Enantioselective Rh-catalyzed hydrogenation of 3-aryl-4-phosphonobutenoates with a P-stereogenic BoPhoz-type ligand

Article abstract of DOI:10.1021/jo101849b

A series of chiral 3-aryl-4-phosphonobutyric acid esters were synthesized in high enantioselectivities (93-98% ee) via the Rh-catalyzed asymmetric hydrogenation of the corresponding 3-aryl-4-phosphonobutenoates using a P-stereogenic BoPhoz-type phosphine-aminophosphine ligand. The methodology has been successfully applied to the asymmetric synthesis of a potential GABA _B antagonist, (R)-phaclofen, in high enantioselectivity.

Full text of DOI:10.1021/jo101849b

pubs.acs.org/joc
Indeed, such methods are among the most studied and widely
Enantioselective Rh-Catalyzed Hydrogenation of
3-Aryl-4-phosphonobutenoates with a P-Stereogenic
BoPhoz-Type Ligand
applied for the enantioselective preparation of a variety of R- or
β-substituted phosphonic acid derivatives (i.e., R-hydroxy-
phosphonates,3 R-aminophosphonates,4 R-alkylphosphonates,5
and 3-phosphonopropanoic acid derivatives6). To the best of
our knowledge, however, enantioselective synthesis of 4-phos-
phonobutyric acid derivatives via the catalytic enantioselective
hydrogenation with chiral metal complexes remains an un-
explored area. These kinds of chiral compounds are very useful
precursors to other optically active phosphonic acid derivatives
such as 3-aminopropane-1-phosphonic acids, which are poten-
tial GABAB antagonists. Herein, we describe the first highly
enantioselective synthesis of a series of chiral 3-aryl-4-phos-
phonobutyric acid esters via a rhodium-catalyzed asym-
metric hydrogenation with a P-stereogenic Bophoz-type
phosphine-aminophosphine ligand.
Zheng-Chao Duan,†,‡ Xiang-Ping Hu,*,† Cheng Zhang,†,‡
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 September 18, 2010
The basic strategy for the synthesis of chiral 3-substituted
4-phosphonobutyric acid esters involved asymmetric hydro-
genation of the corresponding 4-phosphonobutenoates. The
latter can be easily prepared from ketones through a three-step
transformation as outlined in Scheme 1. Initially, the unsat-
urated esters were obtained by the Horner-Wittig reaction, in
which (E)-isomers were formed predominantly.7 Bromination
(3) (a) Burk, M. J.; Stammers, T. A.; Straub, J. A. Org. Lett. 1999, 1, 387–
390. (b) Gridnev, I. D.; Higashi, N.; Imamoto, T. J. Am. Chem. Soc. 2001,
123, 4631–4632. (c) Gridnev, I. D.; Yasutake, M.; Imamoto, T.; Beletskaya,
I. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5385–5390. (d) Liu, H.; Zhou,
Y.-G.; Yu, Z.-K.; Xiao, W.-J.; Liu, S.-H.; He, H.-W. Tetrahedron 2006, 62,
A series of chiral 3-aryl-4-phosphonobutyric acid esters
were synthesized in high enantioselectivities (93-98% ee)
via the Rh-catalyzed asymmetric hydrogenation of the
corresponding 3-aryl-4-phosphonobutenoates using a
P-stereogenic BoPhoz-type phosphine-aminophosphine
ligand. The methodology has been successfully applied to
the asymmetric synthesis of a potential GABAB antagonist,
(R)-phaclofen, in high enantioselectivity.
ꢀ
ꢀ
11207–11217. (e) Rubio, M.; Suarez, A.; Alvarez, E.; Pizzano, A. Chem.
ꢀ
ꢀ
Commun. 2005, 628–630. (f) Rubio, M.; Vargas, S.; Suarez, A.; Alvarez, E.;
Pizzano, A. Chem.;Eur. J. 2007, 13, 1821–1833. (g) Wang, D.-Y.; Hu,
X.-P.; Huang, J.-D.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Xu, X.-F.; Zheng, Z.
Angew. Chem., Int. Ed. 2007, 46, 7810–7813. (l) 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. (m) Qiu, M.; Hu, X.-P.; Huang, J.-D.; Wang, D.-Y.; Deng, J.;
Yu, S.-B.; Duan, Z.-C.; Zheng, Z. Adv. Synth. Catal. 2008, 350, 2683–2689.
