Synthesis of monodentate chiral spiro phosphonites and the electronic effect of ligand in asymmetric hydrogenation

Article abstract of DOI:10.1021/jo049146x

New monodentate chiral phosphonites were synthesized from enantiomerically pure 1,1′-spirobiindane-7,7′-diol. The phosphonites 2 were efficient ligands for the Rh-catalyzed asymmetric hydrogenation of α- and β-dehydroamino acid derivatives, providing the

Full text of DOI:10.1021/jo049146x

Synthesis of Monodentate Chiral Spiro
Phosphonites and the Electronic Effect of
Ligand in Asymmetric Hydrogenation
Yu Fu, Guo-Hua Hou, Jian-Hua Xie, Liang Xing,
Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic
Chemistry, Nankai University, Tianjin 300071, China
FIGURE 1. Chiral spiro monophosphorus ligands.
glzhou@nankai.edu.cn
Received May 20, 2004
applied in asymmetric hydrogenation of functionalized
olefins with good to excellent enantioselectivities. We
demonstrated that the chiral spiro phosphoramidite
(SIPHOS, 1) derived from 1,1′-spirobiindane-7,7′-diol was
highly enantioselective for Rh-catalyzed asymmetric
hydrogenation of R-dehydroamino acid derivatives and
R-arylenamides (Figure 1).8
Abstract: New monodentate chiral phosphonites were
synthesized from enantiomerically pure 1,1′-spirobiindane-
7,7′-diol. The phosphonites 2 were efficient ligands for the
Rh-catalyzed asymmetric hydrogenation of R- and â-dehy-
droamino acid derivatives, providing the amino acids in high
enantioselectivities. The study of electronic effect showed
that the electron-withdrawing substitutent on the P-phenyl
ring of the phosphonite ligand dramatically decreased both
the reactivity and enantioselectivity of the ligand.
In the design of a chiral ligand applied in asymmetric
catalyzed reaction, most considerations are based on the
steric effect.1c By contrast, the electronic effect of ligands
has been less explored.9 In the optimization of SIPHOS
ligands for Rh-catalyzed hydrogenation, we found that
the ligand with smaller N-alkyl groups provided a higher
enantioselectivity.8b,10 However, when the substituents
possessing different electronic properties were introduced
into the rings of the spirobiindane backbone of SIPHOS
ligands, only a weak electronic effect was observed in the
Rh-catalyzed hydrogenations.11 The weakness of the
electronic effect might be attributed to the fact that the
rings of spirobiindane in SIPHOS ligands are not directly
connected to the P-atom and the electronic property of
the substituents could not be efficiently transferred to
the P-atom. To study the real electronic effect of mono-
dentate phosphorus ligand in asymmetric hydrogenation,
we herein describe the synthesis of chiral spiro phospho-
nite ligands 2 and the investigation on their behaviors
in the enantioselective Rh-catalyzed hydrogenations of
R- and â-dehydroamino acid derivatives.
The design and synthesis of new chiral ligands is the
key to developing highly efficient enantioselective transi-
tion-metal-catalyzed reactions. In the past three decades,
a tremendous amount of chelating diphosphane ligands
have been prepared and applied in asymmetric hydro-
genation with excellent enantioselectivities.1 In contrast,
the development of monodentate chiral phosphorus ligands
for asymmetric hydrogenation has not attracted much
attention, although the earliest chiral ligands used by
Knowles and Horner were monophosphines.2 Recently,
the potential of chiral monodentate phosphorus ligands
was rediscovered,3 and several efficient chiral monophos-
phorus compounds, such as phospholane,4 phosphonites,5
phosphites,6 and phosphoamidites,7 were successfully
(1) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH:
New York, 2000. (b) Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (c) Tang,
W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(2) (a) Knowles, W. S.; Sabacky, M. J. J. Chem. Soc., Chem.
Commun. 1968, 1445. (b) Horner, L.; Siegel, H.; Bu¨the, H. Angew.
