Chiral Monophosphites Derived from Carbohydrate: Conformational Effect in Catalytic Asymmetric Hydrogenation

Article abstract of DOI:10.1021/ol035551j

(Equation presented) The carbohydrate-derived chiral monophosphites with additional groups have been synthesized and used for asymmetric hydrogenation of dimethyl itaconate and enamides. Up to 99.6% ee and 98.5% ee have been obtained, respectively.

Full text of DOI:10.1021/ol035551j

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4137-4139
Chiral Monophosphites Derived from
Carbohydrate: Conformational Effect in
Catalytic Asymmetric Hydrogenation
Hanmin Huang, Zhuo Zheng,* Huili Luo, Changmin Bai, Xinquan Hu, and
Huilin Chen*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, P. R. China
zhengz@dicp.ac.cn
Received August 18, 2003
ABSTRACT
The carbohydrate-derived chiral monophosphites with additional groups have been synthesized and used for asymmetric hydrogenation of
dimethyl itaconate and enamides. Up to 99.6% ee and 98.5% ee have been obtained, respectively.
The design and synthesis of efficient chiral phosphorus
ligands has played an important role in the development of
transition-metal-catalyzed asymmetric hydrogenation reac-
tions.1 In general, most of the effective chiral phosphorus
ligands are bidentate. While the synthesis of monophosphorus
ligands is usually simpler than that of diphosphorus com-
pounds, it is often difficult to develop effective catalysts using
chiral monophosphines as ligands, which may be due to some
extent to free rotation of M-P bond.
structure of the Pt-1a complex gave some insights into why
the high enantioselectivities are achieved with this system;
it is because rotation of the ligand around Pt-P bond is
hindered which reduces the number of rotameric forms.2
To further expand the range of ligands and enantioselec-
tivity of this asymmetric hydrogenation process, we designed
a new class of chiral monophosphorus ligands 2, which
contain additional groups in the proper spatial configuration
Recently, some easily prepared and efficient chiral mono-
phosphorus ligands such as 1 have been developed by
Pringle,2 Reetz,3 and Feringa,4 and these have exhibited high
enantioselectivity in asymmetric hydrogenation.5 The X-ray
(5) For other monophosphorus ligands, see: (a) Reetz, M. T.; Sell, T.;
Meiswinkel, A.; Mehler, G. Angew. Chem., Int. Ed. 2003, 42, 790. (b) Jia,
X.; Li, X.; Xu, Li.; Shi, Q.; Yao, X.; Chan, A. S. C. J. Org. Chem. 2003,
68, 4539. (c) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou,
Q.-L. Chem. Commun. 2002, 480. (d) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou,
H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348. (e)
Reetz, M. T.; Mehler, G. Meiswinkel, A.; Sell, T. Tetrahedron Lett. 2002,
43, 7941. (f) Pena, D. M.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L.
J. Am. Chem. Soc. 2002, 124, 14552. (g) Junge, K,; Oehme, G.; Monsees,
A.; Riermeier, T.; Dingerdissen, U.; Beller, M.; Tetrahedron Lett. 2002,
43, 4977. (h) Zeng, Q.; Liu, H.; Cui, X.; Mi, A.; Jiang, Y.; Li, X.; Choi,
M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2002, 13, 115. (i) Jia,
X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43,
5541. (j) van den Berg, M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H.
M.; de Vries, J. G.; Feringa, B. L. AdV. Synth. Catal. 2002, 344, 1003. (k)
Pena, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B.
L. Org. Lett. 2003, 5, 475.
(1) For recent reviews, see: (a) Ohkuma, T.; Noyori, R. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim,
2000; p 1. (b) Brown, J. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
p 121. (c) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(2) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961.
(3) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889.
(4) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de
Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539.
10.1021/ol035551j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