(n) Yu, S.-B.; Huang, J.-D.; Wang, D.-Y.; Hu, X.-P.; Deng, J.; Duan, Z.-C.;
Zheng, Z. Tetrahedron: Asymmetry 2008, 19, 1862–1866. (i) Wassenaar, J.;
Reek, J. N. H. J. Org. Chem. 2009, 74, 8403–8406. (h) Wassenaar, J.; Kuil,
M.; Lutz, M.; Spek, A. L.; Reek, J. N. H. Chem.;Eur. J. 2010, 16, 6509–
ꢀ
ꢀ
6517. (j) Fernandez-Perez, H.; Donald, S. M. A.; Munslow, I. J.; Benet-
Buchholz, J.; Maseras, F.; Vidal-Ferran, A. Chem.;Eur. J. 2010, 16, 6495–
6508. (k) Zupancic, B.; Mohar, B.; Stephan, M. Org. Lett. 2010, 12, 1296–
1299.
Optically active phosphonates, as isosteres of carboxy-
lates, are important substrates in the study of biochemical
processes and reveal diverse and interesting biological and
biochemical properties in their role as enzyme inhibitors, agro-
chemicals, or pharmaceuticals.1 The enantioselective access
to these compounds, in particular by a catalytic method, has
therefore drawn a great deal of attention in the past few
decades.2 Given its inherent efficiency and atom economy,
the catalytic asymmetric hydrogenation of prochiral phos-
phonate derivatives is certainly one of the simplest and the
most efficient approaches to prepare chiral phosphonates.
€
(4) (a) Schollkopf, U.; Hoppe, I.; Thiele, A. Liebigs Ann. Chem. 1985,
555–559. (b) Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori,
R. Tetrahedron Lett. 1995, 36, 5769–5772. (c) Schmidt, U.; Oehme, G.;
Krause, H. Synth. Commun. 1996, 26, 777–781. (d) Holz, J.; Quirmbach, M.;
€
€
Schmidt, U.; Heller, D.; Sturmer, R.; Borner, A. J. Org. Chem. 1998, 63,
8031–8034. (e) Grassert, I.; Schmidt, U.; Ziegler, S.; Fischer, C.; Oehme, G.
Tetrahedron: Asymmetry 1998, 9, 4193–4202. (f) Dwars, T.; Schmidt, U.;
€
Fischer, C.; Grassert, I.; Kempe, R.; Frohlich, R.; Drauz, K.; Oehme, G.
Angew. Chem., Int. Ed. 1998, 37, 2851–2853.
^
(5) (a) Henry, J.-C.; Lavergne, D.; Ratovelomanana-Vidal, V.; Genet, J.-P.;
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,
^
D.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron: Asymmetry 2001, 12,
319–327. (c) Goulioukina, N. S.; Dolgina, T. M.; Bondarenko, G. N.; Beletskaya,
I. P.;Ilyin, M. M.;Davankov, V. A.;Pfaltz, A.Tetrahedron: Asymmetry 2003, 14,
1397–1401. (d) Wang, D.-Y.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Zheng,
Z. J. Org. Chem. 2009, 74, 4408–4410. (e) Cheruku, P.; Paptchikhine, A.; Church,
T. L.; Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8285–8289.
(6) (a) Badkar, P. A.; Rath, N. P.; Spilling, C. D. Org. Lett. 2007, 9, 3619–
3622. (b) Wang, D.-Y.; Hu, X.-P.; Hou, C.-J.; Deng, J.; Yu, S.-B.; Duan, Z.-C.;
Huang, J.-D.; Zheng, Z. Org. Lett. 2009, 11, 3226–3229.
(7) (a) Allan, R. D.; Bates, M. C.; Drew, C. A.; Duke, R. K.; Hambley,
T. W.; Johnston, G. A. R.; Mewett, K. N.; Spence, I. Tetrahedron 1990, 46,
2511–2524. (b) Varala, R.; Adapa, S. R. Synth. Commun. 2006, 36, 3743–
3747.
(1) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
1990, 31, 5587–5590. (b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free,
C. A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.; Petrillo,
E. W., Jr. J. Med. Chem. 1995, 38, 4557–4569. (c) Wang, C.-L. J.; Taylor,
T. L.; Mical, A. J.; Spitz, S.; Reilly, T. M. Tetrahedron Lett. 1992, 33, 7667–
7670. (d) Dellaria, J. F., Jr.; Maki, R. G. Tetrahedron Lett. 1986, 27, 2337–
2340. (e) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D.
