A flexible enantioselective synthesis of the isofurans

Article abstract of DOI:10.1021/jo048863o

Recently, the isolation of a new class of human arachidonic acid tetrahydrofuran oxidation products, the isofurans (IsoF's), was reported. These new compounds are available from natural sources only in microgram quantities as mixtures. The enantioselectiv

Full text of DOI:10.1021/jo048863o

A F lexible En a n tioselective Syn th esis of th e Isofu r a n s
Douglass F. Taber,* Yongchun Pan, and Xia Zhao
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received J uly 5, 2004
Recently, the isolation of a new class of human arachidonic acid tetrahydrofuran oxidation products,
the isofurans (IsoF’s), was reported. These new compounds are available from natural sources only
in microgram quantities as mixtures. The enantioselective preparation of a versatile epoxide
intermediate and its conversion to the enantiomerically pure isofurans SC-∆13-9-IsoF and 15-epi-
SC-∆13-9-IsoF are described. This synthesis will make these metabolites available for physiological
evaluation.
SCHEME 1
In tr od u ction
Recently, the isolation of a new class of human arachi-
donic acid oxidation products, the isofurans (IsoF’s), was
reported.1,2 These new compounds (Scheme 1) are pro-
duced in vivo by a free radical mechanism, independent
of the cyclooxygenase enzymes. Because these compounds
are tetrahydrofuran derivatives that are related biosyn-
thetically to the isoprostanes, they were termed isofurans
(IsoF’s). Interestingly, with increased oxidative stress, the
production of the isoprostanes falls, and free radical
conversion of arachidonic acid switches to the isofurans.
Even though they are nonenzymatic oxidation prod-
ucts, the isoprostanes have been found to have significant
physiological activity. It is therefore important to also
investigate the physiological role of the isofurans. To this
end, we have developed a general synthetic strategy that
will allow the preparation of each of the enantiomerically
pure diastereomers of the several regioiosomers of the
isofurans. We have illustrated this approach with the
synthesis of the two isofurans that are closest in structure
to the enzymatically produced prostaglandins, SC-∆13-
9-IsoF (3a ) and 15-epi-SC-∆13-9-IsoF (3b).
Resu lts a n d Discu ssion
Syn th etic Ap p r oa ch . Our interest was to develop a
flexible route to the isofurans, such that each of the
enantiomerically pure diastereomers could be prepared
using a divergent strategy, branching from advanced
intermediates. One such advanced intermediate would
be the substituted tetrahydrofuran compound 2.
We envisioned that the tetrahydrofuran 2 could be pre-
pared by cascade cyclization3 of the diol epoxide 1. Al-
though there are four different modes of epoxide opening
available to the diol 1, it seemed likely that exo cycliza-
tion would dominate over endo cyclization and that five-
membered ring formation would be faster than four-mem-
(1) Fessell, J . P., Porter, N. A.; Moore, K. P.; Sheller, J . R.; Roberts,
L. J ., II. Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 16713.
10.1021/jo048863o CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/23/2004
7234
J . Org. Chem. 2004, 69, 7234-7240

Isofuran Synthesis
SCHEME 2
bered ring formation. Ring closure of the intermediate
alkoxide would then lead to the epoxide 2.3 We expect to
observe this same selectivity for five-membered ring for-
mation with the other three syn-diol diastereomers of 1.
Eight different regioisomers of the IsoF’s have been
observed,1 each of which can exist as 16 racemic diaster-
eomers. Thus, there are 256 enantiomerically pure Iso-
F’s,4 representative examples of which are illustrated in
Scheme 1. The relative and absolute configuration of 2
can be easily varied by the use of the opposite enanti-
omers of catalysts in the Sharpless asymmetric epoxi-
dation and dihydroxylation reactions. We therefore expect
that the synthetic approach outlined here will allow the
preparation of each of the enantiomerically pure diaster-
eomers of the several regioisomers of the isofurans.5
P r ep a r a tion of th e Tr ien e Alcoh ol 8. We projected
that the diol 1 could be prepared (Scheme 2) from the
triene 8, which in turn would be available from the
bromodiene 6 by homologation with propargyl alcohol.
While the dimethyl acetal corresponding to 6 was known,
we thought that the acetal derived from 2,2-dimethyl-
propane-1,3-diol 5 would be more stable. This turned out
to be a good choice, as the epoxide 2 derived from 5 was
nicely crystalline.
Following the literature precedent, our synthesis
(Scheme 2) started with the conversion of (E,E)-sorbal-
dehyde 4 to its silyl enol ether.6 Bromination of the crude
enol ether followed by quenching with 2,2-dimethylpro-
pane-1,3-diol 5 afforded the bromoacetal 6.7 This allylic
bromide was coupled with propargyl alcohol to give the
acetylenic alcohol 7.8 Reduction of the alkyne 7 using
Red-Al,9 Na/NH3,10 or Li/1,3-diaminopropane11 gave rear-
rangement to the allene. Reduction of the alkyne 7 using
LiAlH4 in THF12 led to partial decomposition of the
acetal. The allylic alcohol 8 was isolated, but only in poor
yield. The best results for the reduction of 7 to 8 were
obtained when powdered LiAlH4 was employed and the
reaction was carried out in dry diethyl ether.
sulfonate 10 was subjected to the Sharpless asymmetric
dihydroxylation using AD-mix-R.14 We had thought that
the desired target alkene would be the more electron-
rich of the two, and so would react preferentially. This
turned out to be true, but only marginally so. The dihy-
droxylation afforded a 1.3:1 mixture of the easily separ-
able regioisomeric diols 1 and 11. Fortunately, the unde-
sired regioisomer 11 was readily recycled to 9 (43%
overall) by thermal fragmentation15 of the derived cyclic
ortho ester.16
With the diol 1 in hand, we were ready to attempt the
key cyclization. We tried the reaction both with potas-
sium carbonate in methanol17 and with potassium tert-
butoxide in THF.18 The reaction in methanol was cleaner,
even though it was necessary to operate at 0 °C, as higher
P r ep a r a tion a n d Cr ysta lliza tion of 2. The allylic
alcohol 8 was carried on to the epoxy alcohol 9 by the
Sharpless asymmetric epoxidation.13 The derived benzene-
(2) An IsoF-type compound has been reported as a product from
enzymatic oxidation of arachidonic acid: (a) Pace-Asciak, C. Biochem-
istry 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.
(3) (a) A similar cascade cyclization was developed in our group
several years ago: Taber, D. F.; Bhamidipati, R. S.; Thomas, M. L. J .
Org. Chem. 1994, 59, 3442. (b) For a related acid-catalyzed cyclization,
see: Sivakumar, M.; Borhan, B. Tetrahedron Lett. 2003, 44, 5547.
(4) For a detailed account of isofuran nomenclature, see: Taber, D.
F.; Morrow, J . D.; Roberts, L. J . Prostaglandins Other Lipid Mediators
2004, 73, 47.
(5) For the only synthetic efforts reported to date toward IsoF type
structures, see: (a) J ust, G.; Oh, H. Can. J . Chem. 1981, 59, 2729. (b)
J ust, G.; Luthe, C.; Oh, H. Tetrahedron Lett. 1980, 21, 1001. Following
our nomenclature, these would be 8-epi-ST-∆13-9-IsoF and 8-epi-15-
epi-ST-∆13-9-IsoF.
(6) (a) Iqbal, J .; Khan, M. A. Synth. Commun. 1989, 19, 515. (b)
Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J .
Tetrahedron 1987, 43, 2089.
(14) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z.