Chem., Int. Ed. Engl. 1968, 7, 942.
(3) For reviews, see: (a) Lagasse, F.; Kagan, H. B. Chem. Pharm.
Bull. 2000, 48, 315. (b) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int.
Ed. 2001, 40, 1197. (c) Ansell, J.; Wills, M. Chem. Soc. Rev. 2002, 31,
259.
The phosphonites 2 were easily prepared by the
reaction of optically pure 1,1′-spirobiindane-7,7′-diol and
the corresponding dichloroarylphosphine (ArPCl2) in the
presence of Et3N (Scheme 1) at room temperature in 56-
81% yields. To minimize the influence of steric hindrance,
the substituents were introduced into the para position
of the P-phenyl group.
(4) (a) Guillen, F.; Fiaud, J. C. Tetrahedron Lett. 1999, 40, 2939.
(2) Junge, K.; Oehme, G.; Monsees, A.; Riermeier, T.; Dingerdissen,
U.; Beller, M. Tetrahedron Lett. 2002, 43, 4977.
The Rh-catalyzed hydrogenation of methyl (Z)-2-ac-
etaminocinnamate, which is a standard reaction to test
(5) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D.
J.; Martorell, A.; Orpen, A. J.; Pringle, P. G. Chem. Commun. 2000,
961. (b) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333.
(6) (a) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39,
3889. (b) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333. (c)
Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 2897. (d) Reetz, M. T.;
Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem., Int. Ed. 2003, 42,
790.
(7) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539. (b) van den Berg, M.; Minnaard, A. J.; Haak, R. M.;
Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A.
H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.;
Henderickx, H. J. W.; de Vries, J. G. Adv. Synth. Catal. 2003, 345,
308. (c) Zeng, Q.; Liu, H.; Mi, A.; Jiang, Y.; Li, X. S.; Choi, M. C. K.;
Chan, A. S. C. Tetrahedron 2002, 58, 8799. (d) Jia, X.; Guo, R.; Li, X.;
Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 5541.
(8) (a) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou,
Q.-L. Chem. Commun. 2002, 480. (b) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou,
H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348.
(9) For recent papers, see: (a) Zhang, Z.; Qian, H.; Longmire, J.;
Zhang, X. J. Org. Chem. 2000, 65, 6223. (b) Saito, T.; Yokozawa, T.;
Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv.
Synth. Catal. 2001, 343, 264. (c) Pai, C. C.; Li, Y. M.; Zhou, Z. Y.; Chan,
A. S. C. Tetrahedron Lett. 2002, 43, 2789. (d) Jeulin, S.; de Paule, S.
D.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P.
Angew. Chem., Int. Ed. 2004, 43, 320.
(10) A favorable influence of small groups on the nitrogen in the
MonoPhos ligands was also described by another group; see: Pen˜a,
D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2002, 124, 14552.
(11) Zhu, S.-F.; Fu, Y.; Xie, J.-H.; Liu, B.; Xing, L.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2003, 14, 3219.
10.1021/jo049146x CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
J. Org. Chem. 2004, 69, 8157-8160
8157

TABLE 2. Hydrogenation of r-Dehydroamino Acid
Derivatives with Ligand (S)-2ca
SCHEME 1. Syntheses of Spiro Phosphonite
Ligands 2
substrate (Ar)
eeb (%)
config
C6H5
99
99
98
99
99
98
97
99
98
S
S
S
S
S
S
S
S
S
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
TABLE 1. Asymmetric Hydrogenation of Methyl
(Z)-2-Acetamidocinnamate Using Rh/(S)-2 Catalystsa
a Rh(COD)2BF4/(S)-2c/substrate ) 1:2:100, 6 h, 100% conver-
sions and quantitative yields were obtained in all reactions.
b Determined by chiral GC using Varian Chiralsil-L-Val column
or by chiral HPLC using a Chiralcel OJ or OD column.
