A general approach toward bakkanes: Short synthesis of (±)- bakkenolide-A (Fukinanolide)

Article abstract of DOI:10.1021/ol048726d

(Chemical Equation Presented) An efficient, general, and fully stereocontrolled approach to the family of bakkanes is disclosed. This route highlights a highly diastereoselective Diels-Alder/aldol sequence to furnish the common hydrindane precursor for th

Full text of DOI:10.1021/ol048726d

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3345-3347
A General Approach Toward Bakkanes:
Short Synthesis of (±)-Bakkenolide-A
(Fukinanolide)†
D. Srinivasa Reddy‡
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Malott Hall,
Lawrence, Kansas 66045-7582
dsreddy88@yahoo.com
Received July 5, 2004
ABSTRACT
An efficient, general, and fully stereocontrolled approach to the family of bakkanes is disclosed. This route highlights a highly diastereoselective
Diels−Alder/aldol sequence to furnish the common hydrindane precursor for the synthesis of bakkanes. The projected common intermediate
was transformed to the (±)-bakkenolide-A in a short sequence.
Bakkanes are sesquiterpenoids possessing a cis-hydrindane
skeleton decorated with two quaternary centers and usually
a â-methylene-γ-butyrolactone moiety (Figure 1). Ap-
eremophilanes.1 Varied biological properties have been
attributed to the members of this family, which includes
selective cytotoxicity,2 antifeedant effects,3 and inhibition of
platelet aggregation.4 The interesting biological activity and
structural features present in bakkanes have kept the synthetic
community busy since the first successful synthesis of
bakkenolide-A (1) in 1973 by Evans and Sims.5
Disclosed herein is a general approach to the family of
bakkanes via the common intermediate obtained from a
Diels-Alder/aldol sequence and a short synthesis of bakkeno-
lide-A (1), the most prominent member of this class of
compounds. Bakkenolide-A (1), also known as fukinanolide,
was isolated from the wild butterbur Petasites japonicus,
(1) (a) Fischer, N. H.; Oliver, E. J.; Fischer, H. D. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Eds.; Springer-Verlag: New York, 1979; Vol.38, Chapter 2. (b)
Silva, L. F., Jr. Synthesis 2001, 671-689.
(2) (a) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T.
Phytochemistry 1976, 15, 1713-1715. (b) Wu, T.-S.; Kao, M.-S.; Wu,
P.-L.; Lin, F.-W.; Shi, L.-S.; Liou, M.-J.; Li, C.-Y. Chem. Pharm. Bull.
1999, 47, 375-382.
Figure 1. Selected members of the bakkane family.
(3) (a) Nawrot, J.; Harmatha, J.; Novotny, L. Biochem. Syst. Ecol. 1984,
12, 99-101. (b) Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny, L. Z.
Angew. Entomol. 1984, 98, 394-398. (c) Nawrot, J.; Bloszyk, E.; Harmatha,
J.; Novotny, L.; Drozdz, B. Acta Entomol. BohemosloV. 1986, 83, 327-
335. (d) Kreckova, J.; Krecek, J.; Harmatha, J. Pr. Nauk. Inst. Chem. Org.
Fiz. Politech. Wroclaw. 1988, 33, 105-107.
proximately 50 bakkanes have been isolated from plants to
date, and they are believed to derive biogenetically from
† Dedicated to Professor Goverdhan Mehta.
‡ Present address: Discovery Research, Dr. Reddy’s Laboratories Ltd.,
Bollaram Road, Miyapur, Hyderabad 500 049, A.P., India.
(4) Wu, T.-S.; Kao, M.-S.; Wu, P.-L.; Lin, F.-W.; Shi, L.-S.; Teng,
C.-M. Phytochemistry 1999, 52, 901-905.
10.1021/ol048726d CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004

