C O M M U N I C A T I O N S
Table 2. Ru-Catalyzed Asymmetric Transfer Hydrogenation of
Ketones 5a-q Using Ligand 2
a
References
entry
ketone
base
ligand:Ru
time (h)
conversion (%)
ee (%)
(1) For hydrogenation of ketones, see: (a) Ohkuma, T.; Ooka, H.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675-2676. (b)
Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000,
122, 6510-6511. (c) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008-
2022. (d) Ohkuma, T.; Koizumi, M.; Mu n˜ iz, K.; Hilt, G.; Kabuto, C.;
Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508-6509. (e) Ohkuma, T.;
Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org. Lett. 2004, 6, 2681-
t
1
2
3
4
5
6
7
8
9
5a
5a
5a
5b
5b
5c
5c
5d
5e
5e
5f
KO Bu
4
28
20
40
26
40
40
96
26
28
16
22
16
26
16
26
22
6
91
88
93
83
90
63
91
65
100
100
96
98
98
100
65
56
99
97
99
96
83
97
96
97
97
98
99
99
93
93
95
96
96
96
95
95
97
93
93
98
99
99
90
79
76
82
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
2.5
2.5
2.5
2.5
2.5
2.5
2.5
4
2683. For transfer hydrogenation of ketones, see: (f) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (g) Yamakawa, M.;
Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818-2821.
(h) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org. Lett.
2002, 4, 4373-4376.
t
KO Bu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NaOH
2.5
4
(
2) For other leading references of hydrogenation of ketones, see: (a) Li, X.;
Chen, W.; Hems, W.; King, F.; Xiao, J. Org. Lett. 2003, 5, 4559-4561.
(b) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan, H.-F.;
Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404-4405. (c) Wu, J.; Ji,
J.-X.; Guo, R.; Yeung, C.-H.; Chan, A. S. C. Chem. Eur. J. 2003, 9, 2963-
t
KO Bu
5f
NaOH
NaOH
NaOH
NaOH
2.5
2.5
2.5
2.5
4
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
2
968. (d) Hu, A.; Ngo, H. L.; Lin, W. Org. Lett. 2004, 6, 2937-2940.
e) Genov, D. G.; Ager, D. J. Angew. Chem., Int. Ed. 2004, 43, 2816-
819. (f) Burk, S.; Franci o` , G.; Leitner, W. Chem. Commun. (Cambridge)
(
2
t
KO Bu
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
2005, 3460-3462. (g) Jing, Q.; Zhang, X.; Sun, J.; Ding, K. AdV. Synth.
Catal. 2005, 347, 1193-1197. For recent reviews, see: (h) Blaser, H.-
U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth.
Catal. 2003, 345, 103-151. (i) Clapham, S. E.; Hadzovic, A.; Morris, R.
H. Coord. Chem. ReV. 2004, 248, 2201-2237. (j) Tang, W.; Zhang, X.
Chem. ReV. 2003, 103, 3029-3069. For recent transfer hydrogenation of
ketones, see: (k) Li, X.; Chen, W.; Hems, W.; King, F.; Xiao, J.
Tetrahedron Lett. 2004, 45, 951-953. (l) Li, X.; Wu, X.; Chen, W.;
Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321-3324. (m)
Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett. 2003, 5,
22
22
16
40
26
26
a
Reaction conditions as in Table 1. When (R,R)-2 is used, the products
2103-2106. (n) Hamada, T.; Torii, T.; Onishi, T.; Izawa, K.; Ikariya, T.
have the (R)-configuration.
J. Org. Chem. 2004, 69, 7391-7394. (o) Brandt, P.; Roth, P.; Andersson,
P. G. J. Org. Chem. 2004, 69, 4885-4890. (p) Geldbach, T. J.; Dyson,
P. J. J. Am. Chem. Soc. 2004, 126, 8114-8115. (q) Wu, X.; Li, X.; King,
F.; Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407-3411. (r) V a¨ stil a¨ , P.;
Wettergren, J.; Adolfsson, H. Chem. Commun. (Cambridge) 2005, 4039-
intermediate in the synthesis of the NK1 receptor antagonist
Aprepitant (Table 2, entry 17).11 This reduction was previously
performed by the Merck group using (1S,2R)-cis-amino-2-indanol
as the chiral ligand in a Ru-catalyzed Noyori-type process (ee )
4
041. (s) Dong, Z.-R.; Li, Y.-Y.; Chen, J.-S.; Li, B.-Z.; Xing, Y.; Gao,
J.-X. Org. Lett. 2005, 7, 1043-1045. (t) Guo, R.; Elpelt, C.; Chen, X.;
1
1
Song, D.; Morris, R. H. Chem. Commun. (Cambridge) 2005, 3050-3052.
