Enantiospecific total synthesis of (-)-bakkenolide III and formal total synthesis of (-)-bakkenolides B, C, H, L, V, and X

Article abstract of DOI:10.1021/ol071124k

A concise enantiospecific synthesis of (-)-bakkenolide III was accomplished from (S)-(+)-carvone. The key step involved radical cyclization of an iodoketone intermediate which afforded the cis-hydrindanone skeleton. Further synthetic transformations generated bakkenolide III, which also constitutes the formal total synthesis of (-)-bakkenolides, B, C, H, L, V, and X.

Full text of DOI:10.1021/ol071124k

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3241-3243
Enantiospecific Total Synthesis of
)-Bakkenolide III and Formal Total
(−
Synthesis of (−)-Bakkenolides B, C, H,
L, V, and X
Chiao-Hua Jiang, Annyt Bhattacharyya, and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan, ROC
cksha@mx.nthu.edu.tw
Received May 15, 2007
ABSTRACT
A concise enantiospecific synthesis of (
of an iodoketone intermediate which afforded the cis-hydrindanone skeleton. Further synthetic transformations generated bakkenolide III,
which also constitutes the formal total synthesis of ( )-bakkenolides, B, C, H, L, V, and X.
−)-bakkenolide III was accomplished from (S)-(+)-carvone. The key step involved radical cyclization
−
The sesquiterpenes represent a vast multitude in the fascinat-
ing realm of naturally occurring molecules. Among the
salient members of the sesquiterpenes that bear the hydrin-
dane motif are the picrotoxinin, zizzanes, and the bakkanes.1
The bakkenoids 1a-f and 2a-i (Figure 1) are recognized
by the presence of a cis fused hydrindane core with an
R-spirofused-γ-butyrolactone moiety which is generally
accompanied by a â-methylene unit.2
primarily by Wu and co-workers.2b,4 These bakkenolides
possess novel biological activities which range from selective
cytotoxicity4b,5 to antifeedant effects.6 They, in particular,
Ever since the first isolation of bakkenolide A2a (1a, also
known as fukinanolide2b) by Abe and co-workers in 1968,
over 50 members have been identified so far from both
terrestrial and marine sources.2c They are biogenetically
derived from eremophilanes.2b,3 The C1, C9 dioxygenated
derivatives 2a-i were isolated from Petasites japonicus
Maxim and Petasites formosanus Kitamura (Compositae)
(1) (a) Craven, B. M. Tetrahedron Lett. 1960, 21 and references cited
therein. (b) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Sesquiterpenes; ApSimson, J., Ed.;
John Wiley and Sons: New York, 1983. (c) Katayama, C.; Furusaki, A.;
Nitta, I.; Hayashi, M.; Naya, K. Bull. Chem. Soc. Jpn. 1970, 43, 1976.
(2) (a) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.;
Kitahara, Y. Tetrahedron Lett. 1968, 9, 369. (b) Naya, K.; Takagi, I.;
Hayashi, M.; Nakamura, S.; Kobayashi, M.; Katsumura, S. Chem. Ind.
(London) 1968, 318. (c) Silva, L. F., Jr. Synthesis 2001, 671.
(3) Novotny, L.; Kotva, K.; Toman, J.; Herout, V. Phytochemistry 1976,
11, 2795.
Figure 1. Selected members of bakkanes.
10.1021/ol071124k CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/24/2007

are known to possess inhibitory activity toward Hep G2, Hep
G2,2,15, and P-388 tumor cell lines.4b
metallic reagent to 7 followed by trapping the resulting
enolate with chlorotrimethyl silane and subsequent iodination
could afford iodoketone 6. Radical cyclization of 6 and
further synthetic manipulations could provide 5. Reduction
of compound 5 followed by protection of the alcohol group
and ozonolysis could render hydrindanone 4 (Figure 2).
