Synthesis of the alkenyl-substituted tetracyclic core of the bisabosquals

Article abstract of DOI:10.1016/j.tet.2007.07.033

HCl-catalyzed deprotection and cyclization of benzylic alcohol 15 cleanly provided tricycle 16 by a cis-selective intramolecular Diels-Alder reaction. Acetylation of the phenol, bis epoxidation, and base-catalyzed hydrolysis and cyclization afforded tetra

Full text of DOI:10.1016/j.tet.2007.07.033

Tetrahedron 63 (2007) 10018–10024
Synthesis of the alkenyl-substituted tetracyclic
core of the bisabosquals
*
Jingye Zhou, Mercedes Lobera, Bobbianna J. Neubert-Langille and Barry B. Snider
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 17 May 2007; revised 6 July 2007; accepted 13 July 2007
Available online 19 July 2007
Abstract—HCl-catalyzed deprotection and cyclization of benzylic alcohol 15 cleanly provided tricycle 16 by a cis-selective intramolecular
Diels–Alder reaction. Acetylation of the phenol, bis epoxidation, and base-catalyzed hydrolysis and cyclization afforded tetracycle 19 with the
bisabosqual skeleton, but the opposite stereochemistry at the tertiary alcohol stereocenter. Selective dehydration of the tertiary alcohol to form
the exocyclic alkene, ozonolysis, reductive deoxygenation of the side chain epoxide, and addition of MeMgBr to the ketone from the less
hindered face gave tertiary alcohol 24 with the tetracyclic core of bisabosqual A (1).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
rings of 1 are analogous to those of tetrahydrocannabinoids
(THCs), although the cyclohexane and pyran rings are trans-
fused in the extensively investigated THCs3 and cis-fused in
1. The additional furan ring and tertiary alcohol of 1 pose
additional synthetic challenges.
Bisabosqual A (1) was isolated in 2001 from the culture broth
of Stachybotrys sp. RF-7260, obtained from decaying tree
leaves.1 Three related natural products, bisabosquals B–D,
were isolated from Stachybotrys ruwenzoriensis RF-6853.
Bisabosqual A (1) has broad spectrum antifungal activity in
vitro and inhibits the microsomal squalene synthases from
Saccharomyces cerevisiae, Candida albicans, HepG2 cell,
and rat liver with IC50 values of 0.43, 0.25, 0.95, and
2.5 mg/mL, respectively, suggesting that bisabosqual A
might be useful for the treatment of hypercholesterolemia.
We envisaged that bisabosqual A (1) might be accessible by
oxidative cyclization of cis-fused tricycle 2, which should
be available by an inverse electron demand Diels–Alder
reaction of quinone methide 3 (see Scheme 1). Although
hexahydrocannabinoids are invariably formed with a trans
ring fusion, Rickards found that treatment of 4 with TMSCl
and Et4NBr cleaved the MOM ethers and generated a qui-
none methide that cyclized to give 65% of the cis-fused tet-
rahydrocannabinoid tricycle 5 (see Eq. 1).4
CHO
R1
R1
CHO
R2
R2
OH
O
O
H
O
H
OH
R3
O
C5H11
H
H
C5H11
R3
H
OH
6 equiv TMSCl
MOMO
OMOM
6 equiv Et4NBr
CH2Cl2, 6 h
O
OH
H
1 (bisabosqual A)
2
3
ð1Þ
HO
H
Scheme 1. Retrosynthetic analysis of bisabosqual A.
4
5 (65%)
The novel tetracyclic structure of bisabosqual A (1) was de-
termined by 2D NMR experiments and confirmed by X-ray
crystallography of bisabosqual B.2 The three six-membered
These observations are consistent with MMX calculations of
transition state energies for the intramolecular Diels–Alder
reaction.5 The transition state leading to a trans-fused hexa-
hydrocannabinoid is more stable than the lowest energy
* Corresponding author. Tel.: +1 781 736 2550; fax: +1 781 736 2516;
e-mail: snider@brandeis.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.033

J. Zhou et al. / Tetrahedron 63 (2007) 10018–10024
10019
transition state leading to a cis-fused hexahydrocannabinoid
by 1.2 kcal/mol. The presence of the double bond in the
tether changes the transition state energies such that the
one leading to the cis-fused tetrahydrocannabinoid 5 is
more stable than the one leading to the trans-fused tetra-
hydrocannabinoid by 0.6 kcal/mol.
easily oxidized than the alkene of 9. Treatment of 9 with
bis(collidine)iodonium hexafluorophosphate13 afforded the
diiodo phenol. Reaction with Hg(OAc)2 also occurred on
the aromatic ring.14 Not surprisingly, treatment of 9 with
(CF3CO2)ReO3, (Cl2HCCO2)ReO3, or PCC led to complex
mixtures of products.
Epoxidation of 9 with m-CPBA in CH2Cl2 takes place at the
alkene from the less hindered a-face as reported by Razdan
in a similar system.15 The initially formed epoxy phenol 10
partially cyclized to give tetracycle 11 with the desired ring
system, but the opposite stereochemistry at the tertiary alco-
hol stereocenter. Treatment of this mixture with methanolic
NaOH for 2 h provided 83% of 11.
