Asymmetric hydrogenation of enamides with a new chiral phosphine- phosphinite ligand

Article abstract of DOI:10.1016/j.tetasy.2005.06.004

A new mixed chiral phosphine-phosphinite 4 obtained from enantiomerically pure (S)-(+)-3-boronatodiphenyl-phosphanyl butanoic acid 1 was synthesized in four steps. This new chiral ligand was used in the asymmetric hydrogenation of dehydroamino acids with

Full text of DOI:10.1016/j.tetasy.2005.06.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2455–2458
Asymmetric hydrogenation of enamides with a new
chiral phosphine–phosphinite ligand
*
´
Nicolas Boyer, Matthieu Leautey, Philippe Jubault,
Xavier Pannecoucke* and Jean-Charles Quirion
´ ´ ´ ´ `
Laboratoire d’Heterochimie Organique associe au CNRS, UMR 6014 IRCOF, INSA et Universite de Rouen, 1 rue Tesniere,
76821 Mont Saint-Aignan Cedex, France
Received 23 May 2005; accepted 7 June 2005
Abstract—A new mixed chiral phosphine–phosphinite 4 obtained from enantiomerically pure (S)-(+)-3-boronatodiphenyl-phosphan-
yl butanoic acid 1 was synthesized in four steps. This new chiral ligand was used in the asymmetric hydrogenation of dehydroamino
acids with enantioselectivities being obtained of up to 90.8%.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Hydrolysis of these compounds led to chiral intermedi-
ate 1.6 Herein, we report the synthesis of a new mixed
chiral phosphine–phosphinite 4 obtained from enantio-
merically pure (S)-(+)-3-boronatodiphenyl-phosphanyl
butanoic acid 1. The results of using this ligand in the
asymmetric hydrogenation of dehydroamino acids and
enantioselectivities are also discussed.
Chiral amino acids are important intermediates in pharma-
ceutical industry both as nutritional supplements and as
synthetic intermediates. A convenient synthesis of these
compounds is through the homogeneous catalytic asym-
metric hydrogenation of prochiral amidoacrylic acids or
esters. Rhodium catalysts containing chiral phosphine
ligands have proven to be highly effective for this type
of reaction.1 While the majority of the developments
in this area involve bidendate phosphine, phosphite,
and phosphinite ligands, or mixed phosphine–phos-
phite2 ligands, the corresponding phosphine–phosphi-
nite ligands have only rarely been exploited.3
2. Results and discussion
The synthesis of ligand 4 is outlined in Scheme 1. The
reduction of enantiomerically pure (S)-(+)-3-boronato-
diphenyl-phosphanyl butanoic acid 1 with borane solu-
tion in THF gave the corresponding hydroxyl
phosphine borane 2 in 70% yield. Removal of the bor-
ane protection7 (DABCO, toluene, 40 ꢁC, 8 h) led in
quantitative yields to the phosphine alcohol intermedi-
ate 3. The deprotonation of hydroxy phosphine 3 with
triethylamine followed by treatment with diphenylchloro-
phosphine in the presence of DMAP gave the expected
phosphine–phosphinite ligand 4 in 66% yield. Next,
the cationic Rh(I) complex was prepared by mixing
1 equiv of the ligand with 0.5 equiv of [RhCl(COD)]2
in methanol followed by the addition of 2 equiv of
sodium tetrafluoroborate solution in methanol leading
to the expected complex 5 in nearly quantitative yield. In
the 31P NMR spectrum of 5, resonance peaks of the
two phosphorus nuclei appeared as a doublet of doublet
d 19.3 (dd, JP–P = 38.6, JP–Rh = 149.1 Hz) and 136.1 (dd,
One of the targets in our study of catalytic asymmetry is
the development of effective chiral ligands that can be
easily prepared and successfully applied in asymmetric
synthesis. We have recently reported the synthesis of chi-
ral a-substituted b-amidophosphine boranes either by
diastereoselective alkylation4 of b-amidophosphine bor-
anes using classical O-benzylated phenylglycinol as the
chiral inducer, or by the 1,4-addition of nucleophilic
phosphine boranes species to a,b-unsaturated amides.5
*
Corresponding authors. Tel.: +33 2 35 522426; fax: +33 2 35 522959
(P.J.); tel.: +33 2 35 522427; fax: +33 2 35 522959 (X.P.); e-mail
addresses: philippe.jubault@insa-rouen.fr; xavier.pannecoucke@
insa-rouen.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.004

2456
N. Boyer et al. / Tetrahedron: Asymmetry 16 (2005) 2455–2458
CH3
CH3
O
BH3 / THF
Ph2P
BH3
OH
Ph2P
BH3
OH
0 ˚C to r.t.
