C O M M U N I C A T I O N S
Scheme 1. Catalytic Total Synthesis of Solanapyrone Da
product was formed as a single diastereomer and with excellent
levels of enantioselectivity (98% ee).
In summary, we have developed a powerful new enantioselective
catalytic variant of the intramolecular Diels-Alder reaction using
our LUMO-lowering iminium activation strategy. The synthetic
utility of this new protocol has been demonstrated by the preparation
of cycloadducts incorporating ether and quaternary carbon func-
tionality and via the total synthesis of the marine metabolite solana-
pyrone D (18). Moreover, we have further extended this technology
to execute the first enantioselective, catalytic Type II IMDA
reaction.
a Key: (a) Methyl acetoacetate bis(trimethylsilyl) enol ether, TiCl4,
CH2Cl2, -78 °C, 75%. (b) Dess-Martin Periodinane, CH2Cl2, 71%. (c)
DBU, benzene, 60 °C, 87%. (d) Methyl p-toluenesulfonate, K2CO3, DMF,
room temperature, 81%. (e) LDA, THF, -78 °C to 0 °C; methyl formate,
-78 °C, 57% (91% based on recovered starting material).
It has been established that IMDA cycloadditions of substrates
incorporating heteroatoms in the tether have traditionally been
problematic for Lewis acid catalysis. However, we have found that
ether-aldehyde 11 readily undergoes cycloisomerization using our
organocatalytic protocol to provide oxabicyclic adduct 12 in
excellent yield and stereoselectivity (Table 1, entries 9 and 10).
Moreover, we have found that Decalin ring systems can be readily
assembled using this iminium activation method. For example,
catalyst 2c effects the [4 + 2] addition of undecatrienal 13 to
efficiently provide cycloadduct 14 with excellent levels of enan-
tiocontrol (Table 1, entry 12, 70% yield, >20:1 endo/exo, 93% ee).
Notably, our “first generation” imidazolidinone 1 proved to be
catalytically ineffective in this case (entry 11). This dramatic change
in cycloaddition rate as a function of [4.4.0] versus [4.3.0] ring
formation has been previously established in a number of diaste-
reoselective IMDA studies.3
To demonstrate the chemical utility of our organocatalytic IMDA
reaction, we undertook the total synthesis of the marine metabolite
solanapyrone D (18), a phytotoxic polyketide isolated from the
fungus Altenaria solani.9 Solanapyrone D has previously been
constructed in 19 steps by Hagiwara and co-workers.10 Recognizing
that the trans-fused Decalin backbone of solanapyrone D is an ideal
IMDA retron, we sought to test the scope and limitations of this
new bicyclic ring-forming protocol in a complex target setting. As
shown in Scheme 1, cycloaddition of trienal 15 in the presence of
20 mol % 2‚TfOH afforded Decalin aldehyde 16 in 71% yield11
and 90% ee. Importantly, all four stereocenters of solanapyrone D
were efficiently installed in this single catalytic operation. Aldehyde
16 was then elaborated to pyrone 18 via the aldol adduct 17. Methyl
ether formation, followed by ortho-lithiation with formylative trap
then completed the synthesis of (-)-solanapyrone D (18) in only
six steps from trienal 15, and nine steps from commercial materials.
Finally, we sought to extend our newly developed protocol to
the cyclization of Type II IMDA substrates. The Type II IMDA
(in which the dienophilic function is tethered to the 3-position of
the diene) is an extremely powerful transformation that allows for
the formation of medium ring cycloadducts containing up to three
stereocenters and an anti-Bredt olefin.12 To our knowledge, no
examples of enantioselective catalytic Type II IMDA reactions have
previously been documented.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen, Merck,
and Astellas USA Foundation. W.S.J. and R.M.W. are grateful for
NSF Predoctoral Fellowships.
Supporting Information Available: Experimental procedures for
all new compounds. This material is available free of charge via the
References
(1) For recent reviews of enantioselective Diels-Alder reactions, see: (a)
Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 3, p 1177 and references therein. (b) Oppolzer, W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol 5. (c) Kagan, H. B.; Riant, O. Chem. ReV. 1992,
92, 1007. (d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289.
(2) For examples of enantioselective IMDA reactions, see: (a) Furuta, K.;
Kanematsu, A.; Yamamoto, H.; Takaoka, S. Tetrahedron Lett. 1989, 30,
7231. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc.
1996, 118, 3049. (c) Ishihara, K.; Kurihara, H.; Matsumoto, M.;
Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920. (d) Iwasawa, N.;
Sugimori, J.; Kawase, Y.; Narasaka, K. Chem. Lett. 1989, 1947. (e)
Narasaka, K.; Saitou, M.; Iwasawa, N. Tetrahedron: Asymmetry 1991,
2, 1305. (f) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786. (g)
Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979.
(3) For reviews, see: (a) Roush, W. R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5,
Chapter 4.4. (b) Craig, D. Chem. Soc. ReV. 1987, 16, 187. (c) Fallis, A.
G. Can. J. Chem. 1983, 62, 183. (d) Brieger, G.; Bennett, J. N. Chem.
ReV. 1980, 80, 63.
(4) For examples of diastereoselective IMDA reactions using a chiral auxiliary,
see: (a) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29. (b)
Mukaiyama, M. J. Org. Chem. 1983, 23, 4441. (c) Oppolzer, W.; Dupuis,
D. Tetrahedron Lett. 1985, 26, 5437. (d) Evans, D. A.; Chapman, K. T.;
Bisaha, J. J. Am. Chem. Soc. 1984, 106, 4261. (e) Evans, D. A.; Chapman,
K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238.
(5) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2000, 122, 9874.
(6) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370. (b) Austin, J. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172.
(7) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 1192.
(8) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 32.
(9) (a) Oikawa, H.; Yokota, T.; Ichihara, A.; Sakamura, S. J. Chem. Soc.,
Chem. Commun. 1989, 1284. (b) Oikawa, H.; Yokota, T.; Sakano, C.;
Suzuki, Y.; Naya, A.; Ichihara, A. Biosci. Biotechnol. Biochem. 1998,
62, 2016.
(10) Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M.;
Okamoto, T.; Kobayashi, M.; Yamamoto, I.; Ohtsubo, S.; Kato, M.; Uta,
H. J. Org. Chem. 2002, 67, 5969.
(11) Diene 15 was contaminated with 15% of the Z,E-diene isomer. Yield
reported based on the conversion of the E,E-diene substrate to IMDA
product.
(12) For an excellent review of the Type II IMDA, see: Bear, B. R.; Sparks,
S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 821.
We were pleased to find that, upon treatment with 20 mol %
2‚pTSA in CH2Cl2 at room temperature, Type II IMDA substrate
19 underwent cyclization to afford [5.3.1] cycloadduct 20 in 65%
yield (72% yield based on 10% recovered diene). Remarkably, this
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