2. Results and discussion
Deprotonation of the bis MOM ether of orcinol (6)6 at the 2-
position with n-BuLi in THF followed by the addition of cit-
ral (7) afforded 90–100% of 8 as a z60:40 E/Z mixture that
was used without purification (see Scheme 2).7,8 In our
hands, treatment of crude alcohol 8 with TMSBr,9 TMSCl
and Et4NBr, or TMSCl and Bu4NBr in CH2Cl2 at 25 ꢀC
did not give tricyclic phenol 9. Use of TMSBr at ꢁ78 ꢀC pro-
vided the MOM ether of 9 (not shown) in 60% yield, which
can also be obtained in 70% yield with TMSCl and NaI at
ꢁ20 ꢀC.10 Eventually, we found that complete cyclization
of 8 and deprotection to give 9 can be effected in 58% overall
yield from 6 by heating 8 in a 1:6 mixture of 3 M aqueous
hydrochloric acid and MeOH at 60 ꢀC for 2 h. Tricycle 9
is somewhat unstable and can only be purified on MeOH-
deactivated silica gel.
The rigidity of the ring system allowed us to develop an
efficient procedure to convert 11 to the desired alcohol
14. Treatment of 11 with MsCl and excess Et3N in CH2Cl2
provided 89% of an 84:16 mixture of 12 and the endocyclic
isomer. Formation of the less stable alkene 12 is favored be-
cause only the methyl protons can adopt the required anti-
periplanar orientation to the equatorial leaving group.
Oxidative cleavage of the alkene mixture with OsO4 and
NaIO4 gave ketone 13. Addition of MeMgBr to the ketone
in THF occurred selectively from the less hindered a-face
to afford the desired tertiary alcohol 14 in 64% yield from
alkene 12. The spectral data of the cyclohexanol protons
and carbons of 14 correspond closely to those of bisabosqual
A (1), while those of 11 are quite different. In particular, Me-
COH absorbs at d 1.25 in 14 and d 1.31 in 1, but at d 0.87 in
the epimeric alcohol 11, in which the methyl group of the
tertiary alcohol is in the shielding cone of the aromatic ring.
Me
Me
n-BuLi, THF, 25 °C
MOMO
OMOM
then
MOMO
OMOM
HO
OHC
6
7
8
We then turned our attention to the preparation of 24,
containing the unsaturated side chain of the bisabosquals.
Deprotonation of 66 with n-BuLi in THF followed by addi-
tion of 6E-farnesal16 afforded 15 as an E/Z mixture that par-
tially decomposed on chromatography (see Scheme 3).
Although benzylic alcohol 15 could be isolated in 73% yield,
the overall yield of acetate 17 from 6 was higher when crude
15 was used for the intramolecular Diels–Alder reaction.
Cyclization of 15 and deprotection to give phenol 16 were
achieved by heating 15 in a 1:6 mixture of 3 M aqueous hy-
drochloric acid and MeOH in a 60 ꢀC oil bath for 3 h. The
yield of 16 decreased at higher temperatures. Chromato-
graphic purification was best carried out after acetylation
of crude phenol 16 in 1:1 Ac2O/pyridine for 12 h at 25 ꢀC
to give acetate 17. This three-step sequence afforded 90%
pure 17 in 48% overall yield from 6.
1:6 3 M aq HCl/MeOH
60 °C, 2 h
Me
Me
Me
H
1) m-CPBA
CH2Cl2
O
H
O
12 h
OH
O
O
OH
O
H
H
H
2) NaOH
MeOH
H
H
OH
11 (83%)
9 (58% from 6)
δ 0.87
10
1) MsCl, Et3N, CH2Cl2 14 h
2) OsO4, NaIO4, THF/H2O, 48 h
Me
Me
We were initially disappointed to find that epoxidation of ei-
ther 16 or 17 with 1 equiv of m-CPBA occurred selectively
on the side chain double bond rather than on the desired cy-
clohexene double bond. However, on further consideration,
epoxidation of the side chain double bond would protect
this double bond during the oxidative cleavage of the exocy-
clic double bond of 20 that generates cyclohexanone 22.
MeMgBr, THF
O
O
H
O
H
H
O
H
H
H
δ 1.25
OH
X
12, X = CH2 (89% of 84:16 mixture)
14 (64% from 12)
13, X = O
Scheme 2. Synthesis of tetracyclic model 14.
