1. Substituent Effects and Nearly Degenerate Transition States:
Rational Design of Substrates for the Tandem Wolff-Cope Reaction
Julius Su, Richmond Sarpong, Brian Stoltz, William A. Goddard III
Materials and Process Simulation Center,
California Institute of Technology

2. The Target-Driven Development
of a Facile Tandem Wolff-Cope
Rearrangement for the Synthesis
of Fused Carbocyclic Skeletons
[n-7] bicyclic motif is common to many natural products

3. … of a Facile Tandem Wolff-
Cope Rearrangement …
A modified Cope reaction
with synthetic utility.
“Standard” Cope reaction:
driven by release
of strain energy
Ketene-assisted Cope:
fused bicycle
a,b-unsaturated
system
unconjugated olefin
Product has desired functionality already in place

4. … of a Facile Tandem Wolff-
Cope Rearrangement …
Wolff rearrangement
generates ketenes from
a-diazoketones:
together form the tandem Wolff-Cope rearrangement

5. Some substrates do not undergo Wolff-Cope rearrangement 

6. Transition state structure suggests threshold for reaction failure
Perfect agreement
with experiment.
reaction works
reaction fails
( kcal/mol)

7. An alternate transition state with the right threshold energy
substituents
spaced further
apart, near
constant DG‡
low-lying alternate path
responsible for reaction
failure!

8. The ketene functionality causes alternate pathway to be accessible
no ketene
with ketene

9. Product instability normally keeps alternate path inaccessible
ring strain associated
with trans double bond
in 7-membered ring
DG ~ 28.9 kcal/mol
Hammond posulate disfavors alternate pathway

10. The ketene functionality preferentially stabilizes trans transition state
cis
no ketene
with ketene
now cis, trans transition states are nearly degenerate

11. Cope transition states are a mix of aromatic/radical character
Distinguishing
features
synchronous
6e-, aromatic
asynchronous,
radical-like
high DEtriplet-singlet
low DEtriplet-singlet
important
GVB pairs:

12. Trans transition state has more radical character
DEt-s = 31.6
more radical
character
DEt-s=51.0
some radical
character
Ketenes stabilize radicals:

13. Trans transition state has more radical character: more evidence
trans ts is more suspectible to radical stabilization!

14. Also, there is a
third transition state ...
geometric constraints may
prevent resonance.

15. Designing substrates that rearrange: two strategies
Stabilize cis transition state:
Successfully used
to rearrange bis-
quarternary substrate.
DGts = 16.0 kcal/mol
13.1

16. Designing substrates that rearrange: two strategies
Destabilize trans
transition state via
diaxial interactions.
DDGcis-trans = –4.0,
predicted to rearrange
Observed to cyclize, but
with cyclopropane ring intact.
1’, 4’ substitution

17. More diaxial destabilization of trans transition state
4’ substitution always
problematic, cannot
be “rescued” by 1’
substitution.
Going to larger groups
(TMS to Me to tBu)
helps, but not enough.

18. Conclusions: what have we learned?
Substrate scope fully explained by cis vs. trans energies.
Near degeneracy arises from preferential radical stabilization of trans transition state.
Can design new substrates with substitution at “forbidden” sites that will rearrange.