Synthesis of the 5-hydroxymethyl-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural products descurainin and cartorimine

Article abstract of DOI:10.1016/j.tet.2005.10.083

Reaction of pyranulose 6 with styrenes 12c or 13 and Et₃N in CH₂Cl₂ at 25 °C afforded the [5+2] cycloadducts 14c and 15, which were hydrolyzed to give the natural products 1 and descurainin (2) in 24 and 27% overall yield, respectively. Heating pyranulose 6 with cinnamate ester 21 in the presence of 2,6-di-t-butylpyridine in CH₃CN at 175 °C afforded the [5+2] cycloadduct, which was hydrolyzed to give cartorimine (3) in 13% yield.

Full text of DOI:10.1016/j.tet.2005.10.083

Tetrahedron 62 (2006) 5171–5177
Synthesis of the 5-hydroxymethyl-6-aryl-8-oxabicyclo[3.2.1]oct-3-
en-2-one natural products descurainin and cartorimine
*
Barry B. Snider and James F. Grabowski
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, United States
Received 8 February 2005; revised 19 October 2005; accepted 20 October 2005
Available online 31 March 2006
ꢀ
Abstract—Reaction of pyranulose 6 with styrenes 12c or 13 and Et
were hydrolyzed to give the natural products 1 and descurainin (2) in 24 and 27% overall yield, respectively. Heating pyranulose 6 with cin-
3
N in CH
2
Cl
2
at 25 C afforded the [5+2] cycloadducts 14c and 15, which
ꢀ
namate ester 21 in the presence of 2,6-di-t-butylpyridine in CH
cartorimine (3) in 13% yield.
3
CN at 175 C afforded the [5+2] cycloadduct, which was hydrolyzed to give
Ó 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
R
O
O
O
R
+
Wen, He, Xue and Cao isolated the 8-oxabicyclo[3.2.1]oct-
3
O
O
1
Ar
OH
-3
Scheme 1. Retrosynthesis of 1–3.
-ene-2-one 1 in 1986 from Ligusticum chuanxing. Li and
Ar
AcO
co-workers isolated descurainin (2) with an additional me-
thoxy group from the seeds of Descurainia sophia (L.)
Webb ex Prantl which are used as a Chinese traditional
OAc
AcO
1
4
5
6
2
medicine. The structures of both the compounds were as-
signed by spectroscopic analysis. Yin, He and Ye isolated
3
Hendrickson and Farina discovered that these [5+2] cycload-
ditions can be carried out by simply heating 7 and a dipolaro-
the oxabicyclic acid cartorimine (3) from Carthamus tinc-
torius L., which is used as a traditional Chinese medicine
to promote blood circulation. The structure was established
from extensive NMR spectral data interpretation and single
ꢀ
Scheme 2). This reaction has been extensively developed
phile at 130–135 C to afford adducts analogous to 9
(
7
a
4
,5
by Sammes, who found that electron rich dipolarophiles
were more reactive and that the reactions can also be carried
out using Et N to generate the oxypyrylium zwitterion at
room temperature. Further examples of [5+2] cycloaddi-
tions have been reported by Heathcock and Ohmori.
crystal X-ray analysis.
3
O
O
O
8
O
HO2C
O
O
9–11
Sammes reported that reaction of 7, styrene (8a, 6 equiv)
ꢀ
OH
OH
OH
OMe
and Et
the hydroxymethyl and aryl substituents of 1 and descurainin
3
N in CH
2
Cl
2
at 25 C afforded 65% of 9, which lacks
MeO
OMe
8b
(2). Oxypyrylium zwitterion 5 had not been previously
HO
HO
3 (cartorimine)
HO
prepared, but 6 should react similarly to 7 in these reactions.
The para oxygen substituents on styrenes 12 and 13 should
make them more electron rich and therefore more reactive
than styrene (8a) itself.
1
2 (descurainin)
We thought that compounds 1–3 could be prepared by the
5+2] cycloaddition of the appropriate styrene derivative 4
[
with oxypyrylium zwitterion 5, which could be generated
in situ from pyranulose 6 (Scheme 1). This sequence is prob-
ably related to the biosynthesis of 1–3 because the required
styrenes are natural products and 6 is generated by the dehy-
O
O
1
30-135 °C
O
CH2
or
+
6
O
Et3N, CH2Cl2, 25 °C
dration and oxidation of fructose.
Ph
Ph
AcO
H
9
7
8a
*
Corresponding author. Tel.: +1 781 736 2550; fax: +1 781 736 2516;
e-mail: snider@brandeis.edu
Scheme 2.
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.083

5172
B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
2
. Results and discussion
slow addition of 6 over 1 d to a solution of 13 and Et N in
3
CH Cl . However, the yield of 15 did not improve signifi-
2
2
ꢀ
a sealed tube. Yields also decreased using CH CN as the sol-
vent or i-Pr(Et )N as the base.
2
5
-(Acetoxymethyl)furfural (10) was reduced with NaBH in
4
cantly. We obtained lower yields of 15 at 0 or 60 C in
ꢀ
EtOH for 10 min at 0 C. The solution was quenched drop-
wise with HOAc and concentrated. The residue was taken up
in water and treated with bromine in MeOH to give 80% of
1
CH Cl afforded the unstable acetate 6, which was used
without purification (Scheme 3). 4-Hydroxy-3-methoxystyr-
ene (12a) was prepared by decarboxylation of the corre-
sponding cinnamic acid with Cu powder and quinoline at
2
pyridine gave 12b in 92% yield, and reaction of 12a
3
6,12
1.
Acetylation with Ac O, pyridine, and DMAP in
Hydrolysis of the TBS ether of 14c with pyridine$HF in THF
and pyridine, followed by hydrolysis of the acetate ester with
KOH in aqueous MeOH afforded natural product 1 in 94%
2
2
2
1
3
yield (see Scheme 4). The C NMR spectrum in pyridine-
d corresponds well to that reported, except that all peaks
1
5
ꢀ
13
10–240 C. Acetylation of 12a with Ac O, DMAP, and
absorb downfield by 0.4–0.6 ppm from the literature data.
The H NMR spectrum in CDCl does not correspond well
2
1
4
1
3
1
4
with TBSCl and imidazole afforded 12c in 91% yield. Sty-
rene derivative 13 was prepared in 99% yield by a Wittig
reaction on the corresponding benzaldehyde.
to that reported, but the spectrum in pyridine-d does corre-
5
1
5
spond well to literature data suggesting that it may have been
recorded in pyridine-d , rather than CDCl as indicated.
1
5
3
O
CH2
O
CHO
H
1) pyr•HF
THF, pyr
O
1
2
) NaBH , EtOH, 0 °C
4
O
H
H
O
) Br , MeOH/H O
2
2
H
2
) KOH
O
O
OMe
OR
3) Ac O, pyr, DMAP
MeOH, H2O
2
RO
X
OAc
CH2OAc
OH
X
X
AcO
1
6
1, R = H (80%)
, R = Ac
TBSO
10
OMe
HO
1, X = H (94%)
2, X = OMe (descurainin, 87%)
OMe
1
1
1
2a, X = H, R = H
2b, X = H, R = Ac
2c, X = H, R = TBS
1
4c, X = H
15, X = OMe
O
H
Et N, CH Cl
3 2 2
25 °C, 2 d
13, X = OMe, R = TBS
O
H
Scheme 4. Preparation of 1 and descurainin (2).
