Biomedical Engineering Reference
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the seven-membered ring, through an intramolecular palladium-catalyzed carbon-
carbon bond-forming reaction (Scheme 1.5). Cyclization precursor
16
was generated
in seven steps and in enantiomerically pure form from aryl bromide
17
and alkyne
18
via alkyl iodide
. The key carbon-carbon bond-forming reaction was effected by
syringe pump addition of vinyl triflate
19
, over 3 h, to a preheated (90
C) solution of
Pd(PPh
3
)
4
(5mol%) and
i
-Pr
2
NEt (4 equiv) in DMA (
N
,
N
-dimethylacetamide,
0.01M). After stirring for 36 h at 90
C, the desired tetracycle
16
was isolated in
70% yield. Although the adjacent stereocenter had not racemized under these con-
ditions, partial racemization was found to occur at higher reaction temperatures.
Several experiments provided insight into the mechanismof this transformation.
The use of various Lewis acids, including ZnCl
2
, MgBr
2
, and BF
3
20
OEt
2
, in control
experiments ruled out the possibility of a conjugate addition/elimination process for
carbon-carbon bond formation. The potential for nucleophilic catalysis by triphenyl-
phosphine or
i
-Pr
2
NEt was also excluded, indicating that oxidative addition of the vinyl
triflate to Pd(0) must occur for C-H bond functionalization to proceed. Three potential
mechanisms were discussed for the latter event (Scheme 1.6): a Heck pathway (route a),
nucleophilic attack of the electron-rich benzofuran onto the Pd(II) intermediate
21
(S
E
Ar, route b; see also Scheme 1.2a), and oxidative addition of the C-H bond to
generate a Pd(IV) intermediate (route c). On the basis of the complete retention of
stereochemistry at the proximal stereocenter, the authors excluded the Heck pathway,
which would presumably have led to racemic product. However, MacMillan and
coworkers have recently reevaluated the mechanismof this transformation (see below)
and concluded that a Heck pathway cannot be excluded at this time [28].
At this point, it should be noted that the stereocenter of (
)-frondosin B
15
was inadvertently misassigned by Hughes and Trauner. Several syntheses have
independently confirmed that (
)-frondosin B is in fact of (
S
)-configuration instead
of (
R
)-configuration as shown above [28,29]. MacMillan and coworkers have
proposed that the inversion of configuration at the stereogenic center in Trauner's
and Hugues' synthesis must have occurred during the direct alkenylation key step.
Presuming that this transformation proceeds through a Heck pathway (route a,
Scheme 1.6), MacMillan and coworkers invoke a selective protonation of the enol
ether intermediate via stereorelay from the benzofuran C3 stereogenic center to
yield (
S
)-
20
[28].
H
H
syn
addition
syn
β
-H elimination
aromatization
O
O
O
Heck (a)
PdX
H
Me
Me
Me
H-Pd-X
rac-
20
X
X
H
H
H
X
Pd
nucleophilic
attack
Pd(0)
Pd
O
O
O
S
E
Ar (b)
Me
Me
Me
reductive
elimination
16
21
Pd
deprotonation
O
O
X
C-H
oxidative
addition
H
Me
Me
Pd(0)
X
H
Pd
(
R
)-
20
O
via
Pd(IV) (c)
Me
SCHEME 1.6
Proposed mechanisms for Pd(0)-catalyzed benzofuran alkenylation in the
synthesis of (
)-frondosin B.
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