Additonally, they exhibit inhibitory activities against
arachidonic acid and collagen induced platelet aggregation.6a
Thus the novel structural traits coupled with the biological
activities have attracted organic chemists to develop new
synthetic routes to these molecules. While the total synthesis
of bakkenolide A7 and the closely related analogues, that is,
(-)-homogynolide A8a-c (1b) and B8d-f (1c), (+)-palmosalide
C8g (1d), (-)-acetoxyfukinanolide8h (1e), (-)-7-epibakkeno-
lide-A8i (1f) (Figure 1) are well documented, synthesis of
the C1, C9 dioxygenated analogues bakkenolide III, B, C,
D, E, H, L, V, and X (2a-i) are hitherto less known. Their
total syntheses have been reported only by Depre´s et al. via
the cycloadditon of dichloroketene with dimethylcyclo-
hexenes.9 In that report, bakkenolide III is a pivotal
intermediate as it was elaborated into a series of bakkenolides
such as 2b, 2c, and 2f-i.9
Herein, we report the total synthesis of bakkenolide III
(2a) via the highly efficient R-carbonyl radical cyclization
protocol established in our laboratories.10 We envisaged a
highly functionalized hydrindanone core bearing a propar-
gylic ester 3 as a potential precursor to (-)-bakkenolide III
(2a), which in turn could be obtained from the hydrindanone
4. Commercially available (S)-(+)-carvone (8) could give
rise to enone 7. Conjugate addition of the suitable organo-
Figure 2. Retrosynthetic analysis of 2a.
Our synthetic efforts commenced with the reduction of
(S)-(+)-carvone (8) with lithium in liquid ammonia.11
(2S,5S)-(-)-trans-Dihydrocarvone (9) was generated as the
major isomer (trans/cis ) 10:1). Ozonolysis of 9 in methanol
and subsequent treatment with Cu(OAc)2/FeSO4 resulted in
enone 10.12a Addition of methyllithium to 10 provided the
alcohol 11 (dr ) 1:1), which was smoothly oxidized with
(4) (a) Wu, T.-S.; Kao, M.-S.; Wu, P.-L.; Lin, F.-W.; Shi, L.-S.; Teng,
C.-M. Phytochemistry 1999, 52, 901. (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. (c) Shirahata, K.; Kato, T.; Kitahara, Y.; Abe, N. Tetrahedron
1969, 25, 3179 and 4671. (d) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.;
Woods, M. C.; Kitahara, Y.; Ro, K.; Kurihara, T. Tetrahedron Lett. 1968,
9, 1993. (e) Shirahata, K.; Abe, N.; Kato, T.; Kitahara, Y. Bull. Chem. Soc.
Jpn. 1968, 41, 1732.
PCC to produce 712b ([R]23 ) -108.2 c 3.5, CHCl3). CuI-
D
mediated conjugate addition of 4-(trimethylsilyl)-3-butynyl-
magnesium chloride 1210 to 7 ensued by trapping the
resulting enolate with chlorotrimethylsilane generated the
TMS-enol ether 13. As 13 was labile to chromatography, it
was used immediately without purification. Treatment of 13
with a mixture of NaI and m-CPBA resulted in iodoketone
6 as a mixture of diastereomers (dr ) 19:1). The stereo-
chemistry at the newly generated stereocenter C2 is incon-
sequential with respect to the subsequent transformation and
hence was not assigned. The stereochemistry of C3 was
assigned with analogy to earlier observations on closely
related systems (Scheme 1).13 The addition of the Grignard
reagent 12 presumably occurred from the R-face of 7.
Exposure of 6 to the photolytic condition in the presence
of hexabutylditin effected iodine atom transfer cyclization
followed by deiodination with tributyltin hydride/AIBN
afforded vinylsilane ketone 14 as a mixture of E and Z
isomers (E/Z ) 3:1). Upon treatment with NaBH4, prefer-
ential reduction of the E isomer was observed. The steric
(5) (a) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T.
