Published on Web 01/27/2007
Origin of Diastereoselectivity in the Tandem Oxy-Cope/
Claisen/Ene Reaction: Experimental and Theoretical Studies
of the Ring Inversion Mechanism
Effiette L. O. Sauer, James Hooper, Tom Woo, and Louis Barriault*
Contribution from the Center for Catalysis Research and InnoVation, Department of Chemistry,
10 Marie Curie, UniVersity of Ottawa, Ottawa, Canada K1N 6N5
Received September 21, 2006; E-mail: lbarriau@science.uottawa.ca
Abstract: We report herein a detailed investigation into the reaction mechanism of the oxy-Cope/Claisen/
ene reaction. A series of chiral substrates was prepared, subjected to the tandem sequence, and the
enantiomeric excess of the final products was evaluated. The observed conservation of enantiomeric excess
was taken as evidence that the ring inversion of the intermediary enol ether does not occur. DFT calculations
were used to map out the potential energy surface for the reaction and evaluate the relative energies of
the ring inversions relative to those of the Claisen and ene reactions. Transition state energies thus obtained
were found to support the presence of a high-energy transition state for the ring inversion of B to D provided
R1 * H. In addition, the calculations lent further support to the hypothesis that the selectivity of the
transannular ene reaction is under Curtin-Hammett control.
and a tertiary alcohol at C10 (Figure 1).4 The pervasiveness of
such diterpenoid frameworks in nature makes this reaction
Introduction
The pursuit of new methods for the generation of architectur-
ally complex polycyclic molecules is an ongoing challenge for
the synthetic organic community. Despite recent advances,
however, difficulties remain. In particular, the stereoselective
formation of quaternary carbon centers continues to be a
significant obstacle.1 Moreover, with the ever-increasing em-
phasis being placed on sustainability,2 the need for efficient,
waste-minimizing processes is becoming increasingly important.
Consequently, the use of tandem reaction sequences has emerged
as a particularly enticing means for the diastereoselective
formation of multiple carbon-carbon bonds.3 Any method
which can incorporate both the efficiency of a tandem process
and the stereoselective formation of quaternary carbon centers
would thus be a significant advancement.
cascade an attractive method for the synthesis of numerous
natural products.5 Accordingly, several such total syntheses are
underway.6
In our original report,4 an evaluation of the reaction mech-
anism and the origin of its diastereoselectivity was proposed
based on product distributions and a qualitative assessment of
the presumed transannular ene transition states. While our
reasoning was sufficient to explain the original results, a more
rigorous understanding would be advantageous in order to
facilitate the expansion of substrate scope and bring into
realization the potential for this method. Herein, we report an
enhanced view of the reaction mechanism with new experi-
mental findings as well as DFT calculations to expand upon
our initial hypotheses.
In 2004, we reported the development of a highly diastereo-
selective tandem oxy-Cope/Claisen/ene reaction as an efficient
means of generating decalin skeletons possessing multiple
contiguous stereocenters including a quaternary carbon at C9
Results and Discussion
From the reaction mechanism (Figure 2), it is clear that the
diastereoselectivity is controlled by the conformational prefer-
(4) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569.
(5) (a) Myrocin, C: Al-Yahya, M. A.; Muhammad, I.; Mirza, M.; El-Feraly,
F. S. J. Nat. Prod. 1993, 56, 830. (b) Ellestad, G. A.; Kunstmann, M. P.;
Mirando, P.; Morton, G. O. J. Am. Chem. Soc. 1972, 94, 6206. (c)
Teucrolivin, A: Bruno, M.; Omar, A. A.; Perales, A.; Piozzi, F.; Rodriguez,
B.; Savona, G.; de la Torre, M. C. Phytochemistry 1991, 30, 275.
(6) (a) Sauer, E. L. O.; Barriault, L. Org. Lett. 2004, 6, 3329. (b) Morency,
L.; Barriault, L. Tetrahedron Lett. 2004, 45, 6105. (c) Arns, S.; Barriault,
L. J. Org. Chem. 2006, 71, 1809.
(7) Pioneering work of Still demonstrated that the conformation of medium
and large macrocycles affords an effective vehicle in which the asymmetric
synthesis of stereogenic centers can be achieved. See: (a) Still, W. C.;
Galynker, I. Tetrahedron 1981, 37, 3981. (b) Still, W. C. J. Am. Chem.
Soc. 1977, 99, 4186. (c) Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493.
(d) Still, W. Curr. Trends Org. Synth., Proc. Int. Conf., 4th 1983, 233. (e)
Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. Chem. Soc. 1983,
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(1) For recent reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (c)
Christoffers, J., Baro, A., Eds. Quaternary Stereocentres: Challenges and
Solutions for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2005.
(d) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (e) Douglas,
C. J.; Overmann, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (f)
Barriault, L.; Denissova, I. Tetrahedron 2003, 59, 10105. (g) Christoffers,
J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (h) Christoffers, J.;
Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (i) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 110, 402.
(2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: New York, 1998.
(3) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Tietze, L. F. Chem.
ReV. 1996, 96, 115. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem.
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York, 1992.
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J. AM. CHEM. SOC. 2007, 129, 2112-2119
10.1021/ja066830f CCC: $37.00 © 2007 American Chemical Society