A model synthesis of the bicyclic core structure of the furanoheliangolide sesquiterpenes

Article abstract of DOI:10.1016/S0040-4039(00)01198-9

A bicyclo[6.2.1]undecane structure, a model for the core structure of several biologically active furanoheliangolide sesquiterpenes, was synthesized through a retro-aldol reaction from a tricyclo-[6.2.1.0^2,7]undecane. The required tricyclic compound was prepared by a Diels-Alder reaction followed by minor transformations. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01198-9

Tetrahedron Letters 41 (2000) 7001±7004
A model synthesis of the bicyclic core structure of the
furanoheliangolide sesquiterpenes
Mauricio Gomes Constantino,* Adilson Beatriz and Gil Valdo Jose da Silva
Â
Departamento de Quõmica, Faculdade de Filoso®a, CieÃncias e Letras de RibeiraÄo Preto,
Universidade de SaÄo Paulo, Avenida Bandeirantes, 3900, 14040-901-RibeiraÄo Preto-SP, Brazil
Received 8 June 2000; revised 17 July 2000; accepted 18 July 2000
Abstract
A bicyclo[6.2.1]undecane structure, a model for the core structure of several biologically active fur-
anoheliangolide sesquiterpenes, was synthesized through a retro±aldol reaction from a tricyclo-
[6.2.1.02,7]undecane. The required tricyclic compound was prepared by a Diels±Alder reaction followed by
minor transformations. # 2000 Elsevier Science Ltd. All rights reserved.
In the last few years we have been interested in developing methods for the synthesis of certain
Brazilian biologically active natural products belonging to the class of furanoheliangolides. They
are sesquiterpenoids containing a peculiar macrocyclic structure, a bicyclo[6.2.1]undecane;
goyazensolide (1), which has cytotoxic and schistosomicidal properties,1 is a typical example. Our
recent success in preparing compound 2, which contains most of the structural features of the
bicyclic core found in these sesquiterpenes, prompted us to disclose our preliminary results.
Our synthetic strategy consisted of preparing a tricyclo[6.2.1.02,7]undecane structure (5)
through a simple Diels±Alder reaction, and breaking the bond C2±C7 to obtain the desired bicyclo-
[6.2.1]undecane structure. Starting with cyclopentadiene and benzoquinone, adduct 5 was
prepared in 90% yield (Scheme 1).2
* Corresponding author. Tel: +55 16 602 3747; fax +55 16 633 8151; e-mail: mgconsta@usp.br
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01198-9

7002
Scheme 1.
The conjugated double bond of 5 was selectively reduced with Zn/AcOH (97%),3 and one of
the carbonyls of product 6 was reduced to furnish keto-alcohol 7 in 92% yield (Scheme 2).4 The
high stereoselectivity observed in this last reduction is clearly due to the cage-like structure of 6.
Scheme 2.
At this point we intended to move the ±OH group of compound 7 to carbon 7 of the tricyclic
ring system; the product thus obtained (compound 12) (see Scheme 4) would be suitable for a
retro-aldol reaction that would e€ect the desired C2±C7 bond breaking. To accomplish this `OH
shift' we decided to try the water elimination±water addition sequence, as there is some evidence
that, in this kind of structure, compounds with a double bond exo to the bicyclic structure (as 8)
form more easily than their isomers (like 11).5
As anticipated, treatment of 7 with MsCl in pyridine under re¯ux produced mainly ole®ns 8, as
a 1:1 mixture of stereoisomers (8a+8b), and compound 11 was not found among the reaction
products (Scheme 3).6 The crude mixture was obtained in 94% yield (calculated as for compound
8 or 9), and the yields in the scheme correspond to products puri®ed by column chromatography.
Scheme 3.
The intended further transformation of 8 into 9, which we expected to be more stable due to
conjugation, proved to be unnecessary. In fact, a considerable amount of 9 was formed in the
elimination reaction, and this allowed us to isolate compounds 8 (as a mixture of isomers 8a+8b)

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and 9 and show that both can be transformed into the desired hydration product 12, by a simple
treatment with acetone/water/p-toluenesulfonic acid (Scheme 4). Under these conditions, either 8
or 9 is transformed in the same equilibrium mixture from which compounds 12 (as a 80:20 mix-
ture of stereoisomers 12a and 12b) could be isolated in 55±60% yield, and compounds 9 (7%) and
8 (10%) could be recovered by column chromatography. Isomers 12a and 12b were also sepa-
rated from each other (in a further column chromatography) and properly characterized,
including a relative stereochemistry determination by NOE experiments.7
Scheme 4.
Finally, treatment of each isomer of compound 12 with NaH in toluene under re¯ux gave rise
to a retro±aldol reaction and furnished the desired bicyclic product 28 in 75% yield after column
chromatography (Scheme 5).
Scheme 5.
We have also experimented on the treatment of 9 with a solution of NaOH in methanol/water,
which could give a nucleophilic addition of OH^ followed by a retro±aldol reaction in the same
pot; this treatment, however, furnished only methoxylated products.
Acknowledgements
The authors thank the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP),
the Conselho Nacional de Desenvolvimento Cientõ®co e Tecnologico (CNPq), and the Coordenadoria
de Aperfeicoamento de Pessoal do Ensino Superior (CAPES) for ®nancial support.

