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CO
2
Bn
RHN
R
CO
2
Me
NHFmoc
NHFmoc
N
N
N
CO
2
Bn
10 steps
NHBoc
O
O
N
N
N
N
20%
H
H
N
Lewis acid
(R = CBz)
Boc
O
O
112
113
114
Hg(OAc)
2
, I
2
CH
2
Cl
2
0°C then rt 30 min
100%
Pd
2
dba
3
(10 mol%)
P(
o
-Tol)
3
(100 mol%)
CuBr (5 mol%), S(CH
3
)
2
DMA, 25°C to 38°C
, 2 h
74%
(R = Boc)
I
N
NHFmoc
O
N
N
H
O
Zn, ICH
2
CH
2
I
TMSCl, DMA
BocHN
CO
2
Bn
BocHN
CO
2
Bn
115
rt, 1 h
ZnI
I
117
116
SCHEME 2.34
Synthesis of
a
-carboline
114
.
2.2.2.6. Cyclic Tripeptides OF4949-III and K-13 Several natural products
exhibit protease inhibition, most notably the two 17-membered cyclic tripeptides
OF4949-III (
118
) and K-13 (
119
), being, respectively, aminopeptidase B [57] and
ACE inhibitors (IC
50
¼
5 nM) [58] (Figure 2.6). The key
step for their synthesis appeared to be an intermolecular (for OF4949-III) or
an intramolecular (for K-13) Negishi cross-coupling between organozinc species
derived from amino acids and peptides, respectively, and aryl iodides. In both cases,
O-
aryltyrosine derivative
350 nM; captopril, IC
50
¼
, prepared in a multigram scale from commercially
available
N
-Boc-tyrosine and 2-fluorobenzaldehyde in a 55% overall yield (Figure 2.6
and Scheme 2.35), was used as a common intermediate [59]. Hence, while it is the
120
OMe
OH
O
-aryltyrosine
O
O
O
-aryltyrosine
CO
2
H
NH
2
O
NHAc
(2nd step)
CO
2
H
HN
O
(2nd step)
Intermolecular
Negishi coupling
HN
Intramolecular
Negishi coupling
to macrocyclization
NH
O
H
O
Fragment coupling
Fragment
coupling
(1st step)
Ser
(1st step)
H
2
NOC
Tyr-Ser
Asn
Macrocyclization
OH
(3rd step)
OF4949-III
118
K-13
119
FIGURE 2.6
Retrosynthetic analysis of cyclic tripeptides OF4949-III
118
and K-13
119
.
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