O
O
O
+
X
Similar hydrolysis of 15 provided 87% of descurainin (2)
with spectral data in DMSO-d identical to those reported.
O
OAc
6
RO
OMe
AcO
The endo stereochemistry of the synthetic material was ex-
pected based upon earlier studies with 7.
OAc
16 (20-30% from 11)
7–11
It was con-
firmed unambiguously by the NOEs between the aromatic
hydrogens and H and H (see Fig. 1). The two H ’s can be
1
1
1
1
4a, X = H, R = H (~5% from 11)
4b, X = H, R = Ac (18% from 11)
4c, X = H, R = TBS (26% from 11)
5, X = OMe, R = TBS (31% from 11)
2
3
7
assigned based on their coupling constants to H . H
1
is
7exo
ꢀ
coupled to H with J¼8.9 Hz (25 ), while H
is coupled
Scheme 3. Preparation of adducts 14 and 15.
1
7endo
ꢀ
to H with J¼<1 Hz (94 ). The coupling constants between
1
ꢀ
are consistent with those expected. An NOE between H and
ꢀ
H and H
6
(J¼7.3 Hz, 130 ) and H
(J¼10.1 Hz, 8 )
7endo
7exo
Our initial attempt at cycloaddition by treating 6 and 12a
ꢀ
6
with 2 equiv of Et N in CH Cl at 25 C afforded only
3
2
2
H7exo and a much larger NOE between H and H
1
tween H and H
1
than be-
confirm the stereochemical assignment.
7endo
7exo
w5% of the desired adduct 14a (see Scheme 3). We sus-
pected that the free phenol interfered with this reaction, so
we examined the reaction of 6 with the acetate 12b, which
gave the desired adduct 14b in 18% yield. Use of TBS ether
12c gave adduct 14c in better (26%) yield as expected from
Sammes observations that more electron rich dipolarophiles
are more reactive. The yield of cycloadduct 15 from TBS
ether 13 improved to 31%. These reactions were carried
out using 1 equiv of both 6 and 12 or 13. Using 6 equiv of sty-
rene 12 or 13 as reported by Sammes for the reaction of 7 and
styrene (8a) did not improve the yield significantly, compli-
cated purification, and was wasteful of styrene 12 or 13.
The assignment of the opposite stereochemistry in natural
descurainin appears to result from switched assignments
2
for the two H ’s.
7
We examined the reaction of 6 with styrene (8a) to compare
the reactivity of the oxypyrylium zwitterions formed from 6
and 7 because Sammes obtained 9 in 65% yield from 7 and
styrene (6 equiv). Reaction of 6 and styrene (1 equiv) with
Et N in CH Cl gave only 14% of a 7:1 mixture of endo
8
3
2
2
O
H7exo
No isomeric adducts were detected, but we did obtain 20–
30% of a non-polar dimer tentatively assigned structure 16
based on similar dimers obtained from 7 with Et N in
H1
O
H6
H2'
3
ꢀ
5% of a polar dimer that was not fully characterized. These
7b,16
CH Cl at 25 C by Hendrickson and Farina
2
and 10–
2
H7endo
H2' H5'
MeO
H2
1
dimers were most easily isolated by treatment of 6 with Et N
H3
OH
3
H5'
in CH Cl in the absence of dipolarophile, which gave dimer
2
2
HO
16 in 25% yield and the uncharacterized dimer in 13% yield.
The uncharacterized dimer has two CH OAc groups, but no
alkene protons. Formation of dimer 16 was suppressed by
OMe
descurainin (2)
2
Figure 1. NOE’s in synthetic descurainin (2).

B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
5173
adduct 17 and the unexpected exo adduct 19. We isolated
w1% of acetoxy dienone 21 as a byproduct in these reac-
tions. The H NMR spectral data of 21 are similar to those
Acetoxy ester 22 was prepared in 94% yield from 4-hydroxy-
cinnamic acid by esterification with methanolic HCl at re-
flux and acetylation with Ac O, pyridine, and DMAP in
2
1
1
7–19
of analogous compounds.
Oxypyrylium zwitterion 5
CH Cl . Reaction of 6 and 22 with Et N in CH Cl at
2
2
3
2
2
ꢀ
the desired cycloadduct. Thermal reaction in CH CN at
ꢀ
can eliminate acetate to give 20. Attack of acetate on the
cationic center will give acetoxy dienone 21. Even though
25 C or with EtN(i-Pr) in CH CN at 80 C did not afford
2
3
3
ꢀ
2
1 is isolated in only 1% yield, this may be a major reaction
150–175 C was more successful, but not completely repro-
pathway since 21 should polymerize readily under the basic
reaction conditions. The competing formation of 21 may be
responsible for the lower yields of [5+2] cycloadducts
obtained from 6 than from 7. Heathcock postulated that
2-methyl-6-methylene-2H-pyran-3(6H)-one, which differs
from 21 only in the 2-substituent, was formed from 2,6-di-
ducible. Eventually, we concluded that residual pyridine
from the preparation of 22 was important for the success
of the reaction. Heating a 0.2 M solution of crude 6 in
CH CN with 6 equiv of 22 and 1 equiv of 2,6-di-t-butylpyr-
3
ꢀ
the crude bis acetoxymethyl ester of 3. Hydrolysis with KOH
idine in a sealed tube in a 175 C oil bath for 14 h afforded
methyl-3-oxypyrylium zwitterion by internal proton trans-
fer. This compound was not isolated, but the dimer
formed by the [5+2] cycloaddition of the exo-methylene
group to the oxypyrylium zwitterion was formed in 52%
yield.
in 4:1 EtOH/H O at reflux for 20 h and preparative TLC af-
2
9
forded 16% (from 11) of a 4:1 mixture of cartorimine (3)
and the stereoisomer 23, which were separated by reverse
phase HPLC. A similar reaction using pyridine, instead of
2,6-di-t-butylpyridine, afforded only 4% of a 3:1 mixture
of 3 and 23. The analogous cycloaddition of 6 with 8b
(6 equiv) provided 31% (from 11) of 18 regio- and stereo-
specifically, confirming that the electron-withdrawing car-
bomethoxy group of 22 retards the reaction (Scheme 6).
Reaction of 6 with styrene (8a, 6 equiv) under Sammes con-
ditions gave 41% of a 7:1 mixture of 17 and 19 indicating
that lower yields of [5+2] cycloadducts are obtained from
the oxypyrylium zwitterion 5 obtained from 6 (41% of 17
and 19) than from the parent oxypyrylium zwitterion ob-
O
O
HO2C
H7
H5
8
b
O
tained from 7 (65% of 9). Careful chromatography pro-
vided 36% of a w10:1 mixture rich in the endo adduct 17
and 5% of aw10:1 mixture rich in the exo adduct 19, whose
structure was established by COSY and 1D NOESY experi-
ments. The spectra of 1–3, 14, 15, and 17 are very similar in-
dicating that they all have the same stereochemistry, whereas
the chemical shifts and coupling constants of 19 are quite
different (Scheme 5).
