Biomedical Engineering Reference
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Me
Me
Me
Me
Me
Me
Me
Me
Me
O
OMe
O
O
O
O
Me
O
Me
G-I
(10 mol%)
CH
2
Cl
2
, 40°C, 3 h
Me
Me
Me
O
Me
Me
86%
OMe
O
O
OH
Me
p
-BrBzO
p
-BrBzO
O
188
(48%)
190
O
O
O
(
±
)-Coleophomone B
Me
CH
2
N
2
Et
2
O, 0°C
+
O
Me
Me
p
-BrBzO
187
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
Me
Me
G-I
(10 mol%)
CH
2
Cl
2
, 40°C, 3 h
Me
Me
Me
MeO
80%
O
O
OH
OMe
p
-BrBzO
O
p
-BrBzO
189
(32%)
191
(
±
)-Coleophomone C
SCHEME 5.42
Diastereoselective desymmetrization by ring-closing metathesis in the total
synthesis of (
)-coleophomone C by Nicolaou et al.
et al. conveniently synthesized the ring-closing metathesis precursors
188
and
189
from a common trione precursor
187
upon its treatment with diazomethane. Remark-
ably, metathesis precursors
underwent ring closure in the presence of
Grubbs first generation catalyst to afford macrocycles
188
and
189
in 86% and 80%
yields, respectively, each as a single stereoisomer. For both substrates, the metathesis
event took place engaging selectively the diastereotopic prenyl group
syn
to the
neighboring methyl substituent. Furthermore, each of metathesis precursors
190
and
191
188
and
189
afforded a single geometric isomer at the newly formed double bond, corre-
sponding to the
E
and
Z
configurations required for coleophomones B and C,
respectively. Subsequent functional group transformations of macrocycles
190
and
191
then delivered the targeted natural products, constituting a highly stereoselective
synthesis featuring the application of ring-closing olefin metathesis in diastereose-
lective desymmetrization (Scheme 5.42) [75].
In a conceptually different application of diastereoselective metathesis reac-
tion, Shair and coworkers employed this technology where the newly generated
asymmetric element is in the form of an atropisomerism. With a biomimetic approach
in mind, Shair's total synthesis of the cytotoxic marine natural product (
)-long-
ithorone A required the atropdiastereoselective preparation of paracyclophanes
195
and
, where their 1,3-disubstituted diene motifs suggested the enyne ring-closing
metathesis as a suitable strategy for their constructions. Thus, metathesis precursors
193
198
and
196
were conveniently prepared from a common intermediate
192
, where the
strategically positioned benzylic TBS ethers within
would serve as
stereochemical directing elements in the atropdiastereoselective macrocyclic ring
closure. Indeed, treatment of
193
and
196
193
and
196
with Grubbs first generation catalyst
smoothly delivered paracyclophanes
in 42% yield (two steps, upon TBS
ether removal) and 31% yield, respectively, where the former exhibited
194
and
197
20:1
atropdiastereoselectivity and the latter with a much inferior atropdiastereoselectivity
of 2.8:1. The observed diastereoselectivity was predicted based on the A
1,3
strain
induced by the benzylic TBS ether. Having served their purpose as stereochemical
controlling elements in the cyclizations, the benzylic hydroxyl groups within
H
194
and
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