Biomedical Engineering Reference
In-Depth Information
O
OH
AcO
O
O
OH
AcO
O
O
HG-II
(10 mol%)
O
HO
N
H
HO
1,2-Dichloroethane
H
O
23°C, 10 h
O
56
57
40%, 51% brsm
(
−
)-FR901464
SCHEME 5.17
Alkene cross-metathesis in the total synthesis of (
)-FR901464 by
Koide and coworkers.
a final step olefin cross-metathesis between diene
under the
influence of Hoveyda-Grubbs second generation catalyst furnished the targeted
natural product as a single isomer in 40% yield (51% based on recovered starting
material). The sensitive nature of vinyl epoxide
56
and vinyl epoxide
57
necessitated the use of a more
active metal carbene initiator under mild conditions, and 5% of the homodimer of
vinyl epoxide
57
was observed (Scheme 5.17) [36].
The acetogenins are polyketide secondary metabolites found to exhibit wide-
ranging biological properties, including but not limited to cytotoxic, antitumoral,
antiparasitic, pesticidal, antimicrobial, and immunosuppressive activities [37]. Their
mechanism of action was suggested to be based on the inhibition of ATP production
via the blockage of mitochondrial complex I. Recognizing the structural complexity
of the tetrahydrofuran-containing long-chain hydrocarbon in the acetogenin skeleton,
Donohoe et al. elegantly demonstrated their oxidative cyclization method and a late-
stage alkene cross-metathesis in the total synthesis of (
57
)-sylvaticin. In this instance,
in the presence of the Hoveyda-Grubbs second generation catalyst, 4 equiv of
butenolide alkene
þ
59
was used to prevent alkene
58
from undergoing homodimer-
ization, and the cross-metathesis product
was obtained as a single geometric
isomer in 84% yield. Diimide reduction of the newly formed double bond in
60
60
,
followed by global desilylation, then furnished (
þ
)-sylvaticin in 67% yield over two
steps (Scheme 5.18) [38].
The power of alkene cross-metathesis in the synthesis of bioactive molecules has
stretched beyond the context of natural products [39]. Indeed, in a research program
directed toward the preparationof carbohydrate-based antitumor vaccines, Danishefsky
and coworkers demonstrated that in the presence of Hoveyda-Grubbs first generation
catalyst, trisaccharide terminal olefin
62
and amino acid containing terminal olefin
63
underwent smooth alkene cross-metathesis to afford, upon hydrogenation of the newly
OTBS
O
59
O
HG-II
(10 mol%)
OTBS
O
C
10
H
21
C
10
H
21
O
O
O
O
3
H
H
H
H
H
H
H
H
CH
2
Cl
2
, 70°C, 16 h
O
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
84%
58
60
TsNHNH
2
, NaOAc
88%
AcCl, MeOH
76%
OH
OTBS
O
O
C
10
H
21
C
10
H
21
O
O
O
O
7
3
H
H
H
H
H
H
H
H
O
OH
OH
OH
OTBS
OTBS
OTBS
O
61
SCHEME 5.18
Alkene cross-metathesis in the total synthesis of the acetogenin (
þ
)-sylva-
ticin by Donohoe et al.
(
+
)-Sylvaticin
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