Mixtures of chiral and achiral monodentate ligands in asymmetric Rh-catalyzed olefin hydrogenation: Reversal of enantioselectivity

Article abstract of DOI:10.1016/S0040-4039(03)00976-6

The recently described method of combinatorial asymmetric transition metal catalysis based on the use of mixtures of chiral monodentate P-ligands has been extended to include mixtures of chiral and achiral monodentate P-ligands, reversal of enantioselectivity in Rh-catalyzed olefin hydrogenation being possible in appropriate cases.

Full text of DOI:10.1016/S0040-4039(03)00976-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4593–4596
Mixtures of chiral and achiral monodentate ligands in
asymmetric Rh-catalyzed olefin hydrogenation: reversal of
enantioselectivity
Manfred T. Reetz* and Gerlinde Mehler
Max-Planck-Institut f u¨ r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 M u¨ lheim/Ruhr, Germany
Received 25 March 2003; accepted 11 April 2003
Abstract—The recently described method of combinatorial asymmetric transition metal catalysis based on the use of mixtures of
chiral monodentate P-ligands has been extended to include mixtures of chiral and achiral monodentate P-ligands, reversal of
enantioselectivity in Rh-catalyzed olefin hydrogenation being possible in appropriate cases. © 2003 Elsevier Science Ltd. All rights
reserved.
Recently we described a new concept in the area of
combinatorial enantioselective transition metal catalysis
which is based on the use of mixtures of chiral
monodentate ligands. It is relevant whenever in the
transition state of the reaction at least two monoden-
tate ligands (L) are coordinated to the metal (M) of the
highly enantioselective, much more so than either of the
1,4
relevant homocombinations alone.
1
We now demonstrate that appropriate mixtures of chi-
ral and achiral monodentate P-ligands lead to a reversal
of the direction of enantioselectivity of Rh-catalyzed
olefin hydrogenation. In such systems three different
catalysts are again relevant. If the heterocombination is
most reactive, it will largely determine the catalytic
profile of the system (Scheme 1).
active catalyst ML . In the case of a mixture of two
x
a
b
such ligands L and L , three different catalysts exist in
equilibrium with one another, namely the two homo-
a
a
b b
combinations ML L and ML L as well as the hetero-
a
b
a b
combination ML L . If ML L is more reactive and
stereoselective than the two homocombinations, then
enantioselectivity will be enhanced. Upon screening
only a small number of mixtures of chiral BINOL-
As a model reaction we chose the Rh-catalyzed hydro-
genation of the acetamidoacrylate 1, compounds 3–5
and 6–14 serving as the chiral and achiral P-ligands,
respectively. The Rh:P-ligand (total) ratio was adjusted
to 1:2, and the ratio of chiral to achiral P-ligand was
kept constant at 1:1.
2
3
based monophosphonites and monophosphites in Rh-
catalyzed asymmetric olefin hydrogenation, we
discovered that certain heterocombinations are in fact
Scheme 1.
Keywords: asymmetric catalysis; combinatorial chemistry; phosphorus ligands; hydrogenation; rhodium.
*
Corresponding author. Tel.: +49-208-306-2000; fax: +49-208-306-2985; e-mail: reetz@mpi-muelheim.mpg.de
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00976-6

