Chemistry Reference
In-Depth Information
Br
OMe
Br
CuOTf/
240
OMe
N
t
BuOOH, decane
50°C, 2 days
*
N
238
239
241
61% yield
74% ee
O
O
N
N
N
240
Ph
Ph
Scheme 4.62.
Cu - pyBox catalyzed asymmetric C -H bond functionalization.
was reported by Li and coworkers in which alkynyl tetrahydroisoquinoline derivatives
were prepared by a copper-pyBox catalyzed double C-H insertion process called cross-
dehydrogenative coupling (CDC) (Scheme 4.62) [282]. The reaction appears to be a
C-H activation process, which selectively functionalized the 1-methylene group of the
tetrahydroisoquinoline system
239
in 61% yield and 74% ee. In general, this reaction
proceeded in 48-72% yield in 26-74% ee with various alkynes and aryl substituents. The
ortho-methoxy substituent was necessary to achieve high asymmetric induction [282].
A signifi cant advance in selective C-H functionalization was reported by Sames and
coworkers who used a Pt(II)-catalyzed process in the synthesis of (− ) - rhazinilam (
244
),
an antimitotic agent (Scheme 4.63) [19]. Typically, C-H functionalization of complex
molecules is diffi cult to achieve in a selective manner because of functional group intol-
erance and a preference for activation of sp
2
C -H bonds by many transition metal
complexes [283,284]. Many of these problems were overcome in this example. In the
dehydrogenation event, a hydrocarbon fragment (ethyl group) in the complex selectively
undergoes C-H activation. With the use of a chiral ligand on the metal, remarkable
selectivity for functionalization of the
pro
-
R
-ethyl group was observed. For a model
reaction, the four-step sequence shown in Scheme 4.63 was achieved in 60% yield.
However, the yields varied greatly when chiral ligands were used. A range of 62-70%
ee was observed for the transformation. This work culminated in the asymmetric total
synthesis of (−)-rhazinilam [283,284]. Although this example is not catalytic, it demon-
strates that enantioselectivity can be induced by a chiral metal complex in such reactions
and shows great promise for further development of the method.
Bergman, Ellman, and others reported the fi rst highly enantioselective intramolecu-
lar alkylation of ketimines [285,286]. The mechanism of this reaction is believed to
involve substrate-directed oxidative addition of rhodium into the arene C- H bond
[13,285,286]. This methodology affords new cyclization strategies to form six- and fi ve-
membered rings. With the use of a chiral phosphoramidite ligand
246
(Scheme 4.64 ),
the substrate
245
readily undergoes enantioselective cyclization onto the aryl ring to
form the corresponding substituted dihydrobenzofuran or indane in up to 94% yield and
with impressive levels of enantiocontrol (95-96% ee). The methodology has been used
for the synthesis of biologically active compounds, such as dihydropyrroloindoles
(Scheme 4.65) [285,286]. In the key step of the synthesis of protein kinase C inhibitor
