Facile approach to the bicyclo[5.3.0]decane ring system; efficient synthesis of (±)-7-epi-β-bulnesene

Article abstract of DOI:10.1016/S0040-4039(02)00171-5

An efficient strategy for the rapid construction of the guiane bicyclo[5.3.0]decane ring system from appropriately substituted 4-alkyn-1-ols has been developed. This methodology relies on a MeLi-catalyzed tandem 5-exo-dig cyclization/Claisen rearrangement sequence as the key ring forming step.

Full text of DOI:10.1016/S0040-4039(02)00171-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1939–1941
Facile approach to the bicyclo[5.3.0]decane ring system;
efficient synthesis of ( )-7-epi-b-bulnesene
Jalluri S. Ravi Kumar, Michael F. O’Sullivan, Sarah E. Reisman, Catherine A. Hulford and
Timo V. Ovaska*
Department of Chemistry, Connecticut College, 270 Mohegan Avenue, New London, CT 06320, USA
Received 2 January 2002; accepted 17 January 2002
Abstract—An efficient strategy for the rapid construction of the guiane bicyclo[5.3.0]decane ring system from appropriately
substituted 4-alkyn-1-ols has been developed. This methodology relies on a MeLi-catalyzed tandem 5-exo-dig cyclization/Claisen
rearrangement sequence as the key ring forming step. © 2002 Elsevier Science Ltd. All rights reserved.
The bicyclo[5.3.0]decane ring system is prevalent in
nature and has been identified as the key structural unit
in a number of biologically active compounds.1 Among
them are the guianes and the tricyclic guanacastenes as
well as the guaianolide sesquiterpenes, characterized by
a g-lactone ring fused to the 5–7 core. Although many
of these interesting natural products have been isolated
and synthesized over the past few decades,2 several
novel biologically active compounds incorporating the
bicyclo[5.3.0] structure have been discovered only
recently. Representative examples of these include the
americanolides,3 some of which exhibit activity against
the human colon cancer cell line, and the unique diter-
pene guanacastepene which was found to possess novel
and potent antibacterial properties.4
pound has been previously synthesized in 13 steps by
Negishi et al.9,10 in 11 steps by Sammes et al.11 and in
10 steps by Oppolzer et al.12 Negishi employed Zr-pro-
moted enyne bicyclization followed by transition metal
or radical catalyzed cyclization of alkenyl iodides as the
key steps for his synthesis,9 and Sammes utilized
intramolecular 1,3-dipolar cycloaddition of a 2-substi-
tuted 3-oxidopyrylium as the primary ring forming
strategy in his approach. Oppolzer’s synthesis relies on
an intramolecular [2+2] cycloaddition of an appropri-
ately substituted enol acetate to afford
a tricy-
clo[5.3.0.01,5]decane intermediate, which subsequently
undergoes base-induced fragmentation to produce the
desired 5-7 ring system.12
We envisioned that the bulnesene framework could be
constructed from an appropriately substituted
acetylenic alcohol using a straightforward one-pot pro-
cess according to the retrosynthetic analysis shown in
Scheme 1. This sequence involves a base-catalyzed 5-
exo-dig cyclization of alkynol 3 to generate the 2-meth-
ylene tetrahydrofuran intermediate 2, which then
undergoes a spontaneous Claisen rearrangement under
thermal conditions to provide the key bicyclic ketone
1.9,11,12 Installation of the exocyclic isopropylidene moi-
ety on the B ring to complete the target 7-epi-b-bul-
nesene is achieved through standard Wittig chemistry.
As part of our ongoing investigation probing the syn-
thetic utility of the tandem anionic cyclization/Claisen
rearrangement process5 for the efficient synthesis of
various cycloheptane-containing polycyclic natural
products,6–8 we have now applied this strategy to the
rapid construction of ( )-7-epi-b-bulnesene. This com-
* Corresponding author. Tel.: 860-439-2488; fax: 860-439-2477;
e-mail: tvova@conncoll.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00171-5