We therefore epoxidized 17 with 2.5 equiv of m-CPBA in
CH2Cl2 at 25 ꢀC for 1 h to give bis epoxide 18 as a 1:1 mix-
ture of diastereomers on the side chain epoxide. Hydrolysis
of the acetate and cyclization with K2CO3 in MeOH at 25 ꢀC
for 45 min afforded tetracyclic alcohol 19 in 54% overall
syn Oxidative cyclization11,12 of 9 would yield the desired
tertiary alcohol 14 in a single step. However, all previous ox-
idative cyclizations have started with unsaturated alcohols,
rather than phenols. The electron rich resorcinol is more

10020
J. Zhou et al. / Tetrahedron 63 (2007) 10018–10024
Dehydration of 19 with Martin’s sulfurane,18 Ph2S(OC
Me
Me
(CF3)2Ph)2, in CH2Cl2 proceeded cleanly, but with consider-
able loss of regioselectivity, to give an inseparable 2:1 mix-
ture of 20 and 21. Oxidative cleavage of the double bond of
20 with OsO4/NaIO4 with or without 2,6-lutidine19 pro-
ceeded in low yield. Ozonolysis of the 2:1 mixture of 20
and 21 in CH2Cl2 containing pyridine at ꢁ78 ꢀC followed
by reduction with activated Zn20 provided epoxy ketone 22
in 43% overall yield from epoxy alcohol 19. Reductive
deoxygenation of 22 by Cornforth’s procedure17 with
Zn(Cu), NaI, and NaOAc in HOAc at 25 ꢀC for 30 min af-
forded alkenyl ketone 23 in 53% yield. Slightly lower yields
were obtained with activated Zn or Zn(Ag) and much lower
yields were obtained with unactivated Zn dust. Epoxy ketone
23 was obtained in 0–20% yield with Cp2TiCl2/Zn,21 WCl6/
BuLi,22 or NaI/TMSCl in CH3CN.23
n-BuLi, THF, 25 °C
then 6E-farnesal
MOMO
HO
15 (73%)
OMOM
MOMO
OMOM
6
1:6 3 M aq HCl/MeOH
60 °C, 3 h
Me
H
Me
2.5 equiv m-CPBA
CH2Cl2, 1 h
O
OR
H
O
OAc
H
O
O
Addition of MeMgBr to ketone 23 in THF occurred selec-
tively from the less hindered a-face to afford the desired ter-
tiary alcohol 24 in 78% yield. The spectral data of the
cyclohexanol protons and carbons of 24 correspond closely
to those of bisabosqual A (1), while those of 19 are quite dif-
ferent. In particular, MeCOH absorbs at d 1.24 in 24 and at
d 1.31 in 1, but at d 0.86 and 0.87 in the two diastereomers of
the epimeric epoxy alcohol 19, in which the methyl group of
the tertiary alcohol is in the shielding cone of the aromatic
ring (see Fig. 1). The stereochemistry at C7 of 24 was estab-
lished by an NOE from H5 at d 3.61 to H8 at d 1.73–1.64 and
d 1.61–1.52, but not to H14 at d 1.39.
H
16, R = H
1:1 Ac2O/pyr
25 °C,12 h
18
17, R = Ac
(90% pure, 48% from 6)
K2CO3, MeOH
25 °C, 45 min
Me
Me
Me
Ph2S(OC(CF3)2Ph)2
(Martin Sulfurane)
CH2Cl2, 25 °C, 3 h
O
O
O
H
O
H
O
H
O
H
O
H
+
H
H
H
H
OH
CH2
O
O
The spectra of 1 and 24 are very similar except for H4, C4,
and C7 (see Table 1 and Fig. 1 for atom numbering scheme).
20
21
19 (54% from 17)
The absorptions are further downfield in both the 1H and 13
C
O3, CH2Cl2, pyr
-78 °C then
Zn, 25 °C 3 h
NMR spectra of 1 as expected, because the two aldehydes of
1 are electron withdrawing whereas the aromatic methyl
group of 24 is electron donating. The methoxy protons of
25, which are analogous to H4 of 1, absorb at d 3.93 in
CDCl3,24 whereas the methoxy protons of 26, which are
analogous to H4 of 24, absorb at d 3.76 in CCl4.25
Me
Me
Zn(Cu), NaI
NaOAc
Me
H
AcOH
MeMgBr, THF
25 °C, 30 min
O
O
O
25 °C, 5 h
H
H
H
O
O
O
O
H
H
H
H
H
Me
CHO
O
O
CHO
O
OH
HO
HO
O
Me
Me
24 (78%)
22 (43% from 19)
23 (53%)
Me
δ 3.76
Me
δ 3.93
26
25
Scheme 3. Synthesis of alkenyl-substituted tetracyclic model 24.
In conclusion, we have developed a short and efficient route
to the tetracyclic core of the bisabosquals that effectively
deals with the side chain unsaturation. We are currently
yield from dienyl acetate 17. The spectra of the two diaste-
reomers of 19 were surprisingly different, suggesting that
they might differ in the stereochemistry at one or more of
the ring positions, rather than simply at the epoxide on the
side chain. Fortunately, Cornforth reductive deoxygen-
ation17 of the diastereomeric mixture with Zn, NaI, and
NaOAc in HOAc afforded a single compound establishing
that only a mixture of side chain epoxides was present in 19.
CH3
CH3
δ 0.86-0.87
O
O
4
O
7
O
8
Me
5
OH
Conversion of tertiary alcohol 19 to the exocyclic alkene 20
and then to ketone 22 proved much more challenging than
for model 11 without the functionalized side chain. Treat-
ment of 19 with MsCl and excess Et3N in CH2Cl2 provided
4:1 to 8:1 mixtures of 20 and 21 in only 5–30% yield.
10 CH2
H
11
H
12
3
Me
9
Me
15
δ 1.24
OH
1
O
Me
2
6
14
H
H
H
H
13
19
24
Figure 1. Three-dimensional structures of 19 and 24.

J. Zhou et al. / Tetrahedron 63 (2007) 10018–10024
10021
Table 1. Comparison of the 1H and 13C NMR spectra of bisabosqual A (1)
and tetracyclic model 24
gel (hexanes) gave 825 mg (58%) of tricycle 9 that was
90–95% pure. Further chromatography on non-deactivated
silica gel resulted in decomposition to give less pure 9:
1H NMR 6.24 (s, 1), 6.22 (br s, 1), 6.12 (s, 1), 4.92 (br s,
OH), 3.58–3.53 (br, 1), 2.18 (s, 3), 2.00–1.89 (m, 3), 1.74–
1.66 (m, 1), 1.68 (s, 3), 1.52–1.42 (m, 1), 1.39 (s, 3), 1.27
(s, 3); 13C NMR 154.8, 153.8, 137.3, 135.0, 121.8, 110.7,
109.3, 108.7, 76.2, 40.0, 31.4, 29.7, 25.9, 25.2, 23.7, 20.9,
20.6; HRMS (DEI) calcd for C17H22O2 (M+) 258.1620,
found 258.1612.
