Chemistry Reference
In-Depth Information
250
, indole
248
was cyclized to the tricyclic compound
249
in 61% yield and 90% ee
[287] . The fi rst total synthesis of (+)-lithospermic acid employed similar methodology,
but a chiral auxiliary approach was necessary to achieve high enantioselectivity [286].
Recently, the asymmetric synthesis of (
)-incarvillateine was accomplished using a dia-
stereoselective cyclization as one of the key steps based on the intramolecular C- H
activation protocol [288]. Two of the three stereogenic centers in an intermediate were
controlled in this reaction, which gave up to 64% de in the critical step [288].
The scope of the aforementioned cyclization protocol was recently expanded by
demonstrating that 1,2-disubstituted and 1,1,2-trisubstituted alkenes can readily undergo
the reaction while retaining high levels of enantioinduction [289]. The reactions gener-
ally proceeded in 40-96% yield and 70-96% ee with various alkyl and phenyl substitu-
tion patterns. Some examples are shown in Figure 4.20 (
251a - d
and
253a - b
) along with
the chiral ligands
252
and
254
that were employed [289]. Only
syn
- products were
observed regardless of the confi guration of the starting alkene. This allowed for the use
of
E
/
Z
mixtures of alkenes as starting materials [289]. A range of variously substituted
chiral indanes, dihydrobenzofurans, and dihydropyrroloindoles can be obtained with this
technology, a potentially powerful tool for the asymmetric synthesis of biologically
active compounds [289] .
These examples highlight the power of the intramolecular alkylation methodology as
they demonstrate that a catalytic aromatic C-H bond activation reaction is feasible and
that high levels of enantiocontrol can be achieved in such systems.
Pd(II)-catalyzed enantioselective activation of sp
2
C -H bonds with monoprotected
amino acids as chiral ligands was reported recently by Yu and coworkers [290]. These
results represent a signifi cant addition to emerging asymmetric methodologies based on
traditional C-H activation. By employing the protected amino acid
257
(Table 4.14 ) in
catalytic amounts with Pd(OAc)
2
, the desymmetrization of triaryl system
255
was
achieved with various boronic acids to form
258
in 43 - 96% yield and 54 - 95% ee [290] .
ā
Me
NBn
Chiral ligand:
R
O
O
P
N
251
R =
O
a
b
c
d
Me
Et
i
-Bu
Ph
82% yield, 90% ee
76% yield, 91-92% ee
69% yield, 90% ee
93% yield, 87% ee
252
Me
NBn
Chiral ligand:
Me
Ph
Me
O
R'
P
N
O
O
Me
253
R' =
Ph
a
b
Me
Ph
80% yield, 91-93% ee
50% yield, 89-90% ee
254
Figure 4.20.
Expanded scope of intramolecular hydroarylation.