ligand
solvent
timeb (h)
eec (%)
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-1
MeOH
CH2Cl2
acetone
THF
EtOAc
toluene
toluene
toluene
toluene
toluene
toluene
4
2
74
91
81
95
96
98
97
99
93
82
97
4
tivities.10 However, for most of these catalytic systems,
high enantioselectivity can only be obtained when pure
Z- or E-isomers of â-(acylamino)acrylate substrates are
used in the hydrogenation. Very few catalysts have been
reported to be efficient for the hydrogenation of Z/E
mixtures of â-(acylamino)acrylates.12a,13 Since the â-(acyl-
amino)acrylates are normally formed as a mixture of Z-
and E-isomers, the development of a new efficient
catalyst that can hydrogenate the mixture of two isomers
is significantly important.
3
2
3
3
2
10
24
4
a Rh(COD)2BF4/2/substrate ) 1:2:100. b Time for 100% conver-
sion. Quantitative yields were obtained in all reactions. c Deter-
mined by chiral GC using a Varian Chiralsil-L-Val column. The
absolute configurations of product were S.
The hydrogenation of methyl (Z/E)-â-(acetamino)cin-
namate (Z/E ) 88:12) was used to optimize reaction
conditions. Screening of solvents showed that the CH2-
Cl2 was the suitable solvent for obtaining high enantio-
selectivity. The comparison of ligand was performed in
CH2Cl2 under 100 bar H2 at room temperature. The
results are summarized in Table 3. The reactivities of
ligands 2a and 2b were similar to those of ligand
SIPHOS, while their enantioselectivities (92% ee) were
higher than that of ligand SIPHOS (90% ee). By intro-
ducing an electron-donating p-methoxy group, ligand 2c
slightly increased the enantioselectivity to 93% ee. But
ligands 2d and 2e, with electron-withdrawing groups,
gave incomplete reactions and much lower enantioselec-
tivities.
the efficiency of new phosphorus ligands, was chosen to
study the electronic effect in ligands 2. The reaction was
carried out in different solvents, and the toluene was
found to be the best choice. In toluene, the hydrogenation
product was obtained in quantitative yield and 98% ee
by using ligand 2a under 10 bar H2 at room temperature
for 3 h (Table 1). This result is slightly better than that
obtained by using phosphoramidite ligand SIPHOS (97%
ee in 4 h). The spiro phosphonite ligands with different
substituents were compared in toluene. The ligand 2c
bearing an electron-donating p-methoxy group was found
to have slightly higher reactivity and enantioselectivity
than its parent ligand 2a, producing the hydrogenation
product in 99% ee. However, the ligands 2d and 2e,
which contained electron-withdrawing substituents on
the P-phenyl group, had much lower reactivities and
enantioselectivities.
Using ligand 2c, a variety of R-dehydroamino acid
derivatives were hydrogenated in quantitative yield with
excellent enantioselectivities (97-99% ee). The electronic
and steric nature of a substituent on the phenyl ring of
substrate had little influence on the enantioselectivity
of the reaction (Table 2).
Catalytic asymmetric hydrogenation of â-(acylamino)-
acrylate derivatives provides a convenient method for the
synthesis of â-amino acid derivatives and has attracted
much attention. Among the ligands used in the Rh-
catalyzed hydrogenation of â-(acylamino)acrylate deriva-
tives, the diphosphines have been most effective.12 Re-
cently, monophosphoramidites were also successfully
employed in the Rh-catalyzed asymmetric hydrogenation
of â-(acylamino)acrylates, giving excellent enantioselec-
Different (Z/E)-â-aryl-â-(acetamino)acrylates (Z/E ) 98:
2-50:50) were hydrogenated by the rhodium complex of
2c (Table 3). The electronic property of a substituent also
has a significant influence on the reaction rate and
enantioselectivity. The substrates with an electron-
(12) For a review, see ref 1c. For recent papers, see: (a) Zhou, Y.-
G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 4952. (b) Tang, W.; Wu, S.; Zhang. X. J. Am. Chem. Soc. 2003,
125, 9570. (c) Tang, W.; Wang, W.; Chi, Y.; Zhang, X. Angew. Chem.,
Int. Ed. 2003, 42, 3509. (d) Holz, J.; Monsees, A.; Jiao, H.; You, J.;
Komarov, I. V.; Fischer, C.; Drauz, K.; Bo¨rner, A. J. Org. Chem. 2003,
68, 1701. (e) Wu, J.; Chen, X.; Guo, R.; Yeung, C.-H.; Chan, A. S. C. J.
