Biomedical Engineering Reference
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chain or in the presence of acidic protons. Hence, cyclic tripeptide OF4949-III
118
was obtained in 12 steps and 20% overall yield starting from Boc-tyrosine.
Alternatively, the intramolecular Negishi cross-coupling was used for the
macrocylization leading to K-13
119
. Hence, after treatment of the modified
diiodinate tripeptide
with activated zinc, the diluted Pd(0) catalysis afforded
the corresponding 17-membered macrocyclic tripetide
125
in a modest 35% yield.
The question that remained to be answered was whether the zinc was inserted into the
aromatic or the aliphatic carbon-iodine bond. If it is known [64] that from a kinetic
point of view the insertion of zinc is faster into the aliphatic carbon-iodine bond, the
absence of by-products coming from the insertion of the zinc into the aromatic-iodine
bond tends to confirm this hypothesis. Hence, K-13
126
119
was obtained in 12 steps and
9.6% overall yield starting from Boc-tyrosine.
2.2.3. Synthesis of Macrocycles
2.2.3.1. Amphidinolides T Amphidinolide T macrolides are a series of natural
products produced by marine dinoflagellates of the genus
Amphidinium
[65], charac-
terized by a pronounced cytotoxicity toward various cancer cell lines. The synthesis of
amphidinolides T
1
,T
3
,T
4
,andT
5
[66] involved a highly diastereo-selective SnCl
4
-
mediatedalkylationbetweena furanosyl sulfone derivative
132
to afford a ketone that was reduced diastereoselectively with L-selectride or LiAlH
4
to
give the corresponding iodinated alcohols (12
S
)-
131
anda silyl enol ether
133
and (12
R
)-
134
after a few
manipulations. The assembly of the southern fragment was achieved through a
palladium-catalyzed acyl-Negishi reaction [67-70] between the polyfunctionalized
organozinc species
. The 19-membered
ringmacrocycle is then formedvia a ring-closingmetathesis (RCM) catalyzedbyGrubbs'
second-generation catalyst and a hydrogenation reaction (Figure 2.7 and Scheme 2.36).
133
or
134
and an enantiopure acid chloride
135
(2nd step)
Acyl-Negishi
coupling
OH
O
O
HO
(1st step)
Diasteroselective
alkylation
O
O
O
O
O
O
(3rd step)
Amphidinolide T1
127
Amphidinolide T3
128
Ring closing
metathesis
Hydrogenation
O
O
HO
HO
O
O
O
O
O
O
Amphidinolide T4
129
Amphidinolide T5
130
FIGURE 2.7
Retrosynthetic analysis of amphidinolide T macrolides.
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