Biomedical Engineering Reference
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(1.5 equiv) in
t
-BuOH at 110
C over 36 h in 85% yield. This reaction was performed
on a 4 g scale to afford the desired product as a single diastereomer, demonstrating the
robustness of thismethod.With the challengingTrpC6-LeuC
b
bond formed, the total
synthesis of celogentin C (
55
) was completed in 18 steps using simple amino acid
building blocks.
Mechanistically, this C-H bond functionalization has been proposed to proceed
via a Pd(II)/Pd(IV) pathway [57,58]. Chelation of electrophilic Pd(II) to the amino-
quinoline auxiliary promotes regio- and diastereoselective C-H bond cleavage,
generating the sterically favored
trans
-palladacyclic complex
. An analogous
Pd(II) species had previously been isolated by Corey and coworkers in their
evaluation of the sp
3
C-H bond acetoxylation of
a
-amino acid derivatives [58]
i
.
Oxidative addition of the aryl iodide to
60
60
is then proposed to generate Pd(IV)
intermediate
, which can reductively eliminate the desired product with concom-
itant catalyst regeneration via salt metathesis in the presence of AgOAc.
Auxiliary-directed Pd(II)-enabled sp
3
C-H bond functionalization was relied
upon in two key carbon-carbon bond forming events in the synthesis of the teleocidin
B4 core (
61
) by Sames and coworkers, the auxiliary-directed Pd(II)-enabled sp
3
C-H
bond functionalization relied upon two key carbon-carbon bond forming events
(Scheme 1.16) [61]. Schiff base
62
was chosen as a key synthetic intermediate owing
to its ability to chelate palladium and direct cyclometalation of the adjacent
tert
-butyl
group. More important, this intermediate tolerates directing group removal via
hydrolysis, an important feature since the latter is absent from the desired product.
A screening of metal salts revealed that PdCl
2
(1.2 equiv) in the presence of NaOAc
(3 equiv) furnished cyclometalated product
64
in 75% yield. The
ortho
-methoxy
substituents in the directing group appeared to play a pivotal role as no cyclopalla-
dated product was detected in their absence. Key to the stability of complex
63
is
the lack of a
b
-hydrogen atom that could lead to the formation of undesired olefin
by-products. This intermediate underwent transmetalation with boronic acid
64
65
OMe
OMe
OMe
B(OH)
2
(4 equiv) (
E
/
Z
= 3:1)
Ag
2
O (1.1 equiv)
PdCl
2
(1.2 equiv)
NaOAc (3 equiv)
OMe
OMe
OMe
65
6 steps
45%
N
N
N
AcOH, 100°C
75%
DMF, 90°C, 8.5 h
82-86%
Pd
O
O
O
Me
H
Me
Me
63
64
66
(
E
/
Z
= 3:1)
OMe
OMe
OMe
OMe
OMe
OMe
PdCl
2
(1.2 equiv)
NaOAc (3 equiv)
AcOH, 70°C
CO (35-40 atm)
MeOH, rt, 12 h
MsOH
N
N
N
CH
2
Cl
2
-78°C to rt
Pd
MeO
CO
2
Me
O
Me
O
Me
H
83%
69
68
(dr = 6:1)
67
O
OMe
OH
NH
3 steps
39%
OH
Me
N
Silica gel
CHCl
3
/Et
2
O
NH
O
N
O
65% (3 steps)
H
Teleocidin
B4
70
(obtained in pure
diastereomeric form after recrystallization)
Teleocidin B4 Core
62
SCHEME 1.16
Synthesis of teleocidin B4 by Sames and coworkers.
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