91%), the Corey borane-based reduction leading to 93-95% ee.
(
u) Baratta, W.; Herdtweck, E.; Siega, K.; Toniutti, M.; Rigo, P.
The present Ru-based catalyst system is the first one composed
Organometallics 2005, 24, 1660-1669. For recent reviews, see: (v)
solely of P-ligands for ketone reduction with high stereoselectivity.
Although detailed structural and mechanistic studies remain to be
carried out, we have observed an unusual phenomenon which is
worthy of mention: Upon extending the reaction time to some
degree, there seems to be very little, if any, erosion of enantiopurity
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-2061.
(
w) Everaere, K.; Mortreux, A.; Carpentier, J.-F. AdV. Synth. Catal. 2003,
3
45, 67-77.
(
3) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Mu n˜ iz,
K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288-8289.
(4) Schlatter, A.; Kundu, M. K.; Woggon, W.-D. Angew. Chem., Int. Ed. 2004,
3, 6731-6734.
4
of the products, which may be expected due to the reversibility of
transfer hydrogenation in 2-propanol.1,2 In contrast to other transfer
(5) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004,
1
26, 986-987. (b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills,
hydrogenation systems in which reduction needs to be terminated
at the optimal time, the present system appears to be relatively
insensitive in this regard. A preliminary examination of the structure
of the (pre)catalyst in 2-propanol points to several Ru species.
In summary, the combination Ru/2 constitutes the most general
catalyst system for the asymmetric reduction of aryl/alkyl and alkyl/
alkyl ketones known to date. Since BINOL is currently one of the
cheapest chiral auxiliaries commercially available, the method is
of industrial interest. Further optimization and illumination of the
source of enantioselectivity are goals for the future.
M. J. Am. Chem. Soc. 2005, 127, 7318-7319.
(6) (a) Xu, Y.; Alcock, N. W.; Clarkson, G. J.; Docherty, G.; Woodward, G.;
Wills, M. Org. Lett. 2004, 6, 4105-4107. (b) Xu, Y.; Clarkson, G. C.;
Docherty, G.; North, C. L.; Woodward, G.; Wills, M. J. Org. Chem. 2005,
70, 8079-8087.
(7) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J.
Am. Chem. Soc. 1987, 109, 7925-7926. (b) For a review of metal hydride
reductions, see: Itsuno, S. Org. React. 1998, 52, 395-576.
(
8) (a) Reetz, M. T.; Gosberg, A.; Goddard, R.; Kyung, S.-H. Chem. Commun.
Cambridge) 1998, 2077-2078. (b) Reetz, M. T. Pure Appl. Chem. 1999,
71, 1503-1509. (c) Reetz, M. T.; Gosberg, A. Int. Pat. Appl. WO 00/
(
1
4096, March 16, 2000. (d) Reetz, M. T.; Moulin, D.; Gosberg, A. Org.
Lett. 2001, 3, 4083-4085.
(
9) See also: van der Vlugt, J. I.; Paulusse, J. M. J.; Zijp, E. J.; Tijmensen,
Acknowledgment. We thank the Fonds der Chemischen In-
dustrie for generous support.
J. A.; Mills, A. M.; Spek, A. L.; Claver, C.; Vogt, D. Eur. J. Inorg. Chem.
2004, 4193-4201.
(
10) Reetz, M. T.; Li, X. German Patent Appl. DE-A 102005025797.6.
Supporting Information Available: Typical procedures for asym-
metric transfer hydrogenation; complete ref 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Brands, K. M. J.; et al. J. Am. Chem. Soc. 2003, 125, 2129-2135.
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