), 263
(10); HRMS calcd for C20H26O2Na (M + Na) 321.1831, obsd
321.1824.
73.6, 71.1 55.7, 55.1; IR (cm-1) 3348, 3266, 2932; MS m/z (%)
511 (M + Na, 100), 413 (10), 239 (15); HRMS calcd for C26H32O7-
SNa (M + Na) 511.1766, obsd 511.1771; [R]D +17 (c 2.81, CH2-
Cl2).
Epoxide 10. To a solution of (-)-diethyl D-tartrate (2.28 g, 11.07
mmol) in dry CH2Cl2 (50 mL) was added titanium(IV) isopropoxide
(3.09 g, 10.88 mmol) at -30 to -20 °C. The mixture was stirred
for 30 min. A solution of diene 9 (3.0 g, 10.07 mmol) in CH2Cl2
(65 mL) was added, and the mixture was sirred at -30 to -20 °C
for 20 min. tert-Butyl hydroperoxide (4.75 mL, 5.6 M in CH2Cl2,
26.57 mmol) was then added dropwise over 10 min. The resulting
mixture was stirred at -30 to -20 °C for 15 h. Aqueous (+)-L-
tartaric acid (10% w/w, 21.6 mL) was added, then the mixture was
stirred at -20 °C for 30 min, allowed to warm to room temperature,
and stirred for 1 h. Aqueous NaOH (1 N, 59.0 mL) was added at
0 °C, and the resulting mixture was stirred for 1 h. The reaction
mixture was then partitioned between water and CH2Cl2. The
combined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to give epoxide 10 as a colorless
oil (2.25 g, 7.17 mmol, 72% yield). TLC Rf(MTBE/petroleum ether
Epoxide 3. To a solution of diol 4 (2.66 g, 5.45 mmol) in MeOH
(110 mL) was added finely powdered K2CO3 (1.50 g, 10.9 mmol).
The mixture was stirred at room temperature for 4 h. Then the
mixture was concentrated and the residue was partitioned between
CH2Cl2 and water. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to give
epoxide 3 as a colorless oil (1.18 g, 3.54 mmol, 65% yield). TLC
1
Rf(MTBE/petroleum ether ) 3:1) ) 0.55; H NMR δ 1.56-1.71
(m, 5H), 2.17-2.22 (m, 3H), 2.54 (dt, J ) 2.4, 7.1 Hz, 2H), 2.62
(dd, J ) 3.0, 4.4 Hz, 1H), 2.83 (t, J ) 4.4 Hz, 1H), 3.22-3.24 (m,
1H), 3.46 (t, J ) 6.3 Hz, 2H), 3.84 (dt, J ) 3.1, 10.2 Hz, 1H),
4.17-4.22 (m, 2H), 4.48 (s, 2H), 7.33 (br s, 5H); 13C NMR δ u
138.5, 81.6, 76.4, 72.8, 69.8, 45.6, 34.8, 28.9, 25.6, 19.5, 18.6, d
128.3, 127.6, 127.5, 82.7, 77.6, 71.6, 53.5; IR (cm-1) 3449, 2938,
2861; MS m/z (%) 353 (M + Na, 100), 331 (15), 277 (15); HRMS
calcd for C20H26O4Na (M + Na) 353.1729, obsd 353.1731; [R]D
+30 (c 1.52, CH2Cl2).
1
) 2:1) ) 0.45; H NMR δ 1.55-1.73 (m, 4H), 1.82-1.85 (m,
1H), 2.17-2.21 (m, 2H), 2.29-2.34 (m, 2H), 2.86-2.89 (m, 2H),
2.91-2.93 (m, 1H), 2.98-3.01 (m, 1H), 3.47 (t, J ) 6.4 Hz, 2H),
3.60 (ddd, J ) 4.3, 7.1, 12.5 Hz, 1H), 3.86 (ddd, J ) 2.6, 5.4, 12.5
Hz, 1H), 4.48 (s, 2H), 5.51-5.55 (m, 1H), 5.63-5.67 (m, 1H),
7.33 (br s, 5H); 13C NMR δ u 138.5, 82.1, 77.2, 72.9, 69.9, 61.5,
34.1, 28.9, 25.6, 22.0, 18.6, d 128.3, 128.2, 127.6, 127.5, 125.4,
57.9, 55.0; IR (cm-1) 3439, 2932, 1098; MS m/z (%) 315 (M + H,
100), 297(37), 279(15); [R]D +11 (c 2.71, CH2Cl2).
Alkene 12. To a suspension of Me3SI (1.97 g, 9.67 mmol) in
THF (58 mL) was added n-BuLi (2 M solution in hexane, 4.3 mL)
at -20 to -10 °C under N2. Then the mixture was stirred at -20
to -10 °C for 1 h. A solution of epoxide 3 (638 mg, 1.93 mmol)
in THF (2 mL) was added dropwise. The resulting mixture was
allowed to warm to room temperature slowly and stirred for 10 h.
The reaction mixture was then partitioned between CH2Cl2 and
saturated aqueous NH4Cl. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
give alkene 12 as a colorless oil (465 mg, 1.35 mmol, 70% yield).
