7124
J. Am. Chem. Soc. 2000, 122, 7124-7125
Scheme 1. Complementary Conservation of Molecular
Symmetry (Cs vs C2) in Hypothetical Biogenesis
Revised Structure of Squalene-Derived PentaTHF
Polyether, Glabrescol, through Its Enantioselective
Total Synthesis: Biogenetically Intriguing Cs vs C2
Symmetric Relationships
Yoshiki Morimoto,* Toshiyuki Iwai,† and Takamasa Kinoshita
Department of Chemistry, Graduate School of Science
Osaka City UniVersity, Sumiyoshiku, Osaka 558-8585, Japan
ReceiVed March 2, 2000
There are numerous examples of biologically active polycyclic
natural products that are biosynthesized by sequential cascade
cyclizations of acyclic precursors. Polycarbocyclic triterpenes such
as steroids are derived from squalene precursors1 and polyethers
such as antibiotics,2 marine toxins,3 and acetogenins4 are derived
from polyepoxides. It is of great interest to consider the
biogenesis5 of the highly symmetric squalene-derived triterpene
polyethers, glabrescol (1), teurilene (2), and longilene peroxide
(3) (Scheme 1). Cytotoxic polyethers teurilene (2) and longilene
peroxide (3) were isolated from the red alga Laurencia obtusa
by Kurosawa et al.6 and from the wood of Eurycoma longifolia
by Itokawa et al.,7 respectively, and their stereostructures were
elucidated by X-ray crystallographic analysis. Glabrescol (1) was
extracted from the branches and wood of Spathelia glabrescens
by Jacobs et al., and the structure was proposed by spectroscopic
methods.8
Considering the familiar examples of biogenesis discussed
above,1-4 these Cs symmetric (meso) polyethers 2 and 1 might
be derived from C2 symmetric (d,l) tetraepoxide 5 and hexa-
epoxide 6, respectively, by sequential cascade cyclizations. On
the other hand, the nearly C2 symmetric polyether 3 could be
obtained via the Cs symmetric tetraepoxide 7 in the same manner,
except for the discriminating enantiotopic terminal epoxides. In
this case, it may be invaluable to realize the complementary
conservation of molecular symmetry between the biogenetic
precursors and natural products (Cs vs C2). Thus, the structurally
symmetric arrays and the biogenetically unique features coupled
with their biological activities have prompted a significant
synthetic effort for these polyethers.9 In this contribution, we
report the first enantioselective total synthesis of glabrescol10 and
that the Cs symmetric stereostructure 1 originally proposed by
Jacobs et al. must be revised to the optically pure C2 symmetric
4.
such THF rings via epoxides. In practice, our synthesis began
with the readily available Cs symmetric diepoxide 99b correspond-
ing to the central THF ring of 1 (Scheme 2). Attachment of
geranyl side chains to 9 was carried out in 64% yield over two
steps to afford tetraenediol 10. Monoacetylation12 of the diol 10
produced substrate 11, and set the stage for the key sequential
V-catalyzed anti oxidative cyclizations. The previous reaction
conditions for the double cyclizations reported by Shirahama9a
and McDonald11 required AcOH in the reaction media to promote
the in situ ring-opening of the epoxide intermediates into THF
rings. Application of similar reaction conditions using AcOH to
11 for 4-5 h resulted in incomplete termination at the epoxide
and monocyclized intermediates along with a small amount of
dicyclized products. However, use of TFA instead of AcOH
dramatically improved the results. Optimized conditions for the
double cyclization of 11 (0.02 equiv VO(acac)2, 2.5 equiv TBHP,
2 equiv TFA, CH2Cl2, room temperature, 30 min) provided the
desired triTHF ether 12 as a major product in 28% yield over
two steps, together with 23% of the other minor diastereomers.
The treatment of 12 under similar conditions gave the original
meso structure 113 as the predominant product in 30% yield.