1H NMR
13C NMR
1
24
1
24
1
2
3
4
5
6
7
8
1.55, 1.28
1.79, 1.21
1.8–1.4, 1.3–1.1
1.8–1.4, 1.3–1.1
16.3
16.4
35.1
69.5
90.5
33.7
36.5
81.0
38.3
22.4
123.7
131.9
25.6
17.6
22.2
29.8
34.9
69.1
93.8
33.3
35.9
83.5
38.7
22.2
123.1
132.5
25.6
17.6
22.1
29.5
4.97 (d, 8.8)
3.66 (dd, 8.8, 6.6)
2.05
4.69 (d, 8.5)
3.61 (dd, 8.5, 6.1)
1.96–1.88
1.67, 1.57
2.08
5.03
1.8–1.4
2.12–2.03
5.04
3.4. (3R,3aR,9aR,9bS)-rel-2,3,3a,9,9a,9b-Hexahydro-
3,6,9,9-tetramethyl-1H-benzofuro[4,3,2-cde][1]benzo-
pyran-3-ol (11)
9
10
11
12
13
14
15
1.65
1.59
1.46
1.31
1.65
1.59
1.39
1.24
A solution of m-CPBA (276 mg, 1.357 mmol) in CH2Cl2
(20 mL) was added dropwise to a solution of 9 (254 mg,
0.984 mmol) in CH2Cl2 (54 mL) at 0 ꢀC. The reaction
mixture was warmed to 25 ꢀC and stirred for 12 h. The
solvent was evaporated and the bright orange residue
was dissolved in Et2O. The solution was then washed
with Na2SO3, NaHCO3, and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was
taken up in MeOH (40 mL) and 4% NaOH (25.1 mL)
was added to the solution. The reaction mixture was
stirred at 25 ꢀC for 2 h. The MeOH was evaporated and
the aqueous phase was extracted with Et2O. The combined
extracts were washed with brine, dried (MgSO4), and con-
centrated under reduced pressure. Flash chromatography
of the residue on MeOH-deactivated silica gel (hexanes)
adapting this to more highly functionalized resorcinols
needed for the synthesis of the bisabosquals.
3. Experimental section
3.1. General procedures
NMR spectra were recorded at 400 MHz in CDCl3 unless
otherwise indicated. Chemical shifts are reported in d, cou-
pling constants in hertz, and IR spectra in cmꢁ1
.
1
gave 224 mg (83%) of 11: H NMR 6.19 (s, 1), 6.16 (s,
3.2. a-(2,6-Dimethyl-1,5-heptadienyl)-2,6-bis(methoxy-
methoxy)-4-methyl-benzenemethanol (8)
1), 4.85 (br d, 1, J¼8.6), 3.72 (dd, 1, J¼8.6, 6.7), 2.26
(s, 3), 1.97 (ddd, 1, J¼11.6, 6.7, 6.1), 1.74–1.65 (m, 2),
1.48–1.36 (m, 1), 1.41 (s, 3), 1.34 (s, 3), 0.96 (dddd, 1,
J¼14.3, 11.0, 11.0, 4.3), 0.87 (s, 3); 13C NMR 161.2,
151.9, 140.4, 107.57, 107.51, 102.4, 93.6, 79.0, 73.2,
37.6, 35.2, 34.8, 26.7, 26.0, 24.6, 22.1, 19.3; HRMS
(DEI) calcd for C17H22O3 (M+) 274.1569, found
274.1558.
n-BuLi (6.6 mL of a 1.6 M solution in hexanes, 10.6 mmol)
was added to a solution of 66b (2 g, 9.43 mmol) in THF
(88 mL) at 0 ꢀC. The reaction mixture was warmed to
25 ꢀC and stirred for 2 h. The reaction mixture was cooled
to 0 ꢀC and citral (7) (2.1 mL, 12.1 mmol) in THF (15 mL)
was added dropwise. The reaction mixture was then stirred
at 25 ꢀC for 3 h, quenched with NH4Cl, and extracted with
Et2O (3ꢂ40 mL). The combined extracts were washed
with brine, dried (MgSO4), and concentrated under reduced
pressure to yield 3.78 g (110%) of 8 as a z6:4 E/Z mixture
that was about 90% pure by 1H NMR analysis: 1H NMR 6.63
(s, 2), 5.900 (dd, 0.6ꢂ1, J¼10.9, 9.1), 5.897 (dd, 0.4ꢂ1,
J¼12.2, 9.1), 5.70 (br d, 0.4ꢂ1, J¼9.1), 5.68 (br d, 0.6ꢂ1,
J¼9.1), 5.24–5.18 (m, 4), 5.06 (t, 1, J¼6.7), 3.59 (d,
0.6ꢂ1, J¼10.9, OH), 3.53 (d, 0.4ꢂ1, J¼12.2, OH), 3.50
(s, 0.6ꢂ6), 3.49 (s, 0.4ꢂ6), 2.30 (s, 3), 2.08–2.20 (m, 2),
2.08–1.95 (m, 2), 1.64 (s, 3), 1.55 (s, 3).