O
H6
OH
AcO
1
) CH CN, 175 °C
2,6-di-t-butylpyridine
3
AcO
HO
6
2
) KOH, EtOH, H O, ∆
2
3
(cartorimine, 13% from 11)
MeO2C
HO
H6
O
H5
O
O
O
O
R
H
H
H
Et N, CH Cl
O
3
2
2
O
H
Ph
25 °C, 2 d
H7
+
CO H OH
R
H
H
22 OAc
O
H
2
Ph
Ph
23 (3% from 11)
OAc
OAc
AcO
17, R = H
12% from 1 equiv of 8a)
(36% from 6 equiv of 8a)
8, R = Me (~2% from 11)
19
(
AcO
8a, R = H
(5% from 6
equiv of 8a)
6
8b, R = Me
O
O
1
Me
H
8
b
Ph
O
H
CH CN, 175 °C
,6-di-t-butylpyridine
O
3
H
Ph
2
O
AcO
O
O
OAc
18 (31% from 11)
AcO
6
AcO
O
O
O
Scheme 6. Preparation of cartorimine (3) and 18.
CH2
CH2
AcO
AcO
21 (~1%)
The spectral data of 3 are identical to those previously re-
ported. Small NOEs from the aromatic hydrogens to the
5
20
4
Scheme 5.
hydroxymethyl group of both 3 and 23 established that the
minor product is a stereo- rather than a regioisomer. The vic-
A competition experiment was carried out by reaction of 6
and Et N with 1 equiv of both 13 and styrene (8a). We ob-
tained a 5:1 mixture of 15 and 17, indicating that the sigma
withdrawing, but pi donating, para oxygen substituent on the
phenyl ring of 13 makes it five times as reactive as the parent
styrene.
inal coupling constants support this assignment. JH5,H6
¼
1.5 Hz in 3 and 7.9 Hz in 23, while JH6,H7¼7.5 Hz in 3 and
4.3 Hz in 23. These coupling constants are consistent with
those expected from MM2 calculations and analogous to
those in the related stereoisomeric adducts formed from oxy-
3
1
0
pyrylium zwitterions and dimethyl fumarate.
We now turned our attention to the preparation of cartori-
mine (3), which required the use of a less reactive cinnamate
dipolarophile. Introduction of even a methyl substituent on
the double bond of the styrene dipolarophile decreases its re-
Although natural products 1–3 are probably biosynthesized
by similar [5+2] cycloadditions of achiral compounds, they
ꢀ
ꢀ
were isolated with small [a] (+1.7 for 2, ꢁ2.6 for 3) or
D
D3 (+0.01 for 1) indicating that they are not completely race-
mic. However, a [5+2] cycloaddition in a chiral environment
could lead to an optically enriched product as was observed.
activity. Reaction of 6 with 6 equiv b-methylstyrene (8b)
ꢀ
and Et N at 25 C gave adduct 18 in onlyw2% yield.
3

5174
B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
In conclusion, we have completed the first syntheses of 1,
descurainin (2), and cartorimine (3) using a possibly bio-
mimetic [5+2] cycloaddition to efficiently construct the fully
functionalized 8-oxabicyclo[3.2.1]octenone skeleton. Reac-
tion of 6 with styrenes 8a, 12, or 13 and Et N in CH Cl pro-
(d, 1, J¼1.2), 6.99 (br s, 2), 6.68 (dd, 1, J¼17.6, 10.8),
5.70 (d, 1, J¼17.6), 5.25 (d, 1, J¼10.8), 3.86 (s, 3), 2.32
1
3
(s, 3); C NMR 169.1, 151.0, 139.3, 136.6, 136.2, 122.7,
118.9, 114.1, 109.8, 55.8, 20.6; IR (neat) 1764.
3
2
2
ꢀ
ceeds at 25 C, while reaction of 6 with cinnamate ester 21 is
ꢀ
3.1.4. (1,1-Dimethylethyl)(4-ethenyl-2-methoxyphenoxy)
dimethylsilane (12c). TBSCl (524 mg, 3.48 mmol) and
14
best carried out at 175 C with 2,6-di-t-butylpyridine as
a proton scavenger.
imidazole (494 mg, 7.26 mmol) were added in succession
to a solution of 2-methoxy-4-vinylphenol (12a) (435 mg,
.90 mmol) in dry CH Cl (15 mL) under N and the re-
1
3
2
2
2
2
ꢀ
3. Experimental
sulting solution was stirred for 2 h at 25 C. The solution
was diluted with CH Cl (20 mL), washed with brine
2
2
3
.1. General procedures
(2ꢂ20 mL) and dried over MgSO . The solution was con-
4
centrated under reduced pressure to give 762 mg of a yellow
liquid. Flash chromatography on silica gel (9:1 hexanes/
EtOAc) yielded 698 mg (91%) of 12c as a yellow oil: H
NMR spectra were recorded at 400 MHz in CDCl unless
3
1
otherwise indicated, chemical shifts are reported in d, and
coupling constants in Hertz. The silica gel used for chroma-
tography was deactivated with methanol unless otherwise in-
NMR 6.93 (d, 1, J¼1.8), 6.87 (dd, 1, J¼8.2, 1.8), 6.80 (d,
13
1, J¼8.2), 6.64 (dd, 1, J¼17.1, 10.4), 5.60 (d, 1, J¼17.1),
ꢁ
1
dicated. IR spectra are reported in cm
.
5.14 (d, 1, J¼10.4), 3.83 (s, 3), 0.99 (s, 9), 0.15 (s, 6);
C
NMR 150.9, 145.1, 136.6, 131.5, 120.8, 119.3, 111.7,
3
.1.1. 6-[(Acetyloxy)methyl]-6-hydroxy-2H-pyran-3
6H)-one (11). A solution of 5-acetoxymethyl-2-furancar-
109.5, 55.4, 25.7 (3C), 18.4, ꢁ4.7 (2C); IR (neat) 1414, 1278.
(
boxyaldehyde (10, 1.006 g, 5.98 mmol) in EtOH (17 mL)
was added to a suspension of NaBH (113 mg, 2.99 mmol)
4
3.1.5. 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3,5-di-
TBSCl (1.015 g, 6.73 mmol)
1
5
methoxybenzaldehyde.