70 %
2
1
DABCO / toluene
40 ˚C, 99 %
CH3
CH3
Ph2PCl, THF
Et3N, DMAP, 0˚C
Ph2P
OH
67 %
Ph2P
OPPh2
3
4
CH3
+
1. [RhCl(COD)]2 / MeOH
Ph2P
O
-
BF4
2. NaBF4 / MeOH
96 %
PPh2
Rh
(COD)
5
Scheme 1.
JP–P = 38.6, JP–Rh = 169.8 Hz) show that the phosphine–
phosphinite 4 coordinates to the rhodium in a bidendate
fashion.
hydrogen pressure, and substrate/catalyst ratio were
investigated. The results are summarized in Table 1.
Hydrogenation of 6a proceeded under an atmospheric
pressure of hydrogen in methanol and dichloromethane
(entries 1 and 5) to give the expected product with good
enantioselectivities (83.4–90.8% ee). When the substrate
concentration was lowered, we had to perform the
Asymmetric hydrogenations of methyl (Z)-a-acetamido-
cinnamate 6a and a-(N-acetamido)acrylate 6b were car-
ried out (Scheme 2). The effects of various reaction
parameters, such as solvent, substrate concentration,
CO2CH3
CO2CH3
5, solvent
H2
R
NHAc
R
NHAc
6a: R = Ph
6b: R = H
Scheme 2.
Table 1. Asymmetric hydrogenation of a-dehydroaminoacids 6a and 6b catalyzed by 7a
Entry
Substrate
S/C ratio
Solvent
Substrate (mol Lꢀ1
)
H2 (bars)
Time (h)
Conv (%)
eeb (%)
1
2
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
200
200
1000
200
200
200
200
200
200
200
MeOH
MeOH
MeOH
Acetone
CH2Cl2
AcOEt
MeOH
MeOH
CH2Cl2
AcOEt
0.25
0.13
0.13
0.25
0.25
0.25
0.25
0.10
0.25
0.25
1
1
1
1
100
76.5
100
37.2
100
2
83.4
88.8
84.4
89.6
90.8
—
3
10
1
21
1
4
5
1
1
6
1
1
7
1
1
100
100
43.6
14.4
83.4
88.1
90.7
83.6
8
1
1
9
10
1
1
1
1
a All reactions were carried out at room temperature.
b The ee values were determined by HPLC analysis as described in the literature. All products were in an (S)-configuration, based on the comparison
with published data.8

N. Boyer et al. / Tetrahedron: Asymmetry 16 (2005) 2455–2458
2457
asymmetric hydrogenation under 10 bars of pressure of
hydrogen for 21 h to obtain quantitative conversion
(entry 3). Conversely, asymmetric hydrogenation led to
low conversion in acetone (37% conversion, 89.6% ee,
entry 4) and in ethyl acetate (2% conversion, entry 6).
THF (4.1 mL, 4.1 mmol). The solution was stirred for
an hour at room temperature. The mixture was cooled
to 0 ꢁC, then water (5 mL) was added. The aqueous
phase was extracted with CH2Cl2 (3 · 15 mL). The
organic layers were dried over MgSO4. The solvent was
removed under vacuum and the residue subjected to col-
umn chromatography over SiO2 with cyclohexane–
EtOAc (v/v = 7:3) as an eluent to give the title compound
Hydrogenation of 6b in methanol led to quantitative
conversion and good enantioselectivity. Changing the
solvent (entries 9 and 10) provided good levels of enantio-
selectivity but much lower conversions.
20
1
2 as a white oil: ½aꢁ ¼ þ5.0 (c 1.1, CHCl3); H NMR
D
(300 MHz): d 0.5–0.8 (m, 3H), 1.05 (dd, J = 6.9,
16.6 Hz, 3H), 1.4–1.6 (m, 1H), 1.7–1.8 (m, 1H), 1.85 (s,
1H), 2.7–2.9 (m, 1H), 3.5–3.7 (m, 2H), 7.3–7.5 (m, 6H),
7.6–7.8 (m, 4H). 13C NMR (75.5 MHz): d 12.2 (d, J =
1.7 Hz), 25.3 (d, J = 37.7 Hz), 32 (d, J = 2.85 Hz), 58.7
(d, J = 12.6 Hz), 127, 127.4, 127.7, 127.8, 130.1, 130.2,
131.6, 131.7. 31P NMR (121.5 MHz): d 25.3. Anal. Calcd
for C16H22BOP: C, 70.59; H, 8.08. Found: C, 70.32; H,
8.21.
Finally, we carried out the asymmetric hydrogenation,
under an atmospheric pressure of hydrogen, in metha-
nol, of dimethyl itaconate. Under these conditions we
obtained the expected hydrogenated product in quanti-
tative conversion within an hour in 41.2% ee with an
(S)-configuration.
