Biomedical Engineering Reference
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a Michael-type fashion (abbreviated in Scheme 9.8) to give compound
in 67%
yield. In this domino double Michael addition reaction, a tetrahydropyran and a
cyclohexane ring are formed in a single process with stereocontrol at each of the
newly formed stereogenic centers. However, the configuration of the methyl
substituent at C4 was later epimerized to generate the correct stereochemistry
required for the natural product.
In 2004, Sorensen and coworkers examined domino reactions initiated by
intramolecular Michael additions in the preparation of the
Trichoderma harzianum
natural product harziphilone
38
[20]. This compound is an inhibitor of the binding
of virus expression protein (REV) with the REV-responsive element of mRNA,
which might be important for the human immunodeficiency virus (HIV) regulation.
However, later it was discovered that harziphilone
(45)
(45)
was not active in CEM-SS cell
protection from HIV-1.
In the synthesis of
was treated with a catalytic
amount of 1,4-diazabicyclo[2.2.2]-octane (DABCO) at room temperature to pro-
duce the zwitterion
45
, the enantiopure diol
40
in a reversible reaction (Scheme 9.9). Subsequent intra-
molecular 1,4-addition and proton transfer resulted in the second zwitterion
41
, still
containing the DABCO moiety. This intermediate was then proposed to either
undergo a
43
b
-eliminationtogive
44
followedbya6
p
-electrocyclic reaction to
furnish the natural product
or be subjected to an intramolecular substitution.
Surprisingly, the described domino reaction, despite its complexity, gave the desired
45
N
N
N
N
Me
O
Me
O
Me
O
HO
HO
HO
N
N
HO
HO
•
O
HO
CHCl
3
, rt, 24 h
O
Me
O
Me
Me
40
41
42
Me
O
N
N
HO
Me
O
O
HO
O
HO
Me
HO
Me
44
43
Me
O
HO
substitution
O
HO
Me
(+)-Harziphilone
45
SCHEME 9.9
Synthesis of (
þ
)-harziphilone
(45)
.
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