Chemistry Reference
In-Depth Information
8B.7.2.1.2. Applications in Syntheses of Biologically Active Compounds
In many appli-
cations, the allylic substitution has been combined with an RCM reaction. This strategy
was fi rst realized by Evans et al. with Rh-catalyzed allylic aminations [320] and etheri-
fi cations [321] .
An example is the synthesis of the prostaglandin analogue
TEI - 9826
described in
Scheme 8B.81 [322]. The sodium salt of the malonic amide of the Weinreb type can be
considered an equivalent of the enolate of a methyl ketone. The allylic alkylation gave
the substitution product with 99% ee as 1:1 mixture of epimers. Further steps furnished
a dienone suited as substrate for RCM to give 4-(
n
- octyl) - cyclopent - 2 - enone. This was
transformed into the prostaglandin analogue
TEI - 9826
by aldol condensation. A related
route was used for a synthesis of a lactam analogue of brefeldin C [319].
Na
O
O
O
OMe
Me
MeO
2
C
OMe
Me
MeO
N
N
R
OCO
2
Me
R
[Ir(COD)Cl]
2
/
L60/
TBD,
THF, rt
R=Ph
R=Me
R=
n
-Octyl
b
/
l
= >98:2, 98% ee (88%)
b
/
l
= 94:6, 95% ee (76%)
b
/
l
= 84:16, 99% ee (62%)
R=
n
-Octyl
O
O
O
CO
2
Me
Grubbs' II
CH
2
Cl
2
n
-Octyl
n
-Octyl
T EI-9826
Scheme 8B.81.
Ir-catalyzed allylic alkylation with a malonic amide and application in the synthesis
of the prostaglandin analogue
TEI- 9826
.
A formal synthesis of the serotonin reuptake inhibitor (− ) - paroxetine has been pre-
sented by Hamada et al. (Scheme 8B.82) [306a]. The intermediary piperidine derivative
was obtained from the allylic alkylation product in excellent 70% overall yield. The
corresponding allylic alkylation product with a
p
- chlorophenyl substituent was trans-
formed into (
R
) - baclofen hydrochloride (cf. Alexakis et al.) [299a] .
8B.7.2.1.3. Intramolecular Alkylations
Intramolecular allylic substitutions often pose
diffi culties. For example, Pd-catalyzed intramolecular allylic alkylations are usually run
at a low concentration because of competitive polymerization. In contrast, Ir-catalyzed
cyclizations can be run without problems at 2 M concentration. Nevertheless, problems
arise because of the competing noncatalyzed background reaction. In case of the fi ve -
and the six-membered rings (Scheme 8B.83) [315], satisfactory yields were obtained by
preparing the malonate anion at − 78 ° C. The ligand
L60
proved to be the best suited
once more. However, these conditions were not suitable for the vinylcyclopropane and
-butane. In these cases, application of the salt-free conditions gave excellent results [312].