3.5. (3aR,9aR,9bS)-rel-2,3,3a,9,9a,9b-Hexahydro-
6,9,9-trimethyl-3-methylene-1H-benzofuro[4,3,2-cde]-
[1]benzopyran (12)
MsCl (0.8 mL, 10.2 mmol) was added dropwise to a solution
of 11 (157 mg, 0.573 mmol) and Et3N (2.7 mL, 18.8 mmol)
in CH2Cl2 (23 mL) at 0 ꢀC. The reaction mixture was
warmed to 25 ꢀC and stirred for 14 h. The reaction was
then quenched with 2 M HCl and extracted with Et2O. The
combined extracts were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Flash
chromatography of the residue on MeOH-deactivated silica
gel (hexanes) gave 130 mg (89%) of an 84:16 mixture of 12
and the endocyclic isomer: 1H NMR (12) 6.25 (s, 1), 6.16 (s,
1), 5.33 (br d, 1, J¼7.9), 5.14 (br s, 1), 4.81 (br s, 1), 3.68 (br
dd, 1, J¼7.9, 7), 2.27 (s, 3), 2.24 (ddd, 1, J¼12, 3, 3), 2.00
(ddd, 1, J¼12, 6, 6), 1.88–1.75 (m, 2), 1.40 (s, 3), 1.34 (s,
3.3. (6aR,10aS)-rel-6a,7,8,10a-Tetrahydro-3,6,6,9-tetra-
methyl-6H-dibenzo[b,d]pyran-1-ol (9)
A 3 M solution of HCl (22 mL, 65 mmol) was added to a
solution of crude 8 (2.0 g, 5.49 mmol) in MeOH (130 mL).
The reaction mixture was heated in a 60 ꢀC oil bath for
2 h, cooled to 25 ꢀC, quenched with saturated NaHCO3,
and extracted with Et2O. The combined extracts were
washed with brine, dried (MgSO4), and concentrated under
reduced pressure to give 1.48 g (104%) of crude 9. Flash
chromatography of the residue on MeOH-deactivated silica
1
3), 0.92–0.82 (m, 1); H NMR (partial data for endocyclic
isomer) 5.50 (br d, 1, J¼5.2), 5.20 (br d, 1, J¼8), 3.77–
3.72 (m, 1), 2.25 (s, 3); 13C NMR 160.4, 151.9, 144.8,
140.0, 110.3, 107.7, 106.7, 103.3, 86.6, 78.7, 39.7, 36.5,
31.8, 26.4, 26.2, 23.7, 22.2; HRMS (DEI) calcd for
C17H20O2 (M+) 256.1463, found 256.1471.

10022
J. Zhou et al. / Tetrahedron 63 (2007) 10018–10024
3.6. (3aR,9aR,9bS)-rel-1,2,3a,9,9a,9b-Hexahydro-6,9,9-
trimethyl-3H-benzofuro[4,3,2-cde][1]benzopyran-3-one
(13)
IR (neat) 3318, 2919, 2854, 1664, 1611; HRMS (EI+) calcd
for C26H40O5 (M+) 432.2876, found 432.2871.
3.9. (6S,6aR,10aS)-rel-6a,7,8,10a-Tetrahydro-3,6,9-tri-
methyl-6-(4-methyl-3-pentenyl)-6H-dibenzo[b,d]pyran-
1-yl acetate (17)
OsO4 (42 mL of a 2.5% solution in t-BuOH, 0.004 mmol)
and NaIO4 (53 mg, 0.246 mmol) were added to a solution
of 12 (21 mg, 0.082 mmol) in THF/H2O (2:1, 1 mL). The re-
action mixture was stirred at 25 ꢀC for 48 h and concen-
trated under reduced pressure. The residue was taken up
in H2O and extracted with EtOAc. The combined extracts
were washed with Na2S2O3 and brine, and dried (MgSO4).
Flash chromatography of the residue on MeOH-deactivated
silica gel (9:1 hexanes/EtOAc) gave 19 mg (92%) of 80%
Aqueous hydrochloric acid (30 mL, 3 M) was added drop-
wise to a solution of crude 15 (3.38 g) in MeOH (180 mL)
at 60 ꢀC. The resulting solution was heated in a 60 ꢀC oil
bath for 3 h and cooled to 25 ꢀC. The reaction was quenched
with saturated NaHCO3 (40 mL) and extracted with Et2O
(3ꢂ50 mL). The combined Et2O extracts were washed
with brine, dried (MgSO4), and concentrated to give crude
16.
1
pure ketone 13: H NMR 6.36 (s, 1), 6.18 (s, 1), 5.04 (d,
1, J¼7.3), 4.07 (dd, 1, J¼7.3, 7.3), 2.40–2.28 (m, 3), 2.26
(s, 3), 2.10–2.05 (m, 1), 1.46 (s, 3), 1.40 (s, 3), 1.38–1.23
(m, 1); 13C NMR 208.4, 160.5, 151.3, 141.1, 108.3,
104.6, 103.3, 87.4, 78.5, 39.1, 39.0, 38.7, 26.7, 26.4, 22.7,
22.1.
