Biomedical Engineering Reference
In-Depth Information
1. Pd(OAc)
2
(30 mol%)
PPh
3
(60 mol%)
NaOPiv (3 equiv)
DMA, 110°C, 1.5 h
O
HO
O
O
CO
2
Me
HO
CO
2
Me
HO
CO
2
Me
Me
OH
EDCI
DMAP
CH
2
Cl
2
, 3 h
78%
MeO
MeO
MeO
I
Me
I
Me
H
+
H
2. NaBH
4
, MeOH/THF
-40°C, 3 h
86%
Cl
Cl
Cl
OH
OH
OH
OMOM
OMOM
OMe
OMOM
OMe
OMe
2
3
4
5
MeO
Me
O
O
COOH
OMe
OHHO
NH
OHHO
CO
2
Me
Protecting group manipulation
Diastereomeric resolution
10 steps
Cl
HO
Me
Me
O
46%
MeO
29% (5 steps)
HO
OH
HO
OH
Pradimicinone
1
6
SCHEME 1.3
Synthesis of pradimicinone by Suzuki and coworkers.
application of intramolecular direct arylation due to its tricyclic core containing a
biaryl linkage and a seven-membered ring. Leblanc and Fagnou applied two halide-
selective palladium-catalyzed cross-coupling reactions prior to a challenging intra-
molecular direct arylation step in their formal enantioselective synthesis of this
compound in 2005 (Scheme 1.4) [20]. Starting from alkyne
,
possessing in total three carbon-halide bonds of varying reactivities, a Sonogashira
reaction selectively afforded the desired propargyl ketone. Next, an (
S
)-pinene/9-
BBN-mediated asymmetric reduction followed by the protection of the resulting
alcohol as a MOM ether afforded
8
and acyl chloride
9
in 69% yield over three steps. Diimide reduction
of the triple bond and subsequent bromide-selective palladium-catalyzedmethyl ester
formation yielded the direct arylation precursor
10
in hand, the key
intramolecular reaction was investigated. It should be noted that, at the time, the
formation of a seven-membered ring by direct arylation as well as the use of an aryl
chloride as a coupling partner had limited precedent [21]. A combination of Pd(OAc)
2
11
. With
11
OMOM
H
O
1. PdCl
2
(PPh
3
)
2
(1 mol%), CuI (3 mol%)
Et
3
N (1.3 equiv), THF, rt, 20 h
2. 9-BBN, (
S
)-pinene, THF, reflux
then NaOH, H
2
O
2
, 2.5 h
3. NaH, MOMBr, 0°C to rt, 1 h
Br
1.
p
-Toluenesulfonyl hydrazide
NaOAc, DME/H
2
O, reflux
2. PdCl
2
(PPh
3
)
2
(5 mol%)
K
2
CO
3
(3 equiv), CO (5 atm)
MeOH (15 equiv), DMF, 95°C
78%
MeO
Br
MeO
Cl
+
Cl
MeO
Cl
MeO
OMe
OMe
8
9
10
(ee = 97%)
69%
1. Pd(OAc)
2
(10 mol%)
Ligand (10 mol%)
K
2
CO
3
(2 equiv)
DMA, 145°C, overnight
2. MeOH, HCl, reflux, 1 h
69% (entry 4)
NHAc
OH
OMOM
ref (22)
MeO
CO
2
Me
MeO
CO
2
Me
MeO
CO
2
Me
MeO
H
Cl
OMe
OMe
OMe
MeO
MeO
Allocolchicine
7
11
14
(ee = 97%)
OMOM
OMOM
Pd(OAc)
2
(10 mol%)
Ligand (10-40 mol%)
K
2
CO
3
(2 equiv)
OMOM
MeO
CO
2
Me
MeO
CO
2
Me
+
MeO
CO
2
Me
MeO
H
Cl
MeO
H
H
DMA, 130-145°C
overnight
OMe
MeO
OMe
OMe
11
12
13
Entry
Ligand
Ligand (mol%)
Temp (°C)
130
130
130
145
Conv (%)
12
:
13
Ligand
1
2
3
4
Ph-DavePhos
Ph-DavePhos
DavePhos
DavePhos
40
10
10
10
88
15
64
94
0.3 : 1
5.0 : 1
12.0 : 1
14.0 : 1
PR
2
NMe
2
R = Ph : Ph-DavePhos
R = Cy : DavePhos
SCHEME 1.4
Formal enantioselective synthesis of allocolchicine by Leblanc and Fagnou.
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