Chiral phosphite-phosphoroamidites: A new class of ligand for asymmetric catalytic hydrogenation

Article abstract of DOI:10.1039/b109043g

A series of novel phosphite-phosphoroamidite ligands, derived from readily available D-xylose, has been used for the first time in the asymmetric Rh-catalyzed hydrogenation of a series of α,β-unsaturated carboxylic acid derivatives with excellent enantios

Full text of DOI:10.1039/b109043g

Chiral phosphite–phosphoroamidites: a new class of ligand for
asymmetric catalytic hydrogenation
Montserrat Diéguez,* Aurora Ruiz and Carmen Claver
Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, Pl. Imperial Tarraco 1, 43005
Tarragona, Spain. E-mail: dieguez@quimica.urv.es; Fax: 34 977559563; Tel: 34 977558046
Received (in Cambridge, UK) 5th October 2001, Accepted 9th November 2001
First published as an Advance Article on the web 6th December 2001
A series of novel phosphite–phosphoroamidite ligands,
derived from readily available -xylose, has been used for
the first time in the asymmetric Rh-catalyzed hydrogenation
of a series of a,b-unsaturated carboxylic acid derivatives
with excellent enantioselectivity (ee up to > 99%).
The modular nature of these sugar ligands allows a facile
D
systematic variation in the configuration of the stereocenter at
carbon atom C-3 at the ligand bridge and in the biphenyl
substituents, so the optimum configuration for maximum
stereoselectivity can be determined. Thus, we investigated how
the different groups attached to the para positions of the
bisphenol moieties affected enantioselectivity using ligands 1
and 2, which have the same configuration on the carbon atom C-
3. We also investigated the influence of the stereogenic
carbonatom C-3 by comparing diastereomeric ligands 3 and 4
with ligands 1 and 2, which have the opposite configuration at
C-3 and the same substituents in the biphenyl moieties.
In the first set of experiments, we used the rhodium-catalyzed
hydrogenation of 7 to scope the potential of ligands 1–4. The
reaction proceeded smoothly at room temperature. The catalysts
were prepared in situ by adding the corresponding phosphite–
phosphoroamidite ligands to [Rh(cod)2]BF4 as a catalyst
precursor.13 The results are given in Table 1.
Many chiral phosphorus compounds have been synthesized as
ligands for enantioselective metal-catalyzed hydrogenation.1
Most of them are homodonor ligands, mainly diphosphines1,2
and diphosphinites.3 However, the combination of different
functionalities in a ligand has already proved beneficial in
enantiodiscrimination.4 In this context, we have recently
reported the successful application of mixed phosphine–
phosphite ligands in asymmetric hydrogenation.5
In the last few years, a group of less electron-rich phosphorus
compounds—phosphite6 and phosphoroamidite7 ligands—have
also demonstrated their potential utility in asymmetric hydro-
genation. Therefore we here report the development of a new
class of chiral phosphite–phosphoroamidite ligands (1–4),
which have the advantages of both types of ligands for
asymmetric hydrogenation (Fig. 1). These ligands are derived
Interestingly, both enantioselectivity and activity notably
improved when the hydrogen pressure was raised from 1 bar to
2.5 bar (entry 1 vs. 2). However, further increasing the hydrogen
pressure had a positive effect on the activity, while the
enantioselectivity remained the same (entries 3 and 5). This
contrasts with the decrease in enantioselectivity usually ob-
served with bidentate ligands when the hydrogen pressure is
raised.1a,7a,14 This allowed us to perform the reaction at lower
catalyst concentration without loss in enantioselectivity and
good activity (entry 6).
from natural
D-xylose so they also have the advantages of
carbohydrates, such as availability at low price and facile
modular construction, which makes tedious optical resolution
procedures unnecessary and facilitates regio- and stereose-
lective introduction of different functionalities.8 To the best of
our knowledge this is the first example of phosphite–phosphor-
oamidite ligands applied to hydrogenation.9
The addition of one fold excess of ligand did not affect the
outcome of the reaction (entry 4). An increase in enantiose-
lectivity ( > 99%, entry 7) combined with good activity was
found by lowering the reaction temperature. There were no
changes in the enantioselectivities over time, which indicates
that no decomposition of the catalyst took place.
Table 1 Asymmetric hydrogenation of 7 with [Rh(cod)2]BF4/1–4a
Fig. 1 Phosphite–phosphoroamidite ligands 1–4.
Ligands 1–410 incorporate a chiral furanoside backbone,
which determines their underlying structure, and one amino
group at the C5 position. The amino furanosides 511 (Scheme 1)
serve as basic frameworks to which several phosphoric acid
biphenol esters 612 are attached.
Entry
Ligand
PH2/bar
% Conv. (t/h)b
% eec
65 (R)
1
2
1
1
1
1
1
1
1
2
3
4
1
2.5
5
100 (20)
45 (8)
97 (R)
96 (R)
96 (R)
97 (R)
97 (R)
> 99 (R)
86 (R)
34 (R)
30 (R)
3
100 (8)
100 (8)
100 (1.5)
100 (10)
100 (12)
86 (8)
4d
5
5
30
30
30
5
5
5
6e
7f
8
9
10
46 (8)
40 (8)
a [Rh(cod)2]BF4 = 0.01 mmol. Ligand/Rh = 1.1. Substrate/Rh = 100.
c
CH2Cl2 = 6 mL. T = 25 °C. b % Conversion measured by GC.