Enantioselective synthesis of chiral α-aryl or α-alkyl substituted ethylphosphonates via Rh-catalyzed asymmetric hydrogenation with a P-stereogenic BoPhoz-type ligand

Article abstract of DOI:10.1021/jo900417m

(Chemical Equation Presented) An enantioselective synthesis of optically active 1-aryl or 1-alkyl substituted ethylphosphonates, based on the first Rh-catalyzed asymmetric hydrogenation of corresponding α,β- unsaturated precursors with a P-stereogenic BoPhoz-type ligand under the mild condition, was developed, in which a wide range of 1-aryl or 1-alkyl substituted ethylphosphonates were achieved in up to 98% ee.

Full text of DOI:10.1021/jo900417m

for organic chemists. The present methods for achieving the
optically enriched forms of 1-arylethylphosphonates include the
enantioselective methylation of benzylphosphonic acid deriva-
tives bearing chiral auxiliaries3 and the photo-Arbuzov rear-
rangement of optically active 2-(1-phenylethoxy)-1,3,2-diox-
aphosphorinanes.4 These methods, however, are not catalytic.
They require stoichiometric chiral materials or special reagents
that are difficult to handle. The need for the development of an
efficient and catalytic method for the preparation of enantiopure
1-arylethylphosphonates is therefore apparent.5 Recently, Geneˆt
et al. reported that optically active 1-phenylethylphosphonic acid
or its ester can be prepared by the Ru-catalyzed asymmetric
hydrogenation of corresponding R,ꢀ-unsaturated precursors.6
However, the hydrogenation required vigorous conditions (80
°C and 10 bar of H2 for acid, 80 °C and 80 bar of H2 for ester)
and gave only moderate enantioselectivities. Using a PHOX/Ir
catalyst,7 Beletskaya, Pfaltz, and co-workers found that the
hydrogenation of 1-arylethenylphosphonates could be performed
under milder conditions (5 bar of H2 and 40 °C) than the Ru-
catalyzed hydrogenation and provided higher enantioselectivi-
ties. However, the substrate with a MeO group showed very
low reactivity, affording only 78% conversion even after 115 h
at a catalyst loading of 2 mol %. Therefore, the search for a
new and versatile catalytic system for enantioselective hydro-
genation of 1-arylethenylphosphonates is still a highly desirable
objective.
Enantioselective Synthesis of Chiral r-Aryl or
r-Alkyl Substituted Ethylphosphonates via
Rh-Catalyzed Asymmetric Hydrogenation with a
P-Stereogenic BoPhoz-Type Ligand
Dao-Yong Wang,†,‡ Xiang-Ping Hu,*,† Jun Deng,†,‡
Sai-Bo Yu,†,‡ Zheng-Chao Duan,†,‡ 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 24, 2009
Recently, we8 and other groups9 have demonstrated that the
BoPhoz-type phosphine-aminophosphine ligands are highly
efficient in the catalytic asymmetric hydrogenation of various
An enantioselective synthesis of optically active 1-aryl or
1-alkyl substituted ethylphosphonates, based on the first Rh-
catalyzed asymmetric hydrogenation of corresponding R,ꢀ-
unsaturated precursors with a P-stereogenic BoPhoz-type
ligand under the mild condition, was developed, in which a
wide range of 1-aryl or 1-alkyl substituted ethylphosphonates
were achieved in up to 98% ee.
(3) Bennani, Y. L.; Hanessian, S. Tetrahedron 1996, 52, 13837–13866. (b)
Kranz, M.; Denmark, S. E. J. Org. Chem. 1995, 60, 5867–5877. (c) Denmark,
S. E.; Chen, C.-T. J. Am. Chem. Soc. 1995, 117, 11879–11897.
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Bentrude, W. G. J. Am. Chem. Soc. 1988, 110, 6908–6909. (c) Bhanthumnavin,
W.; Arif, A.; Bentrude, W. G. J. Org. Chem. 1998, 63, 7753–7758.
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Beletskaya, I. P.; Dolgina, T. M. Tetrahedron Lett. 1998, 39, 3473–3476. (b)
Goulioukina, N. S.; Dolgina, T. M.; Beletskaya, I. P.; Henry, J.-C.; Lavergne,
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Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825–4828. (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, 2011–2014. (c) Deng, J.; Hu, X.-P.; Huang, J.-D.; Yu, S.-B.; Wang,
D.-Y.; Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2008, 73, 2015–2017. (d) Qiu, M.;
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Optically active 1-arylethylphosphonates have received con-
siderable attention in the past few years in bioorganic and
medicinal chemistry1 because of their interesting biological
properties as bioisosteric derivatives of 2-arylpropionic acids
such as naproxen,2 which is a well-known nonsteroidal anti-
inflammatory drug. However, achieving high enantioselectivity
in the synthesis of these compounds is still a challenging task
† Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
‡ Graduate School of Chinese Academy of Sciences.
