BINAP with 1-hydroxycyclopentyl groups (1d) was com-
parable to BINAP, while the 4,4′-BINAP with diethylphos-
phonate ester groups (1c) performs slightly better than
BINAP. Ru precatalyst 2b derived from 4,4′-(TMS)2-BINAP
gave the best results: a variety of R-phthalimide ketone
substrates 3b-g were hydrogenated with complete conver-
sion and very high ee values of 95.6-98.4% under 1500 psi
of H2 in EtOH at 80 °C over a period of 72 h. This level of
enantioselectivity is better than that afforded by BINAP but
slightly lower than those reported by Zhang et al. using
TunePhos-derived Ru catalysts. Interestingly, the influence
of the 4,4′-substituents on BINAP seen here is different from
our earlier results on asymmetric hydrogenation of â-aryl
â-ketoesters and aromatic ketones.6 For the asymmetric
hydrogenation of â-aryl â-ketoesters and aromatic ketones,
the bulky substituents on the 4,4′-positions of BINAP
indiscriminatingly led to ee enhancement. The asymmetric
hydrogenation of R-phthalimide ketones seems to intricately
depend on other factors such as the dihedral angle of the
biaryl diphosphines.10
Encouraged by the positive 4,4′-effects of 1b on the
asymmetric hydrogenation of R-phthalimide ketones, we
examined its utility in the asymmetric hydrogenation of 1,3-
diaryl diketones. Asymmetric hydrogenation of 1,3-diketones
is one of the simplest and most efficient ways to synthesize
enantiopure 1,3-diols, which serve as important chiral
synthons.8 Although there are numerous reports on highly
enantioselective hydrogenations of 1,3-dialkyl diketones,11
the asymmetric hydrogenation of 1,3-diaryl diketones is
significantly more challenging with the notable exception
of a ferrocene-based chiral phosphine (Taniaphos) reported
by Knochel et al.12-14
Table 2. Asymmetric Hydrogenation of 1,3-Diaryl Diketonesa
(R, R′)
5a (H, H)
cat.
ee %
46
de %
88
cat.
ee %
de %
2b
2c
2b
2b
2b
2b
2b
2b
2b
>99
99
99
>99
>99
99
>99
>99
>99
>99
94
94
95
>99
92
97
97
99
2a
5b (4-Me, 4′-Me)
5c (3-Me, 3′-Me)
5d (2-Me, 2′-Me)
5e (4-Cl, 4′-Cl)
5f (4-Me, H)
2a
2a
2a
2a
2a
2a
2a
50
38
80
46
50
45
43
83
76
90
73
80
80
71
5g (4-Cl, H)
5h (4-Me, 4′-Cl)
a All of the reactions were carried out at 50 °C with 0.5 mol % catalyst
under 1500 psi of hydrogen in 40 h, and the ee values were determined by
HPLC on a Diacel Chiralcel OD or OJ or Chiralpak AD column (see
Supporting Information). All conversions were >95% as judged by the
integrations of the NMR spectra for the crude products. For unsymmetrical
diols, de stands for the excess of homochiral isomers over heterochiral
isomers.
We have also compared the effectiveness of 2a and 2b in
the asymmetric hydrogenation of several symmetrical and
unsymmetrical 1,3-diaryl diketones 5b-h under identical
conditions. As shown in Table 2, precatalyst 2b gave ee’s
and de’s much higher than those of 2a for all of the
symmetrical and unsymmetrical 1,3-diaryl diketones. The
ee’s are 99% or higher for all of the substrates with different
substitution patterns on the aryl group. The para-substituents
however seem to slightly deteriorate the de’s in these
reactions. When the hydrogenation of 5b with precatalyst
2b was stopped after 5 h, the reaction mixture contained 60
mol % of hydroxyketone intermediate (93% ee), 35 mol %
of diol 6b (98% ee, 92% de), and <5 mol % of diketone
2b. This control experiment seems to indicate that the slightly
low de’s observed for the para-substituted diketones are a
result of the lower enantio-differentiation during the diketone
hydrogenation to the hydroxyketone intermediate (but not
during the hydrogenation of hydroxyketones to diols). To
our knowledge, this is the first Ru catalyst for the hydroge-
nation of a broad spectrum of 1,3-diaryl diketones with
excellent ee’s and de’s.
Given the structural similarity of 1,3-diaryl diketone and
â-aryl â-ketoester, we believe that the ee enhancement of
this reaction by the bulky 4,4′-substituents on BINAP occurs
via a similar mechanism to the asymmetric hydrogenation
of â-aryl â-ketoester. Molecular modeling using PC Spartan
indeed shows that the aryl groups of both Ru-coordinated
1,3-diaryl diketones and hydroxyketone substrates experience
significant repulsive interactions with the bulky TMS groups
on the 4,4′-positions of 1b in their disfavored transition states
(see Supporting Information).
The asymmetric hydrogenation of dibenzoylmethane was
first tested with 2a as the precatalyst. With 0.5 mol % of
(R)-2a in anhydrous methanol, dibenzoylmethane was com-
pletely hydrogenated to (S,S)-enriched 1,3-diphenylpropane-
1,3-diol with 46% ee and 88% de under 1500 psi of hydrogen
at 50 °C (Table 2). In comparison, both ee’s and de’s were
significantly enhanced when 4,4′-substituted BINAPs were
used in place of BINAP. For example, dibenzoylmethane
was completely hydrogenated to 1,3-diphenylpropane-1,3-
diol in 99% ee and 99% de with 2b and in 99% ee and 94%
de with 2c, respectively.
(11) (a) Roos, G. H. P.; Donovan, A. R. Tetrahedron: Asymmetry 1999,
10, 991. (b) Ito, K.; Harada, T.; Tai, A. Bull. Chem. Soc. Jpn. 1980, 53,
3367. (c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc.
1988, 110, 629. (d) Chen, Y. C.; Wu, T. F.; Deng, J.-G.; Liu, H.; Cui, X.;
Zhu, J.; Jiang, Y. Z.; Choi, M. C. K.; Chan, A. S. C. J. Org. Chem. 2002,
67, 5301.
(12) (a) Lotz, M.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
41, 4708. (b) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel,
P. Angew. Chem., Int. Ed. 1999, 38, 3212. (c) Tappe, K.; Knochel, P.
Tetrahedron: Asymmetry 2004, 15, 91.
(13) ,3-Diaryl diketones were reduced by sodium borohydride with
excellent ee’s but low de’s with chiral ketoiminato cobalt complexes as
catalysts. See: Yamada, T.; Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno,
T.; Ohtsuka, Y.; Miyazaki, D.; Mukaiyama, T. Chem. Eur. J. 2003, 9, 4485.
(14) ,3-Diaryl diketones have also been successfully reduced to chiral
1,3-diols by Ru-catalyzed transfer hydrogenation reactions developed by
Ikariya et al. See: (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem.
2002, 67, 1712. (b) Cossy, J.; Eustache, F.; Daiko, P. I. Tetrahedron Lett.
2001, 42, 5005.
In summary, we have successfully applied 4,4′-substituted
BINAPs in the asymmetric hydrogenation of protected amino
ketones and 1,3-diaryl diketones. By taking advantage of
bulky 4,4′-substituents on the BINAP moiety, excellent ee’s
Org. Lett., Vol. 7, No. 3, 2005
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