M.; Xu, D.; Zhang, X. L. J . Org. Chem. 1992, 57, 2768. (b) Xu, D.;
Crispino, G. A.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114, 7570.
(c) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(7) Lancois, D.; Maddaluno, J . Tetrahedron Lett. 1998, 39, 2335.
(8) Taber, D. F.; Green, J . H.; Zhang, W.; Song, R. J . Org. Chem.
2000, 65, 5436.
(9) Denmark, S. E.; J ones, T. K. J . Org. Chem. 1982, 47, 4595.
(10) Boland, W.; Hansen, V.; J aenicke, L. Synthesis 1979, 114.
(11) Kovarova, I.; Streinz, L. Synth. Commun. 1993, 23, 2397.
(12) Grant, B.; Djerassi, C. J . Org. Chem. 1974, 39, 968.
(13) Hanson, R. M.; Sharpless, K. B. J . Org. Chem. 1986, 51, 1922.
(15) Shiragami, H.; Irie, Y.; Shirae, H.; Yokozeki, K.; Yasuda, N. J .
Org. Chem. 1988, 53, 5170.
(16) Mansuri, M. M.; Starrett, J . E.; Wos, J . A.; Tortolani, D. R.;
Brodfuehrer, P. R.; Howell, H. G.; Martin, J . C. J . Org. Chem. 1989,
54, 4780.
(17) Burke, S. D.; J iang, L. Org. Lett. 2001, 3, 1953.
(18) Ho, D. K.; McKenzie, A. T.; Byrn, S. R.; Cassady, J . M. J . Org.
Chem. 1987, 52, 342.
J . Org. Chem, Vol. 69, No. 21, 2004 7235

Taber et al.
SCHEME 3
to first protect it (Scheme 3) before proceeding with the
construction of the two side chains. It seemed sensible
to extend the upper side chain first, since the epoxide of
2 was already primed for SN2 opening.
For the upper side chain, Lewis-acid assisted opening
of the epoxide 2 with the lithium anion derived from the
commercially available nitrile required some optimiza-
tion. Using BF3‚OEt2 as the Lewis acid, the reaction
temperature proved to be critical. An extended reaction
time at low temperature was required to give efficient
conversion to the alkyne 12.20 Partial hydrogenation
using P-2 Ni catalyst followed by hydrolysis then afforded
the cis-alkene 13.8,21
Con str u ction of th e Low er Sid e Ch a in . The next
step in the synthesis was the addition of a pentyl unit to
complete the isofuran skeleton. While it would have been
possible to control the allylic alcohol stereocenter by
enantioselective addition, we in fact wanted to prepare
both diastereomers of the isofurans. Direct addition of
pentylmagnesium bromide to 13 indeed gave the triol as
the expected 1:1 mixture of diastereomers. These alco-
hols, however, ran together on TLC with each of the
solvent systems that we tried.
The solution to this problem turned out to be to first
re-silylate the secondary alcohols of 13. We found that
the ring OH silylated much more readily than did the
side-chain OH. In practice, it was most convenient to
carry the diol 13 on to the bis-silylated intermediate. The
addition of pentylmagnesium bromide then gave a 1:1
ratio of the separable alcohols 14a and 14b.
Assign m en t of th e C-15 Absolu te Con figu r a tion .
The choice of silyl protecting group was dictated by the
need for a UV chromophore, so we could develop the
analytical HPLC separation of 14a and 14b. The mixture
of 14a and 14b was then oxidized to the C-15 ketone,
and the enone so prepared was reduced with (S)-DIP-
Cl,19,20 which was expected to give predominantly 14a .
This allowed us to assign the absolute configuration at
C-15 of the two alcohol diastereomers.
temperatures (even room temperature) and longer reac-
tion times resulted in epoxide ring opening of 2 by
methanol.
Syn th esis of th e Isofu r a n s. The final step in our
synthesis was the hydrolysis, separately, of the nitriles
14a and 14b. When nitrile 14a was heated in 15% NaOH
and EtOH at 105 °C,8,21 the desired carboxylic acid 3a
was isolated in low yield. However, when the hydrolysis
was carried out on the deprotected compound, which was
obtained by exposure of 14a to TBAF, the desired
carboxylic acid 3a was isolated in excellent yield. For
better characterization, the isofuran 3a was converted
to its methyl ester 15a by treatment with trimethylsi-
lyldiazomethane.22 In a similar fashion, nitrile 14b was
converted into isofuran 3b and its methyl ester 15b.
Neither the Sharpless asymmetric epoxidation nor the
dihydroxylation proceeds with perfect enantiocontrol. We
therefore expected that 2 would be contaminated with
minor amounts of other diasteromers. As it turned out,
the epoxide 2 was easily separated from trace contami-
nants by recrystallization. X-ray analysis confirmed both
the relative and the absolute configuration of this central
intermediate.
In ver sion of th e Secon d a r y Alcoh ol. The epimeric
alcohol 2a will be the precursor to the ST series of the
isofurans (Scheme 1). The inversion to prepare 2a was a
delicate transformation, as 2 was prone to further cy-
clization by intramolecular addition of the secondary al-
cohol to the epoxide. Nevertheless, the secondary alcohol
of 2 participated efficiently in Mitsunobu inversion19 to
give, after methanolysis, the inverted alcohol 2a .
Con str u ction of th e Up p er Sid e Ch a in . Because of
the propensity of the secondary alcohol of 2 to cyclize by
intramolecular addition to the epoxide, it was necessary
The synthetic isofurans 3a and 3b were congruent
1
(TLC, HPLC-MS) with the natural substances. The H
NMR data for the methyl esters 15a and 15b were very
similar to those reported5 for the methyl esters of 8-epi-
ST-∆13-9-IsoF and 8-epi-15-epi-ST-∆13-9-IsoF.
(20) Sinha, S. C.; Keinan, E. J . Org. Chem. 1999, 64, 7067.
(21) (a) Taber, D. F.; Hoerrner, R. S. J . Org. Chem. 1992, 57, 441.
(b) Magatti, C. V.; Kaminski, J . J .; Rothberg, I. J . Org. Chem. 1991,
56, 3102.
(19) (a) Mitsunobu, O. Synthesis 1981, 1 and references therein. (b)
Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017.
(22) (a) Quan, L. G.; Cha, J . K. J . Am. Chem. Soc. 2002, 124, 12424.
(b) Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 5, 93.
7236 J . Org. Chem., Vol. 69, No. 21, 2004

Isofuran Synthesis
for another 30 min. The solid was filtered and rinsed with
diethyl ether. The combined filtrate was concentrated, and the
resulting residue was chromatographed to give alkene 8 as a
colorless oil (7.80 g, 32.7 mmol, 61% yield): TLC Rf (MTBE/
petroleum ether ) 4:6) ) 0.27; 1H NMR δ 0.72 (s, 3H), 1.21 (s,
3H), 2.84 (t, J ) 5.6 Hz, 2H), 3.50 (d, J ) 10.6 Hz, 2H), 3.65
(d, J ) 10.6 Hz, 2H), 4.10 (d, J ) 3.9 Hz, 2H), 4.89 (d, J ) 4.8
Hz, 1H), 5.60-5.80 (m, 4H), 6.03-6.09 (m, 1H), 6.39 (dd, J )
10.5, 15.6 Hz, 1H); 13C NMR δ u 77.5, 63.8, 35.3, 30.4; d 134.4,
133.6, 130.5, 130.4, 127.5, 100.8, 23.2, 22.1; IR (cm-1) 3416,
1470, 1091; CI MS m/z (rel intensity) 239.2 (30, M + H), 167.1
(47), 128.1(100), 115.0 (42); HRMS calcd for C14H23O3 (M +
H) 239.1647, obsd 239.1643.