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S.; Teodori, E.; Budriesi, R.; Chiarini, A. Farmaco 1989, 44, 1167–1191. (d)
Bigge, C. F.; Drummond, J. T.; Johnson, G.; Malone, T.; Probert, A. W.;
Marcoux, F. W.; Coughenour, L. L.; Brahce, L. J. J. Med. Chem. 1989, 32,
1580–1590. (e) Bigge, C. F.; Johnson, G.; Ortwine, D. F.; Drummond, J. T.;
Retz, D. M.; Brahce, L. J.; Coughenour, L. L.; Marcoux, F. W.; Probert, A. W.
J. Med. Chem. 1992, 35, 1371–1384. (f) Liu, W.-Q.; Carreaux, F.; Meudal, H.;
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J. P.; Simeonov, A.; Janda, K. D. J. Am. Chem. Soc. 1999, 121, 10461–10467.
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Lett. 2002, 4, 2421–2424. (b) Boaz, N. W.; Large, S. E.; Ponasik, J. A., Jr.;
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9, 472–478. (c) Boaz, N. W.; Ponasik, J. A., Jr.; Large, S. E. Tetrahedron:
Asymmetry 2005, 16, 2063–2066. (d) Li, X.; Jia, X.; Xu, L.; Kok, S. H. L.; Yip,
C. W.; Chan, A. S. C. AdV. Synth. Catal. 2005, 347, 1904–1908. (e) Boaz, N. W.;
Mackenzie, E. B.; Debenham, S. D.; Large, S. E.; Ponasik, J. A., Jr. J. Org.
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4408 J. Org. Chem. 2009, 74, 4408–4410
10.1021/jo900417m CCC: $40.75 2009 American Chemical Society
Published on Web 05/04/2009

TABLE 1. Rh-Catalyzed Asymmetric Hydrogenation of Diethyl
1-Phenylethenylphosphonate 2aa
entry
ligand
solvent H2 (bar) conversion (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Me-DuPHOS CH2Cl2
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
43
33
17
32
17
12
77
86
89
87
70
95
d
18
d
d
92
95
92e
f
FIGURE 1. Representative structures of BoPhoz-type ligands 1a-e
BINAP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
for asymmetric hydrogenation.
TaniaPhos
PPFAPhos
PEAPhos
(Sc,RFc)-1a
(Sc,RFc)-1b
(Sc,RFc)-1c
(Sc,RFc)-1d
>95
>95
>95
>95
>95
81
>95
>95
20
>95
50
<5
>95
>95
>95
<5
prochiral CdC double bonds, especially some challenging
substrates such as ꢀ2- and γ-dehydroamino acid esters. The
easily tunable property of the BoPhoz skeleton makes it an
appropriate tool with which to examine the hydrogenation of
these challenging substrates. For its demonstrated track record
at affecting Rh-catalyzed asymmetric hydrogenations, we
therefore surmise that this ligand class may be also effective
for the Rh-catalyzed asymmetric hydrogenation of 1-aryleth-
enylphosphonates. To the best of knowledge, there is still no
report on the asymmetric hydrogenation of 1-arylethenylphos-
phonates with a chiral Rh catalyst. As a result, herein we report
our results on the enantioselective synthesis of chiral 1-aryl or
1-alkyl substituted ethylphosphonates via the first Rh-catalyzed
asymmetric hydrogenation with a P-stereogenic BoPhoz-type
ligand (Figure 1), in which good enantioselectivities (up to 98%
ee) were achieved for a broad range of substrates under the mild
conditions.
As the substrates without or with less coordinating groups
are more challenging for ruthenium- or rhodium-catalyzed
asymmetric hydrogenation,5,10,11 the difficulty in the catalytic
asymmetric hydrogenation of 1-arylethenylphosphonates with
a Rh catalyst can be anticipated. Our preliminary study found
that most of the highly efficient and extensively used ligands
in the Rh-catalyzed asymmetric hydrogenation such as Du-
PHOS,12 BINAP,13 TaniaPhos,14 PPFAPhos,15 and PEAPhos16
were ineffective for this hydrogenation reaction, providing only
low to moderate enantioselectivities or low catalytic activities
(see Table 1, entries 1-5). In a comparison, BoPhoz proved to
be a superior ligand in terms of catalytic activity and enanti-
oselectivity.
