Synthesis of the tetracyclic core of the bisabosquals

Article abstract of DOI:10.1016/j.tetlet.2004.05.005

HCl-catalyzed deprotection and cyclization of 8b provided tricycle 9b cleanly. Epoxidation of 9b afforded tetracycle 13 with the wrong stereochemistry at the tertiary alcohol. Selective elimination of the tertiary alcohol to give the exocyclic methylene compound, alkene cleavage to form the ketone with OsO₄ and NaIO₄, and addition of MeMgBr to the ketone from the least hindered face gave tertiary alcohol 16 with the tetracyclic core of bisabosqual A (1).

Full text of DOI:10.1016/j.tetlet.2004.05.005

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5015–5018
Synthesis of the tetracyclic core of the bisabosquals
Barry B. Snider* and Mercedes Lobera
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 19 April 2004; accepted 3 May 2004
Abstract—HCl-catalyzed deprotection and cyclization of 8b provided tricycle 9b cleanly. Epoxidation of 9b afforded tetracycle 13
with the wrong stereochemistry at the tertiary alcohol. Selective elimination of the tertiary alcohol to give the exocyclic methylene
compound, alkene cleavage to form the ketone with OsO4 and NaIO4, and addition of MeMgBr to the ketone from the least
hindered face gave tertiary alcohol 16 with the tetracyclic core of bisabosqual A (1).
Ó 2004 Elsevier Ltd. All rights reserved.
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) inhibits the
microsomal squalene syntheses from Saccharomyces
cerevisiae, Candida albicans, HepG2 cell, and rat liver
with IC50 values of 0.43, 0.25, 0.95, and 2.5 lg/mL,
respectively, and has broad antifungal activities against
various yeasts. This activity suggests that bisabosqual A
might be useful for treatment of hypercholesterolemia.
CHO
R1
CHO
R2
O
R3
H
O
H
O
O
H
H
OH
OH
2
1 (bisabosqual A)
R1
R1
R2
R2
OH
The novel tetracyclic structure of bisabosqual A (1) was
determined by 2D NMR experiments and confirmed by
X-ray crystallography of bisabosqual B.2 The three six-
membered rings of 1 are analogous to those of tetra-
hydrocannabinols (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.
HO
R3
O
O
H
HO
H
R3
H
OH
3
4
R1
R1
R2
R2
O
Initially, we thought that the tetracycle of bisabosqual A
might be accessible by an inverse electron demand het-
ero Diels–Alder reaction of quinone methide 2.4 The
furan ring of 2 will force the Diels–Alder reaction to give
the desired cis-ring fusion (see Scheme 1). Quinone
methide 2 could be formed by dehydration of di-
HO
OH
OH
R3
6
R3
CHO
O
7
5
Scheme 1. Retrosynthetic analysis of bisabosqual A (1).
Keywords: Quinone methide; Inverse electron demand Diels–Alder
reaction; Alcohol inversion.
hydrobenzofuranol 4, which would be prepared from
resorcinol 6 and epoxyaldehyde 7. Although we were
able to prepare 4, R1, R2 ¼ H, CHO, R3 ¼ Me, all
* Corresponding author. Tel.: +1-781-736-2550; fax: +1-781-736-2516;
e-mail: snider@brandeis.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.005

