Facile asymmetric synthesis of the core nuclei of xanthanolides, guaianolides, and eudesmanolides

Article abstract of DOI:10.1021/ol034141s

(Matrix presented). Bicyclic and tricyclic γ-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps wer

Full text of DOI:10.1021/ol034141s

ORGANIC
LETTERS
2003
Vol. 5, No. 6
941-944
Facile Asymmetric Synthesis of the
Core Nuclei of Xanthanolides,
Guaianolides, and Eudesmanolides
Bernd Nosse, Rakeshwar B. Chhor, Won Boo Jeong,‡ Claudius Bo1hm, and
Oliver Reiser*
Institut fu¨r Organische Chemie der UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
D-93053 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received January 25, 2003
ABSTRACT
Bicyclic and tricyclic γ-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and
guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps were a copper(I)-catalyzed asymmetric cyclopropanation,
Sakurai allylations, intramolecular ene reactions, and ring-closing metathesis reactions.
γ-Butyrolactones are prominent constituents in biologically
active compounds and are found in about 10% of all natural
products.1 In particular, there are many examples in which
the γ-butyrolactone is part of a more complex ring system,
e.g. in sesquiterpene lactones as depicted in Figure 1.2 An
example for the bicyclic xanthanolides includes xanthatin
1,3 having extraordinarily high antibacterial activity against
methicillin-resistant staphylococcus aureus. The sesquiter-
pene Saussureal (2),4 a potent plant regulator that was isolated
from Saussurea Lappa, belongs to the class of eudesmano-
lides, being characterized by a 5,6,5-tricyclic ring system.
Ixerin Y5 (3) and Arglabin6 (4), having the 5,7,5-tricyclic
ring system of the guaianolides, display strong activities
‡ On leave from C-Tri, Korea Ltd.
(1) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
Figure 1. Biologically active xanthanolides, guaianolides, and
24, 94-110. (b) Koch, S. S. C.; Chamberlin, A. R. In Studies in Natural
eudesmanolides.
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science B.V.: Am-
sterdam, The Netherlands, 1995; Vol. 16, pp 687-725.
(2) (a) Zdero, C.; Bohlmann, F. Phytochemistry 1990, 29, 189-194. (b)
Jakupovic, J.; Ganzer, U.; Pritschow, P.; Lehmann, L.; King, R. M.
Phytochemistry 1992, 31, 863-880.
against breast, colon, ovarian, and lung cancer. Arglabin (4),
being currently under clinical evaluation in Kazakhstan and
the US, inhibits the farnesyl transferase and by this mode
the activation of the RAS proto-oncogene, a process that is
believed to play a pivotal role in 20-30% of all human
tumors.
(3) Sato, Y.; Oketani, H.; Yamada, T.; Singyouchi, K.; Ohtsubo, T.;
Kihara, M.; Shibata, H.; Higuti, T. J. Pharm. Pharmacol. 1997, 49, 1042-
1044.
(4) Talwar, K. K.; Singh, I. P.; Kalsi, P. S. Phytochemistry 1991, 31,
336-338.
(5) Ma, J.-Y.; Wang, Z.-T.; Xu, L.-S.; Xu, G.-J. Phytochemistry 1999,
50, 113-115.
10.1021/ol034141s CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/25/2003

