Modular monodentate phosphoramidite ligands for rhodium-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1021/ja052749l

A new class of monodentate phosphoramidite ligands (DpenPhos) has been developed on the basis of the modular concept for Rh(I)-catalyzed asymmetric hydrogenations of a variety of olefin derivatives, affording the corresponding optically active compounds in excellent yields and enantioselectivities. The ligands have the advantages of facile preparation, tunable structure, and broad scope of substrates in their Rh(I) complex-catalyzed asymmetric hydrogenations. Copyright

Full text of DOI:10.1021/ja052749l

Published on Web 07/09/2005
Modular Monodentate Phosphoramidite Ligands for Rhodium-Catalyzed
Enantioselective Hydrogenation
Yan Liu and Kuiling Ding*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
Received April 28, 2005; E-mail: kding@mail.sioc.ac.cn
After 30 years neglect, the monodentate phosphorus ligand1 got
its renaissance in asymmetric catalysis at the beginning of this
millennium by the pioneering works of Ferringa, de Vries, Reetz,
Pringle, and others.2 Since then, the development of monodentate
phosphorus ligands (e.g., 1 and 2) for asymmetric catalysis has been
a research topic of increasing interest due to the facts of their easy
preparation, good stability, and excellent performance in the
catalysis.2-5 To achieve the highly efficient and enantioselective
catalysis of asymmetric reactions, the tuning of the catalyst to make
a perfect match among chiral ligands, metallic ion, as well as
substrate and so on, is the key issue, in which the adjustment of
the steric and electronic modifications in chiral ligands plays a
central role. Therefore, the development of structurally tunable
ligands will merit the ligand and catalyst diversity. In the present
work, we report our preliminary results on the design, synthesis,
and applications of a new class of monodentate phosphoramidite
ligands 3 (DpenPhos) on the basis of a modular approach.
Figure 1. The impacts of R and R′ in monodentate ligands 3a-h on the
enantioselectivity of Rh(I)-catalyzed hydrogenations of R-dehydroamino acid
derivative 5c (a) and enamide 7a (b).
Ligands 3a-h were then tested in the Rh(I)-catalyzed enantio-
selective hydrogenation of olefin derivatives. The olefin derivatives
5c and 7a were taken as the model substrates, respectively. As
shown in Figure 1a, the enantioselectivity for the hydrogenation
of dehydroamino acid derivative 5c was dramatically enhanced from
52.0 to 99.4% ee with the change of R from the smallest proton
(3a) to the 3,5-di-tert-butylbenzyl group (3f). On the other hand,
the increase of the steric hindrance of substituents at the phosphorus
atom of the ligands (R′) proved to be unfavorable for the
enantioselectivity of the reaction (3h vs 3c). The impact of
substituents R in ligands 3 on the enantioselectivity of the
hydrogenation of enamide derivative 7a showed the similar
tendency of substituent effect (Figure 1b). All these results clearly
indicated that dual steric tuning of both R and R′ groups in the
monodentate DpenPhos ligands is critically important for achieving
maximum asymmetric induction in Rh(I)-catalyzed hydrogenations.
The imidazolidinone backbone in the ligands has provided an
excellent opportunity for facile modular construction of structurally
tunable ligands, which can be considered as one of the advantages
of this class of ligands. The further optimization of H2 pressure
(Supporting Information) disclosed that 99.6% ee of 6c could be
achieved with ligand 3d under 20 atm of H2. Similarly, the
enantioselectivity for the hydrogenation of enamide 7a, up to
97.6% ee, has been achieved using the Rh(I) complex of ligand 3f.
Under the optimized reaction conditions, various dehydro-R-
amino acid derivatives 5a-q could be hydrogenated with the
catalysis of Rh/(R,R)-3d to afford the corresponding R-amino acid
derivatives with extremely high enantiomeric excess values (95.9-
99.9% ee, Table 1, entries 1-17). Either the alkyl or aryl group
situated at the â-position of dehydro-R-amino acid derivatives has
little impact on the enantioselectivity of the reaction. To demonstrate
the efficiency of the catalyst Rh/(R,R)-3d, the hydrogenation of 5a
was also carried out with the reduced catalyst loading (0.1 mol
%), affording the corresponding amino acid derivative 6a in
quantitative yield without significant loss of enantioselectivity (entry
18 vs 1). For the hydrogenation of enamide substrates, the catalyst