5016
B. B. Snider, M. Lobera / Tetrahedron Letters 45 (2004) 5015–5018
attempts to generate quinone methide 2 resulted in
dehydration to form the benzofuran.5
R
Me
n-BuLi, THF, 25 °C
MOMO
HO
OMOM
then
We therefore considered methods for the preparation of
bisabosqual A (1) by oxidative cyclization of cis-fused
tricycle 3, which can be prepared by inverse electron
demand Diels–Alder reaction of quinone methide 5.
Although hexahydrocannabinoids are invariably formed
with a trans-ring fusion, Rickards found that treatment
of 8a with TMSCl and Et4NBr cleaved the MOM ethers
and generated a quinone methide that cyclized to give
65% of the cis-fused tetrahydrocannabinoid tricycle 9a
(see Eq. 1).6
MOMO
OMOM
OHC
10
8b, R = Me
11
(90-100%)
1:6 3 M aq HCl/MeOH
reflux 2 h
Me
Me
R
1) m-CPBA
CH2Cl2
12 h
R
R
O
H
6 equiv TMSCl
6 equiv Et4NBr
CH2Cl2, 6 h
O
OH
O
OH
O
H
H
H
MOMO
HO
OMOM
O
OH
H
2) NaOH
MeOH
H
O
ð1Þ
H
H
OH
H
13 (83%)
9b, R = Me
(58% from 10)
δ 0.87
12
9a, R = C5H11 (65%)
8a, R = C5H11
1) MsCl, Et3N, CH2Cl2 14h
2) OsO4, NaIO4, THF/H2O, 48 h
Deprotonation at the 2-position of the bis MOM ether
of orcinol (10)7 with n-BuLi in THF followed by addi-
tion of citral (11) afforded 90–100% of 8b as a ꢀ60:40
E:Z mixture that decomposed on chromatography (see
Scheme 2). In our hands, treatment of crude 8b with
TMSBr,8 TMSCl and Et4NBr, or TMSCl and Bu4NBr
in CH2Cl2 at 25 °Cgave no 9b. Use of TMSBr at À78 °C
provided 60% of the MOM ether of 9b (not shown),
which can also be obtained in 70% yield with TMSCl
and NaI at À20 °C.9 After extensive experimentation, we
found that complete deprotection of 8b and cyclization
to 9b can be effected in 58% overall yield from 10 by
heating 8b in a 1:6 mixture of 3 M aqueous hydrochloric
acid and MeOH at reflux for 2 h. Tricycle 9b10 is
somewhat unstable and can only be purified on MeOH-
deactivated silica gel.
Me
H
Me
MeMgBr, THF
O
O
H
O
O
H
H
H
H
δ 1.25
OH
X
14, X = CH2 (89% of 84:16 mixture)
15, X = O
16 (64% from 14)
Scheme 2. Synthesis of tetracyclic core 16.
16. Treatment of 13 with MsCl and excess Et3N in
CH2Cl2 provided 89% of an 84:16 mixture of 1416 and
the endocyclic isomer. Formation of the less stable
alkene 14 is favored because only the methyl protons
can adopt the required antiperiplanar orientation to the
equatorial leaving group (see Fig. 1). Oxidative cleavage
of the alkene mixture with OsO4 and NaIO4 gave ketone
15.17 Addition of MeMgBr to the ketone in THF
occurred selectively from the less hindered a-face (see
Fig. 1) to afford the desired tertiary alcohol 1618 in 64%
yield from 14.
syn-Oxidative cyclization11;12 of 9b would yield the
desired tertiary alcohol 16 in a single step. Not sur-
prisingly, treatment of 9b with (CF3CO2)ReO3,
(Cl2HCCO2)ReO3, or PCC led to complex mixtures of
products. All previous oxidative cyclizations have star-
ted with unsaturated alcohols, rather than phenols. The
electron rich phenol should be more easily oxidized than
the alkene. This reactivity order was also observed
during attempted iodocyclization. Treatment of 9b with
bis(collidine)iodonium hexafluorophosphate13 afforded
the diiodo phenol.
The spectral data of the cyclohexanol protons and car-
bons of 16 correspond closely to those of bisabosqual A
(1), while those of 13 are quite different. In particular,
Finally, we decided to epoxidize 9b from the less hin-
dered a-face with m-CPBA in CH2Cl2 as reported by
Razdan and co-workers in a similar system.14 The ini-
tially formed epoxy phenol 12 partially cyclized to give
tetracycle 1315 with the desired ring system, but the
wrong stereochemistry at the tertiary alcohol. Treatment
of this mixture with methanolic NaOH for 2 h provided
83% of 13.
O
O
O
O
O
H
H
OH
H
H
H
H
13
15
The rigidity of the ring system allowed us to develop an
efficient procedure to convert 13 to the desired alcohol
Figure 1. 3-Dimensional structures of 13 and 15.