prepared by the reaction of alcohols with PCl3 in the absence
of Et3N. These were then directly reacted with BINOL in
the presence of Et3N to afford the desired product. Ligands
3-6 were easily purified through a short silica gel plug and
were stable in the solid state.
Figure 1.
The catalytic performance of ligands 3-6 was initially
explored in the enantioselective Rh-catalyzed hydrogenation
reaction of dimethyl itaconate. The catalyst was prepared in
situ by mixing [Rh(COD)2]BF4 and the monophosphite
ligands in CH2Cl2. All the hydrogenation reactions were
typically carried out at room temperature under 10 atm
pressure of H2 and with a substrate, Rh, and ligand ratio of
1.0/0.01/0.022. Although a standard reaction time of 12 h
was chosen, most of the reactions were complete within 3
h.
to effectively restrain the rotation of the M-P bond by
secondary interactions (Figure 1).6
For many years, carbohydrates have been extensively
explored as backbones for chiral ligands due to their easy
modification and ready availability. These features are
beneficial for systematically modifying the structure of the
ligands. Excellent results have been obtained with carbohy-
drate-based bidentate ligands in asymmetric hydrogenation.7,8
However, few good monodentate chiral ligands have been
reported based on carbohydrates.9
Herein, we report the synthesis of a new series of
monophosphite ligands 3-6 based on D-fructose and D-
glucose, and their applications in asymmetric hydrogenation
reactions. To ascertain the importance of the monosaccha-
ride10 component affected enantioselectivity and yield of the
asymmetric hydrogenation process, we evaluated a wide
range of ketalated11 carbohydrate derivatives.
The results of the Rh-catalyzed hydrogenation reactions
are summarized in Table 1 and show that the carbohydrate-
derived monophosphites we have created are efficient ligands
for asymmetric hydrogenation. However, the enantioselec-
tivities proved to be influenced dramatically by the structure
of the ligands. Comparison of the results in Table 1 shows
that the enantiomeric excess depends strongly on the absolute
configuration of carbon atom at C-3 in the carbohydrate
backbone. In general, fructose-derived ligands 4a-d, with
R configuration on carbon atom C-3, produced much higher
enantioselectivities than ligands 3a-d with opposite con-
figuration on C-3. For the ligands 3a-d, (S)-BINOL is
matched cooperatively to the corresponding carbohydrate
backbone, while for ligands 4a-d, (R)-BINOL and the
carbohydrate components are matched. With ligand 4a the
The new ligands 3-6 were synthesized very efficiently
from BINOL and the corresponding monosaccharide alco-
hols, which were synthesized on large scale from D-fructose
and D-glucose (Figure 2).12 The RO-PCl2 intermediates were
(6) ) For a review of the secondary interaction, see: Sawamura, M.; Ito,
Y. Chem. ReV. 1992, 92, 857.
(7) (a) Steiborn, D.; Junicke, H. Chem. ReV. 2000, 100, 4283. (b)
RajanBabu, T. V.; Casalnuovo, A. L.; Ayers, T. A. In AdVances in Catalytic
Process; Doyle, M. P., Ed.; JAI Press: Greenwhich, 1998; Vol. 2, p 1. (c)
Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org. Chem.
1999, 64, 5593. (d) Yonehara, K.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
64, 9381. (d) Hashizume, T.; Yonehara, K.; Ohe, K.; Uemura, S. J. Org.
Chem. 2000, 65, 5197.
(8) For recent advances in this area, see: (a) Dieguez, M.; Ruiz, A.;
Claver, C. J. Org. Chem. 2002, 67, 3796. (b) Park, H.; RajanBabu, T. V.;
Yan, Y.-Y.; Shin, S. J. Am. Chem. Soc. 2001, 123, 10207. (d) Li, W.; Zhang,
Z.; Xiao, D.; Zhang, X. J. Org. Chem. 2000, 65, 3498. (e) Shin, S.;
RajanBabu, T. V. Org. Lett. 1999, 1, 1229.
(9) Saito, S.; Nakamura, Y.; Morita, Y. Chem. Pharm. Bull. 1985, 33,
5284. While our paper was being readied for publication, Reetz reported
the glucose-derived monophosphites 5a,b and 6a,b and their use in enol
esters hydrogenation. See: Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.;
Paetzold, J.; Jensen, J. F. Org. Lett. 2003, 5, 3099.
(10) For review of monosaccharide-derived chiral ligands, see: Hale,
K. J. In Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M.,
Ed.; Elsevier Science: New York, 1993; Suppl. 2, Vol. IE/F/G, Chapter
23b, p 273.
(11) For ketal moiety influence on the catalyst’s activity, see: Nordin,
S. J. M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt, P.; Andersson, P. G.
Chem. Eur. J. 2001, 7, 1431.
(12) (a) Hockett, R. C.; Miller, R. E.; Scattergood, A. J. Am. Chem. Soc.
1949, 71, 3072. (b) James, K.; Tatchell, A. R.; Ray, P. K. J. Chem. Soc. C
1967, 2681. (c) Singh, P. P.; Gharia, M. M.; Dasgupta, F.; Srivastava, H.
C. Tetrahedron Lett. 1977, 439. (d) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang,
J. R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.
Figure 2.
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Org. Lett., Vol. 5, No. 22, 2003

