Kagan and co-workers in 1980,[14] who employed a RhI-
DIOP[15] catalyst for the hydrosilylation of p-methylbenzo-
phenone in 26% ee. Brunner and Kuerzinger reported a re-
lated reaction in 1988[16] that used rhodium complexes to
afford the product in 37% ee.
Over the last decade, the application of copper hydride
complexes that were ligated by enantiomerically pure lig-
ACHTUNGTRENNUNGands in asymmetric hydrosilylation reactions has gained
a considerable amount of attention owing to the advantages
of using inexpensive metals and mild reaction conditions.[17]
Thus, a variety of copper-based catalytic hydrosilylation sys-
tems have been exploited for effecting the stereoselective
reduction of a wide range of simple ketones,[18–22] imines,[23]
as well as the 1,4-reduction of various a,b-unsaturated Mi-
chael acceptors,[24] with moderate to excellent enantioselec-
tivities. With respect to the prochiral diaryl ketonic sub-
strates, in 2005, we reported a CuF2/dipyridylphosphine
(Figure 2, P-Phos 4a or Xyl-P-Phos 4b)[25]/PhSiH3 system
was realized in air by using a copper(II)-dipyridylphosphine
(4a or 4b) catalyst. This catalyst system also exhibited high
efficiency and remarkable practical potential in the stereose-
lective hydrosilylation of a wide range of aryl alkyl and het-
eroaromatic ketones in good to excellent ee values (up to
97%) with a substrate-to-ligand (S/L) molar ratio of up to
50000.[30] Herein, we report the extension of this catalyst
system to the hydrosilylation of diaryl and aryl heteroaryl
ketones. Copper-catalyzed reactions proceeded smoothly in
air and gave access to structurally diverse alcohols in up to
96% ee. Furthermore, this process was applied to the asym-
metric synthesis of optically enriched orphenadrine (1) and
neobenodine (2), which possess potent anticholinergic and
antihistaminic activities.[1a,b]
Results and Discussion
Optimization of the copper-catalyzed reaction conditions: In
an initial study, 2-chlorobenzophenone (5a) was used as
a model substrate (Table 1). When compound 5a was mixed
with ligand (S)-4a (0.4 mol%), CuCl (5 mol%), and PMHS
(4 equiv) as the reductant in toluene at 08C in air, only 57%
conversion into (R)-6a (82% ee) was observed after 1.2 h.
Consistent with previous reports,[24d,e,k,31] the rate of reaction
was increased by adding certain amounts of sterically de-
manding alcohol tBuOH to the reaction mixture (Table 1, cf.
entries 2 and 1). Comparison studies showed that the further
introduction of tBuONa (5 mol%) into the catalyst system
allowed for the complete transformation of diarylketone 5a
into the desired alcohol with no diminution of the ee either
in air or under a N2 atmosphere (Table 1, entries 3 and 4
versus entry 2).[27,29,30] Moreover, less than 40% conversion
was obtained only if tBuONa was added in the absence of
alcohol, although the ee value remained unchanged
(Table 1, entries 5 and 3).
Figure 2. Dipyridylphosphine ligands.
which, to the best of our knowledge, allowed the first highly
asymmetric hydrosilylation of ortho-substituted benzophe-
nones with good to excellent enantioselectivity (up to
98%).[26] In 2008, Lee and Lipshutz[27] demonstrated that
CuH complexed with DTBM-SEGPHOS or DM-SEG-
PHOS[28] were efficient catalysts for the asymmetric hydrosi-
lylation of a broad range of ortho-substituted benzophenone
derivatives and selected aromatic-heteroaromatic ketones in
good to excellent yields and enantioselectivities. In a similar
manner to other reduction methods,[6a,b,13] meta- and para-
substituted benzophenones were converted into their corre-
sponding alcohols with low or moderate ee values[26,27] be-
cause of the lack of asymmetric bias in the transition state.
In addition, upon exposure to the copper-catalyzed hydrosi-
lylation conditions, diaryl ketone substrates often showed in-
ferior reactivity to aryl alkyl ketones under otherwise identi-
cal conditions.
Very recently, we established a new set of reaction condi-
tions to facilitate the copper-catalyzed enantioselective 1,4-
reduction of b-(acylamino)acrylates.[29] In the presence of
stoichiometric polymethylhydrosiloxane (PMHS), a low-cost
and air-stable hydride donor, with tBuONa and tBuOH as
additives, the formation of a range of b-alkyl-b-amino acid
derivatives with high levels of enantiopurity (up to 99%)
The roles of the alcohol and the base in the increased re-
action rate remain unclear at present. It appeared that, in
the initial step of the catalytic cycle, upon combining (S)-P-
Table 1. Effects of additives on the copper-catalyzed hydrosilylation of 2-
chlorobenzophenone (5a).[a]
Entry
Alcohol
Base
Conv. [%][b]
ee [%][c]
1
2
3
–
–
–
57
66
99
99
34
82
78
81
81
82
tBuOH
tBuOH
tBuOH
–
tBuONa
tBuONa
tBuONa
4[d]
5
[a] Reaction conditions: substrate (35 mg, 0.33m in toluene). [b] Conver-
sion was determined by NMR spectroscopy and GC. [c] The ee values
were determined by chiral HPLC analysis; the absolute configuration
was determined by comparison of the retention times with literature data
(see the Supporting Information). [d] Performed under a N2 atmosphere.
&
2
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Chem. Eur. J. 0000, 00, 0 – 0
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