B. B. Snider, M. Lobera / Tetrahedron Letters 45 (2004) 5015–5018
5017
McDonald, F. E.; Singhi, A. D. Tetrahedron Lett. 1997,
38, 7683–7686.
MeCOH absorbs at d 1.25 in 16 and d 1.26 in 1, but at d
0.87 in the epimeric alcohol 13.
12. Schlecht, M.; Kim, H.-J. J. Org. Chem. 1989, 54, 583–587.
13. Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 1999, 77,
206–211.
14. Uliss, D. B.; Razdan, R. K.; Dalzell, H. C.; Handrick,
G. R. Tetrahedron 1977, 33, 2055–2059.
In conclusion, we have developed a short and efficient
route to the tetracyclic core of the bisabosquals. We are
currently extending the sequence to more highly func-
tionalized resorcinols and farnesal, rather than citral, as
needed for the synthesis of bisabosqual A.
15. Preparation of 13: A solution of m-CPBA (276 mg,
1.357 mmol) in CH2Cl2 (20 mL) was added dropwise to a
solution of 9b (254 mg, 0.984 mmol) in CH2Cl2 (54 mL) at
0 °C. The reaction was stirred for 12 h at 25 °Cand
concentrated. The orange residue was taken up in Et2O,
which was washed with Na2SO3, NaHCO3, and brine,
dried (MgSO4), and concentrated. The residue was taken
up in MeOH (40 mL) and 4% NaOH (25.1 mL) was added
to the solution. The reaction was stirred at 25 °Cfor 2 h.
The MeOH was evaporated and the aqueous phase was
extracted with Et2O. The combined extracts were washed
with brine, dried (MgSO4), and concentrated. Flash
chromatography of the residue on MeOH-deactivated
silica gel (hexanes) gave 224 mg (83%) of 13: 1H NMR 6.19
(s, 1), 6.16 (s, 1), 4.85 (br d, 1, J ¼ 8:6), 3.72 (dd, 1,
J ¼ 8:6, 6.7), 2.26 (s, 3), 1.97 (ddd, 1, J ¼ 11:6, 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, J ¼ 14:3, 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 (Mþ) 274.1569, found
274.1558.
Acknowledgements
We are grateful to the National Institutes of Health
(GM-50151) for generous financial support.
References and notes
1. Minagawa, K.; Kouzuki, S.; Nomura, K.; Yamaguchi, T.;
Kawamura, Y.; Matsushima, K.; Tani, H.; Ishii, K.;
Tanimoto, T.; Kamigauchi, T. J. Antibiot. 2001, 54, 890–
895.
2. Minagawa, K.; Kouzuki, S.; Nomura, K.; Kawamura, Y.;
Tani, H.; Terui, Y.; Nakai, H.; Kamigauchi, T. J. Antibiot.
2001, 54, 896–903.
3. (a) Mechoulam, R.; Ben-Shabat, S. Nat. Prod. Rep. 1999,
16, 131–143; (b) Razdan, R. K. In The Total Synthesis of
Natural Products; ApSimon, J., Ed.; Wiley and Sons: New
York, 1981; Vol. 4, pp 185–262.
4. (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron
2002, 58, 5367–5405; (b) Boger, D. L.; Weinreb, S. N.
Hetero Diels–Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987; pp 193–200.
5. Snider, B. B.; Lobera, M.; Zhou, Y. unpublished results.
6. Moore, M.; Rickards, R. W.; Rønneberg, H. Aust. J.
Chem. 1984, 37, 2339–2348.
7. (a) Townsend, C. A.; Davis, S. G.; Christensen, S. B.;
Link, J. C.; Lewis, C. P. J. Am. Chem. Soc. 1981, 103,
6885–6888; (b) Ohta, S.; Nozaki, A.; Ohashi, N.; Mat-
sukawa, M.; Okamoto, M. Chem. Pharm. Bull. 1988, 36,
2239–2243.
16. Preparation of 14: MsCl (0.8 mL, 10.2 mmol) was added
dropwise to a solution of 13 (157 mg, 0.573 mmol) and
Et3N (2.7 mL, 18.8 mmol) in CH2Cl2 (23 mL) at 0 °C. The
reaction was stirred for 14 h at 25 °C, quenched with 2 M
