Biomedical Engineering Reference
In-Depth Information
O
H
O
H
O
H
H
H
378
(20 mol%)
Ethylene, toluene
H
O
O
O
RuL
n
and/or
43%
Pathway 1
L
n
Ru
377
379
380
MeN
NMe
378
(20 mol%)
Ethylene, toluene
Pathway 2
Cl
43%
Ru
Cl
Ph
Cy
3
P
378
O
O
H
H
H
H
steps
O
HO
Me
Me
O
Me
RuL
n
Me
Me
(+)-Cyanthiwigin U
383
O
381
382
SCHEME 9.66
Synthesis of cyanthiwigin U (
383
) by Phillips and Pfeiffer.
(
) is present only in very small amounts. In 2005, Phillips and
Pfeiffer described an enantioselective synthesis of (
þ
)-cyanthiwigin U (
383
) using an
efficient domino ring-opening/ring-closing metathesis protocol (Scheme 9.66) [145].
The Diels-Alder-derived bicyclo[2.2.2.]octene
þ
)-cyanthiwigin U (
383
377
was used as an enantiopure
precursor. Hence, when
377
was treated with catalyst
378
, a variety of possible
intermediates
379
-
381
were obtained, each one of them leading to the same product
382
via different pathways. In pathway 1, initial ring-opening metathesis leads to
ruthenium alkylidenes
379
and
380
, while pathway 2 gives metallacyclobutane
species
. Each of these products eventually undergoes the secondary ring-closing
metathesis to the advanced intermediate
381
. This domino product was eventually
taken through to the natural product in 12 overall steps and a remarkable 17% yield.
(
382
)-Halosaline (
387
), isolated from
Haloxylon salicornicum
, and (
)-swain-
sonine (
), isolated from the fungus
Rhizoctonia leguminicola
, have both been
prepared using a similar strategy involving a domino metathesis process by Blechert
and coworkers [146,147]. Hence, the enantiopure triene
390
384
was treated with 5 mol%
385
of Grubbs first-generation catalyst
to afford carbene metal complex at the
terminal double bond (Scheme 9.67). Subsequent reaction with the internal endo-
cyclic double bond led to siloxane
, which after further transformations provided
the natural product
387
. On the other hand, Swainsonine (
390
), which is known to
exhibit a wide range of biological activities, including the inhibition of glycoprotein
processing enzyme mannosidase II, as well as antimetastatic, antitumor-proliferative,
anticancer, and immunoregulating activities, was synthesized starting from the
enantiopure cyclopentene
386
which underwent a similar ruthenium-mediated
transformation as described previously to give the protected pyrrolidine containing
two stereogenic centers. This process was the key step in the synthesis of
388,
390
spanning
12 steps and 60% overall yield.
There are many more examples of domino metathesis reactions applied to the
synthesis of natural products that unfortunately cannot be discussed here, among them
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