TLC Rf(MTBE/petroleum ether ) 2:1) ) 0.65; 1H NMR δ 1.52-
1.59 (m, 2H), 1.65-1.72 (m, 2H), 1.92 (dd, J ) 3.3, 14.3 Hz, 1H),
2.11 (dd, J ) 3.3, 10.0 Hz, 1H), 2.14-2.20 (m, 2H), 2.52-2.55
(m, 2H), 3.01 (br s, 1H), 3.46 (t, J ) 6.3 Hz, 2H), 3.59 (br d, J )
9.1 Hz, 1H), 3.78 (dt, J ) 2.7, 9.5 Hz, 1H), 4.09-4.13 (m, 2H),
4.40-4.42 (m, 1H), 4.47 (s, 2H), 5.20 (dt, J ) 1.6, 10.6 Hz, 1H),
5.36 (dt, J ) 1.7, 17.2 Hz, 1H), 5.73 (ddd, J ) 5.0, 10.6, 17.2 Hz,
1H), 7.32 (br s, 5H); 13C NMR δ u 138.5, 116.4, 81.4, 76.7, 72.9,
69.9, 33.5, 28.9, 25.6, 19.4, 18.6, d 136.3, 128.3, 127.6, 127.5, 82.5,
80.3, 72.7, 71.1; IR (cm-1) 3339, 2860, 1453; MS m/z (%) 367 (M
+ Na, 100); HRMS calcd for C21H28O4Na (M + Na) 367.1885,
obsd 367.1894; [R]D +38 (c 0.79, CH2Cl2).
Silyl Ether 13. To a solution of alkene 12 (162 mg, 0.47 mmol)
in CH2Cl2 (7.5 mL) was added imidazole (177 mg, 2.59 mmol)
and TBDMSCl (355 mg, 2.36 mmol) at 0 °C. The resulting mixture
was allowed to warm to room temperature slowly and stirred for
12 h. The reaction mixture was then partitioned between CH2Cl2
and water. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give silyl ether
13 as a colorless oil (268 mg, 0.47 mmol, 99% yield). TLC Rf-
(MTBE/petroleum ether ) 1:10) ) 0.55; 1H NMR δ 0.02 (s, 3H),
0.05 (s, 3H), 0.06 (br s, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.53-1.58
(m, 2H), 1.65-1.70 (m, 2H), 1.81-1.87 (m, 1H), 2.07-2.16 (m,
3H), 2.39-2.50 (m, 2H), 3.46 (t, J ) 6.3 Hz, 2H), 3.65-3.67 (m,
1H), 3.73-3.77 (m, 1H), 4.12-4.15 (m, 1H), 4.26-4.30 (m, 1H),
4.48 (s, 2H), 5.11 (dt, J ) 1.6, 10.6 Hz, 1H), 5.23 (dt, J ) 1.7,
17.2 Hz, 1H), 5.81 (ddd, J ) 5.0, 10.6, 17.2 Hz, 1H), 7.32 (br s,
5H); 13C NMR δ u 138.6, 115.7, 80.5, 77.7, 72.8, 69.9, 37.1, 28.9,
25.6, 19.6, 18.7, 18.2, 18.1, d 139.1, 128.3, 127.6, 127.5, 82.2, 80.9,
75.5, 71.9, 25.9, 25.8, -4.1, -4.5, -4.6, -5.2; IR (cm-1) 2928,
2858, 1076; MS m/z (%) 595 (M + Na, 20); HRMS calcd for
C33H56O4Si2Na (M + Na) 595.3615, obsd 595.3632; [R]D +27 (c
1.31, CH2Cl2).
Benzenesulfonate 11. To a solution of epoxide 10 (2.25 g, 7.17
mmol) in CH2Cl2 (40 mL) was added DMAP (44 mg, 0.36 mmol).
The solution was cooled to 0 °C, and Et3N (2.54 g, 25.10 mmol)
was added, followed by benzenesulfonyl chloride (3.17 g, 17.93
mmol) dropwise over 15 min. The mixture was allowed to warm
to room temperature and stirred for 3 h. The reaction mixture was
then partitioned between CH2Cl2 and saturated aqueous NaHCO3.
The combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to give benzenesulfonate
11 as a colorless oil (3.09 g, 6.81 mmol, 95% yield). TLC Rf(MTBE/
1
petroleum ether ) 1:1) ) 0.55; H NMR δ 1.57-1.72 (m, 4H),
2.17-2.21 (m, 2H), 2.24-2.32 (m, 2H), 2.83-2.87 (m, 3H), 2.96-
2.98 (m, 1H), 3.47 (t, J ) 6.3 Hz, 2H), 3.96 (dd, J ) 6.0, 11.4 Hz,
1H), 4.22 (dd, J ) 3.6, 11.4 Hz, 1H), 4.48 (s, 2H), 5.46-5.52 (m,
1H), 5.56-5.61 (m, 1H), 7.31 (br s, 5H), 7.55 (t, J ) 6.6 Hz, 2H),
7.64 (d, J ) 6.6 Hz, 1H), 7.90 (d, J ) 6.6 Hz, 2H); 13C NMR δ u
138.6, 135.7, 82.3, 72.9, 70.1, 69.9, 33.8, 28.9, 25.7, 22.0, 18.6, d
134.0, 129.3, 128.7, 128.3, 127.9, 127.6, 127.5, 124.8, 55.7, 54.0;
IR (cm-1) 2932, 1448, 1100; MS m/z (%) 477 (M + Na, 100), 387
(15), 319 (15); HRMS calcd for C26H30O5SNa (M + Na) 477.1712,
obsd 477.1715; [R]D +26 (c 1.61, CH2Cl2).
Diol 4. A suspension of AD-mix-R (12.0 g) in t-BuOH-H2O
(1:1, v/v, 60 mL) was stirred at room temperature until both phases
were clear, then cooled to 0 °C. Methanesulfonamide (572 mg, 6.01
mmol) was added, followed by benzenesulfonate 11 (2.73 g, 6.01
mmol) dropwise over 5 min. The resulting mixture was stirred at
0 °C for 40 h. Solid NaHSO3 (12.4 g) was carefully added to the
reaction mixture, which was stirred at room temperature for 1 h.
The reaction mixture was then partitioned between EtOAc and brine.
The combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to give diol 4 as a
colorless oil (2.71 g, 5.55 mmol, 92% yield). TLC Rf(MTBE/
petroleum ether ) 3:1) ) 0.15; 1H NMR (D-MeOH) δ 1.80-1.86
(m, 4H), 1.95-2.01 (m, 3H), 2.06-2.12 (m, 1H), 2.45 (dd, J )
2.3, 4.5 Hz, 2H), 2.59 (dd, J ) 6.1, 16.5 Hz, 1H), 2.73 (dd, J )
6.1, 16.5 Hz, 1H), 3.27-3.32 (m, 2H), 3.79 (t, J ) 6.4 Hz, 2H),
3.83 (m, 1H), 4.07 (m, 1H), 4.18 (dd, J ) 6.5, 11.5 Hz, 1H), 4.62
(dd, J ) 2.9, 11.5 Hz, 1H), 4.77 (s, 2H), 7.61 (br s, 5H), 7.92 (t,
J ) 7.5 Hz, 2H), 8.01 (t, J ) 7.5 Hz, 1H), 8.20 (d, J ) 7.5 Hz,
2H); 13C NMR δ u 139.8, 137.2, 82.4, 77.8, 73.8, 72.2, 70.9, 36.2,
29.8, 26.8, 24.3, 19.2, d 135.3, 130.6, 129.4, 129.0, 128.9, 128.6,
Aldehyde 14. A suspension of AD-mix-R (6.08 g) in t-BuOH-
H2O (1:1, v/v, 15 mL) was stirred at room temperature until both
phases were clear, then cooled to 0 °C. Silyl ether 13 (870 mg,
1.52 mmol) was added dropwise over 5 min. The resulting mixture
was stirred at 0 °C for 40 h. Solid NaHSO3 (7.30 g) was carefully
930 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of the Enediol Isofurans
added to the reaction mixture, which was stirred at room temperature
for 1 h. The reaction mixture was then partitioned between EtOAc
and brine. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give the diol
as a colorless oil (718 mg, 1.19 mmol, 78% yield).
28.8, 25.6, 23.9, 18.5, d 128.4, 127.7, 127.6, 84.9, 78.1, 75.4, 52.9;
IR (cm-1) 3432, 2924, 1453; MS m/z (%) 353 (M + Na, 82), 339
(35), 279 (30); HRMS calcd for C20H26O4Na (M + Na) 353.1729,
obsd 353.1721; [R]D +3.8 (c 3.80, CH2Cl2).
Silyl Ether 17. To a solution of epoxide 3 (180 mg, 0.55 mmol)
in CH2Cl2 (8 mL) was added imidazole (93 mg, 1.36 mmol) and
TBDMSCl (164 mg, 1.09 mmol) at 0 °C. The resulting mixture
was allowed to warm to room temperature slowly and stirred for
12 h. The reaction mixture was then partitioned between CH2Cl2
and water. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give silyl ether
17 as a colorless oil (222 mg, 0.50 mmol, 90% yield). TLC Rf-
To a suspension of SiO2 (4.0 g) in CH2Cl2 (13 mL) was added
a solution of NaIO4 (401 mg) in water (2.56 mL) at room
temperature. The resulting mixture was stirred vigorously until a
flaky mixture was formed. A solution of diol (504 mg, 0.83 mmol)
in CH2Cl2 (2 mL) was added slowly and the mixture was stirred at
room temperature for 12 h. The reaction mixture was then filtered
and the filtrate was concentrated. The residue was chromatographed
to give aldehyde 14 as a colorless oil (426 mg, 0.74 mmol, 90%
1
(MTBE/petroleum ether ) 1:4) ) 0.35; H NMR δ 0.09 (s, 3H),
1
0.10 (s, 3H), 0.89 (s, 9H), 1.53-1.58 (m, 2H), 1.65-1.70 (m, 2H),
1.96-2.00 (m, 1H), 2.11-2.17 (m, 2H), 2.22-2.30 (m, 1H), 2.44-
2.49 (m, 2H), 2.65 (dd, J ) 2.1, 4.2 Hz, 1H), 2.77 (dd, J ) 3.0,
4.2 Hz, 1H), 3.04-3.07 (m, 1H), 3.46 (t, J ) 6.3 Hz, 2H), 3.68-
3.73 (m, 1H), 3.82-3.86 (m, 1H), 4.25-4.29 (m, 1H), 4.48 (s,
2H), 7.32 (br s, 5H); 13C NMR δ u 138.6, 81.0, 77.0, 72.9, 69.9,
47.0, 38.7, 29.0, 25.6, 19.5, 18.6, 18.0, d 128.3, 127.6, 127.5, 83.2,
78.6, 71.9, 54.0, 25.7, -4.6, -5.2; IR (cm-1) 2928, 2359, 1067;
MS m/z (%) 467 (M + Na, 65); HRMS calcd for C33H56O4Si2Na
(M + Na) 467.2594, obsd 467.2616; [R]D +34 (c 1.21, CH2Cl2).
Alkene 18. To a suspension of Me3SI (345 mg, 1.69 mmol) in
THF (10 mL) was added n-BuLi (2.15 M solution in hexane, 0.6
mL) at -20 to -10 °C under N2. Then the mixture was stirred at
-20 to -10 °C for 1 h. A solution of silyl ether 17 (150 mg, 0.34
mmol) in THF (1 mL) was added dropwise. The resulting mixture
was allowed to warm to room temperature slowly and stirred for
10 h. The reaction mixture was then partitioned between CH2Cl2
and saturated aqueous NH4Cl. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromatographed
to give alkene 18 as a colorless oil (104 mg, 0.23 mmol, 67% yield).
