Chemistry Reference
In-Depth Information
δ
H
S
δ
H
R
MeO
2
C
III
H
R
Ar
Ar
MeO
2
C
S
MeO
2
C
δ
Ar
IV
R
h
H
δ
II
I
Re
-face attack
Figure 4.11.
Rationale for enantioinduction with Rh
2
(
S
- DOSP)
4
.
The reaction of 1,3-cyclohexadiene with aryl vinyldiazoacetate
155
was used as a key
step in the synthesis of (+)-sertraline (
157
, Scheme 4.43) [231]. The product of the com-
bined C-H activation/Cope rearrangement (
156
) was formed in 60% yield in 99% ee
and was subsequently transformed into (+) - sertraline [231] .
Cl
Cl
Cl
Cl
Cl
Cl
153
Rh
2
(
S
-DOSP)
4
Hexane, 23°C
N
2
60% yield
99% ee
NHMe
CO
2
Me
CO
2
Me
155
156
157
(+)-Sertraline
Scheme 4.43.
Synthetic application of the combined C-H activation/Cope rearrangement.
The scope of the combined C-H activation/Cope rearrangement has been expanded
to other allylic methylene sites, such as dihydropyranone system
158
(Scheme 4.44 ) [234] .
The reaction is compatible with a variety of vinyldiazoacetates
152
, but lower yield is
obtained when R = alkyl because of competing cyclopropanation chemistry. The reac-
tion afforded
159
in 20-87% yield and in 98-99% ee as a single diastereomer [234].
Similar reactions with 1-substituted cyclohexene system
161
(Scheme 4.45 ) generated
the functionalized products
162
in 31-68% yield and 95-99% ee as single diastereomers
[234]. A major side reaction was the direct C-H insertion. Cyclopentene systems usually
suffered from lower yields and competing reaction pathways (direct C-H insertion and
cyclopropanation) [234]. These examples show the remarkable levels of diastereo- and
enantioselectivity that can be achieved with this reaction.
Dihydronaphthalenes emerged as very suitable compounds for this chemistry
[235,236] . Reactions of 1 - methyl - 3,4 - dihydronaphthalene with arylvinyldiazoacetates
produced the formal C-H insertion products as single diastereomers in > 99% ee. This
is very unusual, since direct C-H insertion is known to proceed with moderate diaste-
reoselectivity. It appeared that, in this system, a C-H activation/Cope rearrangement