1940
J. S. Ra6i Kumar et al. / Tetrahedron Letters 43 (2002) 1939–1941
yield.15 The 5-step synthesis of ( )-7-epi-b-bulnesene16
was completed by reacting ketone 1 with isopropylidene-
triphenylphosphorane in DMSO according to the pro-
cedure of Oppolzer et al.12
It should be emphasized that, unlike other reported
syntheses of the bulnesene ring system in which the
crucial ring forming steps result in the formation of a
mixture of stereoisomers,9,11,12 the tandem sequence
described here is completely stereoselective. Thus, the
observed 7S*,8R* stereochemistry in 1 is a conse-
quence of the trans relationship between the methyl and
the propargyl substituents in 5.
Scheme 1. Retrosynthetic analysis for ( )-7-epi-b-bulnesene.
The silyl enol ether 4 was also readily alkylated2b with
3-iodo-1-trimethylsilyl-1-propyne to afford the corre-
sponding trimethylsilyl substituted ketone 7 and subse-
quently converted to alcohol 8 in an excellent yield as
shown in Scheme 3. We have previously reported7 that,
in cases where the triple bond bears a silicon-containing
substituent (TMS or TBDMS) in the 4-alkyn-1-ol sys-
The requisite alkynol 3 was synthesized in three steps
from commercially available 2-cyclopenten-1-one as
depicted in Scheme 2. Thus, conjugate addition using
Me2CuLi in the presence of chlorotrimethylsilane
afforded the known13 silyl enol ether 4 in 57% yield. On
exposure to cesium fluoride and propargyl bromide in
anhydrous acetonitrile at room temperature,14 4 was
converted to trans-2-(2-propynyl)-3-methylcyclopen-
tanone 5 in 60% isolated yield after column chromato-
graphy. The balance of the product mixture consisted
mainly of 3-methylcyclopentanone, undoubtedly
derived from premature protonation of the intermediate
enolate anion. The maximum yield of the desired
ketone product (60%) was obtained through the use of
a syringe pump, allowing slow addition of 4 to the
reaction mixture. The alkylation itself was approxi-
mately 94% diastereoselective in favor of the trans
isomer as judged by GC analysis.
tem,
the
cyclization/sigmatropic
rearrangement
sequence is accompanied by the Brook rearrange-
ment,17 resulting in regiospecific installation of a silyl
enol ether functionality on the seven-membered ring.
As expected, the trimethylsilyl substituted alcohol 8
exhibited analogous behavior on treatment of with
catalytic MeLi (10 mol%) in refluxing phenetole,
affording the silyl enol ether 9 as the ultimate reaction
product. Although readily hydrolyzed with aqueous
acid, 9 can be isolated by careful flash chromatography
on florisil. The formation of this product is significant
in that it provides future opportunities for regioselective
functionalization and further elaboration of bicyclic 5-7
system as a potential route to more complex cyclohep-
tanoid ring systems, such as the guainolide natural
products.
Reaction of ketone 5 with vinyl cerium 6, generated in
situ from the corresponding vinyllithium species, pro-
duced the 1R*,2S* alcohol 3a and the undesired
1S*,2S* diastereomer 3b (8:1 ratio) in a combined yield
of 65%. At this point, the stage was set for the key
intramolecular
cyclization/Claisen
rearrangement
In conclusion, we have achieved a rapid, 5-step synthe-
sis of ( )-7-epi-b-bulnesene starting from commercially
available 2-cyclopenten-1-one using a powerful one-pot
5-exo-dig cyclization/Claisen rearrangement process as
the key ring forming operation. We are currently
exploring the possibility of employing this strategy as a
route to several tricyclic guainolide natural products
through appropriate modification of starting materials
and further elaboration of the 5–7 bicyclic core.
sequence which proceeded without incident on heating
in the presence of catalytic MeLi (5–10 mol%) to
provide the desired bicyclic ketone in 84% isolated
Scheme 2. Synthesis of ( )-7-epi-b-bulnesene.
Scheme 3. Synthesis of bicyclic silyl enol ether 9.

