Total synthesis of the terpenoid buddledone A: 11-membered ring-closing metathesis

Article abstract of DOI:10.1021/ol300400x

The first total synthesis of buddledone A was accomplished in seven steps from methyl ethyl ketone (MEK). The key step in the sequence featured an 11-membered ring formation by ring-closing metathesis.

Full text of DOI:10.1021/ol300400x

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1661–1663
Total Synthesis of the Terpenoid
Buddledone A: 11-Membered
Ring-Closing Metathesis
Zhengxin Cai, Nattawut Yongpruksa, and Michael Harmata*
Department of Chemistry, University of Missouri;Columbia, Columbia, Missouri
65211, United States
HarmataM@missouri.edu
Received February 17, 2012
ABSTRACT
The first total synthesis of buddledone A was accomplished in seven steps from methyl ethyl ketone (MEK). The key step in the sequence featured
an 11-membered ring formation by ring-closing metathesis.
Buddledone A (1, Figure 1) was isolated from the plant
Buddleja globosa, which has been used in traditional
Chinese herbal medicine.1 Other species in this genus have
beenused similarly.2 AlsoisolatedwerebuddledoneB (1b),
buddledins A, B, C, and zerumbone (Figure 1).3 While its
dehydro congener zerumbone (1a) exhibits various pro-
mising biological properties including plant growth-
regulatory,2 cytotoxic,4 anti-inflammatory,5 anticancer
(lung, liver and leukemia),6 and anti-HIV7 activitiy, the
bioactivity of buddledone A has not been reported on
(1) Liao, Y. H.; Houghton, P. J.; Hoult, J. R. S. J. Nat. Prod. 1999, 62,
1241–1245.
(2) (a) Li, Y.-Y.; Lu, J.-H.; Li, Q.; Zhao, Y.-Y.; Pu, X.-P. Eur.
J. Pharmacol. 2008, 579, 134–140. (b) Lee, Y. J.; Kang, D. G.; Kim,
J. S.; Lee, H. S. Exp. Biol. Med. (London, U. K.) 2008, 233, 694–700.
(3) Zerumbone is a major component of the essential oil of wild
Figure 1. Structures of buddledone A and its congeners.
ginger, Zingiber zerumbet: Dev, S. Tetrahedron. 1960, 8, 171–180.
(4) (a) Kalsi, P. S.; Singh, O. S.; Chhabra, B. R. Phytochemistry. 1978,
17, 576. (b) Mathes, H. W. P.; Luu, B.; Ourisson, G. Phytochemistry
extensively, though it is known to not be an inhibitor of the
1980, 19, 2643.
hedgehog/GLI signaling pathway.8
We developed an interest in buddledone A as part of a
broader interest in developing routes to zerumbone ana-
logues and accessing the buddledin family of natural products.
(5) Ozaki, Y; Kawahara, N.; Harada, M. Chem. Pharm. Bull. 1991,
39, 2353–2356.
(6) (a) Kim, M.; Miyamoto, S.; Yasui, Y.; Oyama, T.; Murakami, A.;
Tanaka, T. Int. J. Cancer. 2009, 124, 264–271. (b) Huang, G. C; Chien,
T. Y.; Chen, L. G.; Wang, C. C. Planta Med. 2005, 71, 219–224. (c) Sung,
B.; Jhurani, S.; Ahn, K. S.; Mastuo, Y.; Yi, T.; Guha, S.; Liu, M.;
Aggarwal, B. B. Cancer Res. 2008, 68, 8938–8944.
(7) Dai, J. R.; Cardellina, J. H., II.; McMahon, J. B.; Boyd, M. R.
Nat. Prod. Lett. 1997, 10, 115–118.
(8) Hosoya, T.; Arai, M. A.; Koyano, T.; Kowithayakorn, T.;
Ishibashi, M. ChemBioChem 2008, 9, 1082–1092.
r
10.1021/ol300400x
2012 American Chemical Society
Published on Web 03/20/2012