Phytochemistry 1976, 15, 1713. (b) Kano, K.; Hayashi, K.; Mitsuhashi, H.
Chem. Pharm. Bull. 1982, 30, 1198.
(6) (a) Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny, L. J. Appl.
Entomol. 1984, 98, 394. (b) Nawrot, J.; Harmatha, J.; Novotny, L. Biochem.
Syst. Ecol. 1984, 12, 99. (c) Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny,
L.; Drozdz, B. Acta Entomol. BohemosloV. 1986, 83, 327. (d) Kreckova,
J.; Krecek, J.; Harmatha, J. Pr. Nauk. Inst. Chem. Org. Fiz. Politech.
Wroclaw. 1988, 33, 105. (e) Rosinski, R.; Bloszyk, E.; Harmatha, J.; Knapik,
A. Pr. Nauk. Inst. Chem. Org. Fiz. Politech. Wroclaw 1988, 33, 91; Chem.
Abstr. 1988, 111, 112470.
(7) (a) Evans, D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc.
1977, 99, 5453. (b) Greene, A. E.; Depre´s, J.-P.; Coelho, F.; Brocksom, T.
J. J. Org. Chem. 1985, 50, 3943. (c) Greene, A. E.; Depre´s, J.-P.; Coelho,
F.; Brocksom, T. J. Tetrahedron Lett. 1988, 29, 5661. (d) Hayashi, K.;
Nakaura, H.; Mitsuhashi, H. Chem. Pharm. Bull. 1973, 21, 2806. (e) Back,
T. G.; Payne, J. E. Org. Lett. 1999, 1, 663. (f) Srikrishna, A.; Reddy, T. J.;
Nagaraju, S.; Sattigeri, J. A. Tetrahedron Lett. 1994, 35, 7841. (g) Reddy,
D. S. Org. Lett. 2004, 6, 3345. (h) Constantino, M. G.; de Oliveira, K. T.;
Polo, E. C.; da Siva, G. V. J.; Brocksom, T. J. J. Org. Chem. 2006, 71,
9880.
(8) (a) Hartmann, B.; Kanazawa, A. M.; Depre´s, J.-P.; Greene, A. E.
Tetrahedron Lett. 1993, 34, 3875. (b) Mori, K.; Matsushima, Y. Synthesis
1995, 845. (c) Srikrishna, A.; Reddy, T. J. Indian J. Chem. 1995, 34B,
844. (d) Coelho, F.; Depre´s, J.-P.; Brocksom, T. J.; Greene, A. E.
Tetrahedron Lett. 1989, 30, 565. (e) Srikrishna, A.; Nagaraju, S.; Ven-
kateswarlu, S. Tetrahedron Lett. 1994, 35, 429. (f) Srikrishna, A.; Nagaraju,
S.; Venkateswarlu, S.; Hiremath, U. S.; Reddy, T. J.; Vengopalan, P. J.
Chem. Soc., Perkin Trans. 1 1999, 1, 2069. (g) Hartmann, B.; Depre´s, J.-
P.; Greene, A. E.; deLima, M. E. F. Tetrahedron Lett. 1993, 34, 1487. (h)
Hamelin, O.; Depre´s, J.-P.; Greene, A. E.; Tinant, B.; Declercq, J.-P. J.
Am. Chem. Soc. 1996, 118, 9992. (i) Srikrishna, A.; Reddy, T. J.
Tetrahedron, 1998, 54, 11517.
(10) (a) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-
H.; Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130. (b) Sha,
C.-K.; Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1988, 63, 2699. (c) Sha,
C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875. (d)
Sha, C.-K.; Ho, W.-Y. Chem. Commun. 1998, 24, 2709. (e) Sha, C.-K.;
Jean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1999, 31, 3745.
(11) Hua, H. H.; Venkataraman, S. J. Org. Chem. 1988, 53, 1095.
