Self-assembly of bidentate ligands for combinatorial homogeneous catalysis: Asymmetric rhodium-catalyzed hydrogenation

Article abstract of DOI:10.1021/ja058202o

The first chiral ligand library based on self-assembly through complementary hydrogen-bonding was realized. From a 10 × 4 ligand library, catalysts that show excellent activity and enantioselectivity for the asymmetric rhodium-catalyzed hydrogenation have

Full text of DOI:10.1021/ja058202o

Published on Web 03/10/2006
Self-Assembly of Bidentate Ligands for Combinatorial Homogeneous
Catalysis: Asymmetric Rhodium-Catalyzed Hydrogenation
Martine Weis, Christoph Waloch, Wolfgang Seiche, and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21,
79104 Freiburg, Germany
Received December 2, 2005; E-mail: bernhard.breit@organik.chemie.uni-freiburg.de
Scheme 1. Self-assembly of Chiral Monodentate to Chiral
Bidentate Ligands through Complementary Hydrogen-Bonding on
the Basis of an A-T Base Pair Analogue for Combinatorial
Asymmetric Catalysis
Combinatorial methods have recently been introduced to homo-
geneous metal complex catalysis as a means to accelerate the
catalyst discovery process.1 Many elegant solutions for high-
throughput screening have been developed;2 however, thus far the
combinatorial approach to catalyst discovery and optimization
suffers from the limited access toward structurally diverse and
meaningful ligand libraries. The problem is particularly acute for
the important class of bidentate ligands, which has its origin in the
complexity of bidentate ligand synthesis. In many cases nontrivial
synthetic operations are required, which renders the ligand synthesis
unsuited for automation. A particular challenge is the synthesis of
nonsymmetric bidentate ligands equipped with two different donor
sites.
As one solution to this problem the use of mixtures of two
monodentate ligands has been proven to be useful.3 In these
mixtures three potential catalysts are present simultaneously: the
two homo-combinations and the hetero-combination. However, only
in cases when the hetero-combination is more reactive and at the
same time more selective than the homo-dimer, is optimization
toward a better catalyst possible.
Scheme 2. Library of Chiral Aminopyridine and Isoquinolone
Ligands
We recently introduced an alternative to the classical, covalent
bidentate ligand synthesis, which relies on self-assembly of
monodentate ligands through complementary hydrogen-bonding to
give defined heterodimeric bidentate ligands (Scheme 1).4-6
Thus, on the basis of an A-T base pair analogue, the aminopyr-
idine-isoquinolone system, the first achiral bidentate phosphine
ligand library was generated and screened against regioselectivity
control in the course of the rhodium-catalyzed hydroformylation
of terminal alkenes. These studies allowed us to identify a catalyst
that operated with excellent activity and regioselectivity in prefer-
ence for the linear regioisomer.5
We herein report on the synthesis7 of a new library of chiral
aminopyridine and isoquinolone systems equipped with phosphine
and phosphonite donors and its first application to asymmetric
catalysis, the asymmetric rhodium-catalyzed hydrogenation. From
this chiral ligand library new heterodimeric combinations emerged,
which furnished catalysts performing with enantioselectivities of
up to 99% ee (Scheme 2).
In first experiments, we checked whether the ligand self-assembly
process via complementary hydrogen-bonding is transferable to a
cationic rhodium(I) center. Thus, mixing of one equivalent of the
corresponding aminopyridine ligand, and one equivalent of
isoquinolone based ligand with one equivalent of [Rh(COD)2]BF4
gave in all cases the corresponding heterodimer complexes [RhLaLb-
(COD)]BF4 as proven by mass spectrometry as well as NMR
spectroscopy.7
Table 1. Results of Asymmetric Rhodium-Catalyzed
Hydrogenationa of Acetamidoacrylate
conv.
[%]b
ee
conv.
[%]b
ee
entry
La/Lb
[%]c
entry
La/Lb
[%]c
1d (-)-4a/3-DPICon quant. 56(R) 12f (S)-5a/(S)-6a quant 99(R)
2
3
4
(-)-4a/(S)-6a
6-DPPAP/(S)-6a
(+)-4a/(S)-6a
quant. 86(R) 13
quant. 82(R) 14
quant. 92(R) 15
quant. 94(R) 16
(S)-5a/(S)-5a quant 98(R)
(S)-6a/(S)-6a quant 94(R)
(S)-5a/(R)-6a quant. 80(R)
(S)-5a/(S)-6b quant. 92(R)
(S)-5b/(S)-6a quant. 88(R)
(S)-5b/(R)-6a quant. 63(R)
(S)-5b/(S)-6b quant. 59(R)
(S)-5c/(S)-6a quant. 33(R)
(S)-5c/(R)-6a quant. 83(R)
5e (+)-4a/(S)-6a
6
7
8
9
10
(+)-4a/(S)-6b
(-)-4b/(S)-6a
(+)-4b/(S)-6a
(-)-4c/(S)-6a
(+)-4c/(S)-6a
12
94
70(R) 17
81(R) 18
quant. 89(R) 19
53
77
79(R) 20
82(R) 21
11e (S)-5a/(S)-6a
quant. 99(R)
a All reactions in CH2Cl2, Rh:La:Lb ) 1:1.1-1.3:1.1-1.3, Rh:olefin )
1:100, 1 bar, 24 h. b Determined by NMR. c Determined by chiral GC
analysis (column Hydrodex-â-TBDAc). d 6 bar, 48 h. e 0 °C in ClCH2CH2Cl.
f Rh:olefin ) 1:1000, 1 bar, 24 h.
Scheme 1) with the P-chiral (-)-4a ligand furnished an active
hydrogenation catalyst that performed with moderate enantiose-