Acetic anhydride (6 mL) was added to a pyridine (6 mL) so-
lution of crude 16. The reaction mixture was stirred at 25 ꢀC
for 12 h. The resulting mixture was diluted with Et2O
(60 mL) and washed with H2O (2ꢂ30 mL), NaHCO3
(3ꢂ30 mL), and brine (30 mL), dried (MgSO4), and concen-
trated to give crude 17. Flash chromatography on MeOH-
deactivated silica gel (40:1 hexanes/EtOAc) yielded 1.41 g
(48% for three steps) of 90% pure 17 as a colorless oil: 1H
NMR 6.51 (s, 1), 6.40 (s, 1), 5.86–5.81 (br, 1), 5.07–5.00
(br, 1), 3.45–3.39 (br, 1), 2.33 (s, 3), 2.22 (s, 3), 2.06–1.86
(m, 3), 1.81–1.41 (m, 6), 1.67 (s, 3), 1.63 (s, 3), 1.53 (s, 3),
1.37 (s, 3); 13C NMR 169.0, 153.4, 149.8, 137.2, 135.3,
131.7, 123.9, 121.1, 115.9, 115.3, 115.2, 78.2, 37.4, 37.0,
31.2, 29.6, 25.7, 23.7, 22.9, 22.3, 21.4, 20.9, 20.2, 17.4; IR
(neat) 2966, 2927, 1766; HRMS (Q-TOF) calcd for
C24H33O3 (MH+) 369.2430, found 369.2437.
3.7. (3S,3aR,9aR,9bS)-rel-2,3,3a,9,9a,9b-Hexahydro-
3,6,9,9-tetramethyl-1H-benzofuro[4,3,2-cde][1]benzo-
pyran-3-ol (14)
MeMgBr (0.21 mL, 0.214 mmol) was added to a solution of
partially purified ketone 13 (14 mg, 0.054 mmol) in THF
(1 mL) at 0 ꢀC. The reaction mixture was warmed to 25 ꢀC
and stirred for 1 h, quenched with NH4Cl, and extracted
with EtOAc. The combined extracts were washed with brine,
dried (MgSO4), and concentrated under reduced pressure.
Flash chromatography of the residue on MeOH-deactivated
silica gel (hexanes) gave 10.4 mg (70%) of 14: 1H NMR 6.22
(s, 1), 6.17 (s, 1), 4.70 (br d, 1, J¼8.5), 3.66 (br dd, 1, J¼8.5,
6), 2.26 (s, 3), 1.84 (ddd, 1, J¼11.6, 6, 6), 1.71 (br d, 1,
J¼11.6), 1.60–1.40 (m, 1), 1.42 (s, 3), 1.33 (s, 3), 1.25 (s,
3), 1.26–1.16 (m, 2); 13C NMR 161.4, 151.6, 140.3, 108.1,
107.6, 101.4, 90.5, 78.8, 69.4, 38.6, 34.9, 34.1, 29.6, 26.7,
26.1, 22.2, 16.5; HRMS (DEI) calcd for C17H22O3 (M+)
274.1569, found 274.1570.
3.10. (1aR,3aR,4S,9bS,9cS)-rel-4-[(RS)-2-(3,3-Dimethyl-
oxiranyl)ethyl]-1a,2,3a,4,9b,9c-hexahydro-1a,4,7-tri-
methyl-3H-oxireno[3,4]benzo[1,2-c][1]benzopyran-9-yl
acetate (18)
A solution of m-CPBA (1.05 g, 70%, 4.3 mmol) in CH2Cl2
(30 mL) was added to a solution of 17 (630 mg, 1.7 mmol)
in CH2Cl2 (12 mL). The reaction mixture was stirred for 1 h
at 25 ꢀC and concentrated. The residue was redissolved
in EtOAc (60 mL), washed with saturated Na2SO3
(2ꢂ30 mL), NaHCO3 (2ꢂ30 mL), and brine (30 mL), dried
(MgSO4), and concentrated to give 558 mg of crude 18 as
an oil, which was used directly in the next step. A portion
of the crude product (28 mg) was purified by flash chroma-
tography on MeOH-deactivated silica gel (20:1 hexanes/
EtOAc) to yield bis epoxide 18 (10 mg) as a 1:1 mixture
3.8. a-(2,6,10-Trimethyl-1,5,9-undecatrienyl)-2,6-bis-
(methoxymethoxy)-4-methyl-benzenemethanol (15)
n-BuLi (7.0 mL, 1.6 M in hexane, 11.2 mmol) was added at
0 ꢀC to a solution of 6 (1.70 g, 8.0 mmol) in THF (50 mL).
The resulting solution was warmed to 25 ꢀC and stirred for
4 h. A THF solution (12 mL) of a 2:1 mixture of (2E,6E)-
and (2Z,6E)-farnesal16 (2.46 g, 11.2 mmol) was added drop-
wise to the reaction mixture and the reaction mixture was
stirred at 25 ꢀC for 4 h. The reaction was quenched with sat-
urated NH4Cl (40 mL) and extracted with Et2O (3ꢂ50 mL).