Ep oxid e 9. To dry CH2Cl2 (20 mL) were added diethyl
D-tartrate (1.17 g, 5.65 mmol) and titanium(IV) isopropoxide
(1.60 g, 5.62 mmol) at -30 to -20 °C. The mixture was stirred
for 30 min. A solution of alkene 8 (1.23 g, 5.18 mmol) in CH2-
Cl2 (29 mL) was added, and the mixture was stirred at -30 to
-20 °C for 20 min. tert-Butyl hydroperoxide (3.4 mL, 4.0 M in
CH2Cl2, 13.6 mmol) was then added dropwise over 10 min. The
resulting mixture was stirred at -30 to -20 °C for 14.5 h.
Aqueous L-(+) tartaric acid (10% w/w, 10.5 mL) was added.
The mixture was stirred at -20 °C for 30 min, allowed to warm
to rt, and stirred for 1 h. Aqueous NaOH (1 N, 28.5 mL) was
added at 0 °C, and the resulting mixture was stirred for 1 h.
The reaction mixture was then partitioned between CH2Cl2
and water. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to
give epoxide 9 as a colorless oil (1.19 g, 4.69 mmol, 90%
yield): TLC Rf (MTBE/petroleum ether ) 1:1) ) 0.19; 1H NMR
δ 0.74 (s, 3H), 1.21 (s, 3H), 1.72 (dd, J ) 7.2, 5.6 Hz, 1H), 2.41
(m, 2H), 2.94 (dt, J ) 4.2, 2.4 Hz, 1H), 3.04 (td, J ) 5.3, 2.3
Hz, 1H), 3.51 (d, J ) 10.8 Hz, 2H), 3.60-3.67 (m, 3H), 3.91
(ddd, J ) 12.7, 4.5, 2.6 Hz, 1H), 4.90 (d, J ) 4.8 Hz, 1H), 5.66
(dd, J ) 15.6, 4.8 Hz, 1H), 5.75 (dt, J ) 15.2, 7.2 Hz, 1H), 6.15
(dd, J ) 10.6, 14.8 Hz, 1H), 6.39 (dd, J ) 10.5, 15.6 Hz, 1H);
13C NMR δ u 77.5, 61.6, 34.6, 30.4; d 133.3, 132.2, 130.5, 128.3,
100.7, 58.0, 54.9, 23.2, 22.1; IR (cm-1) 3434, 1392, 1091; HRMS
Con clu sion
We have established what we expect will be a general
route to the isofurans. The key step is the cascade cycli-
zation of the diol 1 to the epoxide 2. This approach will
make each of these natural products, previously known
only in microgram quantities as mixtures, available in
sufficient quantity to assess their individual physiological
activity.
Exp er im en ta l Section
Br om ok eta l 6. To (2E,4E)-2,4-hexadienal (9.19 g, 95.7
mmol) were added, sequentially, pentane (135 mL), TMSCl
(16.0 mL, 126 mmol), and triethylamine (17.0 mL). A solution
of NaI (19.8 g, 126 mmol) in acetonitrile (135 mL) was added
dropwise. The mixture was stirred vigorously for 24 h and then
maintained at reflux for 12 h. The reaction mixture was then
partitioned between pentane and water. The combined organic
extracts were dried (Na2SO4) and concentrated. The residue
was bulb-to-bulb distilled to give 1-(trimethylsilyloxy)hexa-
1,3,5-triene as a colorless oil (10.2 g, 56.8 mmol), bp (pot) )
80-85 °C (10 mmHg). It was used immediately in the next
reaction without further purification.
To a solution of 1-(trimethylsilyloxy)hexa-1,3,5-triene (10.2
g, 56.8 mmol) in DMF (90 mL) was added dropwise a solution
of Br2 (9.10 g, 56.9 mmol) in DMF (20 mL) at -55 °C. After
the addition, the reaction mixture was stirred at -55 to -30
°C for 1.5 h. The mixture was cooled to -55 °C, and a solution
of 2,2-dimethyl-1,3-propanediol (29.7 g, 286 mmol) in DMF (90
mL) was added dropwise over 30 min. The mixture was stirred
at -55 °C overnight and allowed to warm to room temperature.
The mixture was partitioned between diethyl ether and,
sequentially, water, saturated aqueous NaHCO3, and brine.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give bro-
moketal 6 as a colorless oil (10.4 g, 39.8 mmol, 41% yield for
two steps): TLC Rf (MTBE/petroleum ether ) 1:9) ) 0.40; 1H
NMR δ 0.75 (s, 3H), 1.22 (s, 3H), 3.51 (d, J ) 10.6 Hz, 2H),
3.66 (d, J ) 10.6 Hz, 2H), 4.01 (d, J ) 7.9 Hz, 2H), 4.92 (d, J
) 4.5 Hz, 1H), 5.76 (dd, J ) 15.4, 7.9 Hz, 1H), 5.95 (dt, J )
14.9, 7.9 Hz, 1H), 6.28 (dd, J ) 10.8, 14.9 Hz, 1H), 6.41 (dd, J
) 10.8, 15.4 Hz, 1H); 13C NMR δ u 77.5, 32.8, 30.2; d 133.7,
131.9, 131.1, 131.0, 100.2, 23.2, 22.1; IR (cm-1) 1716, 1682,
1640; CI MS m/z (rel intensity) 261.1 (12, M + H), 181.1 (100),
115 (24), 95 (37); HRMS calcd for C11H18O2Br (M + H)
261.0490, obsd 261.0487.
calcd for C14H23O4 (M + H) 255.1596, obsd 255.1600; [R]D
+21 (c 0.553, CH2Cl2).
)
Ben zen esu lfon a te 10. To a solution of epoxide 9 (7.07 g,
27.8 mmol) in CH2Cl2 (160 mL) was added DMAP (0.456 g,
3.73 mmol). The solution was cooled to 0 °C, and Et3N (9.82 g,
97.0 mmol) was added, followed by benzenesulfonyl chloride
(12.2 g, 68.9 mmol) dropwise over 15 min. The mixture was
allowed to warm to rt and stirred for 3.5 h. The reaction
mixture was then partitioned between CH2Cl2 and saturated
aqueous NaHCO3. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed
to give benzenesulfonate 10 as a colorless oil (10.5 g, 26.6
mmol, 96% yield): TLC Rf (MTBE/petroleum ether ) 1:1) )
0.39; 1H NMR δ 0.74 (s, 3H), 1.21 (s, 3H), 2.87 (td, J ) 2.1, 5.3
Hz, 1H), 2.96-2.99(m, 1H), 3.50 (d, J ) 11.1 Hz, 2H), 3.65 (d,
J ) 11.1 Hz, 2H), 4.01 (dd, J ) 5.8, 11.4 Hz, 1H), 4.22 (dd, J
) 3.7, 11.4 Hz, 1H), 4.89 (d, J ) 4.4 Hz, 1H), 5.62-5.69 (m,
2H), 6.11 (dd, J ) 10.4, 14.9 Hz, 1H), 6.36 (dd, J ) 10.4, 15.5
Hz, 1H), 7.55-7.60 (m, 2H), 7.65-7.70 (m, 1H), 7.91-7.94 (m,
2H); 13C NMR δ u 77.5, 70.2, 34.3, 30.4; d 134.2, 133.1, 132.6,
129.6, 129.5, 128.6, 128.1, 100.6, 55.7, 54.1, 23.2, 22.1; IR
(cm-1) 1716, 1682, 1640; HRMS calcd for C20H26O6NaS (M +
Na) 417.1348, obsd 417.1343; [R]D ) +23 (c 0.435, CH2Cl2).
