Transcript No Slide Title

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
O
The Target-Driven Development
of a Facile Tandem Wolff-Cope
Rearrangement for the Synthesis
of Fused Carbocyclic Skeletons
H
H
H
O
OH
O
Me
O
O
H
O
H
H
O
ineleganolide
OH
O
AcO
Me
Me
guanacastepene
H
salvimultine
[n-7] bicyclic motif is common to many natural products
… of a Facile Tandem WolffCope Rearrangement …
A modified Cope reaction
with synthetic utility.
“Standard” Cope reaction:
driven by release
of strain energy
Ketene-assisted Cope:
fused bicycle
O
O
a,b-unsaturated
system
unconjugated olefin
Product has desired functionality already in place
… of a Facile Tandem WolffCope Rearrangement …
Wolff rearrangement
generates ketenes from
a-diazoketones:
Me
MeO
O
N
R
O
N
O
H
R
R
Me
MeO
C
O
H
Me
MeO
N2
O
H
H
O
H
Wolff rearrangement
H
Cope reaction
together form the tandem Wolff-Cope rearrangement
Some substrates do not undergo Wolff-Cope rearrangement
MeO
O
MeO

O
MeO
O
O
H
O
N2
Me
O
O
N2
H
MeO
N2
O
H
N2
O
O
N2
N2
H
O
O
Me

MeO
O
N2
N2
O
O
O
Me
O
N2
MeO
H
O
N2
N2
= good
= bad
O
Me
Me
Transition state structure suggests threshold for reaction failure
O
2
N2
1
3
h
4
O
= good
= bad
5
destabilizing A(1,3)
interaction
Perfect agreement
with experiment.
-CH3 Gts
none 15.8
1
15.0
2
14.6
3
16.6
4
22.3
5
18.3
( kcal/mol)
reaction works
reaction fails
An alternate transition state with the right threshold energy
2
1
4
1
O
3
4
5
3
O
A(1,3)
cis (boat-like)
5
2
substituents
spaced further
apart, near
constant G‡
trans (chair-like)
–CH3 Gcis‡ Gtrans‡ Gcis-trans‡
none 15.8
18.3
–2.5
1
15.0
17.4
–2.4
2
14.6
19.2
–4.6
3
16.6
20.0
–3.4
4
22.4
19.7
2.7
5
18.3
17.3
1.0
low-lying alternate path
responsible for reaction
failure!
The ketene functionality causes alternate pathway to be accessible
31.3
19.8
trans
20.2
trans
O
17.3
H
O
8.1
1.3
H
cis
cis
H
–20.8
O
H
no ketene
with ketene
-28.4
Product instability normally keeps alternate path inaccessible
ring strain associated
with trans double bond
in 7-membered ring
boat
-8.3
chair
chair
11.1
boat
H
H
H
G ~ 28.9 kcal/mol
H
H
H
Hammond posulate disfavors alternate pathway
The ketene functionality preferentially stabilizes trans transition state
31.3
trans
19.8
cis
20.2
O
17.3
H
O
8.1
1.3
H
H
–20.8
O
H
no ketene
with ketene
now cis, trans transition states are nearly degenerate
-28.4
Cope transition states are a mix of aromatic/radical character
Distinguishing
features
synchronous
6e-, aromatic
high Etriplet-singlet
important
GVB pairs:
asynchronous,
radical-like
low Etriplet-singlet
Trans transition state has more radical character
a)
b)
1.66
2.27
1.70
2.03
7
vinyl, trans
c)
Et-s = 31.6
more radical
character
ketene, trans
8
d)
2.01
9
2.38
vi nyl, cis
1.79
10
2.14
ke tene, cis
O
Ketenes stabilize radicals:
Et-s=51.0
some radical
character
O
Trans transition state has more radical character: more evidence
Reactant
TS
H
H
O
boat
9.1
14.0
9.1
chair
0.0
16.5
0.0
boat
18.7
40.8
41.4
chair
0.0
33.6
42.6
boat
0.0
20.6
23.9
chair
1.9
2.0
13.6
trans ts is more suspectible to radical stabilization!
Also, there is a
third transition state ...
O
trans (chair-like),
dGts = 18.3 kcal/mol
Et-s = 31.6 kcal/mol
intermediate aromatic-radical
geometric constraints may
prevent resonance.
H
H
O
O
cis (boat-like)
dGts = 15.8 kcal/mol
Et-s = 51.0 kcal/mol
mostly aromatic
bridged (boat-like),
dGts = 44.3 kcal/mol
Et-s = 17.3 kcal/mol
mostly radical
Designing substrates that rearrange: two strategies
2
1
4
1
O
3
4
5
3
O
5
A(1,3)
2
trans (chair-like)
cis (boat-like)
Stabilize cis transition state:
O
O
Gts = 16.0 kcal/mol
13.1
Successfully used
to rearrange bisquarternary substrate.
Designing substrates that rearrange: two strategies
2
1
4
1
O
3
4
5
3
O
5
A(1,3)
2
Destabilize trans
transition state via
diaxial interactions.
cis (boat-like)
trans (chair-like)
O
Me
Me
1’, 4’ substitution
Gcis-trans = –4.0,
predicted to rearrange
Observed to cyclize, but
with cyclopropane ring intact.
4
1
O
More diaxial destabilization of trans transition state
3
5
2
Gcis‡
Geometry
O
Gtrans‡ Gcis-trans‡
16.0
-
-
13.1
-
-
15.5
19.5
–4.0
20.7
17.9
2.8
O
O
Me
4’ substitution always
problematic, cannot
be “rescued” by 1’
substitution.
Me
Me
TMS
O
Me
Me
t
Bu
O
21.9
20.4
1.6
23.6
22.9
0.7
Me
O
Going to larger groups
(TMS to Me to tBu)
helps, but not enough.
Conclusions: what have we learned?
O
2
O
1
5
H
cis
O
3
4
O
4
1
trans
H
cis
O
3
vs.
5
2
A(1,3)
trans
• 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.