Org. Chem. 2003, 68, 2490. (f) Jerphagnon, T.; Renaud, J.-L.; Demon-
chaux, P.; Ferreira, A.; Bruneau, C. Tetrahedron: Asymmetry 2003,
14, 1973. (g) Dubrovina, N. V.; Tararov, V. I.; Monsees, A.; Kadyrov,
R.; Fischer, C.; Bo¨rner, A. Tetrahedron: Asymmetry 2003, 14, 2739.
(h) You, J.; Drexler, H.-J.; Zhang, S.; Fischer, C.; Heller, D. Angew.
Chem. Int. Ed. 2003, 42, 913.
(13) 3. (a) Tang, W.; Zhang. X. Org. Lett. 2002, 4, 4159. (b) Lee, S.-
G.; Zhang, Y. J. Org. Lett. 2002, 4, 2429. (c) Jerphagnon, T.; Renaud,
J.-L.; Demonchaux, P.; Ferreira, A.; Bruneau, C. Adv. Synth. Catal.
2004, 346, 33.
8158 J. Org. Chem., Vol. 69, No. 23, 2004

TABLE 3. Hydrogenation of Methyl
sodium benzophenone ketyl. Anhydrous EtOAc, acetone, and
CH2Cl2 were distilled from calcium hydride. Anhydrous MeOH
was distilled from magnesium. SPINOL,15 R-dehydroamino
esters,16 and â-dehydroamino esters17 were prepared by reported
methods.
â-Aryl-â-(acetamino)acrylatesa
General Procedure for Synthesis of Spiro Phosphonite
Ligands. To a stirred solution of (S)-SPINOL (250 mg, 1.0
mmol) and Et3N (0.5 mL) in 5 mL of THF was added ArPCl2
(1.2 mmol) slowly at room temperature. The reaction mixture
was stirred at rt for 1 h, and the product was purified by flash
chromatography on a silica gel column using petroleum/EtOAc
as eluent.
ligand
substrate (Ar)
time (h)
convb (%)
eec (%)
(S)-1
Ph
40
40
40
40
48
48
36
36
36
48
48
48
100
100
100
100
70
90
92
92
93
87
40
94
95
98
90
85
91
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2c
(S)-2c
(S)-2c
(S)-2c
(S)-2c
(S)-2c
Ph
Ph
Ph
(S)-O,O′-[7,7′-(1,1′-Spirobiindan)]phenylphosphonite (2a):
oil; 77% yield; [R]20D ) -132 (c 0.5, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 1.98-2.12 (m, 2H), 2.21-3.33 (m, 2H), 2.84-2.92 (m,
2H), 3.01-3.16 (m, 2H), 5.76 (d, J ) 8 Hz, 1H), 6.68 (t, J ) 8
Hz, 1H), 6.91 (d, J ) 8 Hz, 1H), 7.00 (d, J ) 8 Hz, 1H), 7.10 (d,
J ) 8 Hz, 1H), 7.23-7.32 (m, 5H), 7.38-7.42 (m, 1H); 31P NMR
(121 MHz, CDCl3) δ 154.11; 13C NMR (75 MHz, CDCl3) δ 30.8,
31.2, 37.6, 38.2, 38.8, 59.2, 114.5, 117.9, 120.8, 121.0, 121.7,
122.2, 127.4, 128.6, 128.7, 129.1, 130.9, 131.2, 135.0, 140.8, 142.1,
142.6, 145.1, 145.7; IR (KBr) 2950, 2848, 1609, 1584, 1464, 1435,
1323, 1233, 1221, 1162, 1131, 1102, 1063, 1014, 992, 953, 922
cm-1; HRMS (EI) for C23H19O2P calcd 358.1122, found 358.1114.
