2940
A. G. Griesbeck et al. / Tetrahedron Letters 54 (2013) 2938–2941
Perepoxide like structures could only be found for an exo aligned
attack of singlet oxygen on compound 6 (see Supplementary infor-
mation for details). Other perepoxide structures were found to be
no stationary points on the potential energy surfaces for both sub-
strates. There is a thermodynamic preference for the Michael-type
products in both cases. Product 2a is favored by 3.1 kcal/mol and
product 7 by 2.7 kcal/mol (including zero point corrections) but
the experiment shows that thermodynamic effects are not respon-
sible for regioselectivity. Since the regioselectivities are also not in-
duced by any activation barriers, another model is needed to
explain the regioselectivities which elucidates the control via the
descent of the particular pathways. The only stationary point in
the regions where regioselectivity is created is the transition state
(9 and 10 in Fig. 2). It is apparent that the real minimum reaction
path is split in a valley ridge inflection point close to the transition
state from recent studies.4 Scans following the steepest descents
from the stationary points 9 and 10 in the direction of both possi-
ble products of type A and B are able to represent the both reaction
pathways.
Figure 3. Transition structures 9 and 10 with depicted atom distances between
oxygen and the abstracted hydrogen in allylic positions TPSS/TZVP.
This flat area which has to be crossed on the way to product 8
could diminish the likely hood for the generation of 8 and increase
the generation of 7 since the descent toward 7 is almost vertical in
the first steps.
A closer look at the transition structures 9 and 10 gives also an
advice which reaction path is more favored. The O–H distances of
the oxygen that abstracts the hydrogen atoms in the allylic posi-
tions of the unsaturated ketone shown in Figure 3 are very similar
for the acyclic system 10 (the bond lengths are differing only by
0.1 Å). Structure 9 for the cyclic transition state is of much more
asymmetric nature. The oxygen–hydrogen distances are differing
by 0.4 Å so that a transition state arises from the cyclic geometry
that is early for the generation of 7 and a late transition state for
the generation of 8.
Potential energy profiles in higher resolution of the area around
the transition states 9 and 10 are showing markedly different prop-
erties. The descent toward the thermodynamic favored products is
steeper in both cases but there is a flat plateau like region in the
pathway toward the unfavored product B for substrate 6 (Fig. 3).
O
H
The abstraction of the
a-hydrogen by the peroxy group in 9
O
H
(Fig. 3) appears to be more favored than the abstraction of the
0.0
-0.5
-1.0
-1.5
-2.0
a
O
competing b-hydrogens, as the longer O–H distance indicates a
9
stronger O–H-attraction along the negatively curved normal mode
of saddle point 9. In other words the system starts loosing energy
a
on the reaction coordinate with a still long O–H distance. Also the
lower selectivity observed in the formation of 2a and 2b, preferring
the thermodynamically disfavored product 2b, can be explained by
the less pronounced asymmetry of the O–H distances in TS 10.
O
O
OH
O
OH
Conclusion
O
8
7
The divergent regioselectivity effects experimentally deter-
mined for the ene substrates 1 and 6, respectively, are in agree-
ment with the mechanistic two-stage no-intermediate model and
on a computational level correspond to a control mechanism fol-
lowing the steepest decent pathway from the corresponding tran-
sition stages in a valley ridge potential energy surface region.
A
B
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
Displacement [Å]
O
O
H
Acknowledgement
O
10
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
H
This research was supported by the Deutsche Forschungs-
gemeinschaft (DFG).
Supplementary data
O
OH
O
Supplementary data (The detailed energy profiles for the reac-
tion of singlet oxygen with 1 and 6, respectively, are described.)
associated with this article can be found, in the online version, at
OH
O
O
2a
2b
References and notes
A
1. Schenck, G. O. Naturwissenschaften 1948, 35, 28–29.
B
2. (a) Clennan, E. L. Tetrahedron 2005, 61, 6665–6691; (b) Clennan, E. L.
Tetrahedron 2000, 56, 9151–9179.
3. (a) Prein, M.; Adam, W. Angew. Chem., Int. Ed. 1996, 35, 477–494; (b) Alsters, P.
L.; Jary, W.; Nardello-Rataj, V.; Aubry, J.-M. Org. Process Res. Dev. 2010, 14, 259–
262.
-0.3
-0.2
-0.1
0.0
0.1
0.2
Displacement [Å]
0.3
Figure 2. Scans following the steepest descent from transition structures 9 and 10
toward the product regions TPSS/TZVP (resolution higher than in Figure 1). The
pathway from 9 to 8 shows a markedly flat shaped region around the transition
state.
4. (a) Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach, A. G.;
Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk, K. N. J. Am. Chem. Soc.
2003, 125, 1319–1328; (b) Orfanopoulos, M.; Stephenson, L. M. J. Am. Chem. Soc.
1980, 102, 1417–1418; (c) Grdina, M. B.; Orfanopoulos, M.; Stephenson, L. M. J.