Chemistry Reference
In-Depth Information
through a three-step synthesis to give ester
95
in overall yield of 72%. The reaction of
ketone
95
under standard Wittig conditions with the ethyltriphenylphosphonium bromide
salt and
n
-butyl lithium provided the (Z) and (E) isomers of
96
in a 2:1 ratio, respectively.
The subsequent reduction of ester
96
with lithium aluminum hydride provided the mix-
ture of alcohols
97
, followed by oxidation to the corresponding aldehyde
98
. Addition of
the alkyne group to
98
was achieved by employing acetyldiazomethylphosphonate under
the Ohira-Bestmann conditions
54
to give alkyne
99
in 81% yield.
53
The reaction of the
alkyne with dicobalt octacarbonyl in petrol provided the metallocycle
100
in nearly quan-
titative yield.
As shown in Scheme 8.15, a variety of conditions were employed including use of
amine oxides,
6
polymer supported alkyl methyl sulfides,
55
and optimized conditions using
Sugihara's procedure
52
to provide the desired enones
101a
and
101b
(2:1, respectively) in
high yields. Both cyclizations at room temperature with amine oxides as well thermally
mediated cyclizations proved successful. Both diastereomers were separated by silica gel
chromatography with the minor enone
101b
possessing the required
-selectivity of the
methyl group. Pauson was able to further improve the selectivity of the Wittig reaction which
improved the selectivity of the Pauson-Khand intramolecular cyclization to provide
101a
and
101b
(1:2.4, respectively). Furthermore, epimerization conditions were developed by
reacting
101a
with lithium hydroxide in aqueous THF to provide a mixture of
101a
:
101b
in
a ratio of 1:9, respectively. With ample amounts of
101b
now in hand, further transformation
to the target molecules
103
and
104
through cedrene
102
was carried out completing the
formal total synthesis of (
β
±
)-
α
- and
β
-cedrene.
8.11 Additional Applications of the Pauson-Khand Reaction
in Total Synthesis
Honda and Keneda
56
have used an intramolecular Pauson-Khand reaction to gain entry
into the bicyclic ring system contained in (-)-incarvilline
109
. Because it is related to the
biologically active parent compound incarvillateine,
57
(-)-incarvilline has been reported in
studies on potential antinociceptive compounds related to incarvillateine.
58
The synthe-
sis began with alcohol
105,
as shown in Table 8.2, from which the necessary enyne
106
was synthesized in a four-step sequence. The results of the study of the intramolecular
Pauson-Khand cyclization are shown in Table 8.2. The alkyne
106
was first reacted with
a slight excess of dicobaltoctacarbonyl in toluene under thermal conditions to afford the
desired enone
107
and its diastereomer
108
. Optimization with various promoters includ-
ing N-oxides and butyl methyl sulfides [59.52b] provided higher yields of
107
and
108
.
The diastereomer selectivity was rationalized by steric repulsions through the cyclization
intermediates leading to the intramolecular products. The subsequent steps completed the
formal total synthesis of the monoterpene alkaloid (-)-incarvilline
109
.
57
A related example of a Rh(I)-catalyzed [(3
1] homologous Pauson-Khand cycload-
dition has been reported by Yu
60
in the total synthesis of the furanoid sesquiterpene (
+
2)
+
-
agarofuran
115
. Unique to this synthesis was the use of a 1-yne vinyl cyclopropane synthon
and carbon monoxide to construct the key [4.4.0]bicyclic decalin system in
115
. The prior
studies by Yu and co-workers
61
on intramolecular cyclizations using vinylcyclopropane
synthons set the ground work for this total synthesis.
±
)-
α