(S)-O,O′-[7,7′-(1,1′-Spirobiindan)]-4-methylphenylphos-
Ph
Ph
30
4-CH3Ph
2-CH3OPh
4-CH3OPh
4-ClPh
3-BrPh
4-BrPh
100
100
100
100
100
100
a Rh(COD)2BF4/ligand/substrate ) 1:2:100. b Determined by GC.
Quantitative yields were obtained unless mentioned otherwise.
c Determined by chiral GC using a Varian Chiralsil-L-Val column
or chiral HPLC using a Chiralcel OD-H column. The absolute
configurations were R.
1
phonite (2b): oil; 81% yield; [R]20 ) -120 (c 0.5, CH2Cl2); H
D
NMR (300 MHz, CDCl3) δ 1.98-2.16 (m, 2H), 2.22-3.34 (m, 5H),
2.84-2.92 (m, 2H), 3.01-3.18 (m, 2H), 5.80 (d, J ) 8 Hz, 1H),
6.68-6.74 (m, 2H), 6.88-7.26 (m, 7H); 31P NMR (121 MHz,
CDCl3) δ 156.2; 13C NMR (75 MHz, CDCl3) δ 30.8, 31.2, 38.2,
38.8, 59.3, 120.9, 121.8, 122.1, 127.4, 127.9, 128.0, 129.2, 130.8,
131.1, 131.7, 137.8, 138.2, 140.8, 142.6, 145.1, 145.7, 145.9, 149.;
IR (KBr) 2950, 2849, 1584, 1464, 1233, 1221, 1162, 1102, 1014,
992, 922 cm-1; HRMS (FAB) for C24H21O2P + H+ calcd 373.1352,
found 373.1352.
donating substituent afforded faster reaction and higher
enantioselectivity. The highest enantioselectivity (98%
ee) was achieved in the hydrogenation of methyl â-(4-
methoxyphenyl)-â-(acetamino)acrylate. However, the sub-
strates with electron-withdrawing substituents had lower
reaction rates and enantioselectivities. Methyl â-(2-
boromophenyl)-â-(acetamino)acrylate cannot be hydro-
genated at the same conditions.
(S)-O,O′-[7,7′-(1,1′-Spirobiindan)]-4-methoxyphenylphos-
1
phonite (2c): oil; 77% yield; [R]20 ) -160 (c 0.5, CH2Cl2); H
D
In conclusion, we have developed novel chiral mono-
dentate phosphonite ligands with spirobiindane as a
backbone, which are highly effective for the Rh-catalyzed
asymmetric hydrogenations of R- and â-dehydroamino
acid derivatives. The enantioselectivities achieved in hy-
drogenation of (Z/E)-â-aryl-â-(acetamino)acrylates rep-
resent the highest level of enantiocontrol in the hydro-
genation of Z/E mixtures of â-dehydroamino acid deriva-
tives by using monophosphorus ligands. We also demon-
strated that the electron-donating substituents on the
P-phenyl ring of phosphonite ligands 2 have a limited
influence on the enantioselectivity of ligand, while the
electron-withdrawing substituents resulted in a signifi-
cant decrease in both reactivity and enantioselectivity
of ligand. To probe whether this detrimental effect was
caused by the electronic effect of ligand on the catalyst
or by the less efficiency of electron-poor ligand in the
coordination, we compared the coordinative behavior of
ligands 2a, 2c and 2e to rhodium. The coordinations of
all these three ligands to rhodium were complete in 5
min at the reaction conditions,14 which indicated that the
lower reaction rates and enantioselectivities of ligands
with electron-withdrawing substituents were mainly
attributed to the electronic effect of ligand on the catalyst.
