Biomedical Engineering Reference
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OTIPS
OTIPS
OTIPS
G-I
(5 mol%)
H
2
, Pd/C, EtOAc
O
O
O
N
N
N
N
N
N
CH
2
Cl
2
(0.25 mM), reflux, 8 h
then DMSO addition, rt, 12 h
95%
O
O
O
75-85%
12
13
14
OTBS
OTBS
OTBS
2
2
O
OTIPS
H
O
N
N
N
N
O
OH
15
(
−
)-Sarain A
HO
OTBS
SCHEME 5.6
Ring-closingmetathesis in the total synthesis of (
)-sarain A by Overman and
coworkers.
antibiotic necessitated the development of several key transformations in their
synthesis and highlighted the application of the Petasis-Ferrier reaction [15] to
assemble 2,6-
cis
-tetrahydropyranone. The macrocyclic ring closure proceeded
smoothly upon treating diene
16
with the Hoveyda-Grubbs second generation
catalyst (
) under high dilution conditions to afford exclusively the 13-membered
macrocyclic
cis
-alkene
HG-II
required special
attention, and a practical solution was ultimately found by exposing the crude reaction
mixture to air to destroy the metathesis catalyst, followed by catalytic hydrogenation
(Pd/C), to give alcohol
17
. Isolation of the metathesis product
17
in 84% yield over the two steps. Installation of the
exo
- and
endo
-cyclic alkenes and further oxidation state adjustments of this highly advanced
intermediate then enabled the completion of (-)-okilactomycin (Scheme 5.7) [16].
Abyssomicin C, isolated from the marine actinomycete
Verrucosispora
strain
AB 18-032, is an antibiotic whose mode of action involves the inhibition of the
bacterial
p
-aminobenzoic acid biosynthetic pathway [17]. In Nicolaou's total
synthesis of abyssomicin C, the fused tetronate oxabicyclo[2.2.2]octane core was
constructed via an intramolecular epoxide opening reaction, and the strained 11-
membered macrocycle was forged with a ring-closing olefin metathesis reaction, as
depicted by the transformation from
18
19
to
23
. In this instance, diene
19
underwent
macrocyclic ring closure in the presence of
G-II
to furnish a diastereomeric mixture
of allylic alcohols
possessing exclusively
trans
-olefin geometry in 85% yield.
Interestingly, macrocycle
23
was obtained as a single atropisomer. The atropselec-
tivity was rationalized based on the steric congestion imposed between the ruthenium
23
O
O
O
O
O
O
O
O
O
1.
HG-II
(30 mol%)
O
O
O
Pd/C (10%)
O
O
O
O
PhH (0.07 mM)
80°C, 24 h
H
2
, 1 atm
EtOAc, rt, 15 h
84% (2 steps)
O
2. Air, rt, 24 h
OBn
OBn
OH
OH
16
17
18
(
−
)-Okilactomycin
SCHEME 5.7
Ring-closing metathesis in the total synthesis of (-)-okilactomycin by
Smith et al.
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