3. Conclusion
4.3. 3-(S)-Diphenylphosphanyl-butanol 3
In conclusion, a new, simple, chiral phosphine–phosph-
inite ligand has been synthesized and tested for the enan-
tioselective hydrogenation of dehydroamino acids. The
results demonstrate that complex 5 is a highly efficient
catalyst in asymmetric hydrogenation reactions. Further
investigations, especially by modifying the nature of the
group next to the phosphine moiety and the nature of
the phosphinite part, are currently under investigation
within our laboratory and will be reported in due course.
A solution of 2 (665 mg, 3.35 mmol) and DABCO
(1.51 g, 13.5 mmol) in freshly distilled toluene (17 mL)
was heated at 40 ꢁC for 4 h. The solution was then cooled
to room temperature and charged on silica pad (2 cm)
and eluted with 20 mL of toluene. Toluene was removed
under vacuum and the residue dissolved in dichloro-
methane (25 mL). The organic phase was washed with
1 M HCl (25 mL). The aqueous phase was then washed
with dichloromethane (10 mL). The organic layers were
dried over MgSO4. The solvent was removed under vac-
20
D
uum to give the title compound 3 as a yellow oil. ½aꢁ
¼
4. Experimental
4.1. General
ꢀ2.3 (c 1.0, CHCl3); 1H NMR (300 MHz): d 1.5 (br, 1H),
1.6–1.8 (m, 2H), 2–2.1 (m, 2H), 3.7 (t, J = 6.4 Hz, 2H),
7.1–7.5 (m, 10H). 13C NMR (75.5 MHz): d 21.8 (d, J =
13.7 Hz), 31.6 (d, J = 13.7 Hz), 32.2 (d, J = 11.4 Hz),
59.7 (d, J = 10.8 Hz), 127.2–127.6, 132.4–132.7, 136 (d,
J = 13.7). 31P NMR (121.5 MHz): d 0.5. Anal. Calcd
for C16H19OP: C, 74.33; H, 7.35. Found: C, 74.08; H,
7.45.
Optical rotations were measured using a sodium lamp at
ambient temperature and specific rotations are reported
as follows: [a]k (c g/100 mL) with the units of
degree g cmꢀ3. IR spectra were recorded using KBr pel-
lets or NaCl plates, with only partial data reported.
NMR spectra were recorded on a Bruker DX 300 spec-
trometer operating at 300 MHz for proton, 75.4 MHz
for carbon and 121.5 MHz for phosphorus. This probe
is equipped with pulsed-field (z) gradients. Chemical
4.4. 3-(S)-Diphenylphosphanyl-1-diphenylphosphinite
butane 4
To a cooled (0 ꢁC) solution of 3 (80 mg, 0.31 mmol) and
DMAP (6.1 mg, 0.05 mmol) in freshly distilled and de-
gassed THF (6 mL) were added triethylamine (45 lL,
0.32 mmol) and chlorodiphenylphosphine (110 lL,
0.6 mmol). The reaction mixture was stirred for 5 h and
the solvent removed under vacuum. Under argon, the
residue was diluted with freshly distilled and degassed
diethyl ether (5 mL). The solution was charged on an alu-
mina pad [previously dried under vacuum (200 ꢁC)] and
eluted with 20 mL of diethyl ether. The ether solvent was
1
shifts (d) are expressed in ppm relative to TMS for H
and 13C nuclei and to H3PO4 for 31P nuclei. Data are
reported as follows: chemical shift, mulitiplicity (s = sin-
glet, d = doublet, t = triplet, q = quartet, br = broad,
and m = multiplet),
integration.
coupling
constants (Hz),
Solvents were purified by conventional methods prior to
use. TLC was performed on Merck 60F-250 silica gel
plates and column chromatography over silica gel SI
60 (230–240 mesh). Melting points were taken on a
Kofler apparatus and are uncorrected. Elemental analy-
ses were carried out on a Carlo Erba EA 1100 analyzer.
removed under vacuum to give the title compound 4 as a
20
D
colorless oil: ½aꢁ ¼ þ4.5 (c 1.1, CHCl3); 1H NMR
(300 MHz): d 1 (dd, J = 6.9, 15 Hz, 3H), 1.4–1.6 (m, 1H),
1.9–2.1 (m, 1H), 2.5–2.7 (m, 1H), 3.9–4.1 (m, 2H), 7.2–
7.7 (m, 20H). 13C NMR (75.5 MHz): d 16.3 (d,
J = 16.4 Hz), 26.5 (d, J = 9.6 Hz), 35.3 (dd, J = 7.3,
16.9 Hz), 68.2 (dd, J = 12.8, 19.2 Hz), 128–131, 134,
137, 142. 31P NMR (121.5 MHz): d 0.3, 114.0. HRMS
(EI) calcd for C28H28O2P 442.1615. Found 442.1619.
