Enantioselective Rh-catalyzed hydrogenation of 3-aryl- 2phosphonomethylpropenoates by a new class of chiral ferrocenyl diphosphine ligands

Article abstract of DOI:10.1021/ol9012469

A new class of chiral ferrocenyl diphosphine ligands with an imidazole ring, (R_c,S_Fc,)-ImiFerroPhos, has been prepared from acylferrocenes through a five-step transformation and successfully applied in the Rh-catalyzed asymmetric hyd

Full text of DOI:10.1021/ol9012469

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3226-3229
Enantioselective Rh-Catalyzed
Hydrogenation of 3-Aryl-2-
phosphonomethylpropenoates by a New
Class of Chiral Ferrocenyl Diphosphine
Ligands
Dao-Yong Wang,†,‡ Xiang-Ping Hu,*,† Chuan-Jin Hou,† Jun Deng,†,‡ Sai-Bo Yu,†,‡
Zheng-Chao Duan,†,‡ Jia-Di Huang,†,‡ and Zhuo Zheng*,†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China, and Graduate School of Chinese Academy of Sciences,
Beijing 100039, China
xiangping@dicp.ac.cn; zhengz@dicp.ac.cn
Received February 25, 2009
ABSTRACT
A new class of chiral ferrocenyl diphosphine ligands with an imidazole ring, (Rc,SFc)-ImiFerroPhos, has been prepared from acylferrocenes
through a five-step transformation and successfully applied in the Rh-catalyzed asymmetric hydrogenation of various 3-aryl-substituted
2-phosphonomethylpropenoates, in which a series of chiral 3-phosphono-2-arylmethylpropanoic acid derivatives were achieved in ee values
of up to 98%.
Chiral 3-phosphono-2-alkylpropanoic acid derivatives have
received considerable attention in the past few years in
bioorganic and medicinal chemistry because of their impor-
tant biological activities as phosphonate and phosphinate
enzyme inhibitors.1 The present syntheses of enantioenriched
3-phosphono-2-alkylpropanoic acid derivatives mainly fo-
cused on the asymmetric induction using a chiral auxiliary.2
However, not only are these methods not catalytic, requiring
stoichiometric chiral materials, but also in many cases the
diastereoselectivity obtained is unsatisfactory. The need for
the development of an efficient and catalytic method for
enantioselective synthesis of chiral 3-phosphono-2-alkylpro-
panoic acid derivatives is therefore apparent. Very recently,
Spilling et al. have described an example of enantioselective
synthesis of chiral 3-phosphono-2-alkylpropanoic acids or
esters by a catalytic asymmetric hydrogenation of the
corresponding 2-phosphonomethylpropenoate derivatives.3
Given its inherent efficiency and atom economy, the catalytic
asymmetric hydrogenation4 would seem to be an ideal
approach to prepare enantiopure chiral 3-phosphono-2-
alkylpropanoic acid derivatives. However, the research
disclosed that the level of asymmetric induction with Rh/
diphosphine (e.g., DIPAMP, DuPHOS, ferrotane, Tangphos)3
complexes was very low (0-52% ee). Although an improved
† Dalian Institute of Chemical Physics.
‡ Graduate School of Chinese Academy of Sciences.
10.1021/ol9012469 CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

enantioselectivity (up to 91% ee) was observed in the
hydrogenation of 2-phosphonomethylpropenoic acids with
a (R)-Cl-MeO-BIPHEP-Ru catalyst,3 for most substrates, the
enantioselectivities were still less satifactory. Therefore, the
search of a new catalytic system for the enantioselective
hydrogenation of a wider range of 2-phosphonomethylpro-
penoate derivatives is still highly desirable. As a part of our
ongoing efforts in the development of new catalytic hydro-
genation methods for the enantioselective synthesis of chiral
phosphonates,5 herein we report a highly enantioselective
synthesis of chiral 3-phosphono-2-arylmethylpropanoic acid
esters via the rhodium-catalyzed asymmetric hydrogenation
with a new class of chiral diphosphine ligands [(Rc,SFc)-
ImiFerroPhos] based on ferrocenyl and heterocyclic scaffolds.