yield). TLC Rf(MTBE/petroleum ether ) 1:10) ) 0.45; H NMR
δ 0.04 (s, 3H), 0.05 (s, 3H), 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (s,
9H), 0.89 (s, 9H), 1.54-1.58 (m, 2H), 1.66-1.69 (m, 2H), 1.91
(ddd, J ) 2.9, 6.3, 13.6 Hz, 1H), 2.12-2.19 (m, 3H), 2.41-2.47
(m, 2H), 3.46 (t, J ) 6.3 Hz, 2H), 3.75-3.80 (m, 1H), 3.99 (dt, J
) 6.3, 7.8 Hz, 1H), 4.14 (dd, J ) 1.3, 6.2 Hz, 1H), 4.29-4.32 (m,
1H), 4.48 (s, 2H), 7.32 (br s, 5H), 9.66 (d, J ) 1.4 Hz); 13C NMR
δ u 138.6, 80.8, 77.3, 72.9, 69.9, 37.3, 28.9, 25.6, 19.5, 18.6, 18.3,
18.0, d 202.4, 128.3, 127.6, 127.5, 82.7, 79.3, 78.1, 71.9, 25.81,
25.79, -4.5, -4.6, -4.8, -5.2; IR (cm-1) 2929, 2856, 1737; MS
m/z (%) 597 (M + Na, 35), 366 (10); HRMS calcd for C32H54O5-
Si2Na (M + Na) 597.3408, obsd 597.3383; [R]D +30 (c 2.51, CH2-
Cl2).
Enone 15. To a suspension of NaH (74 mg, 1.86 mmol, 60% in
mineral oil) in THF (14 mL) was added a solution of dimethyl
2-oxo-heptylphosphonate (494 mg, 2.23 mmol) in THF (1 mL) at
0 °C under N2. The resulting mixture was stirred at room
temperature for 1 h. A solution of aldehyde 14 (426 mg, 0.74 mmol)
in THF (1 mL) was added slowly and the mixture was stirred at
room temperature for 15 min. The reaction mixture was then
partitioned between ether and saturated aqueous NH4Cl. The
combined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to give enone 15 as a colorless
oil (446 mg, 0.67 mmol, 90% yield). TLC Rf(MTBE/petroleum ether
1
TLC Rf(MTBE/petroleum ether ) 1:4) ) 0.50; H NMR δ 0.09
(s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.55-1.58 (m, 2H), 1.62-1.70
(m, 2H), 1.90 (dd, J ) 3.9, 14.0 Hz, 1H), 2.03 (ddd, J ) 5.0, 9.5,
14.0 Hz, 1H), 2.13-2.18 (m, 2H), 2.47-2.50 (m, 2H), 3.19 (d, J
) 2.2 Hz, 1H), 3.46 (t, J ) 6.3 Hz, 2H), 3.74-3.78 (m, 1H), 4.10-
4.14 (m, 1H), 4.23-4.27 (m, 1H), 4.36-4.38 (m, 1H), 4.48 (s,
2H), 5.15 (dt, J ) 1.7, 10.6 Hz, 1H), 5.38 (dt, J ) 1.7, 17.1 Hz,
1H), 5.71 (ddd, J ) 5.0, 10.6, 17.1 Hz, 1H), 7.32 (br s, 5H); 13C
NMR δ u 138.5, 115.8, 81.3, 76.7, 72.9, 69.8, 33.8, 28.9, 25.6,
19.2, 18.6, 18.1, d 137.0, 128.3, 127.6, 127.5, 82.4, 80.7, 72.4, 71.8,
25.7, -4.8, -5.2; IR (cm-1) 2928, 2856, 1071; MS m/z (%) 481
(M + Na, 100); HRMS calcd for C27H42O4Si1Na (M + Na)
481.2750, obsd 481.2731; [R]D +43 (c 1.11, CH2Cl2).
1
) 1:10) ) 0.60; H NMR δ 0.01 (s, 3H), 0.04 (s, 3H), 0.05 (s,
3H), 0.06 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.20-1.29 (m, 7H),
1.52-1.58 (m, 4H), 1.64-1.69 (m, 2H), 1.83 (ddd, J ) 2.5, 6.5,
12.4 Hz, 1H), 2.05-2.15 (m, 3H), 2.39-2.49 (m, 2H), 2.53 (t, J
) 7.8 Hz), 3.46 (t, J ) 6.4 Hz, 2H), 3.62-3.67 (m, 1H), 3.71-
3.77 (m, 1H), 4.26-4.29 (m, 1H), 4.33 (t, J ) 5.7 Hz, 1H), 4.47
(s, 2H), 6.24 (d, J ) 16.0 Hz, 1H), 6.76 (dd, J ) 5.1, 16.0 Hz,
1H), 7.32 (br s, 5H); 13C NMR δ u 200.9, 138.6, 80.7, 77.4, 72.9,
69.9, 40.3, 37.4, 31.4, 29.7, 28.9, 25.6, 23.9, 22.5, 19.6, 18.7, 18.2,
18.1, d 146.2, 129.6, 128.3, 127.6, 127.5, 82.4, 80.5, 73.9, 71.9,
25.8, 13.9, -4.2, -4.6, -5.2; IR (cm-1) 2929, 1252, 1078; MS
m/z (%) 693 (M + Na, 100), 539 (65); HRMS calcd for C39H66O5-
Si2Na (M + Na) 693.4347, obsd 693.4342; [R]D +48 (c 0.63, CH2-
Cl2).
Alcohol 19. To a solution of alkene 18 (20 mg, 0.044 mmol),
triphenylphosphine (61 mg, 0.22 mmol), and 4-nitrobenzoic acid
(33 mg, 0.20 mmol) in THF (1 mL) was added diisopropyl
azodicarboxylate (71 mg, 0.35 mmol) at 0 °C under N2. Then the
mixture was stirred at room temperature for 18 h. All the volatiles
were removed and the residue was chromatographed to give benzoyl
ester as a white solid (12 mg, 0.020 mmol, 45% yield). TLC Rf-
Alcohol 16. To a solution of epoxide 3 (119 mg, 0.36 mmol),
triphenylphosphine (501 mg, 1.81 mmol), and 4-nitrobenzoic acid
(272 mg, 1.63 mmol) in THF (8 mL) was added diisopropyl
azodicarboxylate (584 mg, 2.89 mmol) at 0 °C under N2. Then the
mixture was stirred at room temperature for 18 h. All the volatiles
were removed and the residue was dissolved in MeOH (2 mL).