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M. T. Reetz, G. Mehler / Tetrahedron Letters 44 (2003) 4593–4596
Table 1 reveals some remarkable trends. Large differ-
ences in rate are involved as reflected by the different
conversions after 24 h of reaction time. In the major-
ity of cases the use of an achiral ligand in combina-
tion with a chiral ligand leads to a decrease in
enantioselectivity, as might be expected. This also per-
tains to such ligands as 6 which actually exist as
are certain triarylphosphines as in 4b/9 (ee=45.4%
(R), entry 45).
The fact that subtle effects must be involved is illus-
trated by the contrasting behavior of tris(1-naphthyl)-
and tris(2-naphthyl)phosphines, 12 and 13, respec-
tively, the former not exerting any effect (entry 4 ver-
sus 48) and the latter causing reversal of
enantioselectivity (entry 49). Moreover, the effect is
5
fluxional enantiomeric conformers. In combination
with 3b, for example (Table 1, entry 24), a racemic
product is observed. It can be speculated that in the
heterocombination two catalysts are involved, namely
Rh-complexes of (R)-3b/(R)-6 and (R)-3b/(S)-6 which
do not lead to improvements, especially in view of
the fact that the homocombination 6/6 is also
involved.
7
not observed when using Feringa’s amidite 5. How-
ever, the present investigation is preliminary, and
8
many more achiral P-ligands and other substrates
need to be studied.
In summary, we have extended our original concept
of using mixtures of different chiral monodentate
Intriguingly, reversal of enantioselectivity is observed
in a number of cases (entries 18, 22, 23, 27, 31, 32,
1
ligands to include combinations composed of chiral
and achiral monodentate P-compounds. Although fur-
ther optimization as well as studies directed towards
uncovering the reason(s) for reversal of enantioselec-
tivity require further work, the results show that a
new and potentially useful concept in combinatorial
3
4, 36, 40, 45, 47, and 49). A notable example is the
6
effect of the phosphinine ligand 14 in combination
with phosphonite 3a leading to ee=58.6% (R) in con-
trast to 3a/3a (ee=93.0% (S)) (entry 1 versus 23).
Importantly, when used alone 14 constitutes a cata-
lyst system which is essentially inactive under the
reaction conditions (entry 14). Other achiral mono-P-
ligands which lead to the reversal of enantioselectivity
9–11
asymmetric catalysis has emerged.
Other types of
reactions such as hydroformylation should be
amenable to this type of catalyst optimization.

