Biomedical Engineering Reference
In-Depth Information
OH
Me
1. 10% Pd/C (15 mol%)
H
2
(1 atm)
EtOAc, rt, 30 min
2. NaH (5 equiv)
MeI (7 equiv)
THF, rt, 1 h
95%
Me
H
H
HO
OH
TBSO
Pd(OAc)
2
(1 equiv)
DMSO (2 equiv)
t
-BuOH/AcOH (4:1)
60°C, 10 h
74%
TBSO
TBSO
7 steps
H
SEM
32%
SEM
HO
HO
COOH
HO
MeO
O
SEM
O
O
(
−
)-Quinic acid
46
47
48
N
T
N
O
Br
Br
i
-PrO B
O
NTs
49
N
N
N
Br
O
OMe
Br
N
OMe
O
Me
Me
Me
TFA
NH
N
B
O
H
H
H
Pd(PPh
3
)
4
(10 mol%)
2M aq Na
2
CO
3
(3.3 equiv)
PhH/MeOH (5:1), 50°C, 65 h
77%
1. NBS (1.6 equiv)
THF, 0°C to rt, 15 min
2.
49
(20 equiv)
n
-BuLi (15 equiv)
THF, -78°C, 15 min
70% (2 steps)
TBSO
TBSO
N
H
8 steps
67%
H
2
N
H
SEM
SEM
HO
MeO
MeO
O
O
O
(+)-Dragmacidin F
(
45
)
51
50
SCHEME 1.13
Synthesis of (
þ
)-dragmacidin F by Stoltz and coworkers.
cross-coupling reaction was performed. Indeed, as previously observed in their related
synthesis of dragmacidin D [55], this reaction is selective for the oxidative addition of
the more electron-deficient pyrazinyl bromide to Pd(0), leaving the 6-bromoindole
fragment untouched. It should be noted that the reaction outcome is highly temperature
dependent and significant erosions in selectivity are observed at higher temperatures
(80
C). From intermediate
, functional group interconversions, a challenging Neber
rearrangement, and finally formation of the aminoimidazole moiety completed the
total synthesis of (
51
þ
45
)-dragmacidin F (
).
1.6. DIRECTING GROUP-ASSISTED PALLADIUM(II)-
ENABLED CARBON-CARBON BOND FORMATION
AT sp
3
C-H BONDS
Selective metalation of arene or alkane C-H bonds may be achieved with the
assistance of Lewis basic directing groups within the substrate [10,45]. These
moieties have been demonstrated to act as ligands for electron-deficient metal centers,
mediating carbon-carbon or carbon-heteroatom bond formation at C-H bonds
through the formation of stable five- or six-membered metalacyclic intermediates.
Since initial examples of stoichiometric cyclometalation reactions using Ru, Rh, Pt,
and Pd first appeared in the literature [56], several catalytic processes employing this
strategy have been reported. Owing to its compatibilitywith a broad scope of directing
groups and its ability to functionalize both sp
2
and sp
3
C-H bonds, a preference for
Pd(II) catalysis has emerged [1l]. Lewis basic functional groups including, but not
limited to, pyridines, oxime ethers, ketones, amides, and oxazolines have all been
employed in these transformations. One should note, however, that while this strategy
efficiently overcomes the hurdle of C-H bond selectivity in targets containing
multiple potential reaction sites, its application in the synthesis of complex natural
products has been less forthcoming. This may be attributed to the nature of some of
these directing groups that may be irremovable, such as pyridine, and unfortunately
not desired in the final target. Significant strides are currently being made to develop
directing groups that may be easily removed or transformed into other desirable
functional groups [10,45].
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