Chemistry Reference
In-Depth Information
Fig. 8.17
Synthesis of ACE inhibitor
48
with two stereogenic centers flanking the silane
four stereoisomers, whereas
71
also has a stereogenic silicon and was a mixture
of eight stereoisomers. The extremely poor inhibition shown by methylsilanol
71
(IC
50
> 3000 nM) relative to
70
(IC
50
14 nM) was evidence that a silanediol group
was important for enzyme inhibition by these structures [
52
].
All four stereoisomers of
48
were prepared, keeping
d
-proline constant, and the
synthesis of one of these is outlined in Fig.
8.17
. The stereochemistry of the methyl
substituent in
48
was obtained from the (
S
)-Roche ester
72
, converting it to opti-
cally active lithium reagent
73
. Coupling difluorodiphenylsilane with metallated
dithiane
74
followed by displacement of the second fluoride by
73
gave
75
which
contains all the carbons of silane
48
. Conversion of the dithiane to the amine in-
volved hydrolysis and reduction of the ketone, without control of stereochemistry.
In this case, both stereoisomers were needed, but it was recognized that in future
work stereocontrol of this transformation needed to be addressed (see Fig.
8.21
).
Mitsunobu displacement of the alcohol with phthalimide, removal of the phthalic
acid group and coupling of the resulting primary amine with benzoyl chloride com-