NMR (300 MHz, CDCl3) δ 1.98-2.12 (m, 2H), 2.20-3.32 (m, 2H),
2.83-2.91 (m, 2H), 3.01-3.16 (m, 2H), 2.80 (s, 3H), 5.79 (d, J )
8 Hz, 1H), 6.70-6.79 (m, 3H), 6.91-7.00 (m, 2H), 7.08-7.27 (m,
4H); 31P NMR (121 MHz, CDCl3) δ 155.48; 13C NMR (75 MHz,
CDCl3) δ 30.8, 31.3, 38.2, 38.9, 55.4, 59.3, 113.4, 120.8, 121.3,
121.7, 122.3, 127.5, 129.2, 129.4, 129.8, 132.7, 133.1, 140.9, 142.6,
145.1, 145.7, 145.9, 150.1, 162.5; IR (KBr) 2949, 2844, 1594,
1500, 1464, 1293, 1253, 1222, 1179, 1162, 1132, 1105, 1014, 991,
921 cm-1; HRMS (FAB) for C24H21O3P + H+ calcd 389.1301,
found 389.1301.
(S)-O,O′-[7,7′-(1,1′-spirobiindan)]-4-chlorophenylphos-
1
phonite (2d): oil; 76% yield; [R]20 ) -120 (c 0.5, CH2Cl2); H
D
NMR (300 MHz, CDCl3) δ 1.98-2.14 (m, 2H), 2.21-3.33 (m, 2H),
2.84-2.92 (m, 2H), 3.02-3.18 (m, 2H), 5.78 (d, J ) 8 Hz, 1H),
6.74 (t, J ) 8 Hz, 1H), 6.93 (d, J ) 8 Hz, 1H), 6.99 (d, J ) 8 Hz,
1H), 7.11 (d, J ) 8 Hz, 1H), 7.18-7.28 (m, 5H); 31P NMR (121
MHz, CDCl3) δ 151.2; 13C NMR (75 MHz, CDCl3) δ 30.8, 31.2,
38.2, 38.9, 59.3, 114.5, 117.9, 120.9, 121.1, 122.0, 127.6, 128.3,
129.1, 132.2, 132.6, 136.3, 136.7, 138.0, 140.7, 142.5, 145.3, 145.8,
149.6; IR (KBr) 2948, 2846, 1918, 1609, 1581, 1464, 1386, 1319,
1300, 1233, 1221, 1161, 1132, 1086, 1012, 991, 952, 921 cm-1
HRMS (EI) for C23H18ClO2P, calcd 392.0733, found 392.0737.
;
(S)-O,O′-[7,7′-(1,1′-Spirobiindan)]-4-trifluoromethylphen-
ylphosphonite (2e): oil; 56% yield; [R]20 ) -108 (c 0.5, CH2-
D
Cl2); 1H NMR (300 MHz, CDCl3) δ 1.98-2.12 (m, 2H), 2.21-
3.34 (m, 2H), 2.84-2.93 (m, 2H), 3.04-3.18 (m, 2H), 5.74 (d, J
) 8 Hz, 1H), 6.69 (t, J ) 8 Hz, 1H), 6.92 (d, J ) 8 Hz, 1H), 7.00
(d, J ) 8 Hz, 1H), 7.13 (d, J ) 8 Hz, 1H), 7.25-7.29 (m, 1H),
Experimental Section
(15) (a) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron:
Asymmetry 1999, 10, 125. (b) Zhang, J.-H.; Liao, J.; Cui, X.; Yu, K.-B.;
Deng, J.-G.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L.; Chung, L.-W.; Ye, T.
Tetrahedron: Asymmtry 2002, 13, 1363.
General Methods. All reactions and manipulations were
performed in an argon atmosphere using standard Schlenk
techniques. Anhydrous toluene and THF were distilled from
(16) Herbst, R. M.; Shemin, D. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. II, p 1.