Diols 1 a n d 11. To benzenesulfonate 10 (7.92 g, 20.1 mmol),
t-BuOH (100 mL), and H2O (100 mL) cooled to 0 °C was added
AD-mix-R (29.3 g). After 10 min, methanesulfonamide (1.93
g, 20.3 mmol) was added. The resulting mixture was stirred
at 0 °C for 42 h. Solid NaHSO3 (30.1 g, 289 mmol) was carefully
added to the reaction mixture. It was stirred at rt for 1 h. The
reaction mixture was then partitioned between EtOAc and
water. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give diol
1 as a colorless oil (4.05 g, 9.45 mmol, 47% yield). Diol 11 was
isolated as a side product (3.15 g, 7.35 mmol, 37% yield).
P r op a r gyl Alcoh ol 7. To a solution of bromoketal 6 (30.4
g, 116 mmol) in acetone (435 mL) was added propargyl alcohol
(8.13 g, 145 mmol), anhydrous K2CO3 (32.2 g, 233 mmol), NaI
(36.4 g, 242 mmol), CuI (24.9 g, 131 mmol), and heptane (24
mL). The mixture was stirred at rt for 45 h and then filtered.
The solid was rinsed with MTBE (200 mL). The filtrate was
concentrated, and the residue was chromatographed to give
propargyl alcohol 7 as a colorless oil (20.3 g, 85.8 mmol, 74%
yield): TLC Rf (MTBE/petroleum ether ) 3:7) ) 0.21; 1H NMR
δ 0.74 (s, 3H), 1.21 (s, 3H), 3.05 (m, 2H), 3.50 (d, J ) 11.0 Hz,
2H), 3.65 (d, J ) 11.0 Hz, 2H), 4.28 (m, 2H), 4.90 (d, J ) 4.8
Hz, 1H), 5.65-5.76 (m, 2H), 6.23-6.30 (m, 1H), 6.40 (dd, J )
10.6, 15.4 Hz, 1H); 13C NMR δ u 83.0, 80.7, 77.4, 51.5, 30.4,
22.2; d 132.8, 130.7, 130.0, 128.5, 100.7, 23.1, 22.1; IR (cm-1
3426, 2227, 1471; CI MS m/z (rel intensity) 237.1 (16, M +
H), 115 (100); HRMS calcd for C14H21O3 (M + H) 237.1491,
obsd 237.1491.
Alk en e 8. To a solution of propargyl acohol 7 (12.63 g, 53.4
mmol) in anhydrous diethyl ether (177 mL) was added care-
fully powdered LiAlH4 (3.45 g, 90.9 mmol) over 15 min at 0
°C. After the addition, the suspension was stirred at rt for 6
h. The reaction mixture was cooled in an ice bath, and 3.5 mL
of cold water was added dropwise over 5 min. After 30 min of
vigorous stirring, 3.5 mL of aqueous NaOH (15% w/v) was
added, and the mixture was stirred for an additional 30 min.
Then 10.5 mL of water was added, and the mixture was stirred
)
J . Org. Chem, Vol. 69, No. 21, 2004 7237

Taber et al.
For diol 1: TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.28; 1H NMR
δ 0.74 (s, 3H), 1.19 (s, 3H), 1.63-1.70 (m, 1H), 1.82 (dt, J )
14.6, 4.2 Hz, 1H), 2.81 (br, 1H), 3.01-3.07 (m, 3H), 3.49 (d, J
) 10.9 Hz, 1H), 3.62-3.67 (m, 3H), 3.96-4.01 (m, 2H), 4.22
(dd, J ) 3.4, 11.4 Hz, 1H), 4.87 (d, J ) 4.3 Hz, 1H), 5.83 (dd,
J ) 4.3, 15.9 Hz, 1H), 5.92 (dd, J ) 5.6, 15.8 Hz, 1H), 7.55-
7.59 (m, 2H), 7.66-7.70 (m, 1H), 7.91-7.93 (m, 2H); 13C NMR
δ u 135.8, 77.4, 70.4, 34.5, 30.3; d 134.2, 133.6, 129.9, 129.5,
128.1, 100.2, 74.4, 72.0, 54.4, 54.3, 23.1, 22.0; IR (cm-1) 3416,
1362, 1107; HRMS calcd for C20H28O8NaS (M + Na) 451.1403,
obsd 451.1413; [R]D ) +16 (c 0.935, CH2Cl2).
For diol 11: TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.49; 1H NMR
δ 0.75 (s, 3H), 1.19 (s, 3H), 2.32-2.36 (m, 2H), 2.66 (d, J ) 6.1
Hz, 1H), 2.88-2.91 (m, 2H), 3.00-3.03 (m, 1H), 3.46-3.51 (m,
3H), 3.67 (d, J ) 11.2 Hz, 2H), 4.00 (dd, J ) 5.9, 11.4 Hz, 1H),
4.24 (dd, J ) 3.7, 11.4 Hz, 1H), 4.41 (br, 1H), 4.58 (d, J ) 3.8
Hz, 1H), 5.64-5.77 (m, 2H), 7.55-7.60 (m, 2H), 7.66-7.70 (m,
1H), 7.91-7.94 (m, 2H); 13C NMR δ u 135.8, 77.3, 70.3, 34.0,
30.7; d 134.2, 132.6, 129.5, 128.1, 126.3, 101.5, 73.9, 70.9, 55.7,
54.1, 23.1, 21.8; IR (cm-1) 3472, 1449, 1188; HRMS calcd for
1362, 1107; HRMS calcd for C14H22O5 270.1467, obsd 270.1472;
[R]D ) +29 (c 0.593, CH2Cl2).
Ep oxid e 2a . To a solution of epoxide 2 (49.5 mg, 0.183
mmol), triphenylphosphine (254 mg, 0.967 mmol), and 4-ni-
trobenzoic acid (147 mg, 0.878 mmol) in THF (3.5 mL) at 0 °C
was added diisopropyl azodicarboxylate (298 mg, 1.47 mmol)
over 5 min. The mixture was stirred at rt for 11 h. The volatiles
were removed, and the residue was chromatographed to give
the p-nitrobenzoate as a colorless oil (70.7 mg, 0.169 mmol,
92% yield): TLC Rf (MTBE/petroleum ether ) 4:6) ) 0.32; 1H
NMR δ 0.75 (s, 3H), 1.22 (s, 3H), 3.51 (d, J ) 10.6 Hz, 2H),
2.18-2.21 (m, 2H), 2.66 (dd, J ) 2.6, 4.9 Hz, 1H), 2.88 (dd, J
) 4.2, 4.7 Hz, 1H), 3.17-3.20 (m, 1H), 3.51 (d, J ) 11.1 Hz,
2H), 3.65 (d, J ) 11.1 Hz, 2H), 4.12-4.19 (m, 1H), 4.64-4.65
(m, 1H), 4.92 (d, J ) 4.2 Hz, 1H), 5.34-5.36 (m, 1H), 5.97 (ddd,
J ) 1.4, 4.2, 15.7 Hz, 1H), 6.07 (ddd, J ) 0.8, 4.9, 15.7 Hz,
1H), 8.19 (d, J ) 9.0 Hz, 2H), 8.30 (d, J ) 9.04 Hz, 1H); 13C
NMR δ u 164.2, 150.9, 135.2, 77.5, 45.8, 33.5, 30.4; d 131.6,
131.0, 129.4, 123.8, 100.1, 83.8, 80.3, 79.6, 52.7, 23.2, 22.1; IR
(cm-1) 1724, 1529, 1274.