ꢀ
in EtOH (13 mL) at 0 C and the resulting solution was
and imidazole (952 mg, 14.0 mmol) were added in succes-
sion to a solution of 4-hydroxy-3,5-dimethoxybenzaldehyde
(1.022 g, 5.61 mmol) in dry CH Cl (40 mL) under N . The
ꢀ
quench the reaction and the EtOH was removed under re-
stirred for 10 min at 0 C. HOAc was added dropwise to
2
2
2
ꢀ
duced pressure. The brown residue was dissolved in H O
2
(40 mL) and a solution of Br2 (0.31 mL, 6.0 mmol) in
MeOH (3 mL) was added dropwise. After 2 h, the solution
resulting solution was stirred for 30 min at 25 C. The solu-
tion was diluted with CH Cl (60 mL), washed with brine
2
2
(2ꢂ100 mL) and dried over MgSO . The solution was con-
4
was basified to pH 5 with saturated NaHCO solution. The
3
centrated under reduced pressure to give 1.980 g of a clear
solid. Flash chromatography on silica gel (4:1 hexanes/
EtOAc) yielded 1.261 g (76%) of the protected aldehyde
resulting aqueous solution was saturated with NaCl and ex-
tracted with EtOAc (4ꢂ40 mL). The organic phase was
ꢀ
1
dried over MgSO and concentrated under reduced pressure
4
as a white solid: mp 69–71 C; H NMR 9.83 (s, 1), 7.10
(s, 2), 3.87 (s, 6), 1.01 (s, 9), 0.16 (s, 6); C NMR 191.0,
ꢀ
those previously reported.
13
(
<30 C) to give 894 mg (80%) of 11 with data identical to
6
,12
151.9 (2C), 140.6, 129.3, 106.6 (2C), 55.8 (2C), 25.6 (3C),
1
8.8, ꢁ4.6 (2C); IR (KBr) 1684.
3
.1.2. 6-Acetyloxy-6-[(acetyloxy)methyl]-2H-pyran-3
6H)-one (6). Ac O (20 mL), dry pyridine (10 mL), and
(
DMAP (130 mg, 1.06 mmol) were added in succession to
3.1.6. (1,1-Dimethylethyl)(4-ethenyl-2,6-dimethoxyphe-
noxy)dimethylsilane (13). LiHMDS (1.0 M) in THF
2
1
5
a solution of 11 (1.967 g, 10.6 mmol) in dry CH Cl
2
(3.5 mL) was added dropwise to a suspension of MeP(Ph) Br
3
2
ꢀ
tionwas allowed to stir at 0 C for 5 min. The above aldehyde
(
for 30 min at 0 C. The solution was washed with 10%
120 mL) under N and the resulting solution was stirred
in dry THF (20 mL) at 0 C under N and the resulting solu-
2
2
ꢀ
CuSO4 solution (100 mL), H O (100 mL), saturated
ꢀ
(733 mg, 2.47 mmol) in dry THF (8 mL) was added dropwise
2
NaHCO solution (100 mL), and brine (100 mL). The or-
3
ganic layer was dried over MgSO and concentrated under re-
4
to the cooled solution and the resulting solution was stirred
for 4 h at 25 C. Saturated NH Cl solution (40 mL) was
ꢀ
added to the solution and the phases were separated. The
4
duced pressure to give 1.541 g of crude brown 6 (w 90% pure)
that was used directly for the cycloadditions: H NMR 7.24
1
aqueous phase was extracted with CH Cl (3ꢂ40 mL) and
2
2
(
4
d, 1, J¼10.4), 6.23 (d, 1, J¼10.4), 4.61 (d, 1, J¼17.4),
the combined organic phases were dried over MgSO and
4
.56 (d, 1, J¼11.6), 4.44 (d, 1, J¼11.6), 4.31 (d, 1,
concentrated under reduced pressure. Flash chromatography
on silica gel (9:1 hexanes/EtOAc) yielded 681 mg (99%) of
1
3
J¼17.4), 2.11 (s, 3), 2.10 (s, 3); C NMR 193.3, 170.2,
ꢀ
1
1
69.4, 143.4, 128.2, 97.4, 68.1, 65.1, 21.3, 20.8.
13 as a clear solid: mp 31–33 C; H NMR 6.62 (dd, 1,
J¼17.4, 11.0), 6.61 (s, 2), 5.61 (d, 1, J¼17.4), 5.15 (d, 1,
14
13
3
.1.3. 2-Methoxy-4-vinylphenol acetate (12b). Ac O
2
J¼11.0), 3.81 (s, 6), 1.00 (s, 9), 0.13 (s, 6); C NMR 151.6
(
0
2.8 mL), dry pyridine (1.4 mL), and DMAP (17 mg,
.140 mmol) were added in succession to a solution of 2-me-
thoxy-4-vinylphenol (12a) (210 mg, 1.40 mmol) in dry
(2C), 137.0, 134.5, 130.3, 111.9, 103.4 (2C), 55.7 (2C),
25.8 (3C), 18.7, ꢁ4.6 (2C); IR (KBr) 1409, 1253.
1
3
CH Cl (14 mL) under N and the resulting solution was
2
3.1.7. endo-5-[(Acetyloxy)methyl]-6-(4-acetyloxy-3-
methoxyphenyl)-8-oxabicyclo[3.2.1]oct-3-en-2-one (14b).
Et N (0.16 mL, 1.1 mmol) was added dropwise to a solution
3
2
2
ꢀ
stirred for 35 min at 0 C. The solution was washed with
0% CuSO solution (15 mL), saturated NaHCO solution
1
4
3
(15 mL), and brine (15 mL). The organic layer was dried
over MgSO and concentrated under reduced pressure to
give 248 mg (92%) of 12b as a yellow oil: H NMR 7.01
of crude 6 (128 mg, 0.561 mmol) and 12b (108 mg,
0.561 mmol) in dry CH Cl (2 mL) under N at 0 C. The
ꢀ
resulting solution was stirred at 25 C for 2 d and was
4
2
2
2
1
ꢀ

B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
5175
concentrated under reduced pressure. Flash chromatography
on silica gel (4:1–1:1 hexanes/EtOAc) yielded 36 mg (18%
from 11) of 14b as a yellow wax: H NMR 6.96 (d, 1
(EtOAc as eluent) by 20 mg (13% from 11) of a dimer of
unknown structure.
1
1
J¼8.0), 6.74 (d, 1, J¼9.8), 6.73–6.72 (m, 2), 6.29 (d, 1,
Data for 16: H NMR 6.85 (d, 1, J¼10.4), 6.33 (d, 1,
J¼9.8), 4.69 (br d, 1, J¼8.9), 4.49 (d, 1, J¼12.2), 4.31 (d,
J¼10.4), 5.01 (d, 1, J¼9.2), 4.81 (d, 1, J¼7.3), 4.80 (dd,
1, J¼9.2, 2.9), 4.45 (d, 1, J¼13.4), 4.384 (d, 1, J¼13.4),
4.38 (d, 1, J¼12.2), 4.29 (d, 1, J¼12.2), 3.29 (dd, 1,
1
1
, J¼12.2), 3.80 (s, 3), 3.52 (dd, 1, J¼9.8, 7.0), 3.00 (ddd,
, J¼13.7, 9.8, 8.9), 2.31 (s, 3), 2.10 (s, 3), 2.04 (br dd, 1,
1
3
13
J¼13.7, 7.0); C NMR 196.1, 170.6, 168.9, 151.1, 151.0,
J¼7.3, 2.9); C NMR 198.3, 189.0, 170.4, 170.2, 150.8,
1
5
39.3, 135.0, 128.6, 122.9, 120.8, 112.8, 83.5, 80.8, 64.8,
5.9, 49.7, 34.1, 20.7, 20.6; IR (neat) 1765, 1745, 1703.