Rh-catalyzed asymmetric hydrogenation of this challenging
substrate class.
The synthetic route for (Rc,SFc)-ImiFerroPhos 1a-i is
illustrated in Scheme 1.
Scheme 1. Preparation of (Rc,SFc)-ImiFerroPhos 1a-i
In the past few years, many ferrocenyl diphosphine ligands
with subtle structural variations have been developed and
successfully employed in a variety of asymmetric catalyses.6
However, ferrocenyl bisphosphine ligands with a heterocycle
remain less explored.7 These ligands are more amenable to
asymmetric catalysis than many other types of chiral ligands
as a result of their easy accessibility and derivatization as
well as special electronic and steric properties. Indeed, new
chiral ImiFerroPhos ligands, with an imidazole ring, can be
easily prepared from acylferrocenes through a modular
procedure, and they display superior enantioselectivity in the
(1) (a) Bartlett, P. A.; Kezer, W. B. J. Am. Chem. Soc. 1984, 106, 4282.
(b) McDermott, A. E.; Creuzet, F.; Griffin, R. G.; Zawadzke, L. E.; Ye,
Q.-Z.; Walsh, C. T. Biochemistry 1990, 29, 5767. (c) Hiratake, J.; Kato,
H.; Oda, J. J. Am. Chem. Soc. 1994, 116, 12059. (d) Morphy, J. R.; Beeley,
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K.; Slusher, B. S. J. Med. Chem. 2001, 44, 4170. (i) Demange, L.; Dugave,
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The chiral ferrocene-based phosphine-amine compounds
(Rc,SFc)-PPFA-R 2 were used as the starting materials, which
can be readily prepared from acylferrocenes through a three-
step transformation according to the literature procedure.8
Heating (Rc,SFc)-2 with imidazole in AcOH afforded (Rc,SFc)-
3 with complete configurational retention at the central
chirality.9 The treatment of (Rc,SFc)-3 with 1.5 molar equiv
of n-BuLi in Et2O at rt or -78 °C followed by trapping with
1.5 molar equiv of ClPR1 gave the target diphosphine
2
ligands (Rc,SFc)-ImiFerroPhos 1a-g in moderate yields. In
a similar synthetic procedure, ligands (Rc,SFc)-1h-i were
prepared from the corresponding phosphine-amine inter-
mediates in moderate yields. (Rc,SFc)-ImiFerroPhos 1a-i are
air-stable and can be handled in air, which makes the
synthesis, use, and storage of these ligands very convenient.
The structure of (Rc,SFc)-ImiFerroPhos 1c was confirmed
by X-ray crystallography (Figure 1).
With these newly developed diphosphine ligands in hand,
we then examined their efficiency in the Rh-catalyzed
asymmetric hydrogenation of this challenging substrate
class, 2-phosphonomethylpropenoates 4.10 Initially, ethyl 2-
(2) (a) Chen, H.; Noble, F.; Mothe´, A.; Meudal, H.; Coric, P.;
Danascimento, S.; Roques, B. P.; George, P.; Fournie´-Zaluski, M. C. J. Med.
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F. J. Organomet. Chem. 2002, 646, 212. (c) Matziari, M.; Yiotakis, A. Org.
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(3) Badkar, P. A.; Rath, N. P.; Spilling, C. D. Org. Lett. 2007, 9, 3619.
(4) de Vries, J. G.; Elsevier, C. J. Handbook of Homogeneous Hydro-
genation; Wiley-VCH: Weinheim, Germany, 2007.
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Z.-C.; Xu, X.-F.; Zheng, Z. Angew. Chem., Int. Ed. 2007, 46, 7810. (b)
Wang, D.-Y.; Huang, J.-D.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Duan, Z.-C.;
Zheng, Z. J. Org. Chem. 2008, 73, 2011. (c) Yu, S.-B.; Huang, J.-D.; Wang,
D.-Y.; Hu, X.-P.; Deng, J.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry
2008, 19, 1862. (d) Duan, Z.-C.; Hu, X.-P.; Wang, D.-Y.; Huang, J.-D.;
Yu, S.-B.; Deng, J.; Zheng, Z. AdV. Synth. Catal. 2008, 350, 1979.