4.2. 3-(S)-Boronatodiphenylphosphanyl-butanol 2
To a cooled (0 ꢁC) solution of 1 (295 mg, 1.03 mmol) in
THF (18 mL) was slowly added 1 M borane solution in

2458
N. Boyer et al. / Tetrahedron: Asymmetry 16 (2005) 2455–2458
Berlin, Chapter 5.1; (b) Ohkuma, T.; Kitamura, M.;
4.5. Rhodium complex 5
Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed., VCH: Weinheim, 2000, Chapter 1.3; (c)
Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
Under an argon atmosphere, an oven-dried Schlenk
tube containing a magnetic stirrer bar was charged with
phosphine–phosphinite 4 (119.3 mg, 0.27 mmol) in
freshly degassed methanol (6 mL). [Rh(COD)Cl]2
(64.4 mg, 0.13 mmol) was then added and the solution
stirred for an hour at room temperature. A solution of
NaBF4 (60 mg, 0.54 mmol) in freshly degassed methanol
(4 mL) was then added via a syringe pump over a 2 h
period. At the end of the addition, the solution was stir-
red for a further hour. The solvents were removed under
vacuum. Freshly distilled diethyl ether (15 mL) was then
added to the residue and the mixture filtered off. The
residue was then washed with chloroform and filtered
to remove salts. Chloroform was then removed under
vacuum to give the title rhodium complex as dark
red crystals. Yield: 96%. 13C NMR (75.5 MHz): d
12.3, 17.8, 26.6, 29.2, 29.5, 64.3, 126–131. 31P NMR
(121.5 MHz): d 19.3 (dd, J = 38.6, 149.1 Hz), 136.1
(dd, J = 38.6, 169.8 Hz).
´
2. (a) Pamiez, O.; Dieguez, M.; Net, G.; Ruiz, A.; Claver, C.
J. Org. Chem. 2001, 66, 8364; (b) Deerenburg, S.; Pamiez,
´
O.; Dieguez, M.; Claver, C.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M. J. Org. Chem. 2001, 66, 7626; (c) Pamiez, O.;
´
Dieguez, M.; Net, G.; Ruiz, A.; Claver, C. Chem. Commun.
2000, 2383; (d) Yan, Y.; Chi, Y.; Zhang, X. Tetrahedron:
Asymmetry 2004, 15, 2173.
3. (a) Monsees, A.; Laschat, S. Synlett 2002, 1011; (b) Nozaki,
K.; Li, W.; Horiuchi, T.; Takaya, H.; Saito, T.; Yoshida,
A.; Matsumura, K.; Imai, T.; Miura, T.; Kumobayashi, H.
J. Org. Chem. 1996, 61, 7658; (c) Brunner, H.; Pieronczyk,
J. J. Chem. Res. Synop. 1980, 76; (d) Park, H.; RajanBabu,
T. V. J. Am. Chem. Soc. 2002, 124, 734, and references cited
therein; For aminophosphine–phosphinite, see (e) Li, X.;
Lou, R.; Yeung, C.-H.; Chan, A. S. C.; Wong, W. K.
Tetrahedron: Asymmetry 2000, 11, 2077; (f) Xie, Y.; Lou,
R.; Li, Z.; Mi, A.; Jiang, Y. Tetrahedron: Asymmetry 2000,
11, 1487; (g) Mi, A.; Lou, R.; Jiang, Y.; Deng, J.; Qin, Y.;
Fu, F.; Li, Z.; Hu, W.; Chan, A. S. C. Synlett 1998, 847; (h)
Agbossou, F.; Carpentier, J.-F.; Hapiot, F.; Suisse, I.;
Mortreux, A. Coord. Chem. Rev. 1998, 178–180, 1615.
´
4. Leautey, M.; Castelot-Deliencourt, G.; Jubault, P.; Panne-
coucke, X.; Quirion, J.-C. J. Org. Chem. 2001, 66, 5566.
Acknowledgements
´
5. Leautey, M.; Castelot-Deliencourt, G.; Jubault, P.; Panne-
coucke, X.; Quirion, J.-C. Tetrahedron Lett. 2002, 43, 9237.
We warmly thank Solvias laboratories for their interest
in this research.
´
6. Leautey, M.; Jubault, P.; Pannecoucke, X.; Quirion, J.-C.
Eur. J. Org. Chem. 2003, 3761.
7. Attempts of direct condensation of hydroxyl phosphine
borane 2 with diphenylchlorophosphine led to a compli-
cated mixture of phosphorus products.
References
1. (a) Brown, J. M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
8. Argouarch, G.; Samuel, O.; Kagan, H. B. Eur. J. Org.
Chem. 2000, 2885.