To a solution of p-nitrobenzoate (11.8 mg, 0.0281 mmol) in
CH3OH (0.5 mL) was added finely powdered K2CO3 (250 mg,
1.81 mmol). The mixture was stirred at rt for 30 min. The
reaction mixture was then partitioned between water and CH2-
Cl2. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give ep-
oxide 2a as a colorless oil (7.2 mg, 0.027 mmol, 95% yield):
TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.38; 1H NMR δ 0.74 (s, 3H),
1.21 (s, 3H), 1.92-2.04 (m, 2H), 2.61 (dd, J ) 2.4, 4.8 Hz, 1H),
2.82 (t, J ) 4.4 Hz, 1H), 3.08-3.11 (m, 1H), 3.49 (d, J ) 10.8
Hz, 2H), 3.65 (d, J ) 10.8 Hz, 2H), 4.10-4.15 (m, 1H), 4.21-
4.24 (m, 1H), 4.29 (dd, J ) 3.2, 5.4 Hz, 1H), 4.88 (d, J ) 4.0
Hz, 1H), 5.86 (dd, J ) 4.0, 16.0 Hz, 1H), 5.93 (dd, J ) 5.6,
16.0 Hz, 1H); 13C NMR δ u 77.4, 45.7, 35.8, 30.5; d 132.8, 129.0,
100.2, 86.3, 78.6, 76.3, 53.1, 23.2, 22.1; IR (cm-1) 3435, 1393,
1095; HRMS calcd for C14H22O5 270.1467, obsd 270.1463; [R]D
) -35 (c 0.520, CH2Cl2).
C
20H28O8NaS (M + Na) 451.1403, obsd 451.1413; [R]D ) +15
(c 0.375, CH2Cl2).
Diol 11 to Alcoh ol 7. A mixture of diol 11 (123 mg, 0.287
mmol), pyridinium p-toluenesulfonate (9.2 mg, 0.037 mmol),
and trimethyl orthoformate (328 mg, 3.09 mmol) in THF (3
mL) was stirred at rt for 18 h. The solvent was evaporated,
and the residue was chromatographed to give the orthoformate
as a colorless oil (90.6 mg, 0.193 mmol, 67%): TLC Rf (MTBE/
petroleum ether ) 4:6) ) 0.21. This was a mixture of
diastereomers.
A mixture of the orthoformate (21.1 mg, 0.0448 mmol),
NaHCO3 (127 mg 1.51 mmol), and acetic anhydride (2 mL)
was stirred at reflux for 1.8 h. The volatiles were evaporated,
and the residue was partitioned between CH2Cl2 and water.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give the
diene acetate as a colorless oil (11.9 mg, 0.0402 mmol, 89%
yield): TLC Rf (MTBE/petroleum ether ) 1:1) ) 0.61; 1H NMR
δ 0.75 (s, 3H), 1.21 (s, 3H), 2.09 (s, 3H), 2.41 (t, J ) 6.2 Hz,
2H), 2.94 (td, J ) 5.2, 2.0 Hz, 1H), 2.99 (m, 1H), 3.51 (d, J )
11.2 Hz, 2H), 3.66 (d, J ) 11.2 Hz, 2H), 3.93 (dd, J ) 12.2, 6.2
Hz, 1H), 4.36 (dd, J ) 12.2, 3.0 Hz, 1H), 4.90 (d, J ) 4.8 Hz,
1H), 5.66 (dd, J ) 15.6, 4.8 Hz, 1H), 5.73 (dt, J ) 15.2, 7.2 Hz,
1H), 6.15 (dd, J ) 10.6, 15.2 Hz, 1H), 6.39 (dd, J ) 10.6, 15.6
Hz, 1H); 13C NMR δ u 171.0, 77.5, 64.6, 34.5, 30.4; d 133.2,
132.4, 130.1, 128.4, 100.7, 55.5, 54.8, 23.2, 22.1.
Alk yn e 12. To a solution of alcohol 2 (0.103 g, 0.381 mmol)
in CH2Cl2 (2.5 mL) at 0 °C were added TBDMSCl (0.126 g,
0.837 mmol) and imidazole (0.0625 g, 0.918 mmol). The
mixture was stirred at rt overnight (12 h). The reaction
mixture was then partitioned between water and CH2Cl2. The
combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to give the silyl
ether as a colorless oil (0.141 g, 0.367 mmol, 97% yield): TLC
1
Rf (MTBE/PE ) 1:1) ) 0.55; H NMR δ 0.06 (s, 3H), 0.07 (s,
3H), 0.73 (s, 3H), 0.89 (s, 9 H), 1.18 (s, 3H), 2.05 (ddd, J )
13.4, 3.4, 1.8 Hz, 1H), 2.31 (m, 1H), 2.68 (dd, J ) 5.1, 2.6 Hz,
1H), 2.80-2.82 (m, 1H), 3.13-3.17 (m, 1H), 3.48 (d, J ) 11.0
Hz, 2H), 3.63 (d, J ) 11.0 Hz, 2H), 3.70-3.75 (m, 1H), 4.23-
4.25 (m, 1H), 4.28-4.30 (m, 1H), 4.87 (d, J ) 3.7 Hz, 1H), 5.78
(dd, J ) 4.1, 15.8 Hz, 1H), 6.05 (ddd, J ) 0.9, 7.4, 15.8 Hz,
1H); 13C NMR δ u 77.4, 77.3, 47.3, 39.4, 30.4, 18.3; d 131.2,
130.2, 100.2, 84.2, 79.3, 74.6, 54.2, 26.0, 23.2, 22.1, -4.6, -4.8;
IR (cm-1) 1392, 1138, 1060; HRMS calcd for C20H36O5NaSi (M
+ Na) 407.2230, obsd 407.2243; [R]D ) +32 (c 0.523, CH2Cl2).
To a solution of diene acetate (9.6 mg, 0.032 mmol) in meth-
anol (1 mL) was added finely powdered K2CO3 (35.5 mg, 0.257
mmol). The mixture was stirred at rt for 30 min. The volatiles
were removed, and the residue was partitioned between CH2-
Cl2 and, sequentially, cold 5% aqueous HCl and saturated aq-
ueous NaHCO3. The combined organic extract was dried (Na2-
SO4) and concentrated. The residue was chromatographed to
give alcohol 7 as a colorless oil (6.0 mg, 0.024 mmol, 73% yield).