147.9, 129.6, 100.9, 81.5, 81.4, 75.9, 66.7, 61.7, 48.5,
20.7, 20.6; IR (neat) br 1745, br 1698, 1043.
1
3.1.8. endo-5-[(Acetyloxy)methyl]-6-[3-methoxy-4-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-phenyl]-8-oxabicy-
clo[3.2.1]oct-3-en-2-one (14c). Et N (0.25 mL, 1.8 mmol)
3
Data for the dimer of unknown structure: H NMR 4.88 (d, 1,
J¼6.1), 4.74 (d, 1, J¼4.3), 4.61 (d, 1, J¼13.4), 4.56 (d, 1, J¼
13.4), 4.46 (br s, 1), 4.27 (d, 1, J¼12.2), 4.23 (d, 1, J¼12.2),
4.02 (br s, 1), 2.80 (d, 1, J¼16.5), 2.72 (dd, 1, J¼16.5, 4.3),
2.68 (br d, 1, J¼6.1), 2.12 (s, 3), 2.11 (s, 3).
was added dropwise to a solution of crude 6 (204 mg,
0
.894 mmol) and 12c (237 mg, 0.896 mmol) in dry CH Cl2
2
(
4 mL) under N . The resulting solution was stirred for 2 d
2
ꢀ
at 25 C and was concentrated under reduced pressure. Flash
chromatography on silica gel (9:1 hexanes/EtOAc) gave
3.1.11. endo-6-(4-Hydroxy-3-methoxyphenyl)-5-(hydroxy-
methyl)-8-oxabicyclo[3.2.1]oct-3-ene-2-one (1). Pyridine$
(HF) (1.4 M, 3.5 mL) (5 mL of pyridine$(HF) in 20 mL of
2
6 mg of an impure 5:2:1 mixture of 14c, 12c, and 21, respec-
x
x
tively, followed by 129 mg (26% from 11) of 14c as a clear
wax. Elution with EtOAc gave 19 mg of impure 16.
pyridine and 20 mL of THF) was added to a solution of 14c
in THF (5 mL) and the resulting solution was stirred at
ꢀ
NaHCO solution and the resulting aqueous solution was ex-
25 C for 12 h. The solution was neutralized with saturated
1
Data for 14c: H NMR 6.75 (d, 1, J¼8.6), 6.68 (d, 1, J¼10.4),
3
6
1
6
.60 (m, 2), 6.27 (d, 1, J¼10.4), 4.67 (br d, 1, J¼8.9), 4.49 (d,
, J¼12.2), 4.28 (d, 1, J¼12.2), 3.77 (s, 3), 3.47 (dd, 1, J¼9.8,
.7), 2.97 (ddd, 1, J¼13.4, 9.8, 8.9), 2.10 (s, 3), 2.02 (br dd, 1,
tracted with EtOAc (3ꢂ100 mL). The combined organic
phases were dried over MgSO and concentrated under
4
reduced pressure to give a brown residue. The residue was dis-
solved in 4:1 MeOH/H O (5 mL), KOH (18 mg, 0.321 mmol)
1
3
J¼13.4, 6.7), 0.99 (s, 9), 0.14 (s, 6); C NMR 196.3, 170.6,
2
ꢀ
1
8
51.4, 150.8, 144.7, 129.2, 128.4, 121.0, 120.8, 112.5, 83.5,
0.8, 65.0, 55.6, 49.4, 33.9, 25.6 (3C), 20.7, 18.4, ꢁ4.6 (2C);
was added, and the resulting solution was stirred at 25 C for
1 h. The solution was acidified to pH 5 using saturated
NaH PO solution and the MeOH was removed under reduced
pressure. The residue was diluted with H O (2 mL), saturated
IR (KBr) 1743, 1704, 1605, 1043; HRMS (DCI/NH ) calcd
3
2
4
+
for C H NO Si (MNH ) 450.2312, found 450.2302.
6
23
36
4
2
with NaCl, and extracted with EtOAc (3ꢂ15 mL). The com-
3
.1.9. endo-5-[(Acetyloxy)methyl]-6-[3,5-dimethoxy-4-
[(1,1-dimethylethyl)dimethylsilyl]oxy]-phenyl]-8-oxabi-
bined organic phases were dried over Na SO and concen-
2
4
[
cyclo[3.2.1]oct-3-en-2-one (15). Et N (0.36 mL, 2.6 mmol)
was added dropwise to a solution of crude 6 (292 mg,
1
trated under reduced pressure to yield 69 mg (94% from
ꢀ
1
14c) of 1 as a tan powder: mp 168–170 C; H NMR
(C D N) 7.19 (d, 1, J¼7.9), 7.06 (d, 1, J¼9.5), 7.05 (br s, 1),
3
5
5
.28 mmol) and 13 (357 mg, 1.28 mmol) in dry CH Cl2
2
6.92 (dd, 1, J¼7.9, 1.8), 6.46 (dd, 1, J¼9.5, 1.2), 5.02 (br, 1,
OH), 4.89 (br d, 1, J¼8.9), 4.30 (d, 1, J¼12.5), 4.13 (d, 1,
J¼12.5), 3.98 (dd, 1, J¼10.1, 7.3), 3.73 (s, 3), 2.90 (ddd, 1,
(
6 mL) under N . The resulting solution was stirred for 2 d
2
ꢀ
at 25 C and was concentrated under reduced pressure. Flash
chromatography on silica gel (4:1 hexanes/EtOAc) gave
1
3
J¼12.8, 10.1, 8.9), 2.19 (br d, 1, J¼12.8, 7.3); C NMR
1
2
8 mg of an impure 2:1 mixture of 15 and 21, followed by
37 mg (31% from 11) of 15 as a clear wax. Elution with
EtOAc gave 78 mg of an impure 2:1 mixture of 16 and 15.
(C D N) 197.8, 155.0, 148.9, 147.9, 129.2, 128.5, 122.3,
5
5
116.9, 113.9, 87.5, 81.5, 63.6, 56.3, 48.1, 34.5; IR (KBr)
3482, 1679, 1608, 1037; UV (EtOH) lmax (log 3) 210 (3.58),
2
30 (sh 3.53), 282 nm (sh 2.85); HRMS (DCI/NH ) calcd
3
1
+
Data for 15: H NMR 6.70 (d, 1, J¼10.4), 6.29 (s, 2), 4.67 (br
for C H NO (MNH ) 294.1341, found 294.1335. The spec-
15 20 5 4
d, 1, J¼8.9), 4.49 (d, 1, J¼11.9), 4.31 (d, 1, J¼11.9), 3.75 (s,
traldatamatchwell withthosereportedfor thenaturalproduct,
ꢀ
6
2
6
1
4
1
), 3.44 (dd, 1, J¼10.1, 7.3), 2.98 (ddd, 1, J¼14.0, 10.1, 8.9),
which was isolated as white needles: mp 184–185 C; CD D3
+0.01 (355 nm, MeOH).
