Biomedical Engineering Reference
In-Depth Information
inhibitor, was first synthesized in 2009 by Takahashi and coworkers and an intra-
molecular copper-mediated Ullmann reaction was one among the key steps for
accomplishing this synthesis [87]. The same year Pettit and coworkers devised a
modified synthetic route to the antineoplastic agents combretastatin D2 and dihy-
drocombretastatin D2 [88]. The biaryl ether was formed in the last steps of the
synthesis using CuBr
S(Me)
2
and K
2
CO
3
(or CuMe in pyridine), however, in low
yields (10-25%). The versatile copper-mediated diaryl ether synthesis method was
successfully used by Jahng and coworkers in 2007 to prepare diarylheptanoids
acerogenins C and L, (
)-pterocarine in moderate to good yields
(49-76%) [89]. Earlier, a modified classical Ullmann reaction was used by N
)-galeon, and (
ogr
adi
and coworkers during the total syntheses of acerogenin C and (
)-acerogenin A [90].
In 2008, Natarajan andKumar devised a direct route based on intramolecular Ullmann
cross-coupling to synthesize acerogenins A and C [91]. It is worth noting that in these
cases the reaction can usually be carried out in the absence of ligands; however, a
stoichiometric amount of copper salt is necessary.
In 2000, Zhu and coworkers developed an efficient method basedon the
copper(I) chloride catalysis to synthesize 2,3-dihydrobenzofurans via the cyclization
of aryl halides and primary alcohols [92]. The method was successfully applied by
Jones and coworkers in the asymmetric total synthesis of corsifuran A to circumvent
the problematic racemization process observed under palladium catalysis
(Scheme 3.35) [93]. Indeed, the authors suggested that during the Pd-mediated
reaction, a Pd(II) aryl oxide intermediate could afford, after
þ
b
-hydride elimination,
a reversible Pd hydride species, thus allowing the decrease of the enantioselectivity.
The hypothesis was supported by a similar observation in the corresponding
Pd-catalyzed amination process [94].
Another elegant example of an intramolecular Ullmann cross-coupling
reaction was reported in 2009 by Kobayashi and coworkers in their synthesis of
(
)-flustramine B (Scheme 3.36) [95]. The authors applied their previously reported
method for preparing spirocyclic oxindoles via a one-pot intramolecular Ullmann
reaction followed by a Claisen rearrangement [96]. Using a catalytic amount of CuCl
and 2-aminopyridine (
L12
), 2-iodoindole (
94
) gave rise to the pyranoindole inter-
mediate
that, in turn, over thermal Claisen rearrangement condition followed by an
unusual deprotection of the MOM group under basic conditions, afforded spirocyclic
oxindole
95
98
in 69% yield.
Br
MeO
Pd or Cu
P(
t-
Bu)
2
OMe
OMe
O
Me
2
N
MeO
HO
Corsifuran A
L16
Catalytic system
Base
Solvent
T
(°C)
Reaction outcome
L16
NaO
t
Bu
PhMe
reflux
100% (conversion); 45% ee
Pd
2
(dba)
3
CuCl
-
NaH
PhMe
reflux
76% yield; 100% ee
SCHEME 3.35
Synthesis of corsifuran A by Jones and coworkers.
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