Biomedical Engineering Reference
In-Depth Information
Negishi
coupling
Intramolecular
Friedel-Crafts
Acylation
O
N
O
OH
N
O
OAc
A
O
F
F
MeO
O
O
O
B
C
DE
C
DE
RO
OH
OH
O
O
O
O
Lactonamycin
185
CDEF ring models
186
(R = Me)
187
(R = PMB)
OH
FIGURE 2.14
Structure of lactonamycin.
OH
N
O
Pd(PPh
3
)
4
(5 mol%)
THF
F
CO
2
H
11 steps
31%
O
MeO
E
N
O
HO
OH
TfO
OMe
F
O
188
189
MeO
E
186
(R = Me 50%)
187
(R = PMB 65%)
reflux
4 steps
OMe
OMe
OR
HO
Br
5 steps (R = Me)
69%
C
MeO
OH
OMe
Zn, BrCH
2
CH
2
Br
THF, 0°C
C
C
192
(R = Me, 85%)
(R = PMB, 92%)
3 steps (R = PMB)
MeO
MeO
190
191
33%
OH
OR
SCHEME 2.45
Synthesis of CDEF ring models.
The key steps in the synthesis of the tetracyclic model system CDEF
186
and
187
are based on a first Negishi cross-coupling to anchor the EF rings to the C ring and
an intramolecular Friedel-Crafts acylation reaction to construct the D ring. The
dihydroisoindole triflate
was obtained in a multigram scale after 11 steps and
31% overall yield starting from 2,4,6-trihydroxybenzoic acid. It was then involved
in a highly efficient Pd(0)-catalyzed cross-coupling reaction with 2,5-dimethoxy-
3-benzyloxy-protected benzylzinc bromide formed from
189
191
to afford compounds
192
in very high yield (for R
¼
Me 85%, for R
¼
PMB 92%) (Scheme 2.45).
2.2.4.4. Bengamides Bengamides are a group of bioactive compounds
extracted from an orange sponge belonging to Jaspidae family in 1986 [96], showing a
potent cytotoxic activity against
g/mL), and
endowed with antibiotics and antihelmintic properties [97]. Intense research activity
has been recently devoted toward the enantioselective synthesis of bengamide E
larynx epithelial carcinoma (10
m
193
and various analogues thereof [98] (Figure 2.15). The synthetic strategy focused on
Epoxide
opening
Amide bond
formation
OH
OMe
O
N
NH
Negishi coupling
OH
OH
O
Bengamide E
193
FIGURE 2.15
Retrosynthetic analysis of bengamide E.
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