1
.10 (s, 3), 2.01 (ddd, 1, J¼14.0, 7.3, 1.7), 1.00 (s, 9), 0.12 (s,
1
3
); C NMR 196.3, 170.6, 151.54 (2C), 151.46, 134.0,
28.27, 128.25, 105.8 (2C), 83.6, 80.8, 65.0, 55.8 (2C),
9.9, 33.9, 25.7 (3C), 20.7, 18.7, ꢁ4.6 (2C); IR (KBr)
3.1.12. endo-6-(4-Hydroxy-3,5-dimethoxyphenyl)-5-
(hydroxymethyl)-8-oxabicyclo[3.2.1]oct-3-ene-2-one
(Descurainin, 2). Pyridine$(HF) (1.4 M, 7.0 mL) (5 mL of
x
745, 1703, 1588, 1031; HRMS (DCI/NH ) calcd for
3
+
C H NO Si (MNH ) 480.2418, found 480.2398.
7
pyridine$(HF) in 20 mL of pyridine and 20 mL of THF) was
x
2
4
38
4
added to a solution of 15 in THF (10 mL) and the resulting
solution was stirred at 25 C for 12 h. The solution was neu-
ꢀ
tralized with saturated NaHCO solution and the resulting
3
.1.10. (1a,2a,6a,7a)-4,7-Di(acetyloxy)methyl-3,11-di-
2
,6
oxa-tricyclo[5.3.1.1. ]dodeca-4,8-diene-10,12-dione
16) Et N (0.20 mL, 1.4 mmol) was added dropwise to a so-
lution of crude 6 (163 mg, 0.714 mmol) in dry CH Cl
3
(
aqueous solution was extracted with EtOAc (3ꢂ
3
200 mL). The combined organic phases were dried over
MgSO and concentrated under reduced pressure to a brown
2
2
(
2
3 mL) under N and the resulting solution was stirred for
2
4
ꢀ
Flash chromatography on silica gel (22:3 hexanes/EtOAc)
yielded 39 mg (25% from 11) of 16 as a clear oil, followed
d at 25 C and was concentrated under reduced pressure.
residue. The residue was dissolved in 4:1 MeOH/H O
2
(10 mL), KOH (18 mg, 0.321 mmol) was added, and the re-
ꢀ
sulting solution was stirred at 25 C for 1 h. The solution was

5176
B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
acidified to pH 5 using saturated NaH PO solution and the
2
J¼10.1), 6.29 (d, 1, J¼10.1), 4.70 (br d, 1, J¼9.2), 4.51
(d, 1, J¼11.9), 4.25 (dd, 1, J¼11.9), 3.55 (dd, 1, J¼9.8,
6.7), 3.00 (ddd, 1, J¼14.0, 9.8, 9.2), 2.10 (s, 3), 2.10–2.05
4
MeOH was removed under reduced pressure. The residue
was diluted with H O (2 mL), saturated with NaCl, and ex-
2
1
3
tracted with EtOAc (3ꢂ30 mL). The combined organic
(m, 1); C NMR 196.1, 170.6, 150.9, 136.1, 128.74,
128.66 (4C), 127.8, 83.6, 80.9, 64.9, 49.7, 33.7, 20.7; IR
(neat) 1744, 1704, 1602, 1030.
phases were dried over Na SO and concentrated under re-
2
4
duced pressure to yield 137 mg (87% from 15) of 2 as a tan
ꢀ
1
powder: mp 183–185 C; H NMR (DMSO-d ) 8.29 (s, 1,
6
1
OH), 6.82 (d, 1, J¼10.1), 6.41 (s, 2), 6.19 (br d, 1, J¼10.1),
Data for 19 were determined from the 10:1 mixture: H
5
1
.13 (t, 1, J¼6.1, OH), 4.50 (br d, 1, J¼8.9), 3.76–3.67 (m,
NMR 7.35–7.21 (m, 6), 6.11 (d, 1, J¼9.8), 4.83 (br d, 1,
J¼8.5), 4.07 (d, 1, J¼11.9), 3.65 (d, 1, J¼11.9), 3.42 (dd,
1, J¼8.9, 3.4), 2.59 (ddd, 1, J¼14.0, 8.5, 3.4), 2.49 (ddd,
), 3.71 (s, 6), 3.60 (dd, 1, J¼12.8, 6.1), 3.46 (dd, 1,
J¼10.1, 7.3), 2.82 (ddd, 1, J¼13.1, 10.1, 8.9), 1.92 (br dd,
1
3
13
1
, J¼13.1, 7.3); C NMR (DMSO-d ) 196.9, 154.5, 147.6
1, J¼14.0, 8.9, 1.9), 2.02 (s, 3); C NMR 196.2, 170.3,
6
(
(
(
2C), 134.7, 127.2, 127.1, 106.3 (2C), 85.8, 79.7, 62.3, 56.0
2C), 47.2, 32.9; HRMS (DCI/NH ) calcd for C H NO
6
MNH ) 324.1447, found 324.1451. The spectral data match
152.9, 139.5, 128.7 (2C), 128.3 (2C), 127.6, 126.2, 84.2,
81.5, 65.3, 49.2, 36.4, 20.6. The 1D NOESY experiments
3
16 22
+
4
showed: (a) NOEs from H at d 4.83 to H
1
at d 2.59
7exo
those reported for the natural product which was isolated as
colorless needles: mp 193–195 C; [a] +1.7 (c 0.23,
(larger) and H7endo at d 2.49 (smaller). (b) NOEs from H6
at d 3.42 to the phenyl protons at 7.35–7.21, the CH OH
ꢀ
MeOH). The 1D NOESY experiments showed: (a) NOEs
20
D
ꢀ
2
2
group at 4.07, H7exo at d 2.59 (smaller) and H7endo at
d 2.49 (larger). (c) NOEs from H7exo at d 2.59 to the phenyl
protons at d 7.35–7.21, H at d 4.83, H at d 3.42, and H
from H at d 6.82 to the phenyl protons at d 6.41, H at
3
2
d 6.19, and the CH OH group at d 5.13, 3.76–3.67 and
2
1
6
7endo
3
.60. (b) NOEs from the phenyl protons at d 6.41 to H at
3
at d 2.49. (d) NOEs from H7endo at d 2.49 to H at d 4.83, H
1
6
d 6.82, H at 6.19, H at d 3.46, and H at d 1.92. (c)
7endo
at d 3.42, and H7exo at d 2.59.