(14) 31P NMR: [Rh(2a)(COD)]BF4 δ 140.7 (d, JRh-P ) 208.8 Hz); [Rh-
(2c)(COD)BF4] δ 141.0 (d, JRh-P ) 197.1 Hz); Rh(2e)(COD)BF4] δ 137.7
(d, JRh-P ) 210.9 Hz).
(17) (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron:
Asymmetry 1991, 2, 543. (b) Krapacho, A. P.; Diamanti, J.; Zayen, C.;
Binghan, R. Org. Synth. 1973, 5, 198.
J. Org. Chem, Vol. 69, No. 23, 2004 8159

7.40-7.45 (m, 2H), 7.53 (d, J ) 8 Hz, 2H); 31P NMR (121 MHz,
CDCl3) δ 149.2; 13C NMR (75 MHz, CDCl3) δ 30.6, 31.0, 38.0,
38.7, 59.1, 114.3, 117.7, 120.5, 121.0, 121.5, 121.9, 124.5, 127.4,
129.1, 130.9, 140.4, 141.9, 142.3, 131.3, 145.1, 145.4, 145.6, 149.1;
IR (KBr) 2957, 2921, 2848, 1925, 1610, 1584, 1465, 1397, 1325,
General Procedure for Asymmetric Hydrogenation of
â-Dehydroamino Esters. A reaction tube equipped with a
stirring bar, in which 5 µmol of Rh(COD)2BF4, 11 µmol of ligand.
and 0.5 mmol of â-dehydroamino ester were added under an
inert atmosphere, was put into an autoclave. After 5 mL of
toluene added, the inert atmosphere was replaced by 10 hydrogen/
release cycles and the reaction mixture was allowed to stir under
100 bar of H2 pressure at room temperature for a proper time.
The resulting mixture was filtered through a short silica column
and submitted to analysis for conversion and ee values.
(R)-Methyl 3-acetylamido-3-phenylpropionate: 93% ee,
chiral GC Varian Chirasil-L-Val column, 25 m × 0.25 mm × 0.25
µm; N2 1.8 mL/min, 120 °C then 1 °C/min to 150 °C, tR ) 27.57
min, tS ) 28.24 min.
1235, 1220, 1163, 1130, 1119, 1060, 1014, 991, 953, 921 cm-1
HRMS (EI) for C24H18F3O2P calcd 426.0996, found 426.0995.
;
General Procedure for Catalytic Asymmetric Hydro-
genation of r-Dehydroamino Esters. A reaction tube equipped
with a stirring bar, in which 5 µmol of Rh(COD)2BF4, 11 µmol
of ligand, and 0.5 mmol of R-dehydroamino ester were added
under an inert atmosphere, was put into an autoclave. After 5
mL of toluene was added, the inert atmosphere was replaced
by 10 hydrogen/release cycles and the reaction mixture was left
stirring under 10 bar H2 pressure at room temperature for a
proper time. The resulting mixture was filtered through a short
silica column and submitted to analysis for conversion and ee
values.
(R)-Methyl 3-acetamido-3-(4-methylphenyl)propionate:
94% ee, chiral GC Varian Chirasil-L-Val column, 25 m × 0.25
mm × 0.25 µm; N2 2.0 mL/min, 120 °C then 1 °C/min to 160 °C,
tR ) 33.07 min, tS ) 33.97 min.
(S)-Methyl 2-acetamido-3-phenylpropionate: 99% ee, chiral
GC Varian Chirasil-L-Val column, 25 m × 0.25 mm × 0.25 µm;
N2, 1.8 mL/min, 90 °C then 4 °C/min to 160 °C, tR ) 17.54 min,
tS ) 18.40 min.
(R)-Methyl 3-acetamido-3-(2-methoxylphenyl)propionate:
i
95% ee, chiral HPLC Chiralcel OD-H column, 25 cm, PrOH/
Hex ) 10:90, 1.0 mL/min, tR ) 21.91 min, tS ) 33.42 min.