Since the synthetic methodology of BoPhoz-type ligands is
highly modular, the optimization of the BoPhoz skeleton was
therefore performed, and some representative results are sum-
marized in Table 1. Ligand screening experiment employed
1-phenylethenylphosphonate 2a as the model substrate and was
carried out in CH2Cl2 at room temperature under a H2 pressure
of 10 bar in the presence of 1 mol % of catalysts prepared in
situ from [Rh(COD)2]BF4 and 1.1 equiv of chiral ligand. After
a systematic investigation of a number of BoPhoz-type ligands,
we determined that those with a trifluoromethyl group on the
4-position of the phenyl ring of aminophosphino moiety tended
to give better results than that obtained with Me-BoPhoz in terms
of enantioselectivity (Table 1, entries 6-10). For instance, ligand
(Sc,RFc,Rp)-1e CH2Cl2
(Sc,RFc,Rp)-1e MeOH
(Sc,RFc,Rp)-1e i-PrOH
(Sc,RFc,Rp)-1e THF
(Sc,RFc,Rp)-1e PhMe
(Sc,RFc,Rp)-1e CH2Cl2
(Sc,RFc,Rp)-1e CH2Cl2
(Sc,RFc,Rp)-1e CH2Cl2
(Sc,RFc,Rp)-1e CH2Cl2
20
50
10
a All reactions were performed with 0.25 mmol of substrate 2a at
room temperature under an indicated H2 pressure in 2 mL of solvent for
24
h unless otherwise specified. Substrate/[Rh(COD)2]BF4/ligand )
1/0.01/0.011. b Conversions were determined by 1H NMR. c The ee
values were determined by HPLC on a chiral column (chiralpak AD-H,
40 °C, 215 nm, n-hexane/2-propanol ) 95/5, flow rate ) 1.0 mL/min).
d Not determined because of low conversions. e Reaction was performed
at a catalyst loading of 0.2 mol %. f [Rh(COD)Cl]2 was used as catalyst
precursor.
1b with a CF3 group on the 4-position of the phenyl ring gave
89% ee and full conversions in the hydrogenation of 2a, while
the presence of a 4-Me substituent in the phenyl ring of ligand
resulted in a reduced enantioselectivity and reactivity (Table 1,
entries 7 and 8). However, the introduction of two CF3 groups
onto the 3,5-positions of the phenyl ring resulted in a decreased
enantioselectivity (Table 1, entry 9). In particular, ligand
(Sc,RFc,RP)-1e, bearing a stereogenic P center in the phosphino
moiety and a 4-CF3 group on the phenyl ring of aminophosphino
moiety, provided the best enantioselectivity of up to 95% ee
(Table 1, entry 10). Subsequent experiments in an effort to attain
higher enantioselectivities by optimizing the reaction conditions
proved unfruitful. As shown in Table 1, strong solvent depen-
dency was observed in the reaction. However, no results
surpassed that obtained in CH2Cl2 (Table 1, entries 10-14).
Lowering or elevating H2 pressure could not improve enanti-
oselectivity (Table 1, entries 15 and 16). Reducing the catalyst
loading to 0.2 mol % also provided good enantioselectivity (92%
ee); however, an elevated H2 pressure (50 bar) was required to
complete the hydrogenation (Table 1, entry 17). Using
[Rh(COD)Cl]2 as the catalyst precursor resulted in extremely
low catalytic activity (Table 1, entry 18).
To demonstrate the flexibility of the present catalytic system,
we subsequently examined the hydrogenation of a series of
1-arylethenylphosphonates 2a-l under the optimized conditions
(1 mol % of catalyst loading prepared in situ from
[Rh(COD)2]BF4 and 1.1 equiv of ligand 1e, performed under
10 bar of H2 pressure in CH2Cl2 at room temperature for 24 h),
and the results are summarized in Table 2. Initially, the effect
of the ester function in R,ꢀ-unsaturated phosphonates was
evaluated, and a series of 1-phenylethenylphosphonates 2a-c
(10) Cheruku, P.; Diesen, J.; Ahdersson, P. G. J. Am. Chem. Soc. 2008, 130,
5595–5599.
(11) Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445–1446.
(b) Horner, L.; Siegel, H.; Bu¨the, H. Angew. Chem., Int. Ed. Engl. 1968, 7, 942.