(6) (a) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9,
2377. (b) Colacot, T. J. Chem. ReV. 2003, 103, 3101. (c) Barbaro, P.;
Bianchini, C.; Giambastiani, G.; Parisel, S. L. Coord. Chem. ReV. 2004,
248, 2131. (d) Atkinson, R. C. T.; Gibson, V. C.; Long, N. J. Chem. Soc.
ReV. 2004, 33, 313. (e) Arraya´s, R. G.; Adrio, J.; Carretero, J. C. Angew.
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(8) (a) Yamamoto, K.; Wakatsuki, J.; Sugimoto, R. Bull. Chem. Soc.
Jpn. 1980, 53, 1132. (b) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani,
M.; Nagashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi,
M.; Yamamoto, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138. (c)
Ohno, A.; Yamane, M.; Hayashi, T.; Oguni, N.; Hayashi, N. Tetrahedron:
Asymmetry 1995, 6, 2495.
(9) (a) Gokel, G. W.; Marquarding, D.; Ugi, I. K. J. Org. Chem. 1972,
37, 3052. (b) Schwink, L.; Knochel, P. Chem.sEur. J. 1998, 4, 950. (c)
Matsumoto, Y.; Ohno, A.; Lu, S.; Hayashi, T.; Oguni, N.; Hayashi, M.
Tetrahedron: Asymmetry 1993, 4, 1763. (d) Fukuzawa, S.; Fujimoto, K.;
Komuro, Y.; Matsuzawa, H. Org. Lett. 2002, 4, 707.
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1747.
Org. Lett., Vol. 11, No. 15, 2009
3227

was further increased to 94% ee with (Rc,SFc)-ImiFerroPhos
1c bearing an i-Pr group (entry 3). However, a phenyl group
in the ferrocenylmethyl position [(Rc,SFc)-ImiFerroPhos 1d]
resulted in a decrease of enantioselectivity to 78% ee (entry
4). Comparison of the results obtained with (Rc,SFc)-ImiFer-
roPhos 1a-d suggested that the steric demand in the
ferrocenylmethyl position of these newly developed ligands
is crucial for achieving high enantioselectivity in the
hydrogenation of this challenging substrate class. Phosphino
groups in these ligands have also greatly affected the
reactivities and enantioselectivities. However, no ligand
showed superior enantioselectivity to that obtained with
(Rc,SFc)-ImiFerroPhos 1c (entries 5-9). It is noteworthy that
both the catalytic activity and enantioselectivity of the Rh/
(Rc,SFc)-ImiFerroPhos 1c complex are sensitive to the solvent
used. The protonic solvents such as MeOH and i-PrOH
tended to give lower conversions and enantioselectivities
(entries 10-11). The reaction proceeded smoothly in THF,
giving slightly lower enantioselectivity (entry 12). Toluene
proved to be an inferior solvent, in which low conversion
was observed (entry 13). Lowering the catalyst loading to
0.1 mol % resulted in the dramatically decreased conversion
(entry 14).
Figure 1. Crystal structure of (Rc,SFc)-ImiFerroPhos 1c. The
hydrogen atoms and solvent were omitted for clarity.
