Biomedical Engineering Reference
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O
O
O
O
S
O
S
O
Cl
HO
N
S
N
N
O
G-II (15 mol%)
O
S
S
S
DMAP, THF
PhH, 4 h, 70°C
70% (2 steps)
88
89
90
1. LiHMDS
THF/HMPA
2. n -BuLi, THF
−
78 °C
3. ICH 2 MgCl
OMe
−
78°C
I
OMe
(76%)
(60%)
MeO
OMe
HO
OH
O
N
N
O
S
O
S
S
N
O
MgCl
SO 2
OMe
OMe
H
OMe
S
92
91
Originally assigned
structure of ( ± )-mycothiazole
SCHEME 5.25 Sulfur-tethered ring-closing metathesis in the total synthesis of the originally
assigned structure of ( )-mycothiazole by Cossy and coworkers.
inconsequential, the tethered approach can still be implemented with exceptional
efficiency. This concept was exemplified by Mootoo and coworkers in their synthesis
of monensin analogues [49]. In their synthetic endeavor, a phthalate linker was chosen
for the proposed tetheredmetathesis reaction, as illustrated by substrate
93
. Treatment
of substrate
93
with Grubbs second generation catalyst smoothly delivered macro-
cycle
in an impressive 91% yield as an undetermined and inconsequential mixture
of E / Z isomers (ca. 4:1). Hydrolytic removal of the phthalate tether (NaOMe),
followed by spiroketalization of the diol and olefinic functionalities within
94
,
enabled the preparation of a series of monensin analogues. This work highlighted
the application of the tethered metathesis strategy to circumvent the formation of
homodimers, a major drawback in cross-metathesis reactions involving type I
metathesis partners (Scheme 5.26).
In a recently reported total synthesis of the antiobesity drug (-)-tetrahydrolip-
statin, Hanson and coworkers expanded the concept of tethered metathesis with a
subsequent cross-metathesis reaction to execute two sequential carbon-carbon bond
95
MOMO
MOMO
R 2
H
R 1
R 2
MOMO
R 1
R 2
G-II (10 mol%)
NaOMe, MeOH
O
O
O
O
OH
CH 2 Cl 2 (0.01 M), reflux, 4 h
85%
OH
O
O
then DMSO addition, rt, 16 h
O
O
R 1
H
91%
93
94
( E / Z = 4:1)
95
HO
R 1 = BnO(CH 2 ) 4 ; R 2 =
O
O
H H
O
O
H
H
H
O
O
O
O
H H
O
H
H
H
H
O
R 1
H
O
96
Monensin spiroketal analogues
SCHEME 5.26 Phthalate-tethered ring-closing metathesis in the synthesis of monensin
analogues by Mootoo and coworkers.
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