Finely powdered K2CO3 (1.0 g) was added at 0 °C under N2. Then
the mixture was stirred at room temperature for 20 min. The reaction
mixture was then partitioned between CH2Cl2 and water. The
combined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to give alcohol 16 as a colorless
oil (76 mg, 0.23 mmol, 64% yield for two steps). TLC Rf(MTBE/
1
(MTBE/petroleum ether ) 1:4) ) 0.55; mp 65-67 °C; H NMR
δ 0.07 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 1.50-1.55 (m, 2H), 1.61-
1.68 (m, 2H), 1.84 (ddd, J ) 1.8, 4.1, 13.7 Hz, 1H), 2.08-2.13
(m, 2H), 2.21 (ddd, J ) 5.3, 8.8, 13.7 Hz, 1H), 2.40-2.47 (m,
2H), 3.43 (t, J ) 6.4 Hz, 2H), 3.85-3.90 (m, 1H), 4.14-4.20 (m,
1H), 4.30-4.32 (m, 1H), 4.47 (s, 2H), 5.32 (d, J ) 10.5 Hz, 1H),
5.43 (d, J ) 16.2 Hz, 1H), 5.69 (dd, J ) 7.3, 7.8 Hz), 5.84 (ddd,
J ) 7.3, 10.5, 16.2 Hz, 1H), 7.32 (br s, 5H), 8.24 (br s, 4H); 13C
NMR δ u 163.8, 150.4, 138.5, 136.0, 120.2, 80.8, 77.1, 72.8, 69.8,
37.2, 28.9, 25.6, 19.7, 18.6, 18.1, d 132.8, 130.8, 128.3, 127.6,
127.5, 123.4, 83.1, 78.6, 78.4, 71.7, 25.8, -4.5, -5.3; MS m/z (%)
630 (M + Na, 25); HRMS calcd for C34H45O7SiNNa (M + Na)
630.2863, obsd 630.2893; [R]D +26 (c 1.81, CH2Cl2).
1
petroleum ether ) 1:1) ) 0.25; H NMR δ1.61-1.78 (m, 5H),
1.96-2.04 (m, 2H), 2.19-2.25 (m, 3H), 2.29-2.34 (m, 1H), 2.53-
2.58 (m, 1H), 2.65 (dd, J ) 2.6, 4.8 Hz, 1H), 2.84 (t, J ) 4.3 Hz,
1H), 3.08-3.11 (m, 1H), 3.53 (t, J ) 6.3 Hz, 2H), 3.89-3.93 (m,
1H), 4.14-4.18 (m, 1H), 4.32-4.35 (m, 1H), 4.54 (s, 2H), 7.34
(br s, 5H); 13C NMR δ u 138.4, 82.3, 75.9, 72.9, 69.8, 45.3, 35.8,
To a solution of benzoyl ester (12 mg, 0.020 mmol) in MeOH
(0.5 mL) was added finely powdered K2CO3 (250 mg, 1.81 mmol)
at 0 °C under N2. Then the mixture was stirred at room temperature
J. Org. Chem, Vol. 71, No. 3, 2006 931

Taber and Zhang
for 30 min. The reaction mixture was then partitioned between CH2-
Cl2 and water. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to give
alcohol 19 as a colorless oil (8 mg, 0.018 mmol, 90% yield). TLC
Rf(MTBE/petroleum ether ) 1:4) ) 0.30; 1H NMR δ 0.08 (s, 3H),
0.10 (s, 3H), 0.90 (s, 9H), 1.54-1.59 (m, 2H), 1.65-1.70 (m, 2H),
1.82 (ddd, J ) 1.1, 4.0, 13.7 Hz, 1H), 2.12-2.16 (m, 2H), 2.20
(ddd, J ) 5.2, 9.2, 13.7 Hz, 1H), 2.45-2.48 (m, 2H), 2.98 (d, 3.8
Hz, 1H), 3.46 (t, J ) 6.4 Hz, 2H), 3.81 (ddd, J ) 3.2, 7.4, 6.6 Hz,
1H), 3.95 (ddd, J ) 4.0, 5.4, 9.3 Hz, 1H), 4.02-4.07 (m, 1H),
4.26-4.29 (m, 1H), 4.48 (s, 2H), 5.17 (d, J ) 10.3 Hz, 1H), 5.32
(d, J ) 17.1 Hz, 1H), 5.83 (ddd, J ) 6.5, 10.3, 17.1 Hz, 1H), 7.32
(br s, 5H), 8.24 (br s, 4H); 13C NMR δ u 138.5 116.8, 81.2, 76.9,
72.9, 69.9, 37.4, 28.9, 25.6, 19.4, 18.6, 18.1, d 137.5, 128.3, 127.6,
127.5, 82.7, 80.9, 75.4, 72.0, 25.8, -4.7, -5.2; MS m/z (%) 481-
(M + Na, 25); HRMS calcd for C27H42O4SiNa (M + Na) 481.2750,
obsd 481.2732; [R]D +39 (c 0.75, CH2Cl2).