(12) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
(13) Noyori, R. Acc. Chem. Res. 1990, 23, 345–350.
(14) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P. Angew.
Chem., Int. Ed. 1999, 38, 3212–3215.
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Wang, D.-Y.; Zheng, Z. Org. Lett. 2006, 8, 4367–4370.
J. Org. Chem. Vol. 74, No. 11, 2009 4409

TABLE 2. Asymmetric Hydrogenation of Substrates 2a-o Using
Rh/(Sc,RFc,Rp)-1e Catalysta
enantioselectivities (92-98% ee) and excellent yields in the first
Rh-catalyzed asymmetric hydrogenation of corresponding 1-aryl
or 1-alkylethenylphosphonates using a P-stereogenic chiral BoPhoz-
type phosphine-aminophosphine ligand. Hydrogenation can be
performed under the mild conditions (10 bar of H2 pressure and
room temperature) and relatively low catalyst loading (up to 0.2
mol %), which represented the best result in the catalytic asym-
metric synthesis of chiral 1-aryl or 1-alkyl substituted ethylphos-
phonates reported so far. It is our hope that this work will provide
a new and practical method to prepare chiral 1-substituted eth-
ylphosphonates and their derivatives.
entry
substrate (R, R1, R2)
2a (Ph, Et, H)
2b (Ph, Me, H)
2c (Ph, i-Pr, H)
2d (o-MeOC6H4, Et, H)
2e (m-MeOC6H4, Et, H)
2f (p-MeOC6H4, Et, H)
2g (p-FC6H4, Et, H)
2h (p-ClC6H4, Et, H)
2i (p-BrC6H4, Et, H)
2j (p-MeC6H4, Et, H)
2k (1-naphthyl, Et, H)
2l (6-methoxy-2-naphthyl, Et, H)
2m (i-Pr, Et, H)
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
95
91
96
98
96
92
96
99
99
96
97
99
95
95
-
95 (S)
93 (-)
95 (-)
94 (+)
96 (-)
96 (-)
95 (-)
94 (-)
95 (-)
95 (S)
92 (+)
97 (-)
98 (+)
29 (-)c
d
Experimental Section
1-Substituted ethenylphosphonates 2a-m and (E)-1-phenylbute-
nylphosphonate 2n were prepared according to the known
methods.6,7,17
General Hydrogenation Procedure. To a solution of [Rh(COD)2]-
BF4 (1.0 mg, 0.0025 mmol) in 1 mL of CH2Cl2, which was placed in
a nitrogen-filled glovebox, was added 1.1 equiv of ligand (Sc,RFc,RP)-
1e. The mixture was stirred at room temperature for 30 min, and then
a solution of a substrate (0.25 mmol) in 1 mL of CH2Cl2 was added.
The reaction mixture was transferred to a Parr stainless autoclave. The
autoclave was purged three times with hydrogen and maintained a
hydrogen pressure of 10 bar. The hydrogenation was performed at
room temperature for 24 h. After carefully releasing the hydrogen,
the solvent was removed. The residue was filtered through a short
SiO2 column to remove the catalyst. The filtrate was concentrated under
reduced pressure, and the enantiomeric excess was determined by
HPLC on a chiral column.
(E)-2n (Ph, Et, Et)
2o (p-FC6H4, H, H)
a All reactions were performed with 0.25 mmol of substrates 2a-o at
room temperature under a H2 pressure of 10 bar in 2 mL of CH2Cl2 for
24 h. Substrate/[Rh(COD)2]BF4/ligand ) 1/0.01/0.011. Full conversions
were obtained in all cases except 2o. b The ee values were determined
by HPLC or GC on a chiral column. The absolute configuration was
determined by comparing the sign of optical rotation with reported data
or by comparison of chiral HPLC elution order with configurationally
defined examples. c Reaction was performed under a H2 pressure of 60
bar. d Not determined because of low conversions.
Diethyl 1-Phenylethylphosphonate (3a):6 colorless oil; 95% ee;
[R]25D ) -7.6 (c 1.06, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.14
(t, J ) 6.9 Hz, 3H), 1.27 (t, J ) 6.9 Hz, 3H), 1.58 (dd, J ) 17.9, 7.0
Hz, 3H), 3.19 (dq, J ) 22.0, 7.0 Hz, 1H), 3.79 (m, 1H), 3.92 (m, 1H),
4.03 (m, 2H), 7.24 (t, J ) 6.9 Hz, 1H), 7.29-7.36 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 15.6, 16.3, 16.4, 38.6 (d, J ) 136 Hz), 61.9,
62.4, 127.0, 128.4, 128.7, 138.0; 31P NMR (162 MHz, CDCl3) δ 30.2;
HPLC (Chiralpak AD-H, elute ) 5% i-propanol/95% n-hexane, flow
rate ) 1.0 mL/min, detector ) 215 nm), (S) t1 ) 7.56 min; (R) t2 )
8.98 min.
