Biomedical Engineering Reference
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OH
n
-C
7
H
15
OH
HO
HO
AuCl (40 mol%
)
MeOH, rt, 4 h
O
O
O
O
n
-C
7
H
15
n
-C
7
H
15
OO
OH
60
OH
PMP
80%
61
62
(dr = 1:1)
ZnCl
2
, MgO
CH
2
Cl
2
, rt, 8 h
86%
O
TEMPO, PhI(OAc)
2
CH
2
Cl
2
, rt, 15 h
81%
O
61
(dr > 20:1)
O
O
n
-C
7
H
15
Cephalosporolide H
63
SCHEME 4.20
Synthesis of the anti-inflammatory agent cephalosporolide H by Dudley
and Tlais.
out to explore the possibility to apply the concept of alkyne ketalization to the
synthesis of natural products.
In their synthesis of the anti-inflammatory agent cephalosporolide H
63
,
Dudley and Tlais took advantage of the gold-catalyzed alkyne ketalization to
generate the spiroketal core of the targeted molecule (Scheme 4.20) [18]. Hence,
the treatment of
b
-hydroxyalkyne
with 40mol% of AuCl in MeOH led to the
formation of a 1:1 mixture of spiroketals
60
61
and
62
. Interestingly, the desired
spiroketal
61
could be obtained in a high diastereoisomeric ratio (
20:1) by simple
H
treatment of the 1:1 mixture of
61
and
62
with ZnCl
2
. A subsequent oxidation of
61
with PhI(OAc)
2
finally furnishes cephalosporolideH
63
in a global 56%yield for the
last three steps.
A thermodynamically controlled diastereoselective Au(I)-catalyzed spiro-
ketalization has been reported by Forsyth and coworkers for the synthesis of the
trioxadispiroketal-containing A-D ring system of azaspiracid
69
(Scheme 4.21) [19].
The treatment of
d
-hydroalkyne
64
by AuCl and PPTS in methanol afforded the
trioxadispiroketal
in 75% yield. This transformation was proposed to proceed via
an initial gold-catalyzed formation of the intermediate vinyl ether
68
. A subsequent
acid-catalyzed addition of the methoxy group located at C13 to carbon C10 of the
generated oxonium
65
was finally
obtained after a transfer of a methyl group to the solvent. Notably, AuCl is the only
metal salt that allows the selective and efficient formation of
66
produces
67
. The desired trioxadispiroketal
68
68
; palladium, silver, or
mercury salts do not give satisfactory results.
An interesting divergence in reactivity was reported by Trost and coworkers
during their total synthesis of the natural product (
[20]. The
spiroketal motif of the targeted molecule was accessed by a metal-catalyzed
spiroketalization of a polyhydroxylated alkyne of type
)-ushikulide A
73
(Scheme 4.22). AuCl was
the catalyst of choice to perform the desired spiroketalization, palladiumand platinum
salts being completely ineffective. Notably, ketals
70
could selectively be
obtained depending on the nature of the solvent (MeOH or THF) and the nature of the
oxygenated functionality at C21 (OH or OBz).
71
or
72
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