Tetrahedron Lett. 1992, 33, 6625–6628.
(2) Modern Phosphonate Chemistry; Savignac, P., Iorga, B., Eds.; CRC
Press: Boca Raton, 2003.
DOI: 10.1021/jo101849b
r
Published on Web 11/09/2010
J. Org. Chem. 2010, 75, 8319–8321 8319
2010 American Chemical Society

Duan et al.
JOCNote
TABLE 1. Asymmetric Hydrogenation of 3-Phenyl-4-Phosphonobu-
tenoates 5a-5da
entry
ligand
FAPhos
WalPhos
substrate (R1, R2) solvent conv. (%)b ee (%)c
1
2
3
4
5
6
7
8
9
5a (IPr, IPr)
5a (IPr, IPr)
5a (IPr, IPr)
5a (IPr, IPr)
5a (IPr, IPr)
5b (Et, IPr)
5c (Et, Et)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
87
100
94
100
100
100
100
100
100
80
25
<10
30
78
85
94
96
98
96
91
95
95
BoPhoz
(Sc,Rp,RFc)-9a
(Sc,Rp,RFc)-9b
(Sc,Rp,RFc)-9b
(Sc,Rp,RFc)-9b
(Sc,Rp,RFc)-9b
(Sc,Rp,RFc)-9b
5d (Me, Me)
5d (Me, Me)
5d (Me, Me)
5d (Me, Me)
5d (Me, Me)
FIGURE 1. Structure of ligands for asymmetric hydrogenation.
SCHEME 1. Synthesis of 4-Phosphonobutenoates 5a-m
10 (Sc,Rp,RFc)-9b
11 (Sc,Rp,RFc)-9b
12 (Sc,Rp,RFc)-9b
toluene
MeOH
iPrOH
100
100
aThe reactions were carried out in 2 mL of solvent for 24 h under 60
bar of H2 with 0.25 mmol of substrate. Substrate/[Rh(COD)2]BF4/
ligand =100/1/1.1. bConversions were determined by GC. cEnantio-
meric excesses were determined by HPLC on a chiral column.
TABLE 2. Asymmetric Hydrogenation of 3-Substituted 4-Phosphono-
butenoates 5d-na
of (E)-3 with N-bromosuccinimide in the presence of benzoyl
peroxide gave the allylic bromides (4) in high yields.
The Arbusov reaction with phosphites gave the target
phosphonates 5.
With these substrates in hand, we attempted to find an
efficient catalyst for the highly enantioselective hydrogena-
tion of these 4-phosphonobutenoic acid esters. We focused
our efforts on searching for an appropriate chiral phosphorus
ligand for their demonstrated track record at affecting Rh-
catalyzed asymmetric hydrogenations of phosphonates. Ini-
tially, 4-(diisopropoxyphosphoryl)-3-phenylbut-2-enoic acid
isopropyl ester 5a was employed as the standard substrate
in the ligand screening with a diverse array of chiral phos-
phorus-containing ligands, which are commercially available
or developed within our research group. A few representative
ligands screened are shown in Figure 1. Surprisingly, poor
enantioselectivity (25% ee) was obtained for a (Rc,Sa)-FAPhos
6, which was effective for the hydrogenation of unfunctio-
nalized β,γ-unsaturated phosphonates (Table 1, entry 1).8
(Rc,RFc)-WalPhos 7 offered full conversion but low enan-
tioselectivity (<10% ee) (entry 2).9 While (Sc,RFc)-BoPhoz 8
displayed poor performance (entry 3),10 higher conversion
and better enantioselectivity were achieved with a modified
BoPhoz-type ligand 9a bearing a P-stereogenic center (entry 4).11
Subsequent optimization of the BoPhoz* skeleton disclosed
that ligand 9b with a CF3 group on the 4-position of the
entry
substrate (R)
(Z)-5d: R = Ph
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
99
96
97
91
99
99
98
92
96
97
98 (-)
95 (-)
97 (-)
93 (-)
95 (-)
96 (S)
97 (-)
96 (-)
94 (-)
93 (-)
(Z)-5e: R = 2-MeOC6H4
(Z)-5f: R = 3-MeOC6H4
(Z)-5g: R = 4-MeOC6H4
(Z)-5h: R = 4-FC6H4
(Z)-5i: R = 4-ClC6H4
(Z)-5j: R = 4-BrC6H4
(Z)-5k: R = 4-NO2C6H4
(Z)-5l: R = 2-naphthyl
(Z)-5m: R = 2-thiophenyl
(Z/E)-5n: R = Me
9
10
11
d
-
d
-
aThe reactions were carried out in 2 mL of CH2Cl2 for 24 h under 60
bar of H2 with 0.25 mmol of substrate. Substrate/[Rh(COD)2]BF4/
ligand =100/1/1.1. bIsolated yields. cThe ee values were determined by
HPLC on a chiral column.. dNot determined due to low conversion
phenyl ring gave the best result (entry 5). Having established
the optimal ligand, we next investigated the effect of the ester
group of phosphonates on this hydrogenation. The results
indicated that the ester group had a significant effect in
enantioselectivities, and the substrate with the less sterically
demanding ester group tended to give better result (entries
5-8). When 4-(dimethoxyphosphoryl)-3-phenylbut-2-enoic
acid methyl ester 5d was used as the hydrogenation substrate,
excellent enantioselectivity (98%) was achieved (entry 8). We
also screened several solvents for the reaction (entries 8-12).
