Scheme 2
.
Tandem Carbonylation/Intramolecular Diels-Alder
Reaction
Figure 1. (-)-Galiellalactone (1), epi-galiellalactone (2a, R1 ) R2
) H), 7,7-dimethyl-epi-galiellalactone (2b, R1 ) R2 ) Me), and
7-benzyl-epi-galiellalactone (2d, R1 ) Bn, R2 ) H).
carbonates, has previously been shown to be useful for the
synthesis of a series of fused tetrahydroindenes.5 As a
tetrahydroindene is the key intermediate in the synthesis of
galiellalactone analogues, and as we already have shown that
the transformation of the tetrahydroindene 10a to epi-
galiellalactone 2a is feasible,4a this strategy was investigated.
The dienyne carbonate 7b was prepared by subjecting
crotonaldehyde 3 to the Corey-Fuchs procedure6 to give
1,1-dibromo-1,3-pentadiene (4), which was transformed to
the corresponding alkenynyl lithium salt (5) to which 2,2-
dimethyl-4-pentenal (6b) was added. The alkoxide formed
was treated with methyl chloroformate in situ to yield the
dienyne carbonate 7b (see Scheme 1). The reaction sequence
catalyst system and reaction conditions, and this was carried
out with 7b. Changing the catalyst to Pd(OAc)2 resulted in
only a minor improvement, while elevated temperature (100
°C) and methanol as solvent resulted in reduced yields.
Exchanging the ligand for Xantphos resulted in acceptable
yields (43%) at ambient pressure,7 while Pd(OAc)2 and DPPP
as the catalyst system using an autoclave at 5 bar of CO at
60 °C gave 17% of the product. Greatly improved yields
(73%) were obtained using Pd(OAc)2 and DPPP under 5 bar
of CO but at a lower temperature, 20 °C, while further
increasing CO pressure decreased the yield. With Pd(OAc)2
and Xanthphos as the catalytic system and elevated CO
pressure (3 bar), the yield was only 3%. Under the conditions
that gave the best results, the reaction was reproducible, also
in larger scale (up to 60 mmol).
Scheme 1. Synthesis of Dienyne Carbonate 7b
In 10b, C4-Me and 5a-H are on the same face of the
molecule, reversed compared to the natural product, although
for our purposes this was not considered critical, as 1 and
epi-galiellalactone (2a) display equal STAT3 activity. The
relative orientation of the C4 methyl and the C5a hydrogen
can be rationalized by the exo transition state of the
Diels-Alder reaction, which is less strained than the endo
as suggested by Okamura et al.8
a Yield is based on 3.
proceeded smoothly in up to at least 100 mmol scale, in good
yields.
New substituent(s) in position 7 require the use of different
R-substituted 4-pentenals (corresponding to 6b in Scheme
1), and several dienyl carbonates were prepared and cyclized
by the optimized procedure discussed above. The 4-pentenals
were, when not commercially available, synthesized from
the corresponding esters9 by reduction with LiAlH4 and a
subsequent Dess-Martin oxidation (see Supporting Informa-
tion for details). The dienyne carbonates 7c-7e were
obtained as diastereomeric mixtures. The two diastereomers
When carbonate 7b was exposed to the conditions
described by Mandai et al.5 (see Scheme 2), the desired
tetrahydroindene 10b was obtained but only in 10% yield.
This is in contrast to the high yields reported using cyclic
dienyne carbonates.5
The poor yield of the tandem carbonylation/intramolecular
Diels-Alder reaction prompted an optimization of the
(5) Mandai, T.; Suzuki, S.; Ikawa, A.; Murakami, T.; Kawada, M.; Tsuji,
J. Tetrahedron Lett. 1991, 32, 7687.
(7) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 7102.
(6) (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769. (b)
Bialy, L.; Waldmann, H. Chem.sEur. J. 2005, 10, 2759. (c) Annabelle,
L. K.; Shun, S.; Tykwinski, R. R. J. Org. Chem. 2003, 68, 6810.
(8) Okamura, W.; Curtin, M. Synlett 1990, 1, 1.
(9) Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Kubanova, P.; Buchta,
V. Bioorg. Med. Chem. 2003, 11, 2843.
Org. Lett., Vol. 12, No. 22, 2010
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Gidloef, Ritha