M. T. Reetz, G. Mehler / Tetrahedron Letters 44 (2003) 4593–4596
4595
a
Table 1. Rh-catalyzed hydrogenation of 1
References
Entry
Ligands
Conversion [%]
ee [%] (config.)
1
. (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G.
Angew. Chem. 2003, 115, 814–817; Angew. Chem., Int.
Ed. 2003, 42, 790–793; (b) Reetz, M. T.; Meiswinkel, A.;
Sell, T.; Mehler, G. Patent Application DE-A
Homocombinations
1
2
3
4
5
6
7
8
9
1
1
1
1
1
3a/3a
3b/3b
4a/4a
4b/4b
5/5
6/6
7/7
8/8
9/9
10/10
11/11
12/12
13/13
14/14
100
100
100
100
100
100
30
100
100
1
92.0 (S)
93.0 (S)
93.0 (S)
95.4 (S)
10247633.0; (c) Sell, T. Dissertation, Ruhr-Universit a¨ t
Bochum, Germany, 2002.
96.8 (S)
2
. (a) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41,
6333–6336; (b) Claver, C.; Fernandez, E.; Gillon, A.;
Heslop, K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.;
Pringle, P. G. Chem. Commun. (Cambridge) 2000, 961–
–
–
–
–
–
–
–
–
–
0
1
2
3
4
9
62.
. Reetz, M. T.; Mehler, G. Angew. Chem. 2000, 112,
047–4049; Angew. Chem., Int. Ed. 2000, 39, 3889–3890.
99
<1
99
<1
3
4
4. Further examples of this principle using mixtures of
different monophosphoramidites have since been
observed by B. Feringa (private communication) to be
published in Org. Biomol. Chem.
Heterocombinations
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
3a/6
3a/7
3a/8
3a/9
3a/10
3a/11
3a/12
3a/13
3a/14
3b/6
100
<1
100
100
44
62
82
100
20
100
1
100
76
69
53
24
100
9
100
61
100
100
100
100
100
100
97
100
99
100
100
100
99
100
100
100
100
99
100
100
99
2.8 (S)
nd
19.0 (S)
19.6 (R)
76.0 (S)
41.2 (S)
70.2 (S)
17.5 (R)
58.6 (R)
Racemic
nd
5
. (a) Reetz, M. T.; Neugebauer, T. Angew. Chem. 1999,
11, 134–137; Angew. Chem., Int. Ed. 1999, 38, 179–181;
b) Blackmond, D. G.; Rosner, T.; Neugebauer, T.;
1
(
Reetz, M. T. Angew. Chem. 1999, 111, 2333–2335;
Angew. Chem., Int. Ed. 1999, 38, 2196–2199.
6. We thank Professor B. Breit (Universit a¨ t Freiburg) for a
sample of compound 14.
7
3b/7
3b/8
. (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.;
van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2000, 122, 11539–11540; (b)
Minnaard, A. J.; van den Berg, M.; Schudde, E. P.; van
Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B.
L. Chim. Oggi 2001, 19, 12–13.
. Preliminary hydrogenation experiments using the b-
phenyl analog of 1 leading to the phenylalanine derivative
show a similar trend. For example, upon using 4b/9
reversal of enantioselectivity is observed (ee=20.5% (R)
versus ee=82.8% (S) employing 4b alone).
. Our approaches are different from the principle of self-
organization of catalysts as for example in the case of
Ti-catalysts formed from two different chiral diols used in
carbonyl ene-reactions, or the principle of selective acti-
vation of racemic catalysts, both described by the pio-
neering work of Mikami. See: (a) Mikami, K.;
Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem.
1.2 (S)
3b/9
3b/10
3b/11
3b/12
3b/13
3b/14
4a/6
3.2 (R)
89.2 (S)
32.0 (S)
77.0 (S)
26.2 (R)
52.6 (R)
43.2 (S)
6.2 (R)
34.8 (S)
10.0 (R)
62.4 (S)
21.0 (S)
42.2 (S)
15.6 (R)
54.2 (S)
90.0 (S)
63.4 (S)
82.4 (S)
45.4 (R)
94.2 (S)
21.0 (R)
95.0 (S)
34.8 (R)
84.2 (S)
84.4 (S)
93.2 (S)
80.8 (S)
64.2 (S)
96.8 (S)
76.0 (S)
97.0 (S)
2.8 (S)
8
4a/7
4a/8
4a/9
4a/10
4a/11
4a/12
4a/13
4a/14
4b/6
9
4b/7
4b/8
4b/9
4b/10
4b/11
4b/12
4b/13
4b/14
5/6
5/7
5/8
5/9
5/10
1997, 109, 2936–2939; Angew. Chem., Int. Ed. Engl. 1997,
36, 2768–2771; (b) Mikami, K.; Matsukawa, S. Nature
1997, 385, 613–615.
10. For key publications of combinatorial asymmetric cataly-
sis, see: (a) Francis, M. B.; Jacobsen, E. N. Angew.
Chem. 1999, 111, 987–991; Angew. Chem., Int. Ed.
1
999, 38, 937–941; (b) Gilbertson, S. R.; Chang,
C.-W. T. Chem. Commun. (Cambridge) 1997, 975–976;
c) Gennari, C.; Ceccarelli, S.; Piarulli, U.; Montal-
(
5/11
5/12
5/13
5/14
99
99
100
100
betti, C. A. G. N.; Jackson, R. F. W. J. Org. Chem.
1998, 63, 5312–5313; (d) Burgess, K.; Lim, H.-J.; Porte,
A. M.; Sulikowski, G. A. Angew. Chem. 1996, 108,
192–194; Angew. Chem., Int. Ed. Engl. 1996, 35, 220–
82.4 (S)
a
(R)-BINOL was used in the synthesis of all chiral P-ligands. In all
222; (e) Krueger, C. A.; Kuntz, K. W.; Dzierba, C.
cases the mixture of ligands was treated with [Rh(cod) ]BF4 in
2
D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284–
4285; (f) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J.
CH Cl2 and hydrogenation was performed at room temperature
2
and 1.3 bar H2 for 24 h, (Rh:substrate=1:1000), as previously
1
described using chiral ligands alone.

4
596
M. T. Reetz, G. Mehler / Tetrahedron Letters 44 (2003) 4593–4596
Am. Chem. Soc. 2002, 124, 10–11; (g) Berkessel, A.;
Riedl, R. J. Comb. Chem. 2000, 2, 215–219; (h) Dahmen,
S.; Br a¨ se, S. Synthesis 2001, 1431–1449.
well as high-throughput screening systems, see: (a) Reetz,
M. T. Angew. Chem. 2001, 113, 292–320; Angew. Chem.,
Int. Ed. 2001, 40, 284–310; (b) Reetz, M. T. Angew.
Chem. 2002, 114, 1391–1394; Angew. Chem., Int. Ed.
2002, 41, 1335–1338.
1
1. For reviews of combinatorial and evolutionary methods
for the generation of enantioselective (bio)catalysts as