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References
1. Vichnewski, W.; Takahashi, A. M.; Nasi, A. M. T. T.; Goncalves, D. C. R. G.; Dias, D. A.; Lopes, J. N. C.;
Goedken, V. L.; Gutierrez, A. B.; Herz, W. Phytochemistry 1989, 28, 1441.
2. Albrecht, W. Ann. 1906, 31, 384.
3. Marchand, A. P.; Reddy, G. M. Synthesis 1991, 198.
4. Marchand, A. P.; Xing, D.; Wang, Y.; Bott, S. G. Tetrahedron: Asymmetry 1995, 6, 2709.
5. Marchand, A. P.; Dong, G. Z.; Shukla, R.; Prasad, A. D.; Bott, S. G. Tetrahedron 1997, 53, 14895.
6. Treatment of the mesylate of 7 (obtained in quantitative yield from 7 with MsCl in triethylamine) with KOBut
produced only compound 13 in good yield (69%).
1
7. Compound 12a: rel-(1S,7S,2R,8R)-7-Hydroxytricyclo[6.2.1.02,7]undec-9-en-3-one: H NMR (300 MHz, CDCl3):
1.21 (td, 1H, J1=J2=14 Hz, J3=3 Hz), 1.51 (dt, 1H, J1=9 Hz, J2=J3=2 Hz), 1.66 (m, 1H), 1.81±2.00 (m, 3H),
2.15 (m, 1H), 2.34 (ddt, 1H, J1=18 Hz, J2=6 Hz, J3=J4 =2 Hz), 2.50 (d, 1H, J=4 Hz), 2.68 (m, 1H), 2.85 (br s,
1H), 3.35 (br s, 1H), 5.96 (dd, 1H, J1=6 Hz, J2=3 Hz), 6.12 (dd, 1H, J1=6 Hz, J2=3 Hz); 13C NMR (75 MHz,
CDCl3): 18.19 (CH2), 35.75 (CH2), 38.89 (CH2), 43.82 (CH), 45.78 (CH2), 54.12 (CH), 61.57 (CH), 81.63 (C),
134.91 (CH), 138.27 (CH), 214.57 (CˆO); IR (®lm) ꢀmax: 3441, 2692, 2887, 965, 733 cm^1; MS m/z (rel. intensity):
160 [M+^H2O] (11), 132 (6), 113 (100), 66 (59), 55 (7), 39 (10). Compound 12b: rel-(1S,2S,7S,8R)-7-
Hydroxytricyclo[6.2.02,7]undec-9-en-3-one: mp 77±80ꢀC; H NMR (300 MHz, CDCl3): 1.32 (d, 1H, J=10 Hz),
1
1.48 (td, 1H, J1=J2=14 Hz, J3=3 Hz), 1.56 (ddt, 1H, J1=10 Hz, J2=4 Hz, J3J42 Hz), 1.81 (d, 1H, J=3 Hz),
1.89 (m, 1H), 2.12 (m, 1H), 2.19±2.37 (m, 2H), 2.54 (m, 1H), 2.76 (tt, 1H, J1=J2=3 Hz, J3=J4=2 Hz), 6.28 (dd,
1H, J1=6 Hz, J2=3 Hz), 6.49 (d, 1H, J1=6 Hz, J2=3 Hz); 13C NMR (75 MHz, CDCl3): 18.38 (CH2), 35.79
(CH2), 38.69 (CH2), 45.20 (CH), 48.33 (CH2), 53.04 (CH), 61.69 (CH), 82.00 (C), 134.18 (CH), 139.27 (CH),
213.54 (CˆO); IR (KBr) ꢀmax: 3441, 2962, 2887, 1692, 1455, 733 cm^1; MS m/z (rel. intensity): 160 [M+^H2O] (12),
132 (6), 113 (100), 66 (59), 55 (7), 39 (10).
8. Compound 2: rel-(1S,8R)-Bicyclo[6.2.1]undec-9-ene-2,6-dione (4): 1H NMR (300 MHz, CDCl3): 1.91 (dd, 1H,
J1=14 Hz, J2=12 Hz), 1.92 (m, 1H), 2.13 (ddd, 1H, J1=13 Hz, J2J35 Hz, J4=2 Hz), 2.17 (d, 1H, J=14 Hz),
2.43±2.53 (m, 3H), 2.55±2.75 (m, 3H), 3.16 (m, 1H), 3.39 (ddd, 1H, J1=12 Hz, J2J33 Hz, J4=2 Hz), 5.90 (dt,
1H, J1=5 Hz, J2=J3=2 Hz), 6.06 (dt, 1H, J1=5 Hz, J2=J3=2 Hz); 13C NMR (75 MHz, CDCl3): 21.20 (CH2),
33.15 (CH2), 36.91 (CH2), 40.73 (CH2), 42.27 (CH), 48.36 (CH2), 58.33 (CH), 130.86 (CH), 137.54 (CH), 211.86
(CˆO), 218.35 (CˆO); MS m/z (rel. intensity): 149 [M+^HCO](57), 123 (9), 113 (9), 66 (100), 55 (56), 43 (56), 29
(13).