Biomedical Engineering Reference
In-Depth Information
*
N
O
NHBoc
NHBoc
NMe
Bn
t
-Bu
H
(20 mol%)
p-
TsOH
O
+
Br
N
Br
N
54
53
55
OH
CHO
NaBH
4
MeOH
steps
78%
(2 steps)
Br
N
Me
Br
N
Boc
Br
N
Boc
H
H
H
(-)-Flustramine B
58
57
56
(ee = 90%)
SCHEME 9.11
Synthesis of flustramine B
58
by MacMillan and coworkers.
providing the central core of (
was achieved with 90% ee and
78% yield. Following this domino process, a five-step sequence led to the natural
product
)-flustramine B
(57)
(Scheme 9.11).
The prostaglandin family of compounds are responsible for a range of bio-
logical activities, including regulation of inflammatory response, lowering of blood
pressure, and contraction of smooth muscle. While the synthesis of prostaglandins
was a surmountable challenge in the 1970s, Shibasaki and coworkers applied a three-
component domino reaction in an enantioselective synthesis of the five-membered
ring contained within PGF
1
a
(64)
58
(Scheme 9.12) [24]. Similarly, an approach to
11-deoxy-PGF
1
a
was also proposed through this method. Hence, the racemic silyl
ether
59
initially underwent a Michael addition with dibenzyl methylmalonate
61
to
give intermediate
allowed the activation of the enone with
concomitant formation of a new stereogenic center at the point of nucleophilic attack
via the transition state
65
. The use of (
S
)-ALB
62
65
. Following this initial process, an aldol addition with
aldehyde
containing the desired
substitution pattern in a 12:1mixture of diastereoisomers in 75%yield (yield based on
malonate
60
as the third substrate provided compound
63
). This compoundwas considered a key intermediate for further syntheses
of prostaglandins especially PGF
1
a
.
A domino Michael/aldol process was also used by the Terashima group to first
make useful precursors for the preparation of the natural product (
61
)-huperzine A
(71)
(Scheme 9.13) [25]. This compound, isolated from
Huperzia serrata
,isa
selective inhibitor of acetylcholinesterase (AChE) and has been shown to have
potential for application in the treatment of Alzheimer's disease. In the enantiose-
lective synthesis of the
N
-heterocyclic core,
66
67
b
-keto ester
and acrolein
underwent
68
an initial Michael addition through the proposed intermediate
controlled by
(
. Following this initial stereocontrolled reaction, a preconceived
secondary aldol addition formed the third ring in a range of yields, depending on the
)-cinchonidine
72
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