composed of monodentate ligand (R,R)-3f was particularly effective.
As shown in Scheme 1, the synthesis of ligands 3 was quite
simple. The key diphenol intermediates 4a-f were readily prepared
from a chiral diamine, (R,R)-1,2-di(2-dimethoxyphenyl)-1,2-ethyl-
enediamine, via a three-step reaction sequence (see Supporting
Information). The monodentate phosphoramidite ligands (R,R)-3
were finally obtained by the reaction of (R,R)-4a-f with hexa-
methylphosphorus triamide (HMPT) or hexaethylphosphorus tri-
amide in good yields. These ligands are stable enough in the air to
be purified by column chromatography on silica gel without special
precaution to water or air.
Scheme 1. Synthesis of Modular Monodentate Ligands 3a-h
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J. AM. CHEM. SOC. 2005, 127, 10488-10489
10.1021/ja052749l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Rh(I)-Catalyzed Enantioselective Hydrogenation of
Dehydro-R-amino Acid Methyl Esters (5) and Acetyl Enamides (7)a
entry
ligand
R in 5 and 7
ee (%) (config)b
Figure 2. Structure of the cation of [Rh{(R,R)-3e}2(cod)]+[OH]-.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18c
19
20
21
22
23
24
25
26
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3f
H (5a)
99.3 (S)
98.4 (S)
99.6 (S)
99.7 (S)
99.0 (S)
98.2 (S)
99.0 (S)
98.6 (S)
98.2 (S)
97.2 (S)
98.4 (S)
99.7 (S)
99.1 (S)
>99.9 (S)
99.1 (S)
99.1 (S)
96.9 (S)
98.8 (S)
97.6 (S)
99.8 (S)
97.4 (S)
99.3 (S)
98.2 (S)
99.7 (S)
96.1 (S)
98.4 (S)
CH3 (5b)
C6H5 (5c)
structural feature is not clear, the orientation of benzyl groups in
the Rh(I) complex should have some impact on the enantiodis-
crimination of the catalytic center. This observation might provide
a rationale for the increase in enantioselectivity of hydrogenations,
as shown in Figure 1.
In conclusion, a new class of monodentate phosphoramidite
ligands (DpenPhos) has been developed based on a modular concept
for Rh(I)-catalyzed asymmetric hydrogenations of a variety of olefin
derivatives, affording the corresponding optically active compounds
in excellent yields and enantioselectivities. The results achieved in
this work will stimulate future studies to explore the new applica-
tions of these modular ligands in other transition-metal-catalyzed
asymmetric reactions,6,7 including generation of a modular com-
binatorial chiral catalyst library using mixtures of ligands.3,8
4-BrC6H4 (5d)
3-BrC6H4 (5e)
2-BrC6H4 (5f)
4-ClC6H4(5g)
3-ClC6H4 (5h)
2-ClC6H4 (5i)
4-CH3OC6H4 (5j)
3-CH3OC6H4 (5k)
3-FC6H4 (5l)
4-O2NC6H4 (5m)
2-O2NC6H4 (5n)
3,4-(CH3O)2C6H3 (5o)
3-AcO-4-CH3OC6H3 (5p)
2-naphthyl (5q)
H (5a)
C6H5 (7a)
3f
3f
3f
3f
3f
3f
3f
4-ClC6H4 (7b)
4-CH3OC6H4 (7c)
4-CH3C6H4 (7d)
4-FC6H4 (7e)
4-BrC6H4 (7f)
3-BrC6H4 (7g)
2-naphthyl (7h)
Acknowledgment. Financial support from the NNSFC, CAS,
and the Major Basic Research Development Program of China
(Grant No. G2000077506) and the Commission of Science and
Technology, Shanghai Municipality, is gratefully acknowledged.
a All of the reactions were carried out at room temperature at a substrate
concentration of 0.2 M for 2 h (substrate/catalyst ) 100:1); the conversion
of substrate was determined by 1H NMR. b Determined by chiral HPLC or
GC; absolute configurations of the products were assigned by comparison
of their optical rotation with literature data. c With 0.1 mol % of catalyst
loading.
Supporting Information Available: Synthesis of chiral ligands and
chiral HPLC or CG analysis of the products (37 pages, print/PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
Under the optimized conditions, a variety of R-arylenamides has
been hydrogenated to afford the corresponding R-arylamine deriva-
tives quantitatively with excellent enantioselectivity (96.0-99.6%
ee, Table 2, entries 19-26). Moreover, both the catalysts Rh/(R,R)-
3d and Rh/(R,R)-3f were also effective for the hydrogenation of
dimethyl itaconate to give corresponding hydrogenated product with
97.2-99% ee in quantitative yield (Supporting Information).
A question is posed regarding how the backbone substituents
affect the enantioselectivities of the reactions. A Rh(I) complex of
ligand 3e has been isolated and characterized by X-ray crystal-
lography to have the formula of [Rh{(R,R)-3e}2(cod)]OH (Figure
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backbone is thus fixed as S configuration with complete diaste-
reoselectivity. Although the reason for the formation of such
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