2
6
NOEs from H at d 6.19 to H at d 6.82 and the phenyl protons
2
3
at d 6.41. (d) NOEs from H at d 4.50 to H
1
and H7endo at d 1.92 (smaller). (e) NOEs from H at d 3.46 to
6
the phenyl protons at d 6.41, the CH OH group at d 5.13,
2
at d 2.82 (larger)
7exo
3
(
.1.14. Methyl (2E)-3-[4-(acetyloxy)phenyl]-2-propenate
22). AcCl (13 mL, 0.18 mol) was added dropwise to MeOH
ꢀ
(36 mL) at 0 C and the resulting solution was stirred at
3
d 2.82 to H at d 4.50, H at d 3.46, and H at d 1.92. (g)
.76–3.67, and H7exo at d 2.82. (f) NOEs from H7exo at
room temperature for 30 min. 4-Hydroxycinnamic acid
6.014 g, 36.6 mmol) was added and the solution was heated
1
6
7endo
(
NOEs from H7endo at d 1.92 to the phenyl protons at d 6.41,
H at d 4.50, and H at d 2.82.
to reflux for 2 h. The reaction was cooled and concentrated
under reduced pressure. The residue was dissolved in dry
CH Cl (360 mL) and cooled to 0 C under N . Ac O
1
7exo
ꢀ
2
2
2
2
3.1.13. endo-5-[(Acetyloxy)methyl]-6-phenyl-8-oxabicy-
clo[3.2.1]oct-3-en-2-one (17) and exo-5-[(acetyloxy)-
(
74 mL), dry pyridine (36 mL) and DMAP (448 mg,
.37 mmol) were added in succession and the resulting solu-
3
tion was stirred for 35 min at 0 C. The solution was washed
methyl]-6-phenyl-8-oxabicyclo[3.2.1]oct-3-en-2-one
(
ꢀ
with 10% CuSO solution (400 mL), water (400 mL), satu-
19). Et N (0.24 mL, 1.7 mmol) was added dropwise to a so-
3
4
lution of crude 6 (196 mg, 0.859 mmol) and styrene
0.10 mL, 0.859 mmol, 1 equiv) in dry CH Cl (4 mL) under
rated NaHCO3 solution (400 mL), and brine (400 mL).
The organic extracts were dried over MgSO and concen-
(
N . The resulting solution was stirred for 2 d at 25 C and
2
2
ꢀ
4
2
trated under reduced pressure to give 7.610 g (94%) of 22:
H NMR 7.67 (d, 1, J¼16.2), 7.54 (d, 2, J¼8.5), 7.12 (d,
was concentrated under reduced pressure. Flash chromatog-
raphy on silica gel (22:3 hexanes/EtOAc) yielded 37 mg
1
1
3
2
, J¼8.5), 6.40 (d, 1, J¼16.2), 3.81 (s, 3), 2.32 (s, 3);
C
(
12% from 11) of a 7:1 mixture of 17 and 19 as a clear oil.
NMR 169.3, 167.4, 152.2, 143.9, 132.3, 129.3 (2C), 122.3
2C), 118.1, 51.9, 21.3.
(
Purification of an identical reaction on a larger amount of sil-
ica gel (9:1 hexanes/EtOAc) gave 17 in lower yield preceded
by 2 mg (1% from 11) ofw90% pure 2-acetoxy-6-methylene-
3.1.15. Cartorimine (3). 2,6-Di-t-butylpyridine (0.45 mL,
2.0 mmol) was added to a solution of crude 6 (459 mg,
2.01 mmol) and 22 (2.664 g, 12.1 mmol, 6 equiv) in dry
1
2
H-pyran-3(6H)-one (21): H NMR 7.15 (d, 1, J¼10.4), 6.28
(s, 1), 6.21 (br d, 1, J¼10.4), 5.17 (dd, 1, J¼1.5, 1.5), 4.91 (br
s, 1), 2.12 (s, 3). A 1D NOESYexperiment showed NOE’s be-
CH CN (10 mL). The resulting solution was degassed using
3
2
0
ꢀ
tween the exo-methylene hydrogen at d 4.91 and H at d 7.15
3
and the other exo-methylene hydrogen at d 5.17.
the freeze-thaw method and heated to 175 C for 14 h in
a sealed tube. The reaction was cooled and concentrated un-
der reduced pressure to give 3.119 g of a black solid. Most of
the unreacted 22 was removed by filtering the black solid
through 50 g of silica gel (3:2 hexanes/EtOAc) to afford
239 mg of crude bis acetoxy ester, which was dissolved in
Et N (0.27 mL, 1.97 mmol) was added dropwise to a solu-
3
tion of crude 6 (298 mg, 1.31 mmol) and 8a (0.90 mL,
7
.9 mmol, 6 equiv) in dry CH Cl (0.65 mL) under N at
2 2 2
ꢀ
ꢀ
0
C. The resulting solution was stirred at 25 C for 16 h
4:1 EtOH/H O (50 mL). KOH (178 mg, 3.18 mmol) was
2
and was concentrated under reduced pressure. Flash chroma-
tography on silica gel (22:3 hexanes/EtOAc) gave 162 mg
added, and the resulting red solution was heated at reflux
for 20 h and cooled. The solution was acidified to pH 3 using
a saturated NaH PO solution and the EtOH was then re-
(
36% from 11) of a 10:1 mixture of 17 and 19 as a clear
oil, followed by 23 mg (5% from 11) of a 10:1 mixture of
9 and 17 as a yellow oil.
2
4
moved under reduced pressure. The resulting aqueous solu-
tion was extracted with CH Cl (3ꢂ50 mL) to remove less
1
2
2
polar impurities. The resulting aqueous solution was satu-
rated with NaCl and extracted with EtOAc (4ꢂ50 mL).
1
Data for 17 were determined from the 10:1 mixture: H
NMR 7.34–7.25 (m, 3), 7.15 (br d, 2, J¼7), 6.65 (d, 1,
The EtOAC solution was dried over MgSO and concentrated
4

B. B. Snider, J. F. Grabowski / Tetrahedron 62 (2006) 5171–5177
5177
under reduced pressure to give 159 mg of crude 3. Prepara-
tive TLC (7:3 CHCl /acetone) yielded 110 mg (16% from
References and notes
3
1
1) of a 4:1 mixture of (1R*,5R,6R,7S)-1-(hydroxy-
1. Wen, Y.; He, S.; Xue, K.; Cao, F. Zhong Cao Yao 1986, 17, 122–
126; Chem. Abstr. 1986, 105, 75884m.
2. Sun, K.; Li, X.; Li, W.; Wang, J.; Liu, J.; Sha, Y. Chem. Pharm.
Bull. 2004, 52, 1483–1486.
methyl)-7-(4-hydroxyphenyl)-4-oxo-8-oxabicyclo[3.2.1]
oct-2-ene-6-carboxylic acid (cartorimine, 3) and its stereo-
isomer (1R*,5R,6S,7R)-1-(hydroxymethyl)-7-(4-hydroxy-
phenyl)-4-oxo-8-oxabicyclo[3.2.1]oct-2-ene-6-carboxylic
acid (23). Separation of 3 and 23 was achieved by HPLC on
3. The structure of 2 was assigned with an exo aryl group. The
synthetic material is identical to the natural product and was
shown by NOE studies to have an endo aryl group.
4. Yin, H.-B.; He, Z.-S.; Ye, Y. J. Nat. Prod. 2000, 63, 1164–1165;
a Zorbex Eclipse XDB-C18 4.6ꢂ250 mm column (9:1 H O/
2
ꢁ
1
MeOH) flow rate¼1 mL min with sample loadings of
1
0
.5 mg: t ¼12.3 (23), t ¼18.3 (3).