(12) (a) Schreiber, S. L. J. Am. Chem. Soc. 1980, 102, 6165. (b) White,
J. D.; Grether, U. M.; Lee, C.-S. Org. Synth. 2005, 82, 108.
(13) Sha, C.-K.; Liao, H.-W.; Cheng, P.-C.; Yen, S.-C. J. Org. Chem.
2003, 68, 8704.
(9) (a) Hamelin, O.; Wang, Y.; Depre´s, J.-P.; Greene, A. E. Angew. Chem.
Int. Ed. 2000, 39, 4314. (b) Brocksom, T. J.; Coelho, F.; Depre´s, J.-P.;
Greene, A. E.; deLima, M. E. F.; Hamelin, O.; Hartmann, B.; Kanazawa,
A. M.; Wang, Y. J. Am. Chem. Soc. 2002, 124, 15313.
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3 in good yields. Treatment of 3 with manganese triacetate
in ethanol effected radical cyclization to install the spiro
framework in 18 according to a modified Depre´s pro-
cedure9b (Scheme 3). Deprotection of the hydroxyl group
Scheme 1. Synthesis of Iodoketone 6
Scheme 3. Synthesis of (-)-Bakkenolide III
congestion due to trimethylsilyl group in the Z isomer
presumably prohibited the reduction of the Z isomer.
Alternatively, the isomeric mixture was treated with trifluo-
roacetic acid to obtain 5. However a small amount of enone
15 was also formed as a side product. Attempts of desilyl-
ation with trifluoroacetic acid using various solvents gave a
mixture of 5 and 15 in varied proportions. Much to our
gratification, conducting the reaction in benzene for 30 min
at 0 °C considerably minimized the formation of 15.
Stereoselective reduction of 5 with NaBH4 cleanly afforded
the alcohol 16 as a single diastereomer. The stereochemistry
of 16 was determined by single-crystal X-ray analysis.14
Treatment of the alcohol 16 with TBS-triflate in presence
of 2,6-lutidine gave 17. Ozonolysis of 17 followed by
reductive workup with dimethyl sulfide afforded 4 (Scheme
2).
with 40% HF in acetonitrile generated the hydroxyketone
19. Samarium(II) iodide reduction of 19 afforded diol 20.
Treatment of 20 with tetrabutylammonium fluoride in THF
effected retro-aldol and aldol condensation to give bakkeno-
lide III (2a).
The spectral data and optical rotation of 2a are in good
agreement with literature data.9b Since bakkenolides B, C,
H, L, V, and X were prepared from bakkenolide III by
Depre´s’s group, synthesis of bakkenolide III also constitutes
the formal total synthesis of bakkenolides B, C, H, L, V,
and X.9b
In conclusion we have accomplished an enantiospecific
total synthesis of (-)-bakkenolide III and the formal
synthesis of the other C1,C9 dioxygenated analogues 2b, 2c,
and 2f-i by employing R-carbonyl radical cyclization as the
key step. Application of this methodology toward the
synthesis of other structurally complex natural products are
under investigation.
Scheme 2. Synthesis of Hydrindinone 4
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China (Taiwan) for financial support.
Supporting Information Available: Full details of
experimental procedures, spectral data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL071124K
(15) Propargyl cyanoformate was prepared from propargyl chloroformate.
For preparation of propargyl chloroformate see: Fukase, Y.; Fukase, K.;
Kusumoto, S. Tetrahedron Lett. 1999, 40, 1169. For conversion of
chloroformate to cyanoformate see: Nii, Y.; Okano, K.; Kobayashi, S.;
Ohno, M. Tetrahedron Lett. 1979, 20, 2517.
Deprotonation of 4 with LDA and subsequent treatment
with propargyl cyanoformate15 provided the propargylic ester
(14) X-ray data for compound 16 will be presented in a full paper.
Org. Lett., Vol. 9, No. 17, 2007
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