Chemistry Reference
In-Depth Information
1. LDA
2. MeI
H
H
Grubbs II
O
O
O
O
H
H
8.416
8.417
Grubbs II
O
H
H
O
O
O
O
O
H
H
8
4
8
.
Scheme 8.113
methodology. The alkyne
8.409
was converted into a propiolic ester
8.410
and this was the substrate for
the ene-yne metathesis, which generated the seven-membered ring
8.411
. The electrophilic double bond
conjugated to the ester was reduced with NaBH
4
and the ester was saponified and cyclized in an interest-
ing procedure involving treatment with CuBr
2
on alumina in a 5-
endo
manner. This gave a mixture of the
-bromolactone
8.413
and the unsaturated lactone
8.414
. The former could be converted into the latter by
simple treatment with a mild base. The synthesis was completed by stereoselective reduction of the butenolide
double bond with nickel boride. A different synthesis of stemoamide can be found in Scheme 4.44.
Intramolecular ene-yne metathesis was also used in a synthesis of dihydroxanthatin to form a seven-
membered ring
8.419
(Scheme 8.113).
126
After ring closure, the butyrolactone
8.417
could be methylated
with good diastereoselectivity. This reaction had to be done after closure of the seven-membered ring, as
the greater rigidity of the bicylic system was needed to obtain diastereoselectivity: methylation before ring
closure was not selective. After methylation, the synthesis was completed by a cross-metathesis reaction with
MVK. Some earlier steps in this synthesis can be found in Scheme 6.33.
Ene-yne metathesis was used to construct one of the rings of galanthamine
8.425
,
127
an
amaryllidaceaae
alkaloid used for the treatment of Alzheimer's disease (Scheme 8.114). The ene-yne
8.421
was attached to a
highly substituted phenol
8.420
by a Mitsunobu reaction. Ene-yne metathesis then generated a six-membered
ring
8.423
. Hydroboration-oxidation of the vinyl group then allowed closure of an additional ring by an
intramolecular Heck reaction. The final ring could then be formed by nucleophilic substitution after allylic
oxidation.
8.3.8 Ene-Yne-Ene Metathesis
A natural extension of ene-yne metathesis is ene-yne-ene metathesis in which the carbene generated by the
reaction of the alkyne is intercepted by a second alkene (Scheme 8.115).
In an unsymmetrical system, in which the two alkene arms are not identical, it is critical to ensure that the
desired “ene” component reacts with the catalyst to start the sequence. If the other “ene” component reacts,
then an isomeric product will be formed (Scheme 8.116). This can usually be achieved by ensuring that
the intended first “ene” component is the least substituted. In a comparison of closely related substrates, the
alkene with the least substitution was the one where the reaction initiated, giving isomeric products depending
on whether R
1
or R
2
was a hydrogen or a methyl group.
128
This question arose in a synthesis of lepadin
8.429
in which the natural product was to be built up from
the simpler unsaturated bicyclic amine
8.430
, using the secondary alcohol to direct reduction of the diene