Our synthetic strategy for the proposed structure of glabrescol
(1) is based on taking its intrinsic symmetry into consideration,
and on the sequential hydroxy-directed anti oxidative cyclizations9a,11
of acyclic bishomoallylic alcohols with vanadium catalyst and
tert-butyl hydroperoxide (TBHP) to stereoselectively construct
1
Unfortunately, the H and 13C NMR spectra of our synthetic 1
were not identical with those of the natural glabrescol kindly
provided by Jacobs.
(9) For the total synthesis of teurilene (2), see: (a) Hashimoto, M.; Harigaya,
H.; Yanagiya, M.; Shirahama, H. J. Org. Chem. 1991, 56, 2299-2311. (b)
Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc. 1999, 121, 6792-
6797. For the synthetic approaches for teurilene (2) and glabrescol (1), see:
(c) Hoye, T. R.; Jenkins, S. A. J. Am. Chem. Soc. 1987, 109, 6196-6198. (d)
Lindel, T.; Franck, B. Tetrahedron Lett. 1995, 36, 9465-9468. (e) Morimoto,
Y.; Iwai, T.; Yoshimura, T.; Kinoshita, T. Bioorg. Med. Chem. Lett. 1998, 8,
2005-2010. After submission of our work, a paper by Corey and Xiong has
independently appeared that reports the total synthesis of the original (incorrect)
glabrescol (1) and three Cs-symmetric diastereomers: (f) Xiong, Z.; Corey,
E. J. J. Am. Chem. Soc. 2000, 122, 4831-4832.
(10) Although there is no report on the biological activities of glabrescol,
the vicinal pentaTHF linkage may be expected to exhibit ionophoric functions
as well as cytotoxicities. See: (a) Schultz, W. J.; Etter, M. C.; Pocius, A. V.;
Smith, S. J. Am. Chem. Soc. 1980, 102, 7981-7982. (b) Wagner, H.; Harms,
K.; Koert, U.; Meder, S.; Boheim, G. Angew. Chem., Int. Ed. Engl. 1996, 35,
2643-2646.
† JSPS Research Fellow.
(1) For reviews, see: (a) Clayton, R. B. Quart. ReV. 1965, 19, 168-200.
(b) Mulheirn, L. J.; Ramm, P. J. Chem. Soc. ReV. 1972, 1, 259-291.
(2) (a) Westley, J. W. In Antibiotics IV. Biosynthesis; Corcoran, J. W., Ed.;
Springer-Verlag: New York, 1981; pp 41-73. (b) Cane, D. E.; Celmer, W.
D.; Westley, J. W. J. Am. Chem. Soc. 1983, 105, 3594-3600.
(3) (a) Shimizu, Y. Chem. ReV. 1993, 93, 1685-1698. (b) Garson, M. J.
Chem. ReV. 1993, 93, 1699-1733. (c) Lee, M. S.; Qin, G.-W.; Nakanishi,
K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234-6241.
(4) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504-540. (b) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem.
Soc. 1998, 120, 4017-4018.
(5) For the possible biogenesis of teurilene (2) and relevant polyethers,
see: (a) Suzuki, M.; Matsuo, Y.; Takeda, S.; Suzuki, T. Phytochemistry 1993,
33, 651-656. (b) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett. 1995,
1043-1044.
(6) Suzuki, T.; Suzuki, M.; Furusaki, A.; Matsumoto, T.; Kato, A.; Imanaka,
Y.; Kurosawa, E. Tetrahedron Lett. 1985, 26, 1329-1332.
(7) Morita, H.; Kishi, E.; Takeya, K.; Itokawa, H.; Iitaka, Y. Phytochemistry
1993, 34, 765-771.
(11) Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022-
6028.
(12) Although it was envisaged that the desirable pentaTHF 1 could be
synthesized from the diol 10 in a single step by the two-directional and
sequential oxidative cyclizations, direct oxidative cyclizations of the diol 10
unfortunately resulted in complex mixtures.
(8) Harding, W. W.; Lewis, P. A.; Jacobs, H.; McLean, S.; Reynolds, W.
F.; Tay, L.-L.; Yang, J.-P. Tetrahedron Lett. 1995, 36, 9137-9140.
10.1021/ja0007657 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000