Novel, highly stable, Os(II) arene/TsDPEN complexes for
asymmetric hydrogenation of prochiral substrates
A novel series of catalytically-active Os(II) complexes has been
described by Professors Peter Sadler and Martin Wills and their
team at the University of Warwick, UK. The catalysts have been
shown to out-perform existing Ru(II) products. The catalysts are
highly stable, readily synthesised in under an hour and may be
stored for several months before use, without loss of activity.
BACKGROUND
Ruthenium arene complexes such as 1 are widely used as
catalysts for asymmetric reductions of ketones and
imines.1 The catalysts typically employ hydrogen gas,
formic acid or isopropanol as the reducing agent. Active
catalysts 2 and 3 have been fully characterised in the RuII
case.2 While other d6 analogues (RhIII and IrIII) of 1 are
known,3 the osmium complexes have never before been
explored.
II
The synthesis of the Ru catalyst 1 involves the reaction
of a [Ru(arene)Cl2]2 complex with an enantiomerically
pure ligand for several hours under basic conditions at
high temperature, with an inert atmosphere.1
INVENTION
A novel approach, which separates heating and basic
conditions, allows access to a new class of osmium
compounds. The resulting complexes are highly stable
under ambient conditions and may be stored for several
months in air without degradation. Interestingly, the
complexes can be synthesised via a unique di-chlorido
pre-catalyst 4 which, while differing from the ruthenium
mono-chlorido species 1, is still active in transfer
hydrogenation reactions.
Upon treatment with a base, pre-catalyst 4 is converted
into active catalyst 5, the OsII analogue of 2. With a
synthetic approach optimised from the RuII synthesis,2
careful control of reaction stoichiometry allows the
direct isolation of osmium 5 in one step without the
need for further purification.
Figure 1. Production of osmium di-chlorido pre-catalyst 4 and
active catalyst 5 by microwave synthesis compared to the
traditional Ru synthesis of 2 (above).
A series of complexes with an extended arene system,
and interchangeable halides have also been synthesised.
The catalysts can be prepared in under an hour. The
synthetic procedures and structures have been
optimised and protected in UK patent application
GB1504281.5.
6
7
Figure 2. Di-iodido analogue 6; biphenyl-capped analogue 7. (S,S)
complexes are shown. The (R,R) analogues are also known.
The novel complexes (4-7), formed in this process, have
been shown to be highly active in asymmetric transfer
hydrogenation (ATH; Table 1) of ketones, in some cases
surpassing the rates of reduction observed with Ru(II)
catalysts. Representative enantioselectivities for the
reduction of acetophenone derivatives are detailed in
Figure 3.
Table 1: Selected ATH reductions of acetophenone (formic
acid/triethylamine - FA/TEA used as reductant).
4
5
6
7
Ru
mol%
0.5
0.5
0.5
0.5
0.5
T/K
310
310
310
310
310
t/h
24
24
24
24
24
conv./% [a] ee/% [a]
98
98
99
99
96
98
99
95
99
99
TOF / h-1
N.D. [b]
63.9 ± 0.34
N.D. [b]
77.5 ± 0.99
22.5 ± 1.42
[a]
Conversion and ee determined by chiral gas chromatography. [b]
-1
Maximum turnover frequency (h ) not determined for catalysts 4 and 6.
BENEFITS OF OUR NOVEL OSMIUM CATALYSTS
The new catalysts no longer require:
o an inert atmosphere during synthesis.
o further purification after synthesis (which may
significantly reduce yield and increase synthetic time).
o preparation near to the time of use.
Direct synthesis and isolation of the active catalyst as well
as a novel pre-catalyst.
Catalysts have advantageous properties of
o higher catalytic rates than Ru analogues
o high reproducibility
o higher stability than Ru analogues
o high enantiomeric excess
o ease of storage
REFERENCES
1.
a) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1996, 118, 2521-2522; b) T. Ikariya, S. Hashiguchi, K.