Our goal was to produce buddledone A by a ring-closing
metathesis (RCM) as the ultimate or penultimate step in
the synthesis. We were concerned that although there are
examples of RCM to form 11-membered rings, particu-
larly in systems with a conformational bias,9 they are not
nearly as common as those that lead to less strained ring
systems.10 Small changes in diastereomer composition can
have dramatic effects on the yields and/or the stereochem-
istry of such reactions.11 Simple substrates can work in the
process, but yields are variable.12 Our plan called for the use
of a relatively simple substrate, one that would not likely have
any particular conformational bias toward ring closure and
would certainly be prone to side reactions like dimerization.
In this communication, we report a straightforward
synthetic strategy toward the total synthesis of buddledone
A that successfully implements an RCM to create an
eleven-membered ring. The retrosynthetic analysis is
shown in Scheme 1. Buddledone A (1) would be prepared
by RCM from triene 3. This compound (3) would be
available through the alkylation of the enolate derived
from enone 5. Finally, 5 would arise from an aldol reaction
between 6 and methyl ethyl ketone (MEK).
metathesis catalysts to afford 1,2-disubstituted alkenes
with said stereochemistry when terminal alkenes are com-
bined via metathesis. However, the 13C NMR of 8 was
complex. We presume this is due to the formation of diaste-
reomers based on the presence of two stereogenic centers in 8,
which result from the metathesis of a racemic precursor.
Our initial attempts to avoid the formation of 8 met with
little success. Various catalytic conditions for ring-closing
metathesis of triene 3 afforded dimer 8 as a major product.
The reactions using the Grubbs second-generation catalyst
(9) and the HoveydaÀGrubbs catalyst (10)13 under an
ethylene atmosphere gave a complex mixture. Moreover,
the capsule-like Lewis acid 11,14 which is an effective Lewis
acid for the formation of medium-sized lactones using
ring-closing metathesis,15 was not useful for our work,
affording the dimer 8in combination with 9after 6 h at reflux
in toluene. We also subjected the dimer 8 to the metathesis
conditions using 20% mol of 10 in DCM. The reaction was
refluxed for 6 h, but the dimer remained in the reaction and
there was no desired product observed by 1H NMR.
Scheme 1. Retrosynthetic Analysis
We believed that the problem with RCM for 3 might have
stemmed, at least in part, from a combination of conforma-
tional freedom and angle strain that prevented product
formation, either kinetically or thermodynamically. We
(9) (a) Winkler, J. D.; Holland, J. M.; Kasparec, J.; Axelsen, P. H.
€
Tetrahedron 1999, 55, 8199–8214. (b) Furstner, A.; Radkowski, K.;
Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc.
2002, 124, 7061–7069. (c) Wipf, P.; Stephenson, C. R. J.; Walczak,
M. A. A. Org. Lett. 2004, 6, 3009–3012. (d) Nicolaou, K. C.;
Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am.
€
€
Chem. Soc. 2005, 127, 8872–8888. (e) Furstner, A.; Muller, C. Chem.
Commun. 2005, 5583–5585. (f) Matsumura, T.; Akiba, M.; Arai, S.;
Nakawa, M.; Nishida, A. Tetrahedron Lett. 2007, 48, 1265–1268. (g)
Lejkowski, M.; Gais, H.-J.; Banerjee, P.; Vermeeren, C. J. Am. Chem.
Soc. 2006, 128, 15378–15379. (h) Tanabe, K.; Fujie, A.; Ohmori, N.;
Hiraga, Y.; Kouima, S.; Ohkata, K. Bull. Chem. Soc. Jpn. 2007, 80,
1597–1604. (i) Cluzeau, J.; Oishi, S.; Ohno, H.; Wang, Z.; Evans, B.;
Peiper, S. C.; Fujii, N. Org. Biomol. Chem. 2007, 5, 1915–1923. (j)
Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904–
12906. (k) Kaewpet, M.; Odell, B.; King, M. A.; Banerji, B.; Scholfield,
C. J.; Claridge, T. D. W. Org. Biomol. Chem. 2008, 6, 3476–3485. (l)
Braddock, D. C.; Millan, D. S.; Perez-Fuertess, Y.; Pouwer, R. H.;
Sheppard, R. N.; Solanki, S.; White, A. J. P. J. Org. Chem. 2009, 74,
ꢁ
€ €
´
1835–1841. (m) Pospısil, J.; Muller, C.; Furstner, A. Chem.;Eur. J.
2009, 15, 5956–5968. (n) Majumda, K.; Chattopadhyay, B.; Ansary, I.
Can. J. Chem. 2009, 87, 472–477.
Treatment of MEK with LDA followed by the aldehyde
6 afforded the aldol adduct 7 in high yield (Scheme 2).
Dehydration using a standard two-step protocol involving
mesylationand elimination gavea nearly quantitative yield
