selectivity, followed by partial epimerization at the allylic
position. The direction of stereoinduction is opposite to that
observed in the acyclic case in Scheme 3 and the steroid
case in Scheme 1.
stable products in both cases. Compound 9B, the equatorial
isomer, is considerably more stable than 9B′ and, it is likely
that steric interactions between the methyl group and the
oxanorbornene bridge are also felt in the transition state. This
result is consistent with previous studies of six-membered
ring-forming intramolecular Diels-Alder reactions of furans
that feature a single stereogenic center in a totally saturated
tether;6 however, highest selectivities were observed in
thermodynamic control.6a,g,i Since Diels-Alder reactions of
isobenzofurans are unlikely to be reversible, the high
stereoselectivity is due to kinetic control. Calculations show
that 9C is more stable than 9C′ by 3.0 kcal/mol in the most
stable conformation. The relative stereochemistry between
the original stereogenic center and the adjacent stereogenic
center is opposite for 9B and 9C.
The reaction was examined for a variety of cyclohexenyl-
methylcarbene complexes of varying substitution pattern, and
the results are depicted in Table 1. In all cases, the original
stereocenter was completely effective in controlling the
stereochemistry of the initial Diels-Alder adduct, and only
compounds 10-cis and/or 10-trans and no other isomers were
observed. As predicted, the overall efficiency of the reaction
was considerably less as the cyclohexene ring became more
hindered, and lower yields were obtained using 10D and 10E.
In most cases, a mixture of stereoisomers was obtained that
could be converted to a single stereoisomer, 10-trans, upon
base treatment. Successful isolation of the pure kinetic
product was successful only in entry E, where there is no
acidic proton at the three-ring junction.
Simulation of the entire Diels-Alder step was undertaken
in order to understand the factors favoring 9C over 9C′
(Figure 2). The simulation was performed using Hartree-
As noted in Table 1 and Schemes 1 and 3, the original
stereogenic center at the â-position of the carbene complex
is completely effective in controlling the stereochemistry
during the Diels-Alder step. In all cases, two different exo
stereoisomers are possible; however, all of the products are
derived from a single diastereomer of intermediate oxa-
norbornene derivative 9. However, the direction of induction
is opposite for the cases of Scheme 3 and the cases in Table
1. In Scheme 3, both the stereogenic center and the alkene
are acyclic, while the stereogenic center and the dienophile
are both within the same ring for the systems in Table 1.
The stereogenic center is part of a ring in the steroidal
examples of Scheme 1. However, the dienophile is acyclic;
the direction of stereoinduction is the same in these cases as
that observed for the examples in Scheme 3. Similar reactions
involving cyclohexene dienophiles proceed in the same
direction of stereoinduction.8
The Diels-Alder step was examined computationally for
the reactions of 2-ethynylbenzaldehyde (1) with carbene
complexes 8B and 8C.9 Comparison of the energies for the
most stable conformations of exo Diels-Alder adducts
(Figure 1) reveals that the observed products are the more
Figure 2. Calculated reaction profile for the Diels-Alder reactions
leading to 9C and 9C′.
Frock calculations using the 6-31G* basis set. The reaction
profile was established by taking the energy-minimized
conformations of 9C (solid line) and 9C′ (dashed line) and
lengthening the C-C bonds formed in the Diels-Alder step
to 3 Å in 10 steps. Although the calculated reaction profile
is based on the retro-Diels-Alder reaction, the graph in
Figure 2 is presented as the forward reaction (the final points
on the right represent 9C and 9C′). The transition state for
9C′ is 5.6 kcal/mol less stable than the transition state for
9C. The cyclohexene ring in the transition state precursor
to 9C′ deviates substantially from the ideal half-chair
(8) (a) Grieco, P. A.; Kaufman, M. D.; Daeuble, J. F.; Saito, N. J. Am.
Chem. Soc. 1996, 118, 2095-2096. (b) Blond, A.; Paltzer, N.; Guy, A.;
D’Hotel, H.; Serva, L. Bull. Soc. Chim. Fr. 1996, 133, 283-293.
(9) The program MacSaprtan Pro v. 1.04 was utilized in this study.
Figure 1. Heats of formation for compounds 9B, 9B′, 9C, 9C′.
Org. Lett., Vol. 4, No. 13, 2002
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