Ep oxid e 2. To a solution of diol 1 (1.61 g, 3.77 mmol) in
CH3OH (18 mL) was added finely powdered K2CO3 (1.06 g,
7.68 mmol). The mixture was stirred at 0 °C for 2 h. The
reaction mixture was then partitioned between water and CH2-
Cl2. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give ep-
oxide 2 as a colorless solid (0.731 g, 2.70 mmol, 72% yield):
mp 94-95 °C; TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.46; 1H NMR
δ 0.74 (s, 3H), 1.21 (s, 3H), 1.82 (ddd, J ) 1.2, 3.6, 14.0 Hz,
1H), 2.28 (ddd, J ) 5.2, 9.2, 14.0 Hz, 1H), 2.65 (dd, J ) 3.0,
4.6 Hz, 1H), 2.68 (d, J ) 6.8 Hz, 1H), 2.86 (t, J ) 4.4 Hz), 3.26
(td, J ) 4.0, 2.8 Hz, 1H), 3.49 (d, J ) 11.2 Hz, 2H), 3.65 (d, J
) 11.2 Hz, 2H), 4.16 (dt, J ) 9.2, 3.6 Hz, 1H), 4.20-4.22 (m,
1H), 4.29 (ddd, J ) 0.8, 3.2, 6.0 Hz, 1H), 4.92 (d, J ) 4.4 Hz,
1H), 5.93 (ddd, J ) 1.2, 4.8, 16.0 Hz, 1H), 6.08 (ddd, J ) 1.2,
6.0, 16.0 Hz, 1H); 13C NMR δ u 77.4, 46.0, 35.9, 30.3; d 130.9,
130.0, 100.4, 83.9, 77.9, 73.1, 53.8, 23.2, 22.1; IR (cm-1) 3416,
To a stirred solution of 5-hexynenitrile (0.301 g, 3.23 mmol)
in THF (2.5 mL) was added dropwise n-BuLi (1.1 mL, 2.5 M
in hexanes, 2.75 mmol) at -75 °C. The solution was stirred at
-75 to -70 °C for 1 h. A solution of the silyl ether (0.228 g,
0.593 mmol) in THF (2.5 mL) was added, followed by the
addition of BF3‚Et2O (0.281 g, 1.98 mmol). After the addition,
the mixture was stirred at -78 to -75 °C for 50 min. The
reaction was quenched with saturated aqueous NH4Cl (0.5
mL). The reaction mixture was then partitioned between water
and CH2Cl2. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to
give alkyne 12 as a colorless oil (0.254 g, 0.532 mmol, 90%
1
yield): TLC Rf (MTBE/PE ) 1:1) ) 0.25; H NMR δ 0.07 (s,
3H), 0.08 (s, 3H), 0.73 (s, 3H), 0.89 (s, 9H), 1.19 (s, 3H), 1.80-
1.87 (m, 2H), 2.02 (ddd, J ) 13.7, 4.0, 1.2 Hz, 1H), 2.17-2.36
(m, 4H), 2.41-2.50 (m, 3H), 3.05 (d, J ) 2.7 Hz, 1H), 3.48 (d,
7238 J . Org. Chem., Vol. 69, No. 21, 2004

Isofuran Synthesis
J ) 11.1 Hz, 2H), 3.63 (d, J ) 11.1 Hz, 2H), 3.92 (m, 1H), 4.15
(dd, J ) 2.8, 7.3 Hz, 1H), 4.22 (dd, J ) 3.4, 11.4 Hz, 1H), 4.87
(dd, J ) 4.0, 0.7 Hz, 1H), 5.79 (ddd, J ) 15.9, 4.0, 0.7 Hz, 1H),
6.02 (ddd, J ) 15.9, 7.3, 1.1 Hz, 1H); 13C NMR δ u 119.5, 79.6,
78.4, 77.4, 77.3, 35.4, 30.4, 24.9, 24.2, 18.4, 18.1, 16.3; d 130.6,
130.4, 100.1, 83.6, 80.3, 74.5, 71.3, 25.9, 23.1, 22.1, -4.7, -4.8;
IR (cm-1) 3470, 2248, 1058; HRMS calcd for C26H43NO5NaSi
(M + Na) 500.2808, obsd 500.2786; [R]D ) +17 (c 0.438, CH2-
Cl2).
132.8, 130.3, 130.2, 130.0, 130.0, 129.3, 128.1, 127.9, 127.8,
127.8, 127.1, 80.8, 79.7, 74.9, 74.7, 27.2, 27.1; IR (cm-1) 2247,
1694, 1112; HRMS calcd for
778.3724, obsd 778.3688; [R]D ) -46 (c 0.434, CH2Cl2).
C47H57NO4NaSi2 (M + Na)
To a stirred solution of the TBDPS-protected aldehyde (74.0
mg, 0.0979 mmol) in THF (0.5 mL) at 0 °C was added
pentylmagnesium bromide in THF (1.25 M, 150 µL, 0.188
mmol). The mixture was stirred at 0 °C for 30 min. The
reaction mixture was partitioned between saturated aqueous
NH4Cl and CH2Cl2. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was analyzed by
HPLC. Column: Partisil 10; detector: UV 254 nm; flow rate:
1 mL/min; mobile phase: hexanes/ethyl acetate 85:15; reten-
tion times: 19.1 min for 14a , 21.6 min for 14b; ratio: 14a /
14b ) 1:1.1. The residue was chromatographed to give alcohol
14a as a colorless oil (29.5 mg, 0.0356 mmol, 36% yield). This
was followed by alcohol 14b (26.9 mg, 0.0325 mmol, 33% yield)
as a colorless oil.
For alcohol 14a : TLC Rf (Et2O/CH2Cl2/petroleum ether )
1:3:6) ) 0.44; 1H NMR δ 0.88 (t, J ) 6.8 Hz, 3H), 1.03 (s, 9H),
1.06 (s, 9H), 1.21-1.43 (m, 8H), 1.51-1.58 (m, 2H), 1.82-1.89
(m, 3H), 2.00-2.09 (m, 2H), 2.13 (t, J ) 7.4 Hz, 2H), 2.23-
2.30 (m, 1H), 3.58-3.63 (m, 1H), 3.87-3.99 (m, 3H), 4.41-
4.46 (m, 1H), 5.18-5.25 (m, 1H), 5.37-5.44 (m, 1H), 5.57 (dd,
J ) 15.6, 6.4 Hz, 1H), 5.70 (dd, J ) 15.6, 7.1 Hz, 1H), 7.33-
7.37 (m, 8H), 7.41-7.45 (m, 4H), 7.58-7.62 (m, 4H), 7.67-
7.73 (m, 4H); 13C NMR δ u 134.5, 134.1, 133.9, 120.0, 38.1,
36.9, 32.3, 32.0, 26.3, 25.4, 25.3, 22.8, 19.7, 19.4, 16.5; d 136.7,
136.4, 136.2, 136.1, 136.0, 130.0, 129.9, 129.0, 128.0, 127.8,
127.8, 127.7, 127.7, 127.4, 82.7, 79.3, 75.0, 74.7, 72.6, 27.3, 27.1,
14.3; IR (cm-1) 3483, 2248, 1112; HRMS calcd for C52H69NO4-
NaSi2 (M + Na) 850.4663, obsd 850.4677; [R]D ) -19 (c 0.670,
CH2Cl2).
Ald eh yd e 13. To a solution of Ni(OAc)2‚4H2O (16.5 mg,
0.0663 mmol) in ethanol (0.6 mL) was added NaBH4 solution
in ethanol (1 N, 65 µL, 0.065 mmol). The black mixture was
evacuated and backfilled with H2 three times. Ethylenedi-
amine (4.5 µL, 0.0673 mmol) was added, followed by alkyne
12 (57.0 mg, 0.119 mmol) in ethanol (0.6 mL). The flask was
evacuated and backfilled with H2. The reaction mixture was
stirred at rt under H2 for 1.5 h. The black suspension was
diluted with MTBE (5 mL), and the mixture was filtered
through a short column packed with flash silica gel (7.0 g).