[(dimethoxyphosphoryl)methyl]-3-phenyl-2-propenoate 4a
was used as a model substrate for ligand screening and
condition optimizing experiments. All reactions were carried
out at room temperature under 10 bar of H2 pressure for 24 h
and with an Rh:ligand ratio of 1:1.1, and the results are
summarized in Table 1. With (Rc,SFc)-ImiFerroPhos 1a
having a methyl substituent in the ferrocenylmethyl position,
4a was hydrogenated to 5a in 76% ee (entry 1). Introducing
an ethyl group [(Rc,SFc)-ImiFerroPhos 1b] increased the
enantioselectivity to 88% ee (entry 2). The enantioselectivity
Having established the optimal ligand and solvent, we next
investigated the effect of the ester functional group of
2-phosphonomethylpropenoates on this hydrogenation. The
results are summarized in Table 2. Initially, the hydrogena-
Table 2. Effect of Ester Functional Group in the Rh-Catalyzed
Hydrogenation of 2-Phosphonomethylpropenoates with
(Rc,SFc)-ImiFerroPhos 1c as Liganda
Table 1. Rh-Catalyzed Asymmetric Hydrogenation of Ethyl
2-[(Dimethoxyphosphoryl)methyl]-3-phenyl-2-propenoate 4a
with (Rc,SFc)-ImiFerroPhos 1a-j as Ligandsa
entry
substrate
R1
Et
Me
t-Bu
Et
R2
convn (%)b
ee (%)c
94
entry
ligand
solvent
convn (%)b
ee (%)c
1
2
3
4
5
4a
4b
4c
4d
4e
Me
Me
Me
i-Pr
Ph
>95
29
79
81
>95
d
-
1
2
3
4
5
6
7
8
(Rc,SFc)-1a
(Rc,SFc)-1b
(Rc,SFc)-1c
(Rc,SFc)-1d
(Rc,SFc)-1e
(Rc,SFc)-1f
(Rc,SFc)-1g
(Rc,SFc)-1h
(Rc,SFc)-1i
(Rc,SFc)-1c
(Rc,SFc)-1c
(Rc,SFc)-1c
(Rc,SFc)-1c
(Rc,SFc)-1c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
i-PrOH
THF
>95
>95
>95
>95
>95
>95
>95
91
>95
81
92
>95
56
<10
76
88
94
78
86
88
52
94
91
83
80
90
77
88
94
82
Et
a Reactions conditions: 2 mL of CH2Cl2, 0.5 mmol of substrate, 1 mol
% of catalyst prepared in situ from [Rh(COD)2]SbF6 and 1.1 equiv of
(Rc,SFc)-ImiFerroPhos 1c, 10 bar of H2 pressure, room temperature for 24 h.
b Conversions were determined by 1H NMR. c Enantiomeric excesses were
determined by HPLC, using a chiralcel OD-H column. d Not determined
because of low conversion.
9
10
11
12
13
14
tion of 2-[(dimethoxyphosphoryl)methyl]-3-phenyl-2-prope-
noates 4a-c with the different ester functional group in the
carboxylic moiety was examined (entries 1-3). It is very
strange that a modest change from an ethyl ester (4a) to a
toluene
CH2Cl2
d
-
a Reactions conditions: 2 mL of solvent, 0.5 mmol of substrate 4a, 1
mol % of catalyst prepared in situ from [Rh(COD)2]SbF6 and 1.1 equiv of
(Rc,SFc)-ImiFerroPhos 1a-i, 10 bar of H2 pressure, room temperature for
24 h. b Conversions were determined by 1H NMR. c Enantiomeric excesses
were determined by HPLC, using a chiralcel OD-H column. d Using 0.1
mol % of [Rh].
(10) The substrates 4a-n, prepared by the reaction of the Baylis-Hillman
adducts with phosphorchloridite in the presence of triethylamine, have
exclusively the Z-configuration. For the literature, see: Janecki, T.; Bodalski,
R. Synthesis 1990, 799.
3228
Org. Lett., Vol. 11, No. 15, 2009

methyl ester (4b) led to the dramatically decreased conver-
sion (entry 1 vs entry 2). The hydrogenation of the substrate
4c with a bulky t-Bu ester function also resulted in the re-
duced conversion and enantioselectivity (entry 3). The in-
troduction of the bulkier ester functional group into the
phosphoryl moiety did not affect the enantioselectivity but
lowered the conversion to 81% (entry 4). On the contrary,
the substrate with a phenyl ester functional group in the
phosphoryl moiety gave full conversions and decreased
enantioselectivity (entry 5). These results suggested that the
ester functional group of 2-phosphonomethylpropenoates has
a significant influence on the conversion and enantioselec-
tivity.