Murata, R. Noyori, in Org. Synth., Vol. 82, John Wiley & Sons, Inc.,
2005, pp. 10-17; c) T. Ikariya, K. Murata, R. Noyori, Org. Biomol.
Chem. 2006, 4, 393-406; d) N. Uematsu, A. Fujii, S. Hashiguchi, T.
Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916-4917. e) S.
Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1995, 117, 7562-7563; f) M. Yamakawa, H. Ito, R. Noyori, R. J.
Am. Chem. Soc. 2000, 122, 1466-1478; g) R. Noyori, M. Yamakawa, S.
Hashiguchi, J. Org. Chem. 2001, 66, 7931-7944; h) M. Yamakawa, I.
Yamada, R. Noyori, Angew. Chem. Int. Ed. 2001, 40, 2818-2821.
2.
a) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew.
Chem., Int. Ed.. 1997, 36, 285-288
3.
a) X. Wu, X. Li, A. Zanotti Gerosa, A. Pettman, J. Liu, A. J. Mills, J.
Xiao, Chem. Eur. J. 2008, 14, 2209-2222; b) X. Wu, J. Xiao, Chem.
Commun. 2007, 2449-2466; c) T. Thorpe, J. Blacker, S. M. Brown, C.
Bubert, J. Crosby, S. Fitzjohn, J. P. Muxworthy, J. M. J. Williams,
Tetrahedron Lett. 2001, 42, 4041-4043. d) K. Murata, T. Ikariya, R.
Noyori, J. Org. Chem. 1999, 64, 2186-2187; e) X. Sun, G. Manos, J.
Blacker, J. Martin, A. Gavriilidis, Org. Proc. Res. Dev. 2004, 8, 909914; f) T. Ohkuma, N. Utsumi, M. Watanabe, K. Tsutsumi, N. Arai; K.
Murata, Org. Lett. 2007, 9, 2565-2567; g) Z. M. Heiden; T. B.
Rauchfuss, J. Am. Chem. Soc. 2009, 131, 3593-3600.
Figure 3: Examples of other alcohols formed in ATH (asymmetric transfer
hydrogenation) reductions; 0.5 mol% catalyst, 310K, 24h.
Turnover number (TON)
200
160
120
7 (Os)
80
5 (Os)
40
1 (Ru)
0
0
2
4
6
8
Time / h
10
12
14
Figure 4: Reaction monitoring for the reduction of acetophenone by Os
and Ru complexes (0.5 mol% catalyst, 310K)
TARGET PARTNERS
The technology is expected to be of interest to companies who
are manufacturing and selling hydrogenation catalysts for
asymmetric reduction reactions.
The patent application also contains details of the synthesis of
a number of catalyst derivatives and their applications to
reductions. We can send you a small sample of approx. 100 mg
of catalyst 5 to evaluate under a Material Transfer Agreement.
PATENT & PUBLICATION
‘Easy to synthesize, robust, organo-osmium asymmetric
transfer hydrogenation catalysts’, J. P. C. Coverdale, C. Sanchez
Cano, R. Soni, G. J. Clarkson, M. Wills and P. J. Sadler, Chem. A
The novel osmium complexes reported herein offer a stable,
alternative catalyst system for asymmetric hydrogenation of
ketones. The catalysts may be prepared in advance of their
use, and retain activity for a period of several months without
the need for an inert atmosphere during synthesis or storage.
They are rapidly synthesised in under an hour. The osmium
catalysts have been found to out-perform existing ruthenium
technologies under identical reaction conditions, and do not
suffer from an induction phase, unlike analogous Ru catalysts.
Eur. J. 2015, 21, 8043–8046.
‘Osmium Catalysts and Method of Synthesis’. UK Patent
Application No. GB1504281.5 filed 13 March 2015.
CONTACT
Further information is available on request from:
Dr Shum Prakash, Warwick Ventures Ltd, Tel: +44 (0) 24 7657
4145, or via email: s.prakash@warwick.ac.uk Warwick
Ventures Ltd is the commercial arm of the University of
Warwick.