However, no results surpassed that obtained in CH2Cl2.
To demonstrate the efficiency of this method, we next
examined a variety of 4-(dimethoxyphosphoryl)-3-arylbut-
2-enoic acid methyl esters under the optimized hydrogenation
(8) (a) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.; Zheng, Z. J.
Org. Chem. 2006, 71, 393–396. (b) Duan, Z.-C.; Hu, X.-P.; Zhang, C.; Wang,
D.-Y.; Yu, S.-B.; Zheng, Z. J. Org. Chem. 2009, 74, 9191–9194.
(9) Sturm, T.; Weissensteiner, W.; Spindler, F. Adv. Synth. Catal. 2003,
345, 160–164.
(10) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Org. Lett. 2002, 4, 2421–2424. (b) Boaz, N. W.; Mackenzie, E. B.; Debenham,
S. D.; Large, S. E.; Ponasik, J. A., Jr. J. Org. Chem. 2005, 70, 1872–1880.
(11) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. J. Am. Chem.
Soc. 2006, 128, 3922–3923.
8320 J. Org. Chem. Vol. 75, No. 23, 2010

Duan et al.
JOCNote
SCHEME 2. Stereoselective Synthesis of (R)-Phaclofen
In summary, we have developed a highly efficient method for
the enantioselective synthesis of 3-aryl-4-phosphonobutyric acid
esters via the first Rh-catalyzed asymmetric hydrogenation of
3-aryl-4-phosphono-butenoate, in which 93-98% ee were
achieved. This method is potentially useful for the preparation
of a number of chiral pharmaceuticals such as (R)-phaclofen.
Further investigation will be reported in due course.
Experimental Section
R,β-Unsaturated esters 3 and allylic bromides 4 were
prepared according to the known methods.7
General Procedure for the Preparation of 3-Aryl-4-phospho-
nobutenoates 5. A solution of allylic bromides 4 (10 mmol) and
trimethyl phosphite (3 equiv., 30 mmol) was heated to 150 °C
and stirred at the same temperature for 3 h. Excess trimethyl
phosphite were removed in vacuo. Flash chromatography of the
residue on silica gel (AcOEt/hexane 1:1) gave pure product.
Methyl 3-(4-chlorophenyl)-4-(dimethoxyphosphoryl)but-2-
conditions, and the results are shown in Table 2. Full
conversions and good to excellent enantioselectivities were
obtained for all of the substrates. The results indicated that
there is only a slight influence on the substitution pattern of
the substituent on the phenyl ring of substrates (entries 2-4).
All three substrates with a methoxy group on the phenyl ring
were hydrogenated in good enantioselectivities (93-97% ee)
(entries 2-4). The electronic properties of the substituent on
the 4-position of the phenyl ring of substrates also showed
little effect on the enantioselectivity, all substrates with a para
substituent were hydrogenated in 93-97% ee (entries 4-8).
4-(Dimethoxyphosphoryl)-3-(2-naphthyl)but-2-enoic acid
methyl ester also worked well, giving an ee-value of up to
94% (entry 9). Good enantioselectivity (93% ee) was also
observed in the hydrogenation of the substrate containing a
thiophene-heteroaryl group (entry 10). However, low con-
version was achieved in the hydrogenation of 3-alkyl-
substituted substrate 5n (entry 11).