showed cytotoxicity toward several carcinoma cell lines, and
is an effective insect antifeedant.6
The Lewis acid mediated intermolecular Diels-Alder reac-
tion10,11 produces the endo-adduct 612 having the aldol
partners (i.e., aldehyde and ketone) in close proximity,
allowing for subsequent intramolecular aldol reaction to give
2. The diastereo- and regioselectivity can be explained on
the basis of secondary orbital interactions and atomic
coefficient preferences, respectively.13 The functionally
embellished cis-hydrindane 2 is an ideal intermediate for the
construction of most of the bakkane family members as it
possesses chemically differentiated olefins for the selective
functionalization of either ring.
Retrosynthetically, most of the bakkanes could be as-
sembled from the functionalized hydrindane precursor 2 with
chemically differentiated olefins. Compound 2 can be
visualized from the Diels-Alder/aldol sequence of tiglic
aldehyde 3 and diene 4 (Scheme 1).
Scheme 1
The efficiency of this approach toward the bakkanes was
readily demonstrated by a rapid construction of bakkeno-
lide-A (1) from the common hydrindane precursor 2. Toward
that goal, both double bonds in 2 were hydrogenated to
give a saturated ketone 7 in a highly stereoselective manner
(>9:1). The stereochemistry shown in compound 7 is based
on the assumption that the hydrogenation occurred from the
convex face of the enone 2. For the construction of the
spirolactone of 1, a quaternary methoxycarbonyl group was
introduced stereoselectively on the five-membered ring with
Mander’s reagent14 via a thermodynamically stable silyl enol
ether.15,5k Once again, the shape of the molecule controlled
the reagent approach from the convex face to give highly
selective reaction. Wittig olefination on keto-ester 8 resulted
in Hayashi’s intermediate 95l in 59% yield (Scheme 3).
The diene 47 was synthesized in high yield from a
commercially available divinyl carbinol 5 and methoxy
propene in the presence of propionic acid or mercuric acetate
in one step via Claisen rearrangement8 (Scheme 2). Reaction
Scheme 2
Scheme 3
of the diene 4 with tiglic aldehyde 3 in the presence of a
Lewis acid followed by base treatment furnished enone 29
in a highly diastereoselective fashion. This transformation
established the requisite stereochemistry of three contiguous
stereogenic centers of the bakkane family of natural products.
Finally, the intermediate 9 was converted to the bakkeno-
lide-A (1), by treatment with SeO2 followed by NaBH4 reduc-
tion of the aldehyde that resulted from overoxidation. This
conversion was carried out in a one-pot sequence by modi-
(5) For the syntheses of bakkanes and related compounds: (a) Evans,
D. A.; Sims, C. L. Tetrahedron Lett. 1973, 14, 4691-4694. (b) Greene, A.
E.; Coelho, F.; Depres, J. P.; Brocksom, T. J. Tetrahedron Lett. 1988, 29,
5661-5662. (c) Hamelin, O.; Depres, J.-P.; Greene, A. E.; Tinant, B.;
Declercq, J.-P. J. Am. Chem. Soc. 1996, 118, 9992-9993. (d) Hamelin,
O.; Wang, Y.; Depres, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000,
39, 4314-4316. (e) Brocksom, T. J.; Coelho, F.; Depres, J.-P.; Greene, A.
E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.;
Wang, Y. J. Am. Chem. Soc. 2002, 124, 15313-15325 and references cited
therein. (f) Srikrishna, A.; Nagaraju, S.; Venkateswarlu, S. Tetrahedron
Lett. 1994, 35, 429-432. (g) Srikrishna, A.; Nagaraju, S.; Venkateswarlu,
S.; Hiremath, U. S.; Reddy, T. J.; Venugopalan, P. J. Chem. Soc., Perkin
Trans. 1 1999, 2069-2076. (h) Srikrishna, A.; Reddy, T. J. ArkiVoc 2001,
Part viii, 9-19 and references cited therein. (i) Back, T. G.; Payne, J. E.
Org. Lett. 1999, 1, 663-665. (j) Back, T. G.; Nava-Salgado, V. O.; Payne,
J. E. J. Org. Chem. 2001, 66, 4361-4368. (k) Mori, K.; Matsushima, Y.
Synthesis 1995, 845. (l) Hayashi, K.; Nakamura, H.; Mitsuhashi, H. Chem.
Pharm. Bull. 1973, 21, 2806-2807.
(6) (a) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.;
Kitahara, Y. Tetrahedron Lett. 1968, 9, 369-373. (b) Naya, K.; Takagi, I.;
Hayashi, M.; Nakamura, S.; Kobayashi, M.; Katsumura, S. Chem. Ind.
(London) 1968, 318-320.
(7) Previously this compound was prepared in minimum of 3 steps. (a)
Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1978,
19, 2075-2078. (b) Gaoni, Y. J. Org. Chem. 1981, 46, 4502-4510. (c)
Yamada, S.; Suzuki, H.; Naito, H.; Nomoto, T.; Takayama, H. J. Chem.
Soc., Chem. Commun. 1987, 332-333.
(8) (a) Bal, S. A.; Helquist, P. Tetrahedron Lett. 1981, 22, 3933-3936.
(b) Mulholland, R. L.; Chamberlin, A. R. J. Org. Chem. 1988, 53, 1082-
1085. (c) Bull, J. R.; Gordon, R.; Hunter, R. J. Chem. Soc., Perkin Trans.
1 2000, 3129-3139.
(9) Stereochemistry was assigned on the basis of literature precedence;
see: refs 10, 11, and 13.
(10) For the synthesis of eremophilanes using similar Diels-Alder
reaction, see: Reddy, D. S.; Kozmin, S. A. J. Org. Chem. 2004, 69, 4860-
4862.
3346
Org. Lett., Vol. 6, No. 19, 2004

