Journal of the American Chemical Society
COMMUNICATION
promoted inverse-demand DielsꢀAlder reaction to set nearly
half of the target’s stereocenters in a single operation; (3) several
highly orchestrated and substrate-specific events to finalize the
target, foremost of which was a particularly challenging ring
expansion; and (4) the observation on several occasions that
remote chiral centers on the rippertane framework possessed the
directing ability to lead to high diastereocontrol for new centers.
(13) We attribute this unique result to the effect of the differential
metal coordination and/or aggregation state. We note that early
approaches to 24 and 26 attempted to use the approach developed in
the following manuscript, but the formation of the correct side chains
proved unachievable through oxidation chemistry: Enquist, J. A.; Stoltz,
B. M. Nature 2008, 453, 1228.
(14) Paquette, L. A.; Belmont, D. T.; Asu, Y. L. J. Org. Chem. 1985,
50, 4667.
(15) Formation of systems such as 26 are quite rare. For conditions
that have worked in select cases, but which did not work for our
substrates, see: Dana, G.; Weisbuch, F. Tetrahedron 1974, 30, 2879.
(16) Crivello, J. V.; Malik, R.; Lai, Y.-L. J. Polym. Sci., Part A: Polym.
Chem. 1996, 34, 3091.
(17) Of other Lewis acids attempted, TiCl4 afforded a small amount
of product (∼16% yield), while neither SnCl4 nor Sc(OTf)3 led to any
reaction. Under thermal conditions, starting material decomposed.
(18) For recent examples, see: (a) El Sous, M.; Ganame, D.;
Tregloan, P.; Rizzacasa, M. A. Synthesis 2010, 3954. (b) Kessler, S. N.;
Wegner, H. A. Org. Lett. 2010, 12, 4062. (c) Abraham, C. J.; Paull, D. H.;
Scerba, M. T.; Grebinski, J. W.; Lectka, T. J. Am. Chem. Soc. 2006,
128, 13370. Formal variants of the process exist as well: Davies, H. M. L.;
Dai, X. J. Org. Chem. 2005, 70, 6680.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental procedures,
b
copies of all spectral data, and full characterization. This material is
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
(19) Formally, we cannot rule out the possibility that this reaction is
a tandem MukaiyamaꢀMichaelꢀaldol reaction instead of an inverse-
demand DielsꢀAlder reaction. Worth noting is that the minor diaster-
eomer still reflects an endo addition based on the other oxygen atom of
the 1,3-dioxane system with respect to the diene.
(20) (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1978, 19, 2417. (b) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293.
(21) The olefination step is the cause of the observed yield; perform-
ing the two steps of methylation and deprotection separately had the same
overall yield with the acid-based deprotection being quantitative.
(22) Use of simple H2 with Pd/C (10%) afforded a 1.1/1 mixture in
favor of the undesired C-12 methyl epimer.
(23) We found that the most critical variant for success was solvent,
with neither benzene nor toluene providing much product. Other Lewis
acids such as Sc(OTf)3 and AlMe3 provided some product in CH2Cl2,
but in reduced yields. In all cases the reaction appeared to stall once it
had been warmed to ꢀ50 °C; more TMSCHN2 led to 8-membered ring
synthesis. For protocals that were tried here without success, see: (a)
Dabrowski, J. A.; Moebius, D. C.; Wommack, A. J.; Kornahrens, A. F.;
Kingsbury, J. S. Org. Lett. 2010, 12, 3598. (b) Moebius, D. C.; Kingsbury,
J. S. J. Am. Chem. Soc. 2009, 131, 878. (c) Maruoka, K.; Concepcion, A. B.;
Yamamoto, H. Synlett 1994, 521. (d) Maruoka, K.; Concepcion, A. B.;
Yamamoto, H. J. Org. Chem. 1994, 59, 4725.
We thank the NSF (CHE-0619638) for an X-ray diffracto-
meter and Prof. Gerard Parkin, Mr. Wesley Sattler, and
Mr. Aaron Sattler for performing all of the crystallographic
analyses. Financial support was provided by Columbia University,
Bristol-Myers Squibb, Eli Lilly, the Swiss Benevolent Society of
New York (predoctoral fellowship to D.A.W.), and the Deutscher
Akademischer Austausch Dienst (postdoctoral fellowship to
J.M.v.H.). S.A.S. is a fellow of the Alfred P. Sloan Foundation.
’ REFERENCES
(1) (a) Prestwich, G. D. Tetrahedron 1982, 38, 1911. (b) Baker, R.;
Walmsley, S. Tetrahedron 1982, 38, 1899.
(2) For the isolation of 2, see: Prestwich, G. D.; Lauher, J. W.;
Collins, M. S. Tetrahedron Lett. 1979, 20, 3828.
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(24) In model systems, we did observe the smooth formation of silyl
enol ether intermediates but never saw such materials in reactions with
compound 29, suggesting that the strain of the system may preclude a
sufficient lifetime to prevent 8-membered ring formation.
(5) Dauben, W. G.; Farkas, I.; Bridon, D. P.; Chuang, C.-P.;
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Miyashita, M.; Yoshikoshi, A. J. Am. Chem. Soc. 1974, 96, 1917. We do
not know the exact stereochemistry about the rearrangement position
in either 33 or 34, which could be the basis for reaction failure.
(26) Formally, compound 20 can be prepared in 4 steps (total step
count of 17) using a more expensive, commercially available starting
material (3-methyl-3-cyclohexenone) which we also prepared from 19:
Polla, M.; Frejd, T. Tetrahedron 1991, 47, 5883.
(6) Schubert, M.; Metz, P. Angew. Chem., Int. Ed. 2011, 50, 2954.
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F.; Wang, K.; Ramachandran, S. A.; Deslongchamps, P. J. Org. Chem. 2006,
71, 7370. (b) Zhao, L.; Burnell, D. J. Org. Lett. 2006, 8, 155. (c) Kato, T.;
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(27) For representative studies leading to highly complex systems
through [4 þ 3] chemistry, see: (a) Groaning, M. D.; Brengel, G. P.;
Meyers, A. I. J. Org. Chem. 1998, 63, 5517. (b) Trost, B. M.; McDougall,
P. J.; Hartmann, O.; Wathen, P. T. J. Am. Chem. Soc. 2008, 130, 14960.
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(28) Kamachi, T.; Kuno, A.; Matsuno, C.; Okamoto, S. Tetrahedron
Lett. 2004, 45, 4677. We used other silanes as well, but obtained similar
results. We believe these explorations are the first with extended dienone
systems.
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(11) Piers, E.; Oballa, R. M. J. Org. Chem. 1996, 61, 8439.
(12) We prepared this piece racemically. It has been formed with
high enantiocontrol through a kinetic resolution mediated by pig liver
esterase with its acylated variant (see ref 11). In our own hands, we were
able to obtain 84% ee through such a resolution process in initial
experiments on a small scale; optimization is expected to enrich that
outcome to the levels originally reported and on a preparative scale.
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dx.doi.org/10.1021/ja202859f |J. Am. Chem. Soc. 2011, 133, 8850–8853