The combined Et2O extracts were dried (MgSO4) and con-
centrated to give crude 15 (3.40 g). A portion of the crude
product (43 mg) was purified by flash chromatography on
MeOH-deactivated silica gel (15:1 hexanes/EtOAc) to yield
15 (23 mg) as a mixture of cis and trans isomers: 1H NMR
6.62 (s, 2), 5.91 (dd, 1, J¼9.2, 9.2), 5.68 (d, 1, J¼9.2),
5.21 (s, 2), 5.20 (s, 2), 5.11–5.04 (m, 2), 3.68–3.60 (m, 1,
OH), 3.49 (s, 6), 2.29 (s, 3), 2.24–2.21 (m, 1), 2.11–1.89
(m, 7), 1.80 (s, 3), 1.67 (s, 3), 1.58 (br s, 3), 1.55 (br s, 3);
13C NMR 154.8 (2C), 138.7, 137.3, 135.1, 131.2, 126.6,
124.3, 123.8, 118.6, 109.0 (2C), 94.4 (2C), 64.3, 56.2
(2C), 39.64, 39.60, 26.6, 26.3, 25.6, 21.8, 17.6, 16.4, 15.9;
1
of diastereomers: H NMR 6.53 (s, 1), 6.51 (s, 1), [3.16–
3.14 (br, 1), 3.13–3.11 (br, 1)], [3.11 (d, 1, J¼6.1), 3.08
(d, 1, J¼6.1)], [2.75 (t, 1, J¼6.1), 2.74 (t, 1, J¼6.1)],
[2.37 (s, 3), 2.36 (s, 3)], 2.27 (s, 3), 2.03–1.03 (m, 9),
1.31 (s, 3), [1.28 (s, 3), 1.26 (s, 3)], 1.26 (s, 3), 1.24 (s,
3); 13C NMR (169.48, 169.43), (154.21, 154.17), (149.57,
149.54), 138.37, (115.79, 115.76), (115.10, 115.05),
(112.81, 112.80), (77.65, 77.49), (64.27, 64.17), (62.27,
62.24), (58.41, 58.37), (58.14, 58.09), (35.47, 35.14),
34.00, 32.34, (25.97, 25.88), 24.80, (23.10, 23.04), (22.75,
22.56), 21.93, (21.05, 21.03), 20.96, (19.38, 19.28),
(18.63, 18.44); IR (neat) 2958, 2927, 1768; HRMS (Q-
TOF) calcd for C24H33O5 (MH+) 401.2328, found
401.2327.

J. Zhou et al. / Tetrahedron 63 (2007) 10018–10024
10023
3.11. (R,3aR,9S,9aR,9bS)-rel-9-[(RS)-2-(3,3-Dimethyl-
3.13. (3aR,9S,9aR,9bS)-rel-9-(4-Methyl-3-pentenyl)-
1,2,3a,9,9a,9b-hexahydro-6,9-dimethyl-3H-benzo-
furo[4,3,2-cde][1]benzopyran-3-one (23)
oxiranyl)ethyl]-2,3,3a,9,9a,9b-hexahydro-3,6,9-tri-
methyl-1H-benzofuro[4,3,2-cde][1]benzopyran-3-ol
(19)
A mixture of sodium acetate (18 mg, 0.22 mmol), sodium
iodide (62 mg, 0.41 mmol), and zinc–copper couple
(54 mg, 0.83 mmol) was added to a solution of 22 (71 mg,
0.21 mmol) in acetic acid (0.6 mL). The resulting solution
was stirred at 25 ꢀC for 30 min. The reaction was quenched
with saturated NaHCO3 (10 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined EtOAc extracts were dried
(MgSO4), and concentrated to give crude 23. Flash chroma-
tography on MeOH-deactivated silica gel (5:1 hexanes/
EtOAc) yielded 36 mg (53%) of pure 23 as a colorless oil:
1H NMR 6.35 (s, 1), 6.18 (s, 1), 5.06 (t, 1, J¼7.2), 5.04 (d,
1, J¼7.6), 4.03 (dd, 1, J¼7.6, 6.4), 2.42–2.31 (m, 3), 2.25
(s, 3), 2.18–2.02 (m, 3), 1.77–1.53 (m, 2), 1.67 (s, 3), 1.61
(s, 3), 1.43 (s, 3), 1.34–1.22 (m, 1); 13C NMR 208.3,
160.5, 151.3, 141.1, 132.2, 123.4, 108.4, 104.7, 103.3,
87.5, 80.8, 38.9, 38.7, 38.4, 36.9, 25.6, 22.8, 22.7, 22.4,
22.1, 17.7; IR (neat) 2966, 2917, 1730, 1623; HRMS
(Q-TOF) calcd for C21H27O3 (MH+) 327.1960, found
327.1965.
K2CO3 (1.0 g) was added to a solution of crude 18 (548 mg)
in MeOH (15 mL). The reaction mixture was stirred at 25 ꢀC
for 45 min. The mixture was diluted with saturated NH4Cl
(15 mL) and extracted with EtOAc (3ꢂ30 mL). The com-
bined EtOAc extracts were dried (MgSO4) and concentrated
to give crude 19. Flash chromatography on MeOH-deacti-
vated silica gel (3:2 hexanes/EtOAc) yielded 330 mg (54%
from 17) of 19 as a 1:1 mixture of diastereomers: 1H NMR
6.19 (s, 1), [6.15 (s, 1), 6.14 (s, 1)], [4.87 (d, 1, J¼8.0),
4.85 (d, 1, J¼8.0)], [3.71 (dd, 1, J¼8.0, 7.4), 3.66 (dd, 1,
J¼8.0, 7.4)], [2.69 (t, 1, J¼6.1), 2.65 (t, 1, J¼6.1)], 2.26
(s, 3), 2.08–2.00 (m, 2), 1.93–1.53 (m, 6), 1.52–1.29 (m,
1), [1.38 (s, 3), 1.35 (s, 3)], 1.27 (s, 3), 1.25 (s, 3), 1.05–
0.93 (m, 1), [0.87 (s, 3), 0.86 (s, 3)]; 13C NMR (161.23,
161.17), (151.64, 151.60), (140.48, 140.42), (107.57,
107.54), (107.44, 107.42), (102.58, 102.53), (93.74,
93.63), (80.71, 80.67), (73.15, 73.11), (64.23, 63.88),
(58.49, 58.31), (35.98, 35.57), (34.97, 34.92), (34.88,
34.82), (34.79, 34.71), (24.77, 24.75), (24.48, 24.40),
(23.63, 23.43), 22.37, (22.15, 22.11), (19.22, 19.16),
(18.61, 18.57); IR (neat) 3432, 2946, 2870, 1623; HRMS
(Q-TOF) calcd for C22H31O4 (MH+) 359.2222, found
359.2221.