HCl, and extracted with Et2O. The combined extracts
were washed with brine, dried (MgSO4), and concentrated.
Flash chromatography of the residue on MeOH-deacti-
vated silica gel (hexanes) gave 130 mg (89%) of an 84:16
mixture of 14 and the endocyclic isomer: 1H NMR (14)
6.25 (s, 1), 6.16 (s, 1), 5.33 (br d, 1, J ¼ 7:9), 5.14 (br s, 1),
4.81 (br s, 1), 3.68 (br dd, 1, J ¼ 7:9, 7), 2.27 (s, 3), 2.24
(ddd, 1, J ¼ 12, 3, 3), 2.00 (ddd, 1, J ¼ 12, 6, 6), 1.88–1.75
(m, 2), 1.40 (s, 3), 1.34 (s, 3), 0.92–0.82 (m, 1); (partial data
for endocyclic isomer) 5.50 (br d, 1, J ¼ 5:2), 5.20 (br d, 1,
J ¼ 8), 3.77–3.72 (m, 1), 2.25 (s, 3); 13CNMR 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 (Mþ) 256.1463, found 256.1471.
8. Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron
Lett. 1984, 25, 2515–2518.
9. Rigby, J. H.; Wilson, J. Z. Tetrahedron Lett. 1984, 25,
1429–1432.
17. Preparation of 15: OsO4 (42 lL of a 2.5% solution in
t-BuOH, 0.004 mmol) and NaIO4 (53 mg, 0.246 mmol)
were added to a solution of 14 (21 mg, 0.082 mmol) in
THF–H2O (2:1, 1 mL). The reaction was stirred at 25 °C
for 48 h and concentrated. 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-deacti-
vated silica gel (9/1 hexane–EtOAc) gave 19 mg (92%) of
10. Preparation of 9b: A 3 M solution of HCl (22 mL,
65 mmol) was added to a solution of 8b (2.0 g, 5.49 mmol)
in MeOH (130 mL). The reaction was heated at reflux 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 to
give 1.48 g (104%) of crude 9b. Flash chromatography of
the residue on MeOH-deactivated silica gel (hexanes) gave
825 mg (58%) of tricycle 9b that was 90–95% pure: 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);
13CNMR 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 (Mþ) 258.1620, found
258.1612.
1
80% pure ketone 15: H NMR 6.36 (s, 1), 6.18 (s, 1), 5.05
(d, 1, J ¼ 7:9), 4.07 (br dd, 1, J ¼ 7:9, 7), 2.41–2.20 (m, 2),
2.26 (s, 3), 1.9–1.6 (m, 2), 1.46 (s, 3), 1.40 (s, 3), 0.9–0.8 (m,
1); 13CNMR 208.4, 160.5, 151.4, 141.1, 108.4, 103.4, 87.5,
78.5, 39.1, 38.7, 29.7, 26.7, 26.4, 22.7, 22.1 (one quaternary
carbon was not observed).
18. Preparation of 16: MeMgBr (0.21 mL, 0.214 mmol) was
added to a solution of partially purified ketone 15 (14 mg,
0.054 mmol) in THF (1 mL) at 0 °C. The reaction was
stirred for 1 h at 25 °C, quenched with NH4Cl, and
extracted with EtOAc. The combined extracts were washed
with brine, dried (MgSO4), and concentrated. Flash chro-
matography of the residue on MeOH-deactivated silica gel
11. (a) Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc.
1997, 119, 6022–6028; (b) McDonald, F. E.; Schultz, C. C.
ꢀ
Tetrahedron 1997, 53, 16435–16448; (c) Gonzalez, I. C.;
Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099–9108; (d)

5018
B. B. Snider, M. Lobera / Tetrahedron Letters 45 (2004) 5015–5018
1
(hexanes) gave 10.4 mg (70%) of 16: H NMR 6.22 (s, 1),
1.26–1.16 (m, 2); 13CNMR 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 (Mþ)
274.1569, found 274.1570.
6.17 (s, 1), 4.70 (br d, 1, J ¼ 8:5), 3.66 (br dd, 1, J ¼ 8:5, 6),
2.26 (s, 3), 1.84 (ddd, 1, J ¼ 11:6, 6, 6), 1.71 (br d, 1, J ¼
11:6), 1.60–1.40 (m, 1), 1.42 (s, 3), 1.33 (s, 3), 1.25 (s, 3),