room temperature for 10 h under H2. The black suspension was
filtered through a short column packed with flash silica gel. The
column was eluted with MTBE (100 mL). The solvent was removed
to give the alkene 24 as a colorless oil (427 mg, 0.54 mmol, 89%
1
yield). TLC Rf(MTBE/petroleum ether ) 1:10) ) 0.85; H NMR
δ 0.00 (s, 3H), 0.02 (s, 6H), 0.03 (s, 3H), 0.04 (s, 3H), 0.05 (s,
3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.88 (s, 9H), 1.19-1.30 (m, 9H),
1.36-1.47 (m, 4H), 1.58-1.65 (m, 2H), 1.81-1.87 (m, 1H), 2.02-
2.08 (m, 3H), 2.23-2.33 (m, 2H), 3.45 (t, J ) 6.3 Hz, 2H), 3.50-
3.58 (m, 2H), 4.05 (dd, J ) 6.2, 12.4 Hz, 1H), 4.22-4.31 (m, 2H),
4.48 (s, 2H), 5.41-5.51 (m, 3H), 5.61 (dd, J ) 6.5, 15.4 Hz, 1H),
7.31 (br s, 5H); 13C NMR δ u 138.7, 72.8, 70.4, 38.4, 36.8, 31.8,
29.4, 27.7, 27.2, 26.2, 24.9, 22.6, 18.3, 18.2, 18.1, d 134.5, 130.7,
130.2, 128.3, 127.6, 127.4, 126.9, 83.2, 80.9, 73.6, 73.2, 72.8, 25.9,
25.8, 14.0, -4.2, -4.3, -4.5, -4.8, -5.1; IR (cm-1) 2928, 1471,
1253; MS m/z (%) 811 (M + Na, 100), 657 (95); HRMS calcd for
C45H84O5Si3Na (M + Na) 811.5524, obsd 811.5543; [R]D +4 (c
1.62, CH2Cl2).
Alcohol 20. To a solution of (-)-DIP-Cl (483 mg, 1.50 mmol)
in THF (15 mL) was added a solution of enone 15 (500 mg, 0.75
mmol) in THF (2 mL) at -78 °C under N2. The resulting mixture
was allowed to warm to room temperature slowly and stirred for
24 h. Then the reaction mixture was partitioned between CH2Cl2
and sequentially 1 N aqueous NaOH and saturated aqueous NH4-
Cl. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give alcohol
20 as a colorless oil (428 mg, 0.64 mmol, 85% yield). TLC Rf-
Alcohol 26. To a solution of naphthalene (146 mg, 1.14 mmol)
in THF (2 mL) was added lithium metal (5.3 mg, 0.76 mmol) at
room temperature under N2. The mixture was stirred at room
temperature until a dark green solution was formed. Then it was
cooled to -25 °C and a solution of alkene 24 (30 mg, 0.04 mmol)
in THF (0.5 mL) was added. The mixture was stirred at -25 °C
for 1 h. The reaction mixture was then partitioned between ether
and saturated aqueous NH4Cl. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromatographed
to give alcohol 26 as a colorless oil (25 mg, 0.037 mmol, 94%
yield). TLC Rf(MTBE/petroleum ether ) 1:4) ) 0.45; 1H NMR δ
0.00 (s, 3H), 0.02 (s, 6H), 0.03 (s, 3H), 0.04 (s, 3H), 0.05 (s, 3H),
0.86 (s, 9H), 0.87 (s, 9H), 0.88 (s, 9H), 1.19-1.27 (m, 8H), 1.33-
1.44 (m, 4H), 1.53-1.58 (m, 3H), 1.84-1.87 (m, 1H), 2.02-2.08
(m, 3H), 2.26-2.33 (m, 2H), 3.52-3.57 (m, 2H), 3.62 (t, J ) 6.5
Hz, 2H), 4.04 (dd, J ) 6.2, 12.4 Hz, 1H), 4.19-4.25 (m, 2H),
5.37-5.53 (m, 3H), 5.61 (ddd, J ) 1.2, 6.5, 15.4 Hz, 1H); 13C
NMR δ u 62.9, 38.4, 36.8, 32.4, 31.8, 27.7, 27.1, 25.7, 24.9, 22.6,
18.3, 18.2, 18.1, d 134.6, 130.5, 130.1, 127.1, 83.1, 80.9, 73.6, 73.2,
72.8, 25.9, 25.8, 14.0, -4.2, -4.3, -4.5, -4.6, -4.8, -5.1; IR
(cm-1) 3339, 2954, 1472; MS m/z (%) 721 (M + Na, 35); HRMS
calcd for C38H78O5Si3Na (M + Na) 721.5055, obsd 721.5073; [R]D
+9 (c 1.25, CH2Cl2).
1
(MTBE/petroleum ether ) 1:4) ) 0.25; H NMR δ 0.02 (s, 3H),
0.04 (s, 3H), 0.05 (s, 6H), 0.87 (s, 9H), 0.88 (s, 9H), 1.20-1.29
(m, 7H), 1.45-1.58 (m, 5H), 1.65-1.70 (m, 3H), 1.84 (ddd, J )
3.5, 7.1, 13.3 Hz, 1H), 2.07-2.16 (m, 3H), 2.36-2.43 (m, 2H),
3.46 (t, J ) 6.4 Hz, 2H), 3.61 (dd, J ) 7.1, 16.2 Hz, 1H), 3.72-
3.78 (m, 1H), 4.05-4.11 (m, 1H), 4.13-4.20 (m, 1H), 4.26-4.33
(m, 1H), 4.48 (s, 2H), 5.65 (t, J ) 4.8 Hz, 2H), 7.32 (br s, 5H);
13C NMR δ u 138.6, 80.6, 77.7, 72.8, 69.9, 37.3, 37.1, 31.7, 28.9,
25.6, 25.0, 22.6, 19.7, 18.7, 18.2, 18.1, d 134.3, 131.4, 128.3, 127.6,
127.5, 82.1, 81.1, 74.5, 72.3, 72.0, 25.9, 25.8, 14.0, -3.9, -4.5,
-5.2; IR (cm-1) 3429, 2928, 1250; MS m/z (%) 695 (M + Na,
85), 523 (75); HRMS calcd for C39H68O5Si2Na (M + Na) 695.4503,
obsd 695.4520; [R]D +21 (c 1.01, CH2Cl2).