lectivity (entry 1). However, replacing the achiral 3-DPICon (2 with
Dob ) PPh2) with the chiral phosphonite derivative (S)-6a led to a
Original catalyst screening was done for the rhodium-catalyzed
hydrogenation of acetamidoacrylate. The most interesting results
from the screen of this 10 × 4 library are depicted in Table 1.
Thus, replacing the achiral 6-DPPAP ligand (1 with Doa ) PPh2,
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10.1021/ja058202o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Rhodium-catalyzed Hydrogenationa of
Methyl-R-acetyl-amino Cinnamate (7) and Dimethylitaconate (8)
cantly improved selectivity (entries 9-11). These preliminary
examples indicate that catalyst/ligand adjustment to a particular
substrate of interest is an important issue, and a combinatorial
approach based on self-assembly is in fact a useful technique to
rapidly identify an optimal catalyst.
In conclusion, the first chiral bidentate phosphorus donor ligand
library based on self-assembly through hydrogen bonding was
generated and screened for rhodium-catalyzed asymmetric hydro-
genation. Bidentate ligand combinations of phosphine/phosphonites
as well as diphosphonite systems were identified that furnished
excellent catalysts performing with enantioselectivities of up to 99%
ee. Application of this and other chiral ligand libraries to asymmetric
catalysis is ongoing in these laboratories.
entry
ligands
substrate
p [bar]
conv. [%]b
ee [%]
1
2
3
4
5
6
7
8
9
(S)-5a/(S)-6a
(S)-5a/(S)-6b
(S)-5a/(S)-5a
(S)-6b/(S)-6b
(S)-5a/(S)-6a
(S)-5a/(S)-6b
(S)-5a/(R)-6a
(S)-5b/(S)-6a
(S)-5b/(S)-6a
(S)-5b/(S)-5b
(S)-6a/(S)-6a
7
7
7
7
8
8
8
8
8
8
8
1
1
1
1
6
6
6
6
quant.
quant.
quant.
33
quant.
quant.
quant.
quant.
quant.
22
90 (R)c
94 (R)c
93 (R)c
73 (R)c
94 (S)d
91 (S)d
90 (S)d
70 (S)d
94 (S)d
38 (S)d
89 (S)d
Acknowledgment. This work was supported by the Fonds der
Chemischen Industrie, the DFG (International Research Training
Group GRK 1038: “Catalysts and catalytic reactions for organic
synthesis”), the Alfried Krupp Award for young university teachers
of the Krupp foundation (to B.B.) and BASF AG. We thank G.
Leonhardt-Lutterbeck for technical, G. Fehrenbach and Dr. R.
Krieger for analytical assistance, and T. Smejkal for preliminary
experiments. M.W. and C.W. are grateful to the Fonds der
Chemischen Industrie for Kekule´ fellowships.
30
30
30
10
11
quant.
a Rh:La:Lb) 1:1.1-1.3:1.1-1.3, Rh:olefin ) 1:100, 24 h. b Determined
by NMR. c Determined by chiral HPLC analysis (column Chiralpak-AD).
d Determined by chiral GC analysis (column G-TA, trifluoracetyl-γ-
cyclodextrin).
catalyst operating with significantly enhanced enantioselectivity
(entry 2). Exchanging (-)-4a with its enantiomer (+)-4a gave an
even better catalyst with 92% ee (entry 4) representing the matched
ligand combination. This result could be improved to 94% ee when
the reaction was run in dichloroethane at 0 °C (entry 5). Any further
variation in the phosphine structure of 4 did not provide any better
catalyst (entries 7-10). However, exchanging the aminopyridylphos-
phine monomer 4 by the corresponding phosphonite system (S)-5a
gave the best catalyst (entry 11). Even at catalyst loadings of 0.1
mol % complete conversion and perfect enantioselectivity (99%
ee, entry 12) was noted. In a control experiment both homocom-
binations for ligands 5a and 6a were tested separately. Both
furnished active hydrogenation catalysts which gave slightly lower
enantioselectivities (entries 13 and 14) than the heterocombination,
which suggests the heterocombination to be not only the prevalent
catalyst but also the kinetically competent species.8 Interestingly,
even the mismatched combination of the two heterodimeric
phosphonites (entry 15) furnished 80% ee. This result is in
agreement with the rather unsymmetrical P-donor arrangement
found in the crystal structure of a square planar platinum complex
of the parent 6-DPPAP/3-DPICon system, reported previously.5
Variation of the ortho-substituents in the BINOL skeleton did not
provide any further improvement (entries 16-21).
A small sublibrary based on the bisphosphonite systems was
screened against asymmetric hydrogenation of methyl-R-acetyl-
amino cinnamate (7) and dimethylitaconate (8) (Table 2). Interest-
ingly, for substrate 7 the optimal ligand combination was found to
be (S)-5a/(S)-6b with 94% ee (entry 2). The same ligand combina-
tion had provided only mediocre results in case of the parent
acetamidoacrylate substrate (Table 1, entry 17). For dimethylita-
conate (8) both (S)-5a/(S)-6a as well as (S)-5b/(S)-6a gave the best
results (94% ee, Table 2, entries 5,9). In the latter case, control
experiments employing the homocombinations clearly showed that
the heterocombination provides a catalyst operating with a signifi-
Supporting Information Available: Ligand syntheses and experi-
mental details. This material is available free of charge via the Internet
at http://pubs.acs.org.
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