Biomedical Engineering Reference
In-Depth Information
(a)
Electrophilic aromatic substitution (S
E
Ar) mechanism
X
Ar
Pd
X
PdAr
H
PdAr
Ar
Y
Y
Y
Y
H
electron-rich
arene
Wheland
intermediate
X
H
Pd(0)
(b)
Concerted metalation-deprotonation (CMD) mechanism
Ar
Pd
X
Ar
‡
Ar
Pd
OOCR
Pd
O
H
PdAr
Ar
R
H
O
electron-deficient
or electron neutral
arene
RCOO
H
Pd(0)
CMD transition-state
SCHEME 1.2
Proposed mechanisms for direct arylation.
The mechanism of C-H bond cleavage in these processes has been extensively
debated in the literature, with two pathways having received significant attention.
In direct arylation reactions featuring electron-rich (hetero)aromatic substrates, an
electrophilic aromatic substitution (S
E
Ar) mechanism is typically proposed involving
a Friedel-Crafts process, where the nucleophilic (hetero)arene reacts with the
electrophilic metal center (Scheme 1.2a
[11]. On the other hand, electron-deficient
and electron-neutral arenes have been proposed to react through a concerted
metalation-deprotonation (CMD) mechanism, involving C-H deprotonation with
concomitant (hetero)arene metalation (Scheme 1.2b) [12]. It should also be noted that
recent studies have demonstrated that this CMD pathway may also be operative in
direct arylation reactions featuring electron-rich arenes [13].
With the advances made in the field of direct arylation over the last decade,
several groups have used this strategy to complete the syntheses of natural product
targets [14]. Selected examples will be discussed to highlight different synthetic
strategies and the resulting developments that have been made in this area.
Owing to its significant antifungal and anti-HIV properties, the pradimicin-
benanomicin class of antibiotics has sparked the interest of the synthetic community
[15]. Members of this class of compounds contain a benzo[
a
]naphthacenequinone
core, an amino acid, and a disaccharide moiety. In 1999, Suzuki and coworkers used a
clever direct arylation strategy to access pradimicinone
)
, the common aglycone to this
class of antibiotics (Scheme 1.3) [16]. Thus, by temporarily tethering arene
1
2
and aryl
iodide
through an esterification, the sterically hindered biaryl bond was formed using
an intramolecular direct arylation reaction. Optimization studies led to the use of Pd
(OAc)
2
(30mol%), PPh
3
(60mol%), andNaOPiv (3 equiv) in
N
,
N
-dimethyl-acetamide
(DMA) at 110
C to achieve the desired transformation [17]. The crude product was
then directly reduced to
3
with NaBH
4
as the authors noted that it was readily
hydrolyzed during purification by silica gel chromatography. Overall, biaryl
5
was
prepared in 86% yield using this two-step protocol. Although the catalyst loading is
relatively high (30mol%), this noteworthy synthesis represents one of the earliest
complex examples in the field [18,19]. Indeed, the direct arylation protocol was
performed in the presence of multiple functional groups, including an aryl chloride, to
selectively produce the highly sterically congested biaryl bond in excellent yield.
Allocolchicine (
5
7
), a potential therapeutic derivative of the microtubule
depolymerizing agent colchicine, represents an interesting synthetic target for the
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