with the different ester group were submitted to this hydrogena-
tion. The results indicated that the ester function has little
influence on the enantioselectivity, and all of 1-phenyleth-
enylphosphonates 2a-c were hydrogenated in high enantiose-
lectivities (Table 2, entries 1-3). A range of diethyl 1-aryleth-
enylphosphonates 2d-l were then prepared and employed in
this hydrogenation. In all cases, the hydrogenation proceeded
to completion and provided the corresponding hydrogenation
product with high enantioselectivities (92-97% ee) as well as
good to excellent yields (Table 2, entries 4-12). The results
revealed that there is no major effect on the substitution pattern
of the substituent on the phenyl ring of substrates. For examples,
all of three substrates with a methoxy group on the phenyl ring
were hydrogenated in 94-96% ee (Table 2, entries 4-6).
Among all of the substrates with a para-substituent tested,
diethyl 1-(4-methoxyphenyl)ethenylphosphonate 2f was hydro-
genated with the best enantioselectivity of 96% ee (Table 2,
entry 6). Good enantioselectivity (92% ee) was also observed
in the hydrogenation of 1-naphthyl substituted substrate 2k
(Table 2, entry 11). In particular, diethyl 1-(6-methoxy-1-
naphthyl)ethenylphosphonate 2l, which showed low reactivity
in the Ir-catalyzed asymmetric hydrogenation, was completely
hydrogenated in excellent enantioselectivity (97% ee) (Table
2, entry 12). 1-Alkyl substituted substrate 2m was also
hydrogenated in 98% ee and 95% yield (Table 1, entry 13).
These results demonstrated the high efficiency of the present
catalytic system, representing the best results reported so far.
However, the present catalytic system is not efficient for the
hydrogenation of trisubstituted substrates (e.g., (E)-2n) (Table
1, entry 14). For the hydrogenation of phosphonic acid substrate
2o, low reactivity was observed (Table 1, entry 15).
Diethyl 1-(6-methoxy-2-naphthyl)ethylphosphonate (3l):7
white solid, mp 58-59 °C; 97% ee; [R]25 ) -16.0 (1.56, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.11 (t, J ) 6.9 Hz, 3H), 1.27 (t, J )
7.0 Hz, 3H), 1.65 (dd, J ) 18.2, 7.2 Hz, 3H), 3.31 (dq, J ) 22.4, 7.2
Hz, 1H), 3.77 (m, 1H), 3.89-3.94 (m, 4H), 4.03 (m, 2H), 7.10-7.14
(m, 2H), 7.47 (d, J ) 8.4 Hz, 1H), 7.69-7.771 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 15.8, 16.3 (d, J ) 5 Hz), 16.5 (d, J ) 5 Hz),
38.4, 55.3, 61.9 (d, J ) 6 Hz), 62.4 (d, J ) 6 Hz), 105.6, 118.9, 126.8,
127.1 (d, J ) 8 Hz), 127.5 (d, J ) 4 Hz), 128.9, 129.3, 133.2 (d, J )
6 Hz), 133.7, 157.6; 31P NMR (162 MHz, CDCl3) δ 30.2; HPLC
(Chiralpak AD-H, elute ) 5% i-propanol/95% n-hexane, flow rate )
1.0 mL/min, detector ) 215 nm), (S) t1 ) 20.88 min; (R) t2 ) 33.03
min.
Acknowledgment. We are grateful for the generous financial
support from the National Natural Science Foundation of China
(20802076, 20873145) and the Knowledge Innovation Program
of the Chinese Academy of Sciences (DICP-S200802). We
thank Dr. Josh Chong for his help in writing.
Supporting Information Available: 1H, 31P, and 13C NMR
spectra, and analysis of ee values of the hydrogenation products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900417M
In conclusion, we have disclosed that a series of chiral 1-aryl or
(17) Krueger, W. E.; Mclean, M. B.; Rizwaniuk, A.; Maloney, J. R.; Behelfer,
1-alkyl substituted ethylphosphonates could be synthesized in high
G. L.; Boland, B. E. J. Org. Chem. 1978, 43, 2877–2879.
4410 J. Org. Chem. Vol. 74, No. 11, 2009