Table 1. Enantioselective Hydrogenation of Dimethyl Itaconate
Catalyzed by Rh-3-6a
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of Various
N-Acetyl R-Arylenamides with 4c as Chiral Liganda
entry ligand ee (%) (config)b entry ligand ee (%) (config)b
entry
substrate (Ar, R)
ee (%) (config)b
1
2
3
4
5
6
7
8
(Ph, H)
95.0 (S)
96.5 (S)
98.5 (S)
98.5 (S)
95.9 (S)
98.5 (S)
96.9 (S)
96.7 (S)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
49.7 (R)
82.5 (S)
18.5 (R)
91.5 (S)
99.6 (R)
99.1 (S)
99.4 (R)
90.3 (S)
9
10
11
12
13
14
15
16
5a
5b
5c
5d
6a
6b
6c
6d
92.8 (R)
99.1 (S)
92.9 (R)
96.9 (S)
93.6 (R)
77.5 (S)
84.3 (R)
81.0 (S)
(p-FC6H4, H)
(p-BrC6H4, H)
(p-ClC6H4, H)
(p-CH3OC6H4, H)
(p-CF3C6H4, H)
(2-naphthyl, H)
(Ph, Me)
a The reactions were carried out in CH2Cl2 at room temperature for 12
h, P(H2) ) 10 atm, substrate/[Rh(COD)2]BF4/ligand ) 1.0/0.01/0.022. 100%
conversion in all cases. b Determined by GC with chiral select 1000 and
CP-Chiralsil-L-Val capillary column; the absolute configuration was
determined by comparing the sign of specific rotation.
a The reactions were carried out in CH2Cl2 at room temperature for 12
h, P(H2) ) 10 atm, substrate/[Rh(COD)2]BF4/ligand ) 1.0/0.01/0.022. 100%
conversion in all cases. b Determined by GC with γ-DEX-225 capillary
column, and the absolute configuration was determined by comparing the
sign of specific rotation.
highest ee value (99.6%) was obtained (Table 1, entry 5).
Similar observations were made with 5 and 6.
To expand the utility of these monophosphite ligands and
further investigate the influence of the carbohydrate com-
ponent, we examined the Rh-catalyzed enantioselective
hydrogenation of 1,1-disubstituted-R-arylenamides (Table 2).
In all cases, the ligand 4c exhibited good to excellent
enantioselectivities (95.0-98.5% ee). The electronic nature
of the para substituents in R-arylenamides appeared to affect
the enantioselectivity observed. Hydrogenation of R-arylen-
amides with electron-withdrawing substituents (entries 2, 3,
4, and 6) on the phenyl ring gave higher enantioselectivity
than those with electron-donating substituents (entry 5). A
mixture of E- and Z-R-arylenamide (entry 8) was also
reduced with high enantioselectivity. It is noteworthy that
the ee values of 95.0-98.5% obtained with monophosphite
ligand 4c are higher than that obtained from MonoPhos4 and
Reetz’s monophosphites5e derived from simple alcohols or
comparable to the result of modified MonoPhos.5b
Table 2. Rh-Catalyzed Asymmetric Hydrogenation of
N-Acetylphenylethenamine with 3-6 as Chiral Ligandsa
entry ligand ee (%) (config)b entry ligand ee (%) (config)b
In conclusion, a new class of monphosphite ligands
containing additional groups derived from D-fructose and
D-glucose have been synthesized and applied in the Rh-
catalyzed hydrogenation of dimethyl itaconate and enamides.
Excellent ee values up to 99.6% and 98.5% have been
achieved. The superb enantioselectivities and the pronounced
effect of carbohydrate backbones in these ligands indicates
that the additional groups orientated in a proper spatial
configuration contained in monophosphites are beneficial for
improvement of enantioselectivity observed. More detailed
studies on the structure of these ligands as well as synthesis
of other new effective chiral monophosphorus ligands
containing additional groups and their applications in asym-
metric catalysis are in progress.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
16.3 (S)
44.7 (S)
19.5 (R)
39.7 (S)
87.7 (S)
4.7 (S)
9
10
11
12
13
14
15
16
5a
5b
5c
5d
6a
6b
6c
6d
93.9 (S)
85.5 (R)
91.7 (S)
95.1 (R)
49.1 (R)
87.1 (S)
49.1 (R)
67.9 (R)
95.0 (S)
10.3 (S)
a The reactions were carried out in CH2Cl2 at room temperature for 12
h, P(H2) ) 10 atm, substrate/[Rh(COD)2]BF4/ligand ) 1.0/0.01/0.022. 100%
conversion in all cases. b Determined by GC with chiral select 1000 capillary
column, the absolute configuration was determined by comparing the sign
of specific rotation.
The results in Table 2 show that the observed enantiose-
lectivity of the reaction was again sensitive to the configu-
ration of carbon atom C-3 of the carbohydrate moiety, which
further confirmed the function of additional groups in the
Rh-complex of these monophosphite ligands. On the other
hand, the absolute configuration of BINOL also influenced
the enantioselectivity of these ligands. The best enantiose-
lectivity (95% ee) was obtained with 4c and 5d using (R)-
BINOL and (S)-BINOL matched with the carbohydrate
backbone (Table 2, entries 7 and 12).
Acknowledgment. Financial support from the National
Science Foundation of China (29933050) is gratefully
acknowledged. We thank professor Yong-Gui Zhou for
useful discussions.
Supporting Information Available: Experimental de-
tails, spectra of new ligands 3-6, and ee value determination
conditions of GC. This material is available free of charge
via the Internet at http://pubs.acs.org.
We subsequently applied the new efficient monophosphite
4c in the Rh-catalyzed hydrogenation of other R-arylen-
amides; the results are summarized in Table 3.
OL035551J
Org. Lett., Vol. 5, No. 22, 2003
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