The column was eluted with MTBE (50 mL). The solvent was
removed to give the alkene as a colorless oil (52.0 mg, 0.11
mmol, 91% yield): TLC Rf (MTBE/PE ) 1:1) ) 0.30; 1H NMR
δ 0.07 (s, 3H), 0.08 (s, 3H), 0.73 (s, 3H), 0.89 (s, 9H), 1.18 (s,
3H), 1.70-1.77 (m, 2H), 2.02 (ddd, J ) 13.6, 4.3, 1.2 Hz, 1H),
2.12-2.25 (m, 5H), 2.41-2.50 (m, 3H), 2.39 (t, J ) 7.1 Hz, 2H),
2.96 (d, J ) 1.6 Hz, 1H), 3.48 (d, J ) 11.1 Hz, 2H), 3.63 (d, J
) 11.1 Hz, 2H), 3.85-3.88 (m, 1H), 4.04-4.07 (m, 1H), 4.11
(dd, J ) 2.8, 11.3 Hz, 1H), 4.24-4.26 (m, 1H), 4.87 (dd, J )
4.0, 0.6 Hz, 1H), 5.42-5.46 (m, 1H), 5.54-5.58 (m, 1H), 5.79
(ddd, J ) 16.0, 4.1, 0.6 Hz, 1H), 6.03 (ddd, J ) 15.9, 7.3, 1.0
Hz, 1H); 13C NMR δ u 120.0, 77.4, 77.3, 35.1, 32.1, 30.4, 26.3,
25.4, 18.4, 16.6; d 130.6, 130.5, 129.4, 128.1, 100.1, 83.4, 81.0,
74.6, 72.1, 25.9, 23.1, 22.1, -4.7, -4.8; IR (cm-1) 3479, 2247,
1059; HRMS calcd for C26H45NO5NaSi (M + Na) 502.2965,
obsd 502.2966; [R]D ) +17 (c 0.519, CH2Cl2).
To a solution of the alkene (28.2 mg, 0.0588 mmol) in
acetone (1.0 mL) was added dropwise aqueous HCl (1 N, 1.0
mL, 1.0 mmol) over 1 min. The mixture was stirred at rt for 2
h. The solvent was evaporated, and the residue was partitioned
between saturated aqueous NaHCO3 and CH2Cl2. The com-
bined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to give aldehyde 13 as a
colorless oil (11.0 mg, 0.0394 mmol, 67% yield): TLC Rf
(acetone/CH2Cl2 ) 2:8) ) 0.31; 1H NMR δ 1.71-1.78 (m, 2H),
2.02 (dd, J ) 14.2, 2.8 Hz, 1H), 2.16-2.26 (m, 4H), 2.31-2.39
(m, 3H), 3.75 (br, 1H), 3.91 (br, 1H), 4.20 (dt, J ) 9.9, 2.4 Hz,
1H), 4.31 (m, 1H), 4.47-4.51 (m, 2H), 5.47-5.55 (m, 2H), 6.40
(ddd, J ) 15.7, 8.1, 1.6 Hz, 1H), 6.93 (dd, J ) 15.7, 4.6 Hz,
1H), 9.57 (d, J ) 8.0 Hz, 1H); 13C NMR δ u 34.8, 32.1, 26.2,
25.1, 16.7; d 194.0, 152.8, 133.2, 130.7, 127.1, 83.1, 81.0, 72.9,
72.1; IR (cm-1) 3397, 2247, 1688; HRMS calcd for C15H22NO4
(M + H) 280.1549, obsd 280.1544; [R]D ) +15 (c 0.415, CH2-
Cl2).
Alcoh ols 14a a n d 14b. To a solution of aldehyde 13 (20.7
mg, 0.0741 mmol) in CH2Cl2 (0.7 mL) at 0 °C were added
TBDPSCl (209.5 mg, 0.762 mmol) and imidazole (24.2 mg,
0.355 mmol). The mixture was stirred at rt for 20 h. The
reaction mixture was then partitioned between water and CH2-
Cl2. The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to give the
TBDPS-protected aldehyde as a colorless oil (45.5 mg, 0.0602
mmol, 81% yield): TLC Rf (MTBE/PE ) 15:85) ) 0.29; 1H
NMR δ 1.01 (s, 9H), 1.05 (s, 9H), 1.53-1.60 (m, 2H), 1.75-
1.83 (m, 1H), 1.89-1.94 (m, 2H), 2.03-2.12 (m, 2H), 2.15 (t, J
) 7.4 Hz, 2H), 2.29-2.36 (m, 1H), 3.69 (dt, J ) 9.7 Hz, 6.0
Hz, 1H), 3.87-3.91 (m, 1H), 4.22-4.25 (m, 1H), 4.48-4.52 (q,
J ) 6.6 Hz, 1H), 5.25-5.28 (m, 1H), 5.43-5.49 (m, 1H), 6.09
(ddd, J ) 15.7 Hz, 8.0 Hz, 1.4 Hz, 1H), 6.56 (dd, J ) 15.7 Hz,
5.3 Hz, 1H), 7.34-7.40 (m, 8H), 7.41-7.47 (m, 4H), 7.54-7.59
(m, 4H), 7.65-7.73 (m, 4H), 9.36 (d, J ) 8.1 Hz, 1H); 13C NMR
δ u 134.2, 133.7, 133.4, 133.4, 119.9, 37.8, 32.2, 26.3, 25.4, 19.7,
19.3, 16.6; d 193.6, 154.5, 136.2, 136.2, 136.1, 136.0, 135.9,
For alcohol 14b: TLC Rf (Et2O/CH2Cl2/petroleum ether )
1:3:6) ) 0.35; 1H NMR δ 0.87 (t, J ) 6.8 Hz, 3H), 1.02 (s, 9H),
1.05 (s, 9H), 1.21-1.43 (m, 9H), 1.47-1.56 (m, 2H), 1.76-1.81
(m, 1H), 1.83-1.90 (m, 2H), 1.95-2.11 (m, 2H), 2.13 (t, J )
7.3 Hz, 2H), 2.20-2.27 (m, 1H), 3.58-3.63 (m, 1H), 3.86-3.90
(m, 1H), 3.94-4.00 (m, 2H), 4.39-4.44 (m, 1H), 5.18-5.25 (m,
1H), 5.37-5.44 (m, 1H), 5.60-5.73 (m, 2H), 7.33-7.37 (m, 8H),
7.40-7.45 (m, 4H), 7.58-7.62 (m, 4H), 7.66-7.72 (m, 4H); 13
C
NMR δ u 134.4, 134.0, 133.9, 133.8, 120.0, 38.1, 37.0, 32.3,
32.0, 26.3, 25.3, 25.3, 22.8, 19.7, 19.4, 16.6; d 136.9, 136.3,
136.2, 136.1, 136.0, 130.0, 129.9, 129.9, 129.8, 129.0, 128.1,
127.8, 127.8, 127.7, 127.7, 127.4, 82.8, 79.3, 74.8, 72.6, 27.3,
27.1, 14.3; IR (cm-1) 3492, 2248, 1112; HRMS calcd for C52H69
-
NO4NaSi2 (M + Na) 850.4663, obsd 850.4641; [R]D ) -20 (c
0.730, CH2Cl2).
