Chemistry Reference
In-Depth Information
HO
H
OH
OH
O
O
H
H
H
H
8.430
8.429
alkene A first
HO
HO
alkene A
a
lkene B first
OH
OH
alkene B
H
H
H
H
8.431
8.432
CO
2
Me
CuBr
+
+
CHO
BnO
PMBHN
8.433
8.434
8.435
BnO
BnO
1. LiAlH
4
2. (COCl)
2
,
DMSO, Et
3
N
3.
OH
CO
2
Me
MgBr
N
N
H
H
8.436
PMB
PMB
8.437
BnO
BnO
H
1. TBSCl, C
3
H
4
N
2
2. H
2
, Pd/C
OH
OTBS
Grubbs I
N
H
H
H
PMB
8.438
8.439
Scheme 8.117
(Scheme 8.117).
129
The bicyclic amine can be further disconnected to the diene-yne substrate
8.431
.The
strategy will only work if alkene A reacts with the catalyst before alkene B can do so. If alkene B reacts first,
the product will be the alternative, undesired [5.3.0] system
8.432
. The solution was to add an extra methyl
group to alkene B, and to leave the secondary alcohol free so that it could exert a directing effect through
coordination. The substrate
8.437
was constructed in a remarkably short sequence by a three-component
coupling of an aldehyde
8.433
,anamine
8.434
and an alkyne
8.435
, followed by a redox sequence and
a Grignard addition, with useable stereoselectivity throughout. The ene-yne-ene metathesis then gave the
desired quinolizidine structure
8.438
exclusively. Interestingly, the first-generation Grubbs catalyst proved
superior to the later versions: lower reactivity, in this case, translates into a lower ability to catalyse side
reactions. The free alcohol group could then be converted into a bulky silyl ether to ensure that hydrogenation
of the diene occurred from the opposite, less-crowded face, delivering the desired diastereoisomer
8.439
.The
synthesis was finished by installation of the side chains.
