3
methylation of the para-hydroxyl, the ester group was
reducted to the corresponding benzyl alcohol (17), next
converted into the silylated dihydrostilbene 18 by a sequence
similar to the one used for the synthesis of 14 from 12a
The biological profile of colchifulvin was evaluated in
assays of cytotoxicity and tubulin binding. Cytotoxicity was
evaluated in HeLa and MeWo cells. As expected,
6
griseofulvin (5) showed only marginal activity (IC50 ca. 100
PM with both cell lines), but colchifulvin (6) was completely
inactive (IC50 >> 100 PM), a surprising observation in the
light of the sub-micromolar potent cytotoxicity associated to
(Scheme 3).
1
8
the spirodienone moiety of several natural products. On the
other hand, colchifulvin was also devoid of affinity for
tubulin, suggesting a complete loss of the biological profile of
the two lead structures, and positioning in a different, and yet
unexplored, area of the spirodienone biological space.
While undoubtedly disappointing in terms of bioactivity, our
efforts in this project are, we believe, worth reporting,
suggesting a possible general entry into the spiro[4.5]deca-
6,9-dien-8-one typical of many oxidatively cyclized bibenzyl
like cannabispiranones, a major class of phenolics from
marijuana and hemp still largely unexplored in terms of
1
9
bioactivity. Furthermore, it suggests that the alkyol-to-silyl
swap might have general use to disciplinate the coupling of
polyphenolic compounds.
Acknowledgments
Alberto Minassi is grateful to the Junta de Andalucia
(P0AGR03751 and FQM134) and the Dirección General de
Investigación of Spain for a PhD fellowship to Azucena Marset.
References and notes
Scheme 3. Synthesis of the silylated dihydrostilbene 18 and its
oxidative spiro-cyclization to colchifulvin (6).
1
.
³Nature is like a tinkerer who does not know exactly what he is
going to produce but uses whatever he finds around him to
produce some kind of workable object. None of the material at the
WLQNHUHU¶VꢀGLVSRVDOꢀKDVꢀDꢀSUHFLVHꢀDQGꢀGHILQLWHꢀIXQFWLRQꢁꢀ(DFKꢀFDQꢀ
be used in different ways. Novelty comes from previously unseen
association of old material. To create is to recombine´ꢀ-DFREꢄꢀ)ꢁꢀ
Science 1977, 196, 1161±1166.
We were gratified to observe that treatment of 18 with PIDA
in the presence of TBAF (tetrabutylammoium fluoride), a
soluble source of fluoride, and in the non-nucleophilic alcohol
trifluoroethanol could cleanly induce the oxidative
spirocyclization, affording the tricyclic compound 19 in an
encouraging 26% yield. The TIPS group remained unscathed
during the oxidative spiro-cyclization, avoiding the erosion of
2.
Kemal M; Wahba Khalil S K; Rao N G; Woolsey N F. J. Nat.
Prod. 1979, 42, 463-468.
Gaony, Y.; Mechoulam, R. Proc. Chem. Soc. 1964, 82.
3
4
.
.
For
a recent review on the pharmacological potential of
chemoselectivity associated to the generation of
a
resveratrol, see: Han. G.; Xia, J.; Gao, J.; Inagaki, Y.; Tang, W.;
Kokudo, N. Drug Discov Ther. 2015, 9, 1-12.
Leung, Y. Y.; Hui, L. L. Y.; Kraus, V. B. Sem. Arthr. Rheum
phenoxonium ion centered on the galloyl ring and not on the
catechol one. The yield was increased to 62% when the
nucleophilicity of the solvent was further reduced by
replacing trifluoroethanol with hexafluoroisopropanol, a
5
6
.
.
2
015, 45, 341-350.
(a) Petersen, A. B.; Ronnest, M. H.; Larsen, T. O.; Clausen M. H.
Chem. Rev. 2014, 114ꢄꢀꢃꢆꢇꢈꢈíꢃꢆꢃꢇꢉꢁꢀꢂEꢅꢀ5DWKLQDVDP\ꢄꢀ.ꢄꢊꢀ-LQGDOꢄꢀ
B.; Asthan, J.; Singh, P.; Balaji, P. V.; Panda, D. BMC Cancer
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1
5
sterically more hindered analogue. rac-Colchifulvin was
then uneventfully obtained by a one-pot fluoridolysis with
16
7.
TBAF and methylation with dimethyl sulphate. Remarkably,
the trimethoxy derivative 14 gave a low yield of colchifulvin
also in the presence of fluoride and hexafluoroisopropanol,
emphasizing the relevance for the spirocyclization of the
alkyl-to-silyl swap. These observations suggest that the spiro-
cyclization might indeed occur in a stepwise fashion, with
first trapping of the ring C (final product numbering)
cyclohexadienyl cation with fluoride and next formation of a
phenoxonium ion hyperconjugative stabilized by the E-silicon
effect (see Scheme 1, 10b). Interestingly, this swap had
already been reported to beneficially affect the oxidation of
8
.
Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.;
Genazzani, A. A. J. Med. Chem. 2006, 49. 3033-3044.
Hu, J. F.; Fan, H.; Xiong, J.; Wu, S. B. Chem. Rev. 2011, 111,
9.
5
465-5491.
1
0. For the total syntheses of different types of spirodienone natural
products, see: (a) Setälä, A.; Rummakko, P.; Sipilä J.; Brunow G.
J. Chem. Soc., Perkin Trans. 1 1999, 461-464. (b) Ward, R. S. H.;
D. D., Tetrahedron 2001, 57, 5633-5639. (c) Wong, Y. S. Chem.
Commun. 2002, 38, 686-687. (c) Nicolaou, K. C.; T. R. Wu, T.
R.; Q. Kang, Q.; and D. Y. Chen,D. Y. Angew. Chem. 2009, 48,
3
440-3443. (d) Xiao, Q.; Jackson, J. J.; Basak, A.; Bowler, J. M.;
Miller, B. G.; Zakarian, A. Nature Chem. 2013, 5, 410-416.
high-yielding example of oxidative cyclization of
11.
A
a
1
7
methoxylated bibenzyl to a spirodienone was reported using a P-
oxo bridged version of PIFA (Dohi, T.; Uchiyama, T.;
Yamashita,D.; Washimi, N.; Kita, Y. Tetrahedron Lett. 2011, 52,
phenol to p-quinols, suggesting that the generalization of
this effect in polyphenolic chemistry is well worth a
systematic investigation.
2212±2215).
2. Moriarty, R, M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244-250
and ref. therein.
1