J. S. Ra6i Kumar et al. / Tetrahedron Letters 43 (2002) 1939–1941
1941
Acknowledgements
8. Ovaska, T. V.; Reisman, S. E.; Flynn, M. A. Org. Lett.
2001, 3, 115–117.
9. Negishi, E.; Ma, S.; Sugihara, T.; Noda, Y. J. Org.
Chem. 1997, 62, 1922–1923.
10. Agnel, G.; Owczarczyk, Z.; Negishi, E. Tetrahedron Lett.
1992, 33, 1543–1546.
11. Bromidge, S. M.; Sammes, P. G.; Street, L. J. J. Chem.
Soc., Perkin Trans. 1 1985, 1725–1730.
12. Oppolzer, W.; Wylie, R. D. Helv. Chim. Acta 1980, 63,
1198–1203.
We are grateful to the National Institutes of Health
(R15 GM60972-01) for financial support of this work.
M.F.O. and C.A.H. acknowledge Boehringer-Ingelheim
Pharmaceuticals, Inc. for summer undergraduate fel-
lowships. S.E.R. acknowledges Pfizer, Inc. for a sum-
mer undergraduate fellowship (S.U.R.F. program).
13. Dieter, R. K.; Dieter, J. W. J. Chem. Soc., Chem. Com-
mun. 1983, 23, 1378–1380.
14. For a general procedure, see: Kita, Y.; Segawa, J.;
Haruta, J.; Yasuda, H.; Tamura, Y. J. Chem. Soc.,
Perkin Trans. 1 1982, 1099–1104.
References
1. Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217–241.
2. For representative synthetic approaches toward to the
bicyclo[5.3.0] ring system, see: (a) Dudley, G. B.; Tan, D.
S.; Kim, G.; Tanski, J. M.; Danishefsky, S. J. Tetra-
hedron Lett. 2001, 42, 6789–6791; (b) Dudley, G. B.;
Danishefsky, S. J. Org. Lett. 2001, 3, 2933–2402; (c)
Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 3,
569–572; (d) Deak, H. L.; Stokes, S. S.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 5152–5153; (e) Lange, G. L.;
Gottardo, C. Tetrahedron Lett. 1994, 35, 8513–8516; (f)
Lange, G. L.; Gottardo, C.; Merica, A. J. Org. Chem.
1999, 64, 6738–6744; (g) Davies, H. M. L.; Doen, B. D.
Tetrahedron Lett. 1996, 37, 3967–3969; (h) Wender, P. A.;
Fuji, M.; Husfield, C. O.; Love, J. A. Org. Lett. 1999, 1,
137–139; (i) Lansbury, P. T.; Serelis, A. K. Tetrahedron
Lett. 1978, 1909–1912; (j) Posner, G. H.; Babiak, K. A.;
Loomis, G. L.; Frazee, W. J.; Mittal, R. D.; Karle, I. L.
J. Am. Chem. Soc. 1980, 102, 7498–7505; (k) Carroll, G.
L.; Allan, A. K.; Schwaebe, M. K.; Little, R. D. Org.
Lett. 2000, 2, 2531–2534.
3. (a) Rodriguez, A. D.; Boulanger, A.; Martinez, J. R.;
Huang, S. D. J. Nat. Prod. 1998, 61, 451–455; (b)
Rodriguez, A. D.; Boulanger, A. J. Nat. Prod. 1997, 60,
207–211.
4. Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am.
Chem. Soc. 2000, 122, 2116–2117.
5. For an early report on this sequence, see: Marvell, E. N.;
Titterington, D. Tetrahedron Lett. 1980, 2123–2124.
6. Ovaska, T. V.; Roark, J. L.; Shoemaker, C. M.; Bordner,
J. Tetrahedron Lett. 1998, 39, 5705–5708.
15. Experimental procedure for the preparation of 1: To a
base-washed, flame-dried 10 mL round-bottomed flask,
equipped with a reflux condenser were added 0.470 g
(2.64 mmol) of 3a and 1.5 mL of anhydrous phenetole.
The solution was then heated under argon to 155°C (bath
temperature), followed by dropwise addition of 1.30 mL
of 0.203 M MeLi in phenetole (0.264 mmol, 10 mol%).
The resulting solution was heated at 155°C for an addi-
tional 5 h. After cooling to room temperature, the mix-
ture was chromatographed on silica gel, first eluting with
1% EtOAc/hexanes to remove phenetole then with 4%
Et2O/20% DCM/pentane to give 0.396 g of the desired
product (84%) as a clear oil after solvent removal under
vacuum. 1H NMR (250 MHz, CDCl3) l 2.93–2.83 (m,
1H), 2.59 (d, J=14.4 Hz, 1H), 2.41–2.29 (m, 7H), 1.89–
1.79 (m, 1H), 1.63 (s, 3H), 1.58–1.42 (m, 1H), 1.28–1.10
(m, 1H), 0.99 (d, J=6.41 Hz, 3H) ppm. 13C NMR (62
MHz, CDCl3) l 213.6, 140.3, 125.9, 47.4, 46.3, 42.6, 41.9,
33.7, 31.7, 31.2, 21.5, 18.1 ppm.
16. 1H NMR (400 MHz, CDCl3) l 2.67 (d, J=14.5 Hz, 1H),
2.54–2.46 (m, 1H), 2.34–2.20 (m, 6H), 1.92–1.83 (m, 1H),
1.82–1.75 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H),
1.54–1.44 (m, 1H), 1.40–1.36 (m, 1H), 1.18–1.05 (m, 1H),
1.03 (d, J=6.64 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) l 140.4, 133.2, 126.4, 122.0, 49.3, 42.7, 37.1, 36.7,
33.9, 31.5, 29.4, 21.9, 20.2, 20.1, 18.6 ppm (lit.12 140.2,
133.2, 126.2, 121.7, 49.6, 42.8, 37.1, 36.8, 33.9, 31.5, 29.6,
21.9, 20.1, 18.7 ppm).
17. Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
7. Ovaska, T. V.; Roses, J. B. Org. Lett. 2000, 2, 2361–2364.