eight- or six-membered ring framework.3 Naturally occurring
1 and 2 are both racemic. Preliminary biological tests have
already shown significant activities of 1 and 2 against gluco-
samine-induced insulin resistance in HepG2 cells at 1 μg/mL.3
sufficient to bring about the entropy-disadvantaged [4π þ
4π] cycloaddition6 in a pseudo-intramolecular fashion in
transition state 5 thus leading directly to the dimerization
product 1. Meanwhile, 3 could readily convert into cyclo-
butene 6 through photochemical 4π-electrocyclization (see
path II, Scheme 1). As hypothesized,3 subsequent cyclobu-
tene ring opening by breaking bond a or b would yield
diradical intermediates 7 or 9, respectively. 7 could further
recombine with another molecule of 3 in transition state 8 to
effect radical-initiated cycloaddition again giving rise to 1.
In a similar fashion, diradical 9 could yield 2 through a
possible transition-state assembly 10.
Scheme 1. Original Biosynthetic Hypothesis to 1 and 2
Scheme 2. Two Practical Routes for the Rapid Synthesis of 3
An inspection on the stereochemical architectures of 1 and
2 quickly reveals their dimeric nature from a much simplified
monomeric precursor, i.e., methyl linderone (structured as 3,
Scheme 1), which itself is a known natural product with
established bioactivities.4 Thus biosynthetically it appears to
be reasonable, as already sketched by Liu and co-workers,
that the formations of 1 and 2 might have been initiated from
3 through formal [4 þ 4] cycloaddition3b and radical-induced
rearrangement pathways,3a respectively. A substantially re-
fined version of their biosynthetic proposal is illustrated in
Scheme 1.
The development of these biosynthetic hypotheses takes
advantage of the ability of the diene moiety in 3 participat-
ing in a photochemical 4π-electrocyclization as well as the
tendency of 3 in engaging itself in intermolecular πꢀπ
stacking (vide infra) owing to its highly polarized electron
density distribution pattern (electron-rich and -poor regions
shown in blue and red, respectively within structure 3).
When 3 organizes itself through a dimeric “head-to-tail”
πꢀπ stacking model as revealed previously by X-ray study
(shown in structure 4, path I, Scheme 1) by Yamin et al.,5
upon irradiation, the conformational packing force may be
With this mechanistic scenario in mind, we set out to
pursue first the critical monomer 3. The total and formal
syntheses of 3 and linderone-related compounds have been
the topics of several published works.7 These investigations
were fueled by very promising bioactivities they displayed. In
particular, antifungal and human chymase inhibition func-
tions were uncovered by Aoyama, Konoike,7a Li, and Clark8
and their corresponding co-workers through detailed struc-
tureꢀactivity profiling. As these compounds are only avail-
able in small amounts from natural sources, clearly more
efficient, practical, and scalable routes to 3 would greatly
support in-depth pharmacological studies on this class of
interesting cylcyclopentendione natural derivatives. We
therefore feel a need to develop an improved synthesis of 3
not only serving the purposes mentioned above but also
providing a higher efficiency toward the total syntheses of our
targets 1 and 2 herein, whose further biological investigations
had been again hampered by their extremely limited natural
availability.3
(4) (a) Leong, Y. W.; Harrson, L. J.; Bennett, G. J.; Kadir, A. A.;
Connolly, J. D. Phytochemistry 1998, 47, 891–894. (b) Kiang, K.; Lee,
H. H.; Sim, K. Y. J. Chem. Soc. 1962, 4338–4345.
(5) The X-ray structure of 3 and its intermolecular packing mode had
been reported; see: Syah, Y. M.; Suastri, N. S.; Latip, J.; Yamin, B. M. Acta.
Crystallogr., Sect. E 2005, 61, o1530ꢀo1531 and its supporting CIF file.
(6) For recent references on photochemical [4π þ 4π] cycloadditions:
(a) Kulyk, S.; Dougherty, W. G., Jr.; Kassel, W. S.; Fleming, S. A.;
Sieburth, S. McN. Org. Lett. 2010, 12, 3296–3299. (b) Chen, P. L.;
Carroll, P. J.; Sieburth, S. McN. Org. Lett. 2010, 12, 4510–4512.
(7) (a) Aoyama, Y.; Konoike, T.; Kanda, A.; Naya, N.; Nakajima,
M. Bioorg. Med. Chem. Lett. 2001, 11, 1695–1697. (b) Lee, H. H.; Tan,
C. H. J. Chem. Soc. C 1967, 1583–1585. (c) Bennett, G. J.; Lee, H. H. J.
Chem. Soc., Perkin Trans. 1 1986, 633–638. (d) Bose, G.; Langer, P.
Synlett 2005, 6, 1021–1023.
(8) (a) Li, X. C.; Ferreira, D.; Jacob, M. R.; Zhang, Q. F.; Kahn, S. I.;
Elsohly, H. N.; Nagle, D. G.; Smillie, T. J.; Kahn, I. A.; Walker, L. A.;
Clark, A, M. J. Am. Chem. Soc. 2004, 126, 6872–6873. (b) Babu, K. S.;
Li, X. C.; Jacob, M. R.; Zhang, Q. F.; Kahn, S. I.; Ferreira, D.; Clark,
A. M. J. Med. Chem. 2006, 49, 7877–7886.
Org. Lett., Vol. 13, No. 9, 2011
2193