3.14. (3S,3aR,9S,9aR,9bS)-rel-9-(4-Methyl-3-pentenyl)-
2,3,3a,9,9a,9b-hexahydro-3,6,9-trimethyl-1H-benzo-
furo[4,3,2-cde][1]benzopyran-3-ol (24)
MeMgBr (0.24 mL, 1.4 M in toluene/THF, 0.33 mmol) was
added to a solution of 23 (27 mg, 0.083 mmol) in THF
(10 mL) at 0 ꢀC. The resulting solution was warmed to
25 ꢀC and stirred for 5 h. The reaction was quenched with
saturated NH4Cl (10 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined EtOAc extracts were dried
(MgSO4) and concentrated to give crude 24. Flash chroma-
tography on MeOH-deactivated silica gel (15:1 hexanes/
EtOAc) yielded 22 mg (78%) of pure 24 as a colorless oil:
1H NMR 6.20 (s, 1), 6.17 (s, 1), 5.04 (t, 1, J¼7.6, H10),
4.69 (d, 1, J¼8.5, H4), 3.61 (dd, 1, J¼8.5, 6.1, H5), 2.25
(s, 3), 2.12–2.03 (m, 2, 2H9), 1.96–1.88 (m, 1, H6), 1.75–
1.45 (m, 4, H1, H2, and 2H8), 1.65 (s, 3), 1.59 (s, 3), 1.39
(s, 3, H14), 1.33–1.13 (m, 2, H1 and H2), 1.24 (s, 3, H15);
13C NMR 161.4, 151.6, 140.3, 131.9, 123.7, 108.1, 107.7,
101.4, 90.5, 81.0, 69.5, 38.3, 36.5, 35.1, 33.7, 29.8, 25.6,
22.5, 22.4, 22.2, 17.6, 16.4; IR (neat) 3442, 2965, 1716,
1626; HRMS (EI+) calcd for C22H30O3 (M+) 342.2195,
found 342.2201. The relative stereochemistry of the side
chain of 24 was established by a 1D NOESYexperiment. Ir-
radiation of H5 at d 3.61 showed an NOE to H8 at d 1.73–1.64
and d 1.61–1.52, but not to H14 at d 1.39.
3.12. (3aR,9S,9aR,9bS)-rel-9-[(RS)-2-(3,3-Dimethyl-
oxiranyl)ethyl]-1,2,3a,9,9a,9b-hexahydro-6,9-dimethyl-
3H-benzofuro[4,3,2-cde][1]benzopyran-3-one (22)
A solution of Martin’s sulfurane (562 mg, 0.84 mmol) in dry
CH2Cl2 (10 mL) was added to a solution of 19 (200 mg,
0.56 mmol) in dry CH2Cl2 (5 mL) at 0 ꢀC. The resulting so-
lution was warmed to 25 ꢀC and stirred for 3 h. The reaction
mixture was concentrated to give a 2:1 mixture of 20 and 21.
The residue was dissolved in CH2Cl2 (25 mL) and pyridine
(0.3 mL). The mixture was cooled to ꢁ78 ꢀC. Ozone was
bubbled through it for 12 min while the reaction was moni-
tored by TLC (every 60 s). The ozone flow was replaced by
an air flow and the reaction was quenched with the addition
of Zn (300 mg, activated) at ꢁ78 ꢀC. The mixture was
slowly warmed to 25 ꢀC over 1 h and stirred at 25 ꢀC for
an additional 2 h. The resulting mixture was filtered. The fil-
trate was concentrated to give crude 22. Flash chromato-
graphy on MeOH-deactivated silica gel (1:1 hexanes/
EtOAc) yielded 82 mg (43% from 4) of 22 as a 1:1 mixture
of diastereomers: 1H NMR 6.36 (s, 1), [6.18 (s, 1), 6.17 (s,
1)], [5.06 (d, 1, J¼7.8), 5.04 (d, 1, J¼7.8)], [4.07 (dd, 1,
J¼7.8, 7.2), 4.02 (dd, 1, J¼7.8, 7.2)], [2.71 (t, 1, J¼6.0),
2.67 (t, 1, J¼6.0)], 2.42–2.28 (m, 3), 2.25 (s, 3), 2.12–2.04
(m, 1), 1.97–1.57 (m, 5), [1.43 (s, 3), 1.40 (s, 3)], 1.29 (s,
3), 1.27 (s, 3); 13C NMR (208.25, 208.17), (160.56,
160.50), 151.10, (141.24, 141.18), (108.42, 108.30),
(104.63, 104.51), (103.54, 103.51), (87.47, 87.43), 80.29,
(64.11, 63.71), (58.55, 58.35), (38.78, 38.76), 38.66,
(37.34, 37.05), (35.03, 34.81), (24.79, 24.77), (23.65,
23.48), (22.77, 22.71), (22.66, 22.50), 22.15, (18.67,
18.64); IR (neat) 2966, 2928, 1732, 1624; HRMS (Q-TOF)
calcd for C21H27O4 (MH+) 343.1909, found 343.1917.
Acknowledgements
We are grateful to the National Institutes of Health (GM-
50151) for generous financial support.
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