of 5. While the enolate derived from 5 could be alkylated
with 6 in THF, the yield of the product was low (29%).
Inclusion of HMPA in the reaction mixture afforded a
good yield (72%) of the alkylation product 3.
ꢀ
The attempts to prepare 1 via ring-closing metathesis of
an R,β-unsaturated ketone precursor 3 under various
conditions were not successful. The reactions afforded a
dimer 8 as a major product in high yield in one case, along
with trace amounts of the cross metathesis product be-
tween styrene and starting material 3, and complex mix-
tures in other cases.
The structure of 8 was established by proton NMR
spectroscopy. The assignment of the E stereochemistry of
the central double bond is based on the predilection of
(10) Prunet, J. Eur. J. Org. Chem. 2011, 3634–3647.
(11) (a) El Sukkari, H.; Gesson, J.-P.; Renoux, B. Tetrahedron Lett.
1998, 39, 4043–4046. (b) Vassilikogiannakis, G.; Margaros, I.; Tofi, M.
Org. Lett. 2004, 6, 205–208.
(12) (a) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429–
1432. (b) Arisawa, M.; Kato, C.; Kaneko, H.; Nishida, A.; Nakagawa,
M. J. Chem. Soc., Perkin Trans. 1 2000, 1873–1876. (c) Ronsheim,
M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 1878–1885.
(13) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179.
(14) Yamamoto, H.; Saito, S. Pure Appl. Chem. 1999, 71, 239–245.
(15) Pentzer, E. B.; Gadzikwa, T.; Nguyen, S. T. Org. Lett. 2008, 10,
5613–5615.
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Scheme 2. Initial Synthetic Approach and Failed RCM
decided to use the ketone functionality as a handle and take
advantage of geminal disubstitution16 at that carbon atom
to address both conformational and strain issues.17 Whether
this rationalization has merit, in fact, has yet to be deter-
mined. Nevertheless, the strategy worked.
The triene 3 was thus transformed to a TMS-protected
cyanohydrin 12 by standard methods in excellent yield.
Initial attempts using 12 and catalyst 10 generated bud-
dledone A after hydrolysis of the corresponding cyanohy-
drin with TBAF in only 10% yield, contaminated with
varying amounts (up to 58%) of the isomerization product
13 (Scheme 3).18 This is an established problem in certain
The spectral data on the synthetic material matched that
in the literature.1 Further, although buddledone A was
reported as an oil, the racemic, synthetic material turned
out to be a low-melting solid and we were able to confirm
its structure by X-ray analysis. Unfortunately, there does
not appear to be any information in the literature regard-
ing a chiral or chiroptical property associated with natural
buddledone A. It will likely require another isolation and
characterization to obtain that information.
Scheme 4. Successful Total Synthesis of Buddledone A
Scheme 3. An Isomerization Reaction
In summary, the terpenoid buddledone A was synthe-
sized successfully from commercially available starting
materials in seven steps with an overall yield of 31%. The
workdemonstrated that bothmodificationofthe substrate
and the reaction conditions could afford an eleven--
membered RCM product in reasonable yield. It should
be possible to use this methodology to make congeners
of zerumbone and the buddledone and buddledin fa-
milies of compounds. Further results will be reported in
due course.
metathesis reactions, and one solution is the oxidative re-
moval of the ruthenium hydride species that are likely re-
sponsible for the process.19 Thus, treating 12 with 20 mol %
of HoveydaÀGrubbs second generation catalyst and
20 mol % of benzoquinone in refluxing toluene yielded
buddledone A (10) with the desired geometry of the double
bond after converting the cyclized cyanohydrin to an enone
by treatment with TBAF in THF (59% yield) (Scheme 4).
Acknowledgment. This work was supported by the Na-
tional Science Foundation to whom we are grateful.
Thanks to Dr. Charles L. Barnes (Missouri-Columbia)
for acquisition of X-ray data.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. X-ray
data for 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
(17) Kotha, S.; Dipak, M. K. Tetrahedron 2012, 68, 397–421.
(18) Compound 13 exhibited a doublet for the newly formed methyl
group.
(19) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
The authors declare no competing financial interest.
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