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COMMUNICATION
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products and their structural analogues.DOI: 10.1039/C5CC09923D
Acknowledgments
Scheme 3. Synthesis of bicyclic spirolactones via Wacker
This research project was financially supported by the State of
Lower Saxony, Hannover, Germany. We also gratefully
acknowledge the German-Israeli-Foundation Grant (GIF I-2330-
1145.5/2012) for financial support. V.V. thanks Minerva-Stiftung
for a post-doctoral fellowship.
lactonization-Heck cyclization sequence.
Notes and references
1
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M. F. Semmelhack and W. R. Epa, Tetrahedron Letters, 1993,
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(a) J. P. Wolfe and M. A. Rossi, J. Am. Chem. Soc., 2004, 126,
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(a) P. M. Dewick, Medicinal Natural Products: A Biosynthetic
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Plant-Derived Natural Products. Springer, New York, 2009.
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Scheme 4. Pd-catalyzed cascade synthesis of oxaspiro-
octanones: 4-exo-trig cyclization. a50% Conversion (ref. 15).
6
At this point, we became intrigued by the possibility of
applying the established cascade protocol to acyclic 1,4-diene
carboxylic acids 29 (Scheme 4). For this transformation, the
mono- and bis-methylated methyleneheptenoic acids were
prepared and subjected to Pd-catalyzed conditions. The
cascades of both substrates were demonstrated to be highly
regioselective, yielding two distinct 4-exo bicyclic frames, 31
and 32 (Scheme 4).12 Even though both 4-exo and 5-endo
cyclizations of 29 are possible,12a,13 in practice, we have only
detected exclusive regioselectivity to solely generate the rigid
and rare 5/4 bicyclic scaffolds of type-30. To our delight, the
dimethyloxaspirooctanone 32 was obtained in very good yield
(80%) under the optimized conditions (Thorpe-Ingold effect).14
The formation of 31, on the other hand, was found to require a
greater amount of catalyst; nevertheless, incomplete
conversion was observed even after prolonged reaction time
(36 h), and the starting material was recovered. The obtained
5/4 bicyclic frames are highly similar to scaffolds of natural
products associated with the families of gelispirolides15 and
bourbonenolides16 (representative examples are shown in
Scheme 4). Thus, we believe our methodology will become a
potential platform for future construction of these natural
products and their structural analogues in a rapid and efficient
manner.
7
8
9
(a) M. Trend, Y. K. Ramtohul, E. M. Ferreira and B. M. Stoltz,
Angew. Chem. Int. Ed., 2003, 42, 2892; (b) R. C. Larock and T.
R. Hightower, J. Org. Chem., 1993, 58, 5298.
10 (a) Conformational Behavior of Six-Membered Rings; E.
Juaristi, Ed.; VCH: New York, 1995. (b) N. L. Allinger, J. A.
Hirsch, M. A. Miller, I. J. Tyminski, and F. A. VanCatledge, J.
Am. Chem. Soc., 1968, 90, 1199.
11 M. A. Arai, M. Kuraishi, T. Arai and H. Sasai, J. Am. Chem.
Soc., 2001, 123, 2907
12 (a) A. Innitzer, L. Brecker and J. Mulzer, Org. Lett., 2007, 9,
4431; (b) K. H. Kim, S. H. Kim, S. Park and J. N. Kim,
Tetrahedron, 2011, 67, 3328.
13 K. Gilmore and I. V. Alabugin, Chem. Rev., 2011, 111, 6513.
14 R. M. Beesley, C. K. Ingold and J. F. Thorpe, J. Chem. Soc.,
Trans., 1915, 1080; (b) M. E. Jung and J. Gervay, J. Am. Chem.
Soc., 1991, 113, 224.
In summary, we have developed an unprecedented cascade
Wacker-type lactonization-Heck reaction for the formation of 15 Compound 31 was isolated along with reduced product as an
inseparable mixture (90% purity; confirmed by GCMS; see SI
section).
16 S. Deng, S-N. Chen, J. Lu, Z. J. Wang, D. Nikolic, R. B. Van
Breemen, B. D. Santarsiero, A. Mesecar, H. H. S. Fong, N. R.
Farnsworth and G. F. Pauli, Phytochem. Anal., 2006, 17, 398.
variously substituted bi- and tricyclic spiranoid lactones of
different topology and stereochemical configurations. The
transformation shows good functional group tolerability and
broad substrate scope, overcoming the difficulties of
previously reported studies. In addition, rarely reported 17 L. Pan, D. D. Lantvit, S. Riswan, L. B. Kardono, H. B. Chai, E. J.
C. de Blanco, N. R. Farnsworth, D. D. Soejarto, S. M. Swanson
and A. D. Kinghorn, Phytochemistry, 2010, 71, 635.
palladium-catalyzed 4-exo-trig Heck-type cyclizations are
demonstrated. We expect this methodology to find immediate
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