Biomedical Engineering Reference
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(10 mol%), phosphine ligand Ph-DavePhos (40mol%), and K
2
CO
3
(2 equiv) in DMA
at 130
C afforded the desired product
12
and dechlorinated by-product
13
, the latter
being favored. Further optimization revealed an important relationship between the
ligand to palladium ratio and the formation of
. Indeed, decreasing this ratio from4:1
to 1:1 led to a significant increase in the formation of cyclized product
13
12
over reduced
product
, however, at the cost of loss in conversion (Scheme 1.4, entries 1 and 2). A
simple ligand change from Ph-DavePhos to DavePhos not only increased the con-
version to 64%but also improved the
13
ratio to 12:1 (Scheme 1.4, entry 3). Finally,
raising the reaction temperature to 145
C gave 94% conversion and a 14:1 ratio of
12
/
13
12
/
13
in 73% isolated yield as a 10:1 mixture of atropisomers (Scheme 1.4,
entry 4). MOM cleavage gave
, providing
12
in 94% yield and 97% ee, an intermediate that had
previously been converted to allocolchicine (
14
7
) by Wulff and coworkers [22].
1.3. PALLADIUM(0)-CATALYZED INTRAMOLECULAR
ALKENYLATION OF sp
2
C-H BONDS
The direct coupling of an alkenyl (pseudo)halide with a simple (hetero)arene C-H
bond to produce an alkenylated (hetero)arene has been investigated due to its
complementary relationship with the Heck reaction [23,24]. Pd(0)-catalyzed alkeny-
lation of sp
2
C-H bonds can be paralleled to direct arylation reactions where the aryl
(pseudo)halide has been replaced by a vinyl (pseudo)halide coupling partner
(see Section 1.2).
In 2002, Hughes and Trauner reported the total synthesis of (
)-frondosin B
15
using a palladium-catalyzed intramolecular alkenylation of a benzofuran C-H bond
as the key cyclization step (Scheme 1.5) [25]. The frondosin family of marine
terpenoids had generated significant attention owing to their potential use as inhibitors
of inflammatory response, for example, in the treatment of rheumatoid arthritis [26],
and their HIV inhibitory properties [27]. Frondosin B represents an appealing
synthetic challenge not only due to its interesting biological activity but also due
to its unusual tetracyclic core. The latter features a 2,3-disubstituted benzofuran
component, a seven-membered ring, and a tetrasubstituted alkene. Hughes and
Trauner chose to join the benzofuran and alkene moieties, simultaneously generating
MeO
Li
1. Pd(PPh
3
)
4
(2.5 mol%)
CuI (5 mol%), Et
3
N (6 equiv)
CH
3
CN, reflux, 22 h
2. TFA, CH
2
Cl
2
, rt
3. K
2
CO
3
, MeOH, reflux
4. MsCl, Et
3
N, THF, 0°C
NaI, acetone, reflux
OMe
OMe
1.
HMPA/THF, -78°C to rt
2. Ion-exchange resin
acetone/H
2
O, reflux
3. NaHMDS, THF, rt
then PhNTf
2
64%
MeO
OMe
H
OAc
I
OTf
Br
+
H
O
O
17
Me
O
Me
19
16
PMBO
Me
67%
18
(ee = 91%)
HO
MeO
1. MeMgBr, THF, -78°C to rt
2. TiCl
4
(1 equiv), Me
2
Zn (2 equiv)
CH
2
Cl
2
, -78°C to rt
3. NaSEt, DMF, reflux
74%
Pd(PPh
3
)
4
(5 mol%)
i
-Pr
2
NEt (4 equiv)
DMA, 90°C, 36 h
O
O
O
70%
Me
Me
)-Frondosin B
15
(
20
−
SCHEME 1.5
Synthesis of (
)-frondosin B by Hughes and Trauner.
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