Chemistry Reference
In-Depth Information
the simpler fragment
5.289
was formed by enantioselective magnesiation-ring opening of dihydrofuran
5.281
to give alcohol
5.291
(Scheme 5.77). Alcohol
5.291
was then chain-lengthened by titanium-catalysed hy-
dromagnesiation, followed by Kumada coupling (Section 2.2) with vinyl bromide. The primary alcohol was
then oxidized to the carboxylic acid
5.289
. The other fragment
5.290
was prepared by diastereoselective
carbomagnesiation. The Grignard reagent
5.293
generated was used in a ring opening of
N
-tosylaziridine.
Protecting-group manipulation yielded the amine
5.294
, which was coupled with the first fragment
5.289
to give an amide. It was found that the best sequence was to carry out glycosylation with the amino sugar
derivative
5.295
prior to ring-closing metathesis using Schrock's catalyst (Figure 8.3). Reduction of the
alkene, with diastereoselectivity provided by the macrocycle conformation, and global deprotection provided
the natural product
5.288
.
5.2.4 The Kulinkovich Reaction
When a titanacyclopropane
5.300
, generated from the reaction of titanium tetraisopropoxide with two equiv-
alents of a Grignard reagent is treated with an ester
5.297
, once again, insertion takes place. The resulting
metallacycle
5.301
is unstable, and loses the ester alkoxy group to form a new carbonyl group
5.302
coordi-
nated to the titanium. The system is now set up for intramolecular nucleophilic attack to form a cyclopropyl
alkoxide
5.303
coordinated to titanium. As the alkoxide
5.304
may be displaced from the titanium by addi-
tional Grignard reagent, the reaction becomes catalytic in titanium. The cyclopropanol product
5.298
is then
obtained upon work-up. This process is known as the Kulinkovich reaction (Scheme 5.79).
92
R
R
(
i
-PrO)
4
Ti, EtMgBr
O
OMe
HO
5.297
5.298
(
i
-PrO)
4
Ti
R
R
work up
2 EtMgBr
BrMg
O
HO
Et
5.298
5.304
(
i
-PrO)
2
Ti
2 EtMgBr
Et
5.299
R
(
i
-PrO)
2
Ti
(
i
-PrO)
2
Ti
(
i
-PrO)
2
Ti
MeO
O
5.300
5.303
R
O
OMe
intramolecular
nucleophilic
attack
5.297
δ
-
(
i
-PrO)
2
Ti
(
i
-PrO)
2
Ti
O
OMe
O
R
MeO
R
5.301
5.302
Scheme 5.79
