Biomedical Engineering Reference
In-Depth Information
Spirofungin A is a polyketide natural product that inhibits the growth of
Candida albicans
and displays antiproliferative properties against several human
cancer cell lines. In comparison to the structurally closely related reveromycin,
spirofungin was also found to be a potent and selective inhibitor of isoleucyl-
tRNA synthase, a previously identified cellular target of reveromycin.
Synthetically, the stereocontrolled introduction of the spiroketal moiety of
spirofungin A represents the most challenging aspect of the synthesis. To
circumvent the diastereoisomeric mixture of spiroketals obtained in Shimizu's
first total synthesis [66], Kozmin and Marjanovic devised and successfully
implemented a tethered approach to provide a temporary configurational lock
during the spiroketalization event. Preparation of the macrocyclic spiroketaliza-
tion precursor
utilized two ingeniously designed metathesis reactions, the first
being a tandem ring-opening/cross-metathesis cascade. In the presence of Grubbs
second generation catalyst, cyclopropene ketal
164
underwent ring-opening
metathesis and subsequently engaged in a cross-metathesis with alkene
161
160
to
afford diene
162
upon desilylation. The so obtained hydroxy diene
162
was
tethered with hydroxy alkene
through a silicon linker, followed by removal of
the dioxane protecting group, to yield trienone
163
164
. Ring-closing metathesis of
trienone
in the presence of Grubbs second generation catalyst took place
uneventfully to afford macrocyclic dienone
164
in 85% yield, in readiness for the
much anticipated spiroketalization. Indeed, upon saturation of the two olefinic
moieties under hydrogenation conditions with concomitant hydrogenolysis of the
two benzyl ethers, spiroketalization proceeded spontaneously to afford macro-
cyclic spiroketal
166
with an impressive 98% yield as a single diastereoisomer.
Further extension and installation of the unsaturated side arms completes a highly
stereoselective synthesis of spirofungin A (Scheme 5.37) [67].
165
OH
OBn
1.
O
TBSO
1.
OO
161
163
OBn
OBn
O
O
G-II
(10 mol%)
Benzene
90°C, 3.5 h, 72%
2. TBAF, 84%
(
i
-Pr)
2
SiCl
2
, imidazole
BnO
O
TBSO
HO
BnO
2. oxalic acid, silica gel, CH
2
Cl
2
O
65% (2 steps)
Si
160
162
i
-Pr
i
-Pr
OTBS
164
Benzene
90°C, 8 h
85%
G-II
(30 mol%)
O
H
H
Me
Me
O
O
OH
OTBS
H
2
, Pd/C
O
H
BnO
BnO
H
O
O
O
OH
O
98%
O
OH
H
O
H
Si
i
-Pr
O
Me
Si
H
Me
H
i
-Pr
OTBS
i
-Pr
i
-Pr
166
165
(
−
)-Spirofungin A
SCHEME 5.37
Tandem ring-opening metathesis/cross-metathesis and silicon-tethered
ring-closing metathesis in the total synthesis of (
)-spirofungin A by Kozmin and
Marjanovic.
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