Silyl Ether 22. To a solution of alcohol 20 (584 mg, 0.87 mmol)
in CH2Cl2 (11 mL) was added imidazole (148 mg, 2.17 mmol) and
TBDMSCl (262 mg, 1.74 mmol) at 0 °C. The resulting mixture
was allowed to warm to room temperature slowly and stirred for
12 h. The reaction mixture was then partitioned between CH2Cl2
and water. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give silyl ether
22 as a colorless oil (622 mg, 0.79 mmol, 91% yield). TLC Rf-
(MTBE/petroleum ether ) 1:10) ) 0.75; 1H NMR δ 0.00 (s, 3H),
0.02 (s, 6H), 0.04 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H),
0.87 (s, 9H), 0.88 (s, 9H), 1.17-1.28 (m, 7H), 1.29-1.44 (m, 2H),
1.45-1.58 (m, 3H), 1.65-1.70 (m, 3H), 1.81-1.88 (m, 1H), 2.00-
2.05 (m, 1H), 2.12-2.16 (m, 2H), 2.36-2.44 (m, 2H), 3.46 (t, J )
6.4 Hz, 2H), 3.57-3.63 (m, 1H), 3.71-3.76 (m, 1H), 4.06 (dd, J
) 6.4, 12.6 Hz, 1H), 4.23 (t, J ) 5.2 Hz, 1H), 4.27-4.31 (m, 1H),
4.48 (s, 2H), 5.47 (dd, J ) 5.5, 15.4 Hz, 1H), 5.61 (dd, J ) 6.4,
15.4 Hz, 1H), 7.32 (br s, 5H); 13C NMR δ u 138.6, 80.3, 77.9,
72.8, 69.9, 38.3, 36.4, 31.8, 28.9, 25.7, 24.9, 22.6, 19.7, 18.7, 18.26,
18.24, 18.1, d 134.7, 130.0, 128.3, 127.6, 127.5, 82.0, 81.0, 73.6,
73.1, 72.1, 25.9, 25.8, 14.0, -4.2, -4.3, -4.6, -4.8, -5.2; IR
(cm-1) 2928, 1471, 1253; MS m/z (%) 809 (M + Na, 98), 655
(100); HRMS calcd for C45H82O5Si3Na (M + Na) 809.5368, obsd
809.5401; [R]D +19 (c 0.25, CH2Cl2).
Acid 28. To a solution of alcohol 26 (25 mg, 0.036 mmol) in
DMF (0.5 mL) was added water (1 drop), followed by PDC (88
mg, 0.233 mmol). The mixture was stirred at room temperature
for 15 h. The dark brown suspension was filtered through a short
column packed with flash silica gel. The column was eluted with
MTBE (50 mL) and then concentrated. The residue was chromato-
graphed to give acid 28 as a colorless oil (13 mg, 0.018 mmol,
51% yield). TLC Rf(ether/5% aqueous NaH2PO4 ) 10:1, ether layer)
1
) 0.50; H NMR δ 0.00 (s, 3H), 0.02 (s, 6H), 0.03 (s, 3H), 0.04
(s, 3H), 0.05 (s, 3H), 0.85 (s, 9H), 0.86 (s, 9H), 0.88 (s, 9H), 1.17-
1.32 (m, 8H), 1.34-1.48 (m, 3H), 1.65-1.72 (m, 2H), 1.80-1.87
(m, 1H), 2.02-2.11 (m, 3H), 2.22-2.28 (m, 2H), 3.31-3.38 (m,
2H), 3.53-3.58 (m, 2H), 4.06 (dd, J ) 6.1, 12.3 Hz, 1H), 4.22-
4.26 (m, 2H), 5.36-5.53 (m, 3H), 5.61 (ddd, J ) 0.8, 6.5, 15.5
Hz, 1H); 13C NMR δ u 178.3, 38.4, 36.8, 33.2, 31.8, 27.7, 26.6,
24.9, 24.5, 22.6, 18.3, 18.1, d 134.6, 130.1, 129.4, 128.1, 83.1, 80.9,
73.6, 73.2, 72.8, 25.89, 25.84, 14.1, -4.2, -4.3, -4.5, -4.6, -4.8,
-5.1; IR (cm-1) 2928, 1710, 1472; MS m/z (%) 735 (M + Na,
70), 394 (100); HRMS calcd for C38H76O6Si3Na (M + Na)
735.4847, obsd 735.4855; [R]D +2.8 (c 2.06, CH2Cl2).
Acid 29. To a solution of alcohol 27 (118 mg, 0.169 mmol) in
CH2Cl2 (2.0 mL) was added a solution of Dess-Martin periodate
(80 mg, 0.187 mmol) in CH2Cl2 (2 mL) under N2. After 30 min,
the reaction mixture was diluted with ether (20 mL) and NaOH
(1.0 M, 1.5 mL) was added. The reaction mixture was stirred at
room temperature for an additional 10 min and then partitioned
between ether and water. The combined organic extracts were dried
Alkene 24. To a solution of Ni(OAc)2‚4H2O (152 mg, 0.61
mmol) in ethanol (6 mL) was add a solution of NaBH4 (1N in
ethanol, 0.61 mL, 0.61 mmol). The black mixture was evacuated
and backfilled with H2 three times. Ethylenediamine (0.05 mL, 0.67
mmol) was added, followed by a solution of silyl ether 22 (480
mg, 0.61 mmol) in ethanol (1 mL). The flask was evacuated and
backfilled with H2 three times. The reaction mixture was stirred at
932 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of the Enediol Isofurans
(Na2SO4) and concentrated. The residue was used directly for the
next reaction.