To explore the synthetic utility of this method, we em-
ployed it as a key step in the enantioselective synthesis of
(R)-phaclofen, a potential GABAB antagonist,12 as shown in
Scheme 2. The studies have disclosed that the GABAB
receptor affinity and antagonist effect of phaclofen resides
in the (R)-enantiomer.13 The present method for obtaining
optically active (R)-phaclofen involved the resolution of
racemic phaclofen, and there is still no report of an asym-
metric method.14 The development of an enantioselective
approach for the synthesis of (R)-phaclofen is therefore
highly desirable. For the synthesis of (R)-phaclofen, (S)-10i
was obtained as a key chiral intermediate in 96% ee by use of
the present hydrogenation method. Hydrolysis of (S)-10i
with aqueous HCl followed by treatment with NaN3 in
sulfuric acid at ambient temperature gave (R)-phaclofen
in 61% yield.
1
enoate (5i). 72% yield; H NMR (400 MHz, CDCl3) δ 3.61
(s, 3H), 3.64 (s, 3H), 3.78 (s, 3H), 3.90 (d, J = 24.4 Hz, 2H), 6.20
(d, J = 5.6 Hz, 1H), 7.35-7.37 (m, 2H), 7.46-7.49 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 28.6 (d, J = 134.0 Hz), 51.4, 52.7,
119.8 (d, J = 10.0 Hz), 128.2, 128.8, 135.4, 138.7, 148.3 (d,
J = 11.0 Hz), 166.4; 31P NMR (162 MHz, CDCl3) δ 27.2; HRMS
calcd for C13H16ClO5NaP [M þ Na] 341.0322, found 341.0320.
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,Rp,RFc)-9b. The mixture was stirred at room temperature for
15 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 a hydrogen pressure of 60 bar was maintained. The
hydrogenation was performed at room temperature for 24 h. After
careful release of 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.
Methyl 3-(4-chlorophenyl)-4-(dimethoxyphosphoryl)-butanoate
(10i): 96% ee; [R]25D = -3.53 (1.4, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 2.07-2.22 (m, 2H), 2.61-2.67 (m, 1H), 2.86-2.91
(m, 1H), 3.52-3.61 (m, 10H), 7.17-7.19 (m, 2H), 7.27-7.29
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 31.2 (d, J = 139.0 Hz),
35.9, 41.3 (d, J = 11.0 Hz), 51.6, 52.1, 52.3, 128.7, 132.8, 141.4
(d, J = 9.0 Hz), 171.6; 31P NMR (162 MHz, CDCl3) δ 31.4;
HRMS calcd for C13H18O5PCl 320.0580, found 320.0572;
HPLC (Chiralpak AS-H, elute: 10% 2-propanol/90% n-hexane,
flow rate: 1.0 mL/min, detector: 215 nm), (S) t1 = 36.0 min;
(R) t2 = 42.6 min.
Acknowledgment. We are grateful for the generous finan-
cial support from the National Natural Science Foundation
of China (20802076, 20873145, and 20972156), the Knowl-
edge Innovation Program of the Chinese Academy of Sciences
(DICP-S200802), and the Planned Science and Technology
Project of Dalian (2009E11SF132).
(12) (a) Kerr, D. I.; Ong, J.; Prager, R. H.; Gynther, B. D.; Curtis, D. R.
Brain Res. 1987, 405, 150–154. (b) Nishikawa, M.; Kuriyama, K. Neurochem.
Int. 1989, 14, 85–90.
(13) Frydenvang, K.; Hansen, J. J.; Krogsgaard-Larsen, P.; Mitrovic, A.;
Tran, H.; Drew, C. A.; Johnston, G. A. R. Chirality 1994, 6, 583–589.
(14) (a) Chiefari, J.; Galanopoulos, S.; Janowski, W. K.; Kerr, D. I. B.;
Prager, R. H. Aust. J. Chem. 1987, 40, 1511–1518. (b) Robinson, T. N.; Cross,
A. J.; Green, A. R.; Toczek, J. M.; Boar, B. R. Br. J. Pharmacol. 1989, 98,
833–840. (c) Hall, R. G. Synthesis 1989, 442–443. (d) Abbenante, G.; Hughes,
R.; Prager, R. H. Aust. J. Chem. 1997, 50, 523–527.
Supporting Information Available: Experimental details,
spectra for new compounds, and analysis of ee values of the
hydrogenation products. This material is available free of
charge via the Internet at http://pubs.acs.org.
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