Very few strategies toward the total synthesis of eudes-
manes, xanthanolides, and guaianolides have been reported,7
but especially Ixerin Y (3) and Arglabin (4) are only available
from natural sources so far.
as the nucleophile (anti/syn ratio 95:5),8b,c seemed to be an
ideal starting point for a subsequent annulation of a seven-
membered ring (Scheme 2).
We have recently developed an asymmetric route to
disubstituted γ-butyrolactones 9 starting with the copper(I)-
bis(oxazolines)-catalyzed cyclopropanation of furan-2-car-
boxylic esters 5 (Scheme 1).8 This way, either enantiomer
Scheme 2. Synthesis of the Core Nucleus of Xanthanolides
Scheme 1. Synthesis of anti-Disubstituted γ-Butyrolactones
98b,c
Introduction of a second allyl group by BF3-mediated
reaction with allylsilanes takes place with moderate diaste-
reoselectivity (3:1 to 4:1) to 10 (major diastereomers shown),
which was set up for ring-closing metathesis (RCM).
By using the ruthenium catalyst 12, which is especially
effective in RCM reactions,9 both 10a and 10b could be
directly converted to the bicyclic derivatives 11a and 11b,
respectively, with no protection of the free hydroxyl group
being necessary. In the course of the ring closure, the
diastereoselectivity changed very little, indicating that both
diastereomers 10a and 10b undergo equally well the me-
tathesis reaction. The major diastereomer of 11b could be
obtained in pure form by recrystallization, and its relative
stereochemistry was established by X-ray crystallography
(Figure 2).
a Conditions: (a) (i) ethyl diazoacetate, Cu(OTf)2 (2 mol %),
(S,S)-tBu-box (2.5 mol %), PhNHNH2 (2 mol %), CH2Cl2, 91%
ee; (ii) recrystallization (pentane), >99% ee, 53%. (b) (i) O3,
CH2Cl2, -78 °C, (ii) dimethyl sulfide, 94%.
of 6 can be readily prepared on a multigram scale in pure
form. Ozonolysis of 6 followed by reductive workup leads
to the aldehyde 7, which undergoes highly diastereoselective
additions with nucleophiles to 8 followed by a retroaldol/
lactonization cascade to 9. Here we would like to report the
application of this strategy toward bi- and tricylic γ-butyo-
lactones as a facile entry to the core nuclei of xanthanolides,
eudesmanolides, and guaianolides.
The lactone 9a, which can be obtained following the
general strategy outlined in Scheme 1 by using allylsilane
(6) (a) Adekenov, S. M.; Mukhametzhanov, M. N.; Kagarlitskii, A. D.;
Kupriyanov, A. N. Khim. Prir. Soedin. 1982, 5, 655-656. (b) Adekenov,
S. M.; Mukhametzhanov, M. N.; Kagarlitskii, A. D.; Agashkin, O. V. IzVest.
Akad. Nauk. Kazak., Ser. Khim. 1983, 2, 54-60. (c) Appendino, G.;
Gariboldi, P.; Menichini, F. Fitoterapia 1991, 62, 275-276. (d) Bottex-
Gauthier, C.; Vidal, D.; Picot, F.; Potier, P.; Menichini, F.; Appendino, G.
Biotechnol. Ther. 1993, 4, 77-98. (e) Shaikenov, T. E.; Adekenov, S. M.;
Williams, R. M.; Baker, F. L.; Prashad, N.; Madden, T. L.; Newman, R.
Oncol. Rep. 2001, 8, 173-179. (f) Wong, H.-F.; Brown, G. D. J. Nat. Prod.
2002, 65, 481-486.
(7) (a) Kuroda, C.; Kobayashi, K.; Koito, A.; Anzai, S. Bull. Chem. Soc.
Jpn. 2001, 74, 1947-1961. (b) Lee, E.; Lim, J. W.; Yoon, C. L.; Sung, Y.;
Kim, Y. W.; Yun, M.; Sangsoo, K. J. Am. Chem. Soc. 1997, 119, 8391-
8392. (c) Kuroda, C.; Ito, K. Bull. Chem. Soc. Jpn. 1996, 69, 9. 2297. (d)
Devreese, A. A.; Clercq, P. J. D.; Vandewalle, M. Tetrahedron Lett. 1980,
21, 4767. (e) Rigby, J. H.; Wilson, J. Z. J. Am. Chem. Soc. 1984, 106,
8217-8224.
Figure 2. X-ray structure of (rac)-11b.
The synthesis of the tricyclic 5,7,5 framework with all-
trans stereochemistry at the ring junctions, found in gua-
ianolides such as 3 and 4, posed an additional challenge for
our synthetic route. Addition of the allylsilane 1310 to 7 does
not only have to proceed under Felkin-Anh control11 at the
aldehyde with respect to the cyclopropyl group, but also must
(8) (a) Bo¨hm, C.; Schninnerl, M.; Bubert, C.; Zabel, M.; Labahn, T.;
Parisini, E.; Reiser, O. Eur. J. Org. Chem. 2000, 2955-2965. (b) Bo¨hm,
C.; Reiser, O. Org. Lett. 2001, 3, 1315-1318. (c) Chhor, R. B.; Nosse, B.;
So¨rgel, S.; Bo¨hm, C.; Seitz, M.; Reiser, O. Chem. Eur. J. 2003, 9, 260-
270.
(9) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751. (c)
Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J.
Org. Chem. 2000, 65, 2204-2207.
942
Org. Lett., Vol. 5, No. 6, 2003