Encouraged by these results, we then examined the Rh-
catalyzed asymmetric hydrogenation of a variety of ethyl
3-aryl-2-[(dimethoxyphosphoryl)methyl]-2-propenoates
4f-m with (Rc,SFc)-ImiFerroPhos 1c under the optimized
conditions (Table 3). In all cases, full conversions and high
yields were achieved. The electronic nature of the para-
substituents on the phenyl ring has some effect on the
enantioselectivity (entries 2-5). The substrate with an
electron-donating group tended to give higher enantioselec-
tivity than those with electron-withdrawing substituents.
Thus, the substrate 4h with an NO2 group was hydrogenated
with 89% ee, while the hydrogenation of a methoxy-
substituted substrate 4i gave the hydrogenation product in
95% ee (entry 4 vs entry 5). It appears that the position of
the substituent on the phenyl ring had a limited effect on
the enantioselectivities. All of the substrates with a methoxy
group in the different position of the phenyl ring were
hydrogenated with similar enantioselectivities (entries 5-7).
The hydrogenation of the substrates with a heteroaromatic
substituent also led to good enantioselectivities. Remarkably,
the hydrogenation of 2-thienyl-substituted substrate 4m
provided the best enantioselectivity of up to 98% ee (entry
9). These results demonstrate the high efficiency of the
present catalytic system in the Rh-catalyzed asymmetric
hydrogenation of this challenging substrate class. However,
this catalytic system is inefficient for the hydrogenation of
alkyl-substituted substrate 4n (entry 10).
In conclusion, we have developed a new family of chiral
ferrocenyl diphosphine ligands with an imidazole ring,
(Rc,SFc)-ImiFerroPhos 1a-i, through a five-step procedure
from acylferrocenes. The modular construction of this ligand
class allows for wide structural diversity. These ligands have
been successfully applied in the Rh-catalyzed asymmetric
hydrogenation of a challenging substrate class, 2-phospho-
nomethylpropenoates, giving the best results reported so far.
The further applications of this new ligand class in asym-
metric catalysis will be disclosed in due time.
Table 3. Rh-Catalyzed Hydrogenation of Ethyl
2-[(Dimethoxyphosphoryl)methyl]-3-aryl-2-propenoate 4f-n
with (Rc,SFc)-ImiFerroPhos 1c as Liganda
entry substrate
R
convn (%)b yield (%)c ee (%)d
1
2
3
4
5
6
7
8
9
4a
4f
4g
4h
4i
4j
4k
4l
Ph
4-FC6H4
>95
>95
>95
>95
>95
>95
>95
>95
>95
<5
98
94
98
91
98
98
99
97
98
-
94
91
92
89
95
92
93
90
98
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-furyl
Acknowledgment. We are grateful to the generous
financial support from the National Natural Science Founda-
tion of China (20802076, 20873145) and the Knowledge
Innovation Program of the Chinese Academy of Sciences
(DICP-S200802). We thank Dr. Josh Chong (ChemHost Inc.,
USA) for his enthusiastic help.
4m
4n
2-thienyl
i-Pr
e
10
-
a Reactions conditions: 2 mL of CH2Cl2, 0.5 mmol of substrate, 1 mol
% of catalyst prepared in situ from [Rh(COD)2]SbF6 and 1.1 equiv of
(Rc,SFc)-ImiFerroPhos 1c, 10 bar of H2 pressure, room temperature for 24 h.
b Conversions were determined by 1H NMR. c Isolated yields. d Enantiomeric
excesses were determined by HPLC, using a chiral AD-H, OD-H, or OJ-H
column. e Not determined because of low conversion.
Supporting Information Available: Experimental details,
optimization data, spectra for new compounds, and analysis
of ee value of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL9012469
Org. Lett., Vol. 11, No. 15, 2009
3229