Chemistry Reference
In-Depth Information
Fig. 8.15
Synthesis of silane-
diol HIV inhibitor
44
8.4.4
Thermolysin Inhibitor
Preparation of a silanediol inhibitor for thermolysin, structure
46
, with two different
organic groups attached to silicon, started with a chloromethyl silane and used an
optically active organolithium reagent, similar to the procedure developed for HIV
inhibitor
44
(Fig.
8.15
). Starting with commercially available chloromethyl trichlo-
rosilane
63
, treatment with phenylmagnesium chloride followed by a 48 % HF work
up led to fluorosilane
64
, Fig.
8.16
. As described by Eaborn, despite the very high
strength of the Si-F bond, fluorosilanes react readily with nucleophiles [
65
]. More-
over, mono- and difluorosilanes are stable to moisture, making them much easier to
handle than chlorosilanes. (note that fluorosilanes have the potential to generate HF
burns and proper precautions must be taken!)
Treatment of silane
64
with enantiomerically pure lithium reagent
65
gave chlo-
romethylsilane
66
. Displacement of the chloride by phthalimide, removal of the
benzyl ether and oxidation led to acid
67
. Coupling with leucine
tert
-butyl ester,
removal of the phthalimide group and coupling with dihydrocinnamoyl chloride
gave penultimate product
68
.
Silanediol
46
was the least sterically hindered protease inhibitor prepared and
therefore had the most potential to polymerize. Subjection of
68
to the procedure
previously used for conversion of the diphenylsilyl to a dihydroxysilyl group, triflic
acid followed by ammonium hydroxide neutralization, led to substantial amounts
