Biomedical Engineering Reference
In-Depth Information
Et
OMe
215
(E/Z = 1:1
)
EDDA
Cbz
NCbz
O
O
NCbz
N
N
N
N
H
H
H
O
O
Boc
Boc
OMe
t-
BuO
O
CHO
H
214
O
O
O
O
213
216
217
O
O
O
O
- CO
2
- acetone
Cbz
N
3
N
N
H
N
H
H
H
15
Boc
OMe
20
H
H
OMe
O
MeO
2
C
(-)-Hirsutine
219
218
(dr > 24 : 1)
O
SCHEME 9.36
Synthesis of (
)-hirsutine
219
by Tietze and coworkers.
Meldrum's acid (
, with a catalytic amount of ethylenediam-
monium diacetate (EDDA) provided a highly advanced intermediate
218
in this total
synthesis with excellent stereoselectivity in a 1,3-induction and a yield of 84%
(Scheme 9.36). It is assumed that the reaction proceeds via the less sterically
demanding conformation of the condensation product
214
), and enol ether
215
, which then undergoes
a hetero-Diels-Alder reactionwith 4-methoxybenzylbutenyl ether
216
215
(
E
:
Z
1:1) from
the
re
-face to give
218
via
217
. This enantiopure product is then taken through to the
natural product (
) in excellent overall yield and stereoselectivity
using again a domino process that consists of ring opening of the lactone, deprotec-
tion, condensation, and hydrogenation employing MeOH/K
2
CO
3
/Pd/C//H
2
.
The synthesis of (
)-hirsutine (
219
) paved the way for the synthesis of two
structurally similar alkaloids: emetine and tubulosine [79]. The naturally occurring
alkaloid emetine possesses interesting biological activities such as antiprotozoal
properties and activity in the treatment of lymphatic leukemia; furthermore, as its
name suggests, it has been applied as emetic. The structurally related tubulosine
was isolated from the dried fruits of
Alangium lamarckii
and the sap of
Pogonopus
speciosus
. It is remarkably active against several cancer cell lines, has inherent inhi-
bition of protein biosynthesis, and has HIV reverse transcriptase inhibitory activity.
Quite recently, some new cannabinoids such as (
)-hirsutine (
219
),
and D have been isolated from the bark of
Machaerium multiflorum
spruce [80].
They have shown microbial activity against
Staphylococcus aureus
and
Plasmodium
falciparum
. On the basis of earlier work of Tietze et al. [81], Lee et al. [82] have used
a formal domino Knoevenagel/hetero-Diels-Alder reaction to prepare (
þ
)-machaeriols A, B (
222
)-machaer-
iols A-C and some unnatural enantiomers. As an example, the synthesis of
222
was
performed by reaction of dihydroxylbenzene derivative stemofuran A (
þ
220
) with
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