The H NMR data were referenced to CD HOD at d 3.50 rather
2
R
R
than d 3.31. Private communication from Prof. Ye, Sept. 10, 2004.
5. For a preliminary communication on the synthesis of cartori-
mine see: Snider, B. B.; Grabowski, J. F. Tetrahedron Lett.
2005, 46, 823–825.
6. Lichtenthaler, F. W.; Brust, A.; Cuny, E. Green Chem. 2001, 3,
201–209.
7. (a) Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980, 45,
3359–3361; (b) Hendrickson, J. B.; Farina, J. S. J. Org.
Chem. 1980, 45, 3361–3363.
1
Data for 3: H NMR (CD OD) 7.07 (d, 2, J¼8.5), 6.80 (d, 1,
3
J¼10.4), 6.71 (d, 2, J¼8.5), 6.18 (br d, 1, J¼10.4), 4.70 (br s,
1
), 3.84 (d, 1, J¼6.7), 3.82 (d, 1, J¼12.5), 3.73 (d, 1,
3
1
3
J¼12.5), 3.13 (br d, 1, J¼6.7); C NMR (CD OD) 197.9,
1
8
58.2, 155.6, 131.1 (2C), 128.9, 128.4, 116.4 (2C), 88.4,
6.1, 64.2, 54.2 (2C) (one quaternary carbon was not
observed). The spectral data matches those reported for the
natural product: mp 206–207 C; [a] ꢁ2.6ꢀ (c 0.005,
ꢀ
25
D
4
MeOH)
8. (a) Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun.
1
982, 1056–1057; (b) Sammes, P. G.; Street, L. J. J. Chem.
1
Data for 23: H NMR (CD OD) 7.47 (d, 1, J¼9.5), 7.09 (d, 2,
Soc., Perkin Trans. 1 1983, 1261–1265; (c) Sammes, P. G.;
Street, L. J.; Kirby, P. J. Chem. Soc., Perkin Trans. 1 1983,
2729–2734; (d) Sammes, P. G.; Street, L. J. J. Chem. Res.,
Synop. 1984, 196–197; (e) Sammes, P. G. Gazz. Chim. Ital.
1986, 116, 109–114.
3
J¼7.6), 6.73 (d, 2, J¼7.6), 6.05 (d, 1, J¼9.5), 3.83–3.64 (m,
2
), 3.19 (d, 1, J¼12.2) (one proton is under the OH peak at
1
d 4.8 and one is proton under the MeOH peak at d 3.31); H
NMR ((CD ) CO) 7.57 (d, 1, J¼10.1), 7.15 (d, 2, J¼8.5),
3
2
6
.81 (d, 2, J¼8.5), 6.01 (br d, 1, J¼10.1), 4.89 (br d, 1,
9. Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. J. Org. Chem.
1996, 61, 9135–9145.
10. (a) Ohmori, N.; Miyazaki, T.; Kojima, S.; Ohkata, K. Chem.
Lett. 2001, 906–907; (b) Ohmori, N. J. Chem. Soc., Perkin
Trans. 1 2002, 755–767.
J¼7.9), 3.83–3.79 (m, 1), 3.77 (d, 1, J¼4.3), 3.37 (d, 1,
1
3
J¼11.6), 3.26 (d, 1, J¼11.6); C NMR (CD OD) 157.8,
3
1
6
56.8, 132.1, 131.2 (2C), 127.8, 116.3 (2C), 88.7, 85.2,
5.5 (four carbons were not observed).
1
1. For a review see: Ohkata, K.; Akiba, K.-Y. Advances in Hetero-
cyclic Chemistry, Vol. 65; Katritzky, A. R., Ed.; Academic:
New York, NY, 1996; pp 354–364.
3
6
.1.16. (1R*,5R,6S,7R)-5-[(Acetyloxy)methyl]-7-methyl-
-phenyl-8-oxabicyclo[3.2.1]oct-3-en-2-one (18). 2,6-Di-
t-butylpyridine (0.19 mL, 0.86 mmol) was added to a
solution of crude 6 (196 mg, 0.86 mmol) and trans-b-methyl-
styrene (0.69 mL, 5.2 mmol, 6 equiv) in dry CH CN (5 mL).
12. Kuo, Y.-H.; Shih, K.-S. Heterocycles 1990, 31, 1941–1949.
13. Shaw, P. E.; Tatum, J. H.; Miyashita, D. H.; Ohinata, K.
J. Agric. Food Chem. 1976, 24, 1186–1189.
3
The resulting solution was degassed using the freeze-thaw
14. Ding, N.; Li, Y.-X.; Chu, S.-D. Youji Huaxue 2004, 24, 898–
901; Chem. Abstr. 2005, 142, 155611z.
15. H a˚ kansson, A. E.; Pardon, K.; Hayasaka, Y.; de Sa, M.; Herder-
ich, M. Tetrahedron Lett. 2003, 44, 4887–4891.
16. Krishna, U. M.; Deodhar, K. D.; Trivedi, G. K.; Mobin, S. M.
J. Org. Chem. 2004, 69, 967–969.
17. Amann, F.; Schaub, C.; M u¨ ller, B.; Schmidt, R. R. Chem.—Eur.
J. 1998, 4, 1106–1115.
18. Shafizadeh, F.; Furneaux, R. H.; Stevenson, T. T. Carbohydr.
Res. 1979, 71, 169–191.
2
0
ꢀ
method and heated to 175 C for 14 h in a sealed tube.
The reaction was cooled and concentrated under reduced
pressure to give 738 mg of a black liquid. Flash chromatog-
raphy on silica gel (22:3 hexanes/EtOAc) yielded 76 mg
(
1
31%) of 18: H NMR 7.32–7.26 (m, 3), 7.14 (dd, 2,
J¼7.0, 1.8), 6.70 (d, 1, J¼9.8), 6.26 (d, 1, J¼9.8), 4.46 (d,
1
, J¼11.9), 4.27 (br s, 1), 4.21 (d, 1, J¼11.9), 3.00 (d, 1,
1
3
J¼6.7), 2.54 (br dq, 1, J¼6.7, 6.7), 1.36 (d, 3, J¼6.7); C
NMR 195.8, 170.6, 151.1, 135.6, 128.9 (2C), 128.7 (2C),
1
28.3, 127.9, 88.0, 84.7, 65.3, 59.4, 43.0, 20.7, 19.6.
19. Lichtenthaler, F. W.; Shigeru, N.; Kohler, P.; Lindner, H. J.
Carbohydr. Res. 1985, 136, 13–26.
2
0. A resealable tube with a threaded Teflon seal containing a solu-
tion of dipolarophile and pyranone in CH CN was frozen in
Acknowledgments
3
a dry ice/acetone bath. The sample was placed under vacuum
at 0.2 torr for 5 min. The tube was sealed and warmed to
room temperature. This process was repeated twice.
We are grateful to the National Institutes of Health (GM-
0151) for generous financial support.
5