Biomedical Engineering Reference
In-Depth Information
Me
N
Me
Me
Me
N
N
N
N
X
O
NH
N
+
N
R
N
R
N
B(OR)
2
R
H
H
100
101
102
(common precursor)
Me
(+)-Complanadine A
99
SCHEME 1.25
Retrosynthetic analysis of (
þ
)-complanadine A by Fischer and Sarpong.
in 53% yield [86]. Owing to the significant steric hindrance at C2, the more active
Pd(TFA)
2
, instead of the more traditional use of Pd(OAc)
2
for oxidative Heck
reactions, was required to obtain
in acceptable yield. Hydrogenation of the nitro
and alkene moieties, followed by removal of the silyl protecting groups and macro-
lactamization delivered (
98
).
The
Lycopodium
alkaloid complanadine A (
)-rhazinicine (
92
) enhances the secretion of nerve
growth factor in human glial cells, making it an attractive compound for the treatment
of neurodegenerative diseases [87]. As a synthetic target, it represents an interesting
challenge due to its unsymmetrical dimeric structure. While its synthesis can be
simplified to the preparation of the monomeric unit lycodine, the unsymmetrical
nature of the dimer requires the selective installation of cross-reactive functional
groups at C3 of one monomer and C2 of the other in order to combine the two halves
(Scheme 1.25). To this effect, Fischer and Sarpong relied on a late-stage Suzuki cross-
coupling reaction between C2 triflate
99
100
and C3 boronic ester
101
in their total
synthesis of complanadineA (
99
) [88]. Compounds
100
and
101
were prepared froma
common synthetic intermediate
102
, employing an Ir-catalyzed C-H borylation
strategy in the case of
101
.
was prepared based on the synthesis of racemic
N
-desmethyl-
a
-obscurine by Schumann and Naumann (Scheme 1.26) [89]. Treat-
ment of
Key precursor
103
with Boc
2
O and triethylamine provided the mono-Boc-protected
intermediate, which was oxidized to pyridinone
103
102
using Pb(OAc)
4
. This species
was finally converted to triflate
in 72% yield using triflic anhydride in pyridine.
Having prepared one of the monomeric units, the preparation of boronic ester
100
was
initiated by removal of the triflate functional group under palladium catalysis.
101
N
Me
Me
Me
O
70% HClO
4
(1.4 equiv)
Dioxane
105°C, 20 h
1. Boc
2
O (1.5 equiv), Et
3
N (2.2 equiv)
THF, 60°C, 12 h (65%, 2 steps)
2. Pb(OAc)
4
(1.25 equiv)
CHCl
3
, rt, 30 min (84%)
3. Tf
2
O (1.2 equiv), Py/CH
2
Cl
2
-78°C to rt (72%)
Pd(OAc)
2
(5 mol%), dppf (5 mol%)
HCOO
N
N
O
OTf
⋅
NH
4
(5 equiv), Et
3
N (2 equiv)
DMF, 60°C, 3.5 h
Me
+
N
N
H
Boc
90%
103
100
O
O
Me
NH
2
1.
100
(1.25 equiv)
PdCl
2
(dppf) (12.5 mol%)
Et
3
SiH (25 mol%)
K
3
PO
4
(3.75 equiv)
DMF, 80°C, 7 h
2. 6N HCl (45 equiv)
70°C, 2 h
42%
N
Me
Me
[Ir(COD)(OMe)]
2
(4 mol%)
dtbpy (8 mol%)
B
2
pin
2
(0.75 equiv)
THF, 80°C, 5.5 h
NH
N
N
N
N
H
O
N
N
Boc
B
O
Boc
H
H
H
75%
(+)-Complanadine A
99
Me
101
104
SCHEME 1.26
Synthesis of (
þ
)-complanadine A by Fischer and Sarpong.
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