Oxid a tion a n d Ch ir a l Red u ction of 14a a n d 14b. To a
stirred mixture of 14a and 14b (11.1 mg, 0.0134 mmol) in CH2-
Cl2 was added Dess-Martin periodinane (18.9 mg, 0.0446
mmol). The reaction mixture was stirred for 20 min and was
then concentrated. The residue was chromatographed to give
the enone as an oil (10.3 mg, 0.0125 mmol, 93%): TLC Rf
(MTBE/petroleum ether ) 1:2.7) ) 0.59; 1H NMR δ 0.89 (t, J
) 6.9 Hz, 3H), 1.01 (s, 9H), 1.06 (s, 9H), 1.17-1.68 (m, 8H),
1.74-1.82 (m, 1H), 1.86-1.92 (m, 2H), 1.99-2.10 (m, 2H), 2.14
(t, J ) 7.4 Hz, 2H), 2.27-2.35 (m, 1H), 2.42 (t, J ) 7.5 Hz,
2H), 3.65 (dt, J ) 9.8, 5.9 Hz, 1H), 3.88-3.92 (m, 1H), 4.14
(td, J ) 6.1, 1.2 Hz, 1H), 4.51 (q, J ) 6.5 Hz, 1H), 5.21-5.27
(m, 1H), 5.40-5.46 (m, 1H), 6.09 (dd, J ) 16.1, 1.3 Hz, 1H),
6.70 (dd, J ) 16.1, 5.8 Hz, 1H), 7.33-7.38 (m, 8H), 7.41-7.46
(m, 4H), 7.56-7.62 (m, 4H), 7.66-7.72 (m, 4H); 13C NMR δ u
200.6, 134.3, 133.8, 133.6, 133.4, 119.9, 39.8, 37.9, 32.3, 31.7,
26.3, 25.4, 23.9, 22.7, 19.7, 19.3, 16.5; d 143.0, 136.3, 136.2,
136.0, 135.9, 131.3, 130.1, 130.1, 129.9, 129.2, 127.9, 127.8,
127.8, 127.1, 81.4, 79.7, 75.0, 74.6, 27.3, 27.1, 14.2; IR (cm-1
)
2246, 1678, 1428; [R]D ) -32 (c 0.595, CH2Cl2).
To a solution of (-)-DIP-Cl (46 mg, 0.14 mmol) in THF (0.4
mL) was added a solution of the enone (11 mg, 0.014 mmol)
in THF (0.5 mL) at -78 °C. The reaction mixture was stirred
at rt for 8 h. The mixture was concentrated, and the residue
J . Org. Chem, Vol. 69, No. 21, 2004 7239

Taber et al.
was partitioned between CH2Cl2 and, sequentially, 15% aque-
ous NaOH and saturated aqueous NH4Cl. The combined organ-
ic extracts were dried (Na2SO4) and concentrated. The residue
was analyzed by HPLC, as above: ratio: 14a /14b ) 3.8:1.
Isofu r a n 3a . To a stirred solution of alcohol 14a (12.3 mg,
0.0149 mmol) in THF (0.5 mL) was added tetrabutylammo-
nium fluoride (0.1 mL, 1 M in THF, 0.1 mmol). After 15 min
of stirring, the mixture was partitioned between water and
CH2Cl2. The combined organic extracts were concentrated. To
the residue were added aqueous NaOH (15%, 0.5 mL) and
ethanol (0.2 mL). The mixture was sealed in a vial and heated
at 105 °C for 11 h. The mixture was cooled in an ice bath and
acidified with NaH2PO4 buffer (0.5 M, 2 mL) and acetic acid
(2 mL). The mixture was extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to give isofuran 3a as a colorless
oil (5.4 mg, 0.0146 mmol, 98% yield): TLC Rf (Et2O/0.5 M
aqueous NaH2PO4/HOAc ) 90:9:1, ether layer) ) 0.25; 1H
NMR δ 0.81-0.90 (m, 3H), 1.25-1.72 (m, 14H), 2.12-2.37 (m,
4H), 3.88 (m, 1H), 4.11 (m, 4H), 5.02 (br, 3H), 5.47 (m, 2H),
5.82 (m, 2H); IR (cm-1) 3382, 1711, 1048; HRMS calcd for
Isofu r a n 3b. The reaction was performed with the alcohol
14b (8.3 mg, 0.014 mmol) in the same manner as described
for the preparation of isofuran 3a to give isofuran 3b (4.7 mg,
0.013 mmol, 89% yield) as a colorless oil: TLC Rf (Et2O/0.5 M
aqueous NaH2PO4/HOAc ) 90:9:1, ether layer) ) 0.25; 1H
NMR δ 0.81-0.89 (m, 3H), 1.25-1.72 (m, 14H), 2.13-2.37 (m,
3H), 3.88 (m, 1H), 4.08-4.21 (m, 4H), 5.02 (br, 3H), 5.47 (br,
2H), 5.75-5.86 (m, 2H); IR (cm-1) 3390, 1713, 1047; HRMS
calcd for C20H34O6Na (M + Na) 393.2253, obsd 393.2235; [R]D
) +14 (c 0.425, CH2Cl2).
Meth yl Ester 15b. The reaction was performed with the
isofuran 3b (8.5 mg, 0.023 mmol) in the same manner as
described for the preparation of isofuran 15a to give methy
ester of isofuran 15b (7.3 mg, 0.019 mmol, 83% yield) as a
colorless oil: TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.38; 1H NMR
δ 0.83-0.89 (m, 3H), 1.25-1.32 (m, 3H), 1.35-1.60 (m, 3H),
1.67-1.74 (m, 2H), 1.99-2.16 (m, 7H), 2.21-2.29 (m, 1H), 2.32
(t, J ) 7.4 Hz, 2H), 3.67 (s, 3H), 3.86-3.91 (m, 1H), 4.04 (q, J
) 6.8 Hz, 1H), 4.11-4.21 (m, 3H), 4.50 (br, 2H), 5.44-5.51
(m, 2H), 5.72 (dd, J ) 15.5 Hz, 5.3 Hz, 1H), 5.84 (dd, J ) 15.5
Hz, 7.3 Hz, 1H); 13C NMR δ u 174.3, 36.7, 34.2, 33.6, 32.4,
31.9, 29.9, 26.9, 25.5, 24.9, 22.8; d 136.5, 131.3, 126.7, 126.4,
83.2, 80.4, 73.1, 72.3, 71.9, 51.8, 14.3; IR (cm-1) 3360, 1738,
1048; HRMS calcd for C20H34O6Na (M + Na) 407.2410, obsd
407.2394; [R]D ) +24 (c 0.365, CH2Cl2).
C
20H34O6Na (M + Na) 393.2253, obsd 393.2239; [R]D ) +28 (c
0.325, CH2Cl2).
Meth yl Ester 15a . To a solution of isofuran 3a (6.8 mg,
0.018 mmol) in CH3OH/benzene (1:4, 0.5 mL) was added
trimethylsilyl diazomethane (2.0 M in hexanes, 30 µL, 0.060
mmol). The mixture was stirred at rt for 1 h. The sovent was
removed, and the residue was chromatographed to give methyl
ester 15a as a colorless oil (7.1 mg, 0.018 mmol, 100% yield):
Ack n ow led gm en t. We thank Dr. L. J . Roberts II
and his associates for carrying out the comparison to
the natural isofuran mixture. We thank the National
Institutes of Health (GM42056) for support of this work.
1
TLC Rf (acetone/CH2Cl2 ) 2:8) ) 0.39; H NMR δ 0.86-0.90
(m, 3H), 1.25-1.32 (m, 3H), 1.48-1.60 (m, 2H), 1.65-1.77 (m,
3H), 2.02-2.29 (m, 7H), 2.32 (t, J ) 7.4 Hz, 2H), 2.47 (br, 1H),
3.31 (br, 1H), 3.67 (s, 3H), 3.85-3.90 (m, 1H), 4.05-4.20 (m,
4H), 5.41-5.54 (m, 2H), 5.80-5.89 (m, 2H); 13C NMR δ u 174.3,
37.1, 34.5, 33.6, 32.1, 32.0, 29.9, 26.9, 25.3, 24.9, 22.8; d 137.9,
132.1, 126.1, 126.0, 84.2, 80.5, 73.1, 72.3, 72.2, 51.8, 14.2; IR
(cm-1) 3390, 1738, 1049; HRMS calcd for C20H34O6Na (M +
Na) 407.2410, obsd 407.2415; [R]D ) +30 (c 0.285, CH2Cl2).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectra for all new compounds and X-ray data
for 2. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O048863O
7240 J . Org. Chem., Vol. 69, No. 21, 2004