NMR δ u 177.9, 36.9, 34.0, 33.1, 31.7, 27.2, 26.4, 25.1, 24.4, 22.6,
d 135.7, 130.7, 128.8, 126.8, 83.5, 80.2, 72.3, 72.0, 70.9, 14.0; IR
(cm-1) 3438, 2928, 1710; MS m/z (%) 393 (M + Na, 66), 335
(100); HRMS calcd for C20H34O6Na (M + Na) 393.2253, obsd
393.2241; [R]D +14 (c 0.485, CH2Cl2).
To a solution of NaH2PO4 (28 mg) in water (0.5 mL) was added
NaClO2 (37 mg) at room temperature. Then a solution of crude
aldehyde in MTBE (1.0 mL) was added. The mixture was stirred
vigorously at room temperature overnight and then partitioned
between ether and water. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
give acid 29 as a colorless oil (106 mg, 0.185 mmol, 88% yield
for two steps). TLC Rf(ether/5% aqueous NaH2PO4 ) 10:1, ether
layer) ) 0.50; 1H NMR δ 0.00 (s, 3H), 0.01 (s, 3H), 0.02 (s, 6H),
0.03 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.88 (s, 9H),
1.17-1.32 (m, 8H), 1.34-1.48 (m, 3H), 1.65-1.72 (m, 2H), 1.80-
1.87 (m, 1H), 2.02-2.12 (m, 3H), 2.22-2.28 (m, 2H), 3.31-3.35
(m, 2H), 3.53-3.59 (m, 2H), 4.07 (dd, J ) 4.8, 9.9 Hz, 1H), 4.22-
4.26 (m, 2H), 5.36-5.53 (m, 3H), 5.61 (dd, J ) 4.8, 12.9 Hz, 1H);
13C NMR δ u 178.8, 38.3, 36.8, 33.3, 31.8, 27.7, 26.6, 24.9, 24.5,
22.7, 18.3, 18.1, d 134.6, 129.9, 129.4, 128.0, 83.1, 80.9, 73.8, 73.0,
72.7, 25.89, 25.84, 14.1, -4.2, -4.3, -4.5, -4.6, -4.9, -5.1; IR
(cm-1) 2929, 2857, 1710; MS m/z (%) 735 (M + Na, 70), 394
(100); HRMS calcd for C38H76O6Si3Na (M + Na) 735.4847, obsd
735.4873; [R]D +14 (c 0.375, CH2Cl2).
IsoF 2b. The same procedure was applied as for the preparation
of 2a. IsoF 2b was prepared as a colorless oil (23 mg, 0.061 mmol,
68% yield). TLC Rf(ether/5% aqueous NaH2PO4/HOAC ) 100:
1
10:1, ether layer) ) 0.45; H NMR δ 0.86 (t, J ) 6.9 Hz, 3H),
1.17-1.33 (m, 6H), 1.41-1.50 (m, 2H), 1.66-1.73 (m, 2H), 1.91
(dd, J ) 2.7, 14.2 Hz, 1H), 2.07-2.19 (m, 3H), 2.29-2.37 (m,
3H), 2.48-2.53 (m, 1H), 3.67-3.70 (m, 1H), 4.00-4.02 (m, 1H),
4.07-4.11 (m, 2H), 4.40-4.42 (m, 1H), 5.45-5.48 (m, 2H), 5.55
(dd, J ) 4.7, 15.6 Hz, 1H), 5.81 (dd, J ) 4.7, 15.6 Hz, 1H); 13C
NMR δ u 177.8, 37.1, 33.9, 33.1, 31.7, 27.2, 26.4, 25.1, 24.4, 22.6,
d 135.4, 131.1, 129.4, 127.3, 84.1, 80.3, 72.8, 72.1, 71.4, 14.5; IR
(cm-1) 3442, 2930, 1706; MS m/z (%) 393 (M + Na, 66), 335
(100); HRMS calcd for C20H34O6Na (M + Na) 393.2253, obsd
393.2237; [R]D -5.5 (c 0.365, CH2Cl2).
Acknowledgment. We thank the National Institutes of
Health (GM42056) for support of this work.
IsoF 2a. To a solution of acid 28 (64 mg, 0.090 mmol) in THF
(0.5 mL) was added TBAF (3 M solution in THF, 0.9 mL). The
mixture was stirred at room temperature for 24 h and concentrated.
The residue was chromatographed to give isoF 2a as a colorless
oil (22 mg, 0.058 mmol, 65% yield). TLC Rf(ether/5% aqueous
NaH2PO4/HOAC ) 100:10:1, ether layer) ) 0.45; 1H NMR δ 0.85
(t, J ) 4.9 Hz, 3H), 1.17-1.33 (m, 6H), 1.41-1.50 (m, 2H), 1.64-
1.72 (m, 2H), 1.93 (d, J ) 14.1 Hz, 1H), 2.09-2.18 (m, 3H), 2.29-
2.40 (m, 3H), 2.46-2.51 (m, 1H), 3.66 (t, J ) 5.7 Hz, 1H), 4.02-
4.09 (m, 3H), 4.36 (d, J ) 5.4 Hz, 1H), 5.41-5.47 (m, 2H), 5.50
(dd, J ) 5.9, 15.7 Hz, 1H), 5.76 (dd, J ) 5.9, 15.7 Hz, 1H); 13C
Note Added after ASAP Publication. There was an error
in Scheme 2 in the version posted ASAP Dec. 31, 2005; the
corrected version posted Jan. 4, 2006.
Supporting Information Available: General experimental
procedures, experimental procedures for the 2b series, and spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO051889A
J. Org. Chem, Vol. 71, No. 3, 2006 933