be anti-selective between the prochiral centers of the two
reaction partners. Indeed, 15a was obtained with excellent
stereocontrol, giving again good anti-selectivity (95:5) of the
substituents placed on the lactone ring, while the anti-
relationship was observed between the two five-membered
rings exclusively (Scheme 3).
Scheme 4. Synthesis of the Core Nucleus 21 of Guaianolides
Scheme 3. Addition of Cyclic Allyl Silanes 13 to 7
The stereochemical outcome of the reaction can be
rationalized by the transition state 14, in which both, the
Felkin-Anh11 as well as the antiperiplanar orientation with
the least sterical hindrance of the carbonyl group and the
C-C double bond of the allylsilane is observed.12 Likewise,
the six-membered allylsilane 13b gave good results, resulting
in the formation of 15b with only minute amounts of the
syn-diastereomer present.
15a proved to be somewhat unstable and was therefore
used as the crude material obtained directly from the reaction.
For the synthesis of the core nucleus of guaianolides,
allylations in the presence of boron trifluoride were carried
out to yield the 1,8-dienes 16 and 18, respectively (Scheme
4, major diastereomer shown). However, it was imperative
to add the allylsilane before introducing the Lewis acid to
prevent an intramolecular carbonyl-ene reaction (vide infra).
Ring-closing metathesis could not be achieved with either
16 or 18, but after conversion to their corresponding
trimethylsilyl ethers 17 and 19 cyclization became possible.
Unfortunately, 17 gave rise to 20 in the presence of the
catalyst 12 in only low yields (34%). It was interesting to
note, however, that apparently the minor diastereomer in 17
reacted preferentially, since the diastereoselectivity changed
from 4:1 in 17 to 1:1 in 20. The diastereomers could be
separated by crystallization, and their relative stereochemistry
was assigned by X-ray structure analysis of (ent)-20, being
prepared from (+)-6 in an analogous way to 20. Attempts
to improve upon the RCM of 17 by employing 2213 as
catalyst were not successful. 20 was obtained in 28% yield;
however, with catalyst 22 the ratio of diastereomers did not
change in the course of the cyclization.
Even more challenging was the RCM of 19, creating a
tetrasubstituted double bond. Indeed, no reaction was ob-
served employing 12, but in the presence of the catalyst 22
the tricylic lactone 21 could be obtained in moderate yield
(48%).
For the synthesis of the core nucleus of eudesmanolides,
the direct ring closure of 15 by an intramolecular carbonyl
ene reaction14 was envisioned. Lewis acids such as SnCl4 or
MeAlCl2 most commonly mediate such coupling reactions.15
In our hands boron trifluoride etherate at room temperature
gave the best results, leading in a remarkably regio- and
stereoselectivereaction to 24 as a single stereoisomer. Their
relative stereochemistry was established by X-ray structure
analysis of 24a. The stereochemical course16 of the reaction
could be rationalized by the transition state 23, in which the
least steric interactions are encountered in the attack of the
carbonyl group.
(10) (a) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada,
M. Synthesis 1981, 1001-1003. (b) Hayashi, T.; Fujiwa, T.; Katsuro, Y.;
Kumada, M. Tetrahedron Lett. 1980, 21, 3915-3918. (c) Monti, H.; Audran,
G.; Fraud, M.; Monti, J.-P.; Le`andri, G. Tetrahedron 1996, 52, 6685-6698.
(11) Leading review: Mengel, A.; Reiser, O. Chem. ReV. 1999, 99,
1191-1223.
(12) (a) Hayashi, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1982,
104, 4963-4965. (b) Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Maruyama,
K. J. Am. Chem. Soc. 1980, 102, 7107-7109.
(13) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8166-8179. (b) Gessler, S.; Randl, S.; Blechert,
S. Tetrahedron Lett. 2000, 41, 9973-9976.
Org. Lett., Vol. 5, No. 6, 2003
943

panation of furan-2-carboxylic methyl ester as the key step
for the enantioselective preparation of γ-butyrolactones. On
the basis of this strategy, further studies toward the total
synthesis of 1-4 are being carried out in our laboratories.
Scheme 5. Synthesis of the Core Nucleus of Eudesmanes
Acknowledgment. This work was supported by the
International Quality Network Medicinal Chemistry (DAAD
and BMBF), C-Tri, Korea, and the Fonds der Chemischen
Industrie. B.N. is grateful to Studienstiftung des Deutschen
Volkes for a fellowship.
Supporting Information Available: Experimental and
analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034141S
(14) Review: Snider, B. B. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 2, pp 527-
561.
(15) Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J. J. Org. Chem.
1982, 47, 4535-4545.
(16) (a) Andersen, N. H.; Uh, H.-S.; Smith, S. E.; Wuts, P. G. M. Chem.
Commun. 1972, 956-957. (b) Andersen, N. H.; Hadley, S. W.; Kelly, J.
D.; Bacon, E. R. J. Org. Chem. 1985, 50, 4144-4151.
In conclusion, a variety of bi- and tricyclic lactones,
representing the core structures of important natural products,
can be readily prepared by using the asymmetric cyclopro-
944
Org. Lett., Vol. 5, No. 6, 2003