(R)-Methyl 3-acetamido-3-(4-methoxylphenyl)propionate:
98% ee, chiral GC Varian Chirasil-L-Val column, 25 m × 0.25
mm × 0.25 µm; N2 1.8 mL/min, 100 °C then 1 °C/min to 170 °C,
tR ) 67.03 min, tS ) 67.82 min.
(S)-Methyl 2-acetamido-3-(4-methylphenyl)propionate:
99% ee, chiral HPLC Chiralcel OJ column, 25 cm, iPrOH/Hex )
10:90, 1.0 mL/min, tR ) 9.33 min, tS ) 15.34 min.
(S)-Methyl 2-acetamido-3-(4-methoxyphenyl)propionate:
(R)-Methyl 3-acetamido-3-(4-chlorophenyl)propionate:
90% ee, chiral GC Varian Chirasil-L-Val column, 25 m × 0.25
mm × 0.25 µm; N2 1.8 mL/min, 120 °C then 1 °C/min to 170 °C,
tR ) 44.35 min, tS ) 45.28 min.
(R)-Methyl 3-acetamido-3-(3-bromophenyl)propionate:
85% ee, chiral GC Varian Chirasil-L-Val column, 25 m × 0.25
mm × 0.25 µm; N2 2.0 mL/min, 120 °C then 1 °C/min to 160 °C,
tR ) 26.28 min, tS ) 26.93 min.
(R)-Methyl 3-acetamido-3-(4-bromophenyl)propionate:
91% ee, chiral GC Varian Chirasil-L-Val column, 25 m × 0.25
mm × 0.25 µm; N2 2.0 mL/min, 120 °C then 1 °C/min to 160 °C,
tR ) 32.08 min, tS ) 32.67 min.
i
98% ee, HPLC Chiralcel OJ column, 25 cm, PrOH/Hex ) 10:
90, 1.0 mL/min, tR ) 6.42 min, tS ) 11.43 min.
(S)-Methyl 2-acetamido-3-(2-chlorophenyl)propionate:
99% ee, chiral HPLC Chiralcel OJ column, 25 cm, iPrOH/Hex )
10:90, 1.0 mL/min, tR ) 11.17 min, tS ) 13.89 min.
(S)-Methyl 2-acetamido-3-(3-chlorophenyl)propionate:
99% ee, chiral HPLC: Chiralcel OJ column, 25 cm, iPrOH/Hex
) 10:90, 1.0 mL/min, tR ) 19.83 min, tS ) 28.34 min.
(S)-Methyl 2-acetamido-3-(4-chlorophenyl)propionate:
98% ee, chiral HPLC Chiralcel OJ column, 25 cm, iPrOH/Hex )
10:90, 1.0 mL/min, tR ) 12.86 min, tS ) 17.21 min.
(S)-Methyl 2-acetamido-3-(2-nitrophenyl)propionate: 97%
ee, HPLC Chiralcel OD column, 25 cm, iPrOH/Hex ) 15:85, 1.0
mL/min, tR ) 19.92 min, tS ) 29.33 min.
Acknowledgment. We thank the National Natural
Science Foundation of China, the Major Basic Research
Development Program (Grant No. G2000077506), the
Ministry of Education of China, and the Committee of
Science and Technology of Tianjin for financial support.
(S)-Methyl 2-acetamido-3-(3-nitrophenyl)propionate: 99%
ee, HPLC Chiralcel OD column, 25 cm, iPrOH/Hex ) 15:85, 1.0
mL/min, tR ) 13.76 min, tS ) 17.20 min.
(S)-Methyl 2-acetamido-3-(4-nitrophenyl)propionate: 98%
ee, HPLC Chiralcel OD column, 25 cm, iPrOH/Hex ) 15:85, 1.0
mL/min, tR ) 17.13 min, tS ) 19.74 min.
JO049146X
8160 J. Org. Chem., Vol. 69, No. 23, 2004