fying the reported procedure.5l All spectral data (IR, 1H and
13C NMR) were found to be identical to those reported by
Back et al.5j The overall yield of 1 was 9% for eight steps
starting from commercially available divinyl carbinol 5.
In short, this letter reports a general approach to the family
of bakkanes via a functionalized common intermediate, using
a Diels-Alder/aldol sequence as the key step. The potency
of this approach was demonstrated by a short synthesis of
bakkenolide-A in eight steps. Synthesis of other bakkanes
and adaptation to an asymmetric version will be the subject
of future directions of this laboratory work.
(11) For other related Diels-Alder reactions: (a) Bonnesen, P. V.;
Puckett, C. L.; Honeychuck, R. V.; Hersh, W. H. J. Am. Chem. Soc. 1989,
111, 6070-6081. (b) Hashimoto, Y.; Nagashima, T.; Kobayashi, K.;
Hasegawa, M.; Saigo, K. Tetrahedron 1993, 49, 6349-6358. (c) Winkler,
J. D.; Kim, H. S.; Kim, S.; Penkett, C. S.; Bhattacharya, S. K.; Ando, K.;
Houk, K. N. J. Org. Chem. 1997, 62, 2957-2962. (d) Baillie, L. C.;
Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc., Perkin Trans.
1 1998, 3471-3478. (e) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000,
2, 1927-1929.
(12) Compound 6 could not be isolated in pure form, and the crude
reaction mixture was subjected to the next step as such.
(13) (a) Sauer, J. Angew. Chem., Int. Ed. Engl. 1967, 6, 16. (b) Houk,
K. N.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95, 4094-4096 (c) Houk,
K. N. Acc. Chem. Res. 1975, 8, 361. (d) Eisenstein, O.; LeFour, J. M.;
Anh, N. T., Hudson, R. F. Tetrahedron 1977, 33, 523.
Acknowledgment. The author thanks Prof. J. Aube´ for
all his support and encouragement.
Supporting Information Available: Detailed descrip-
1
tions of experimental procedures and H, and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
(15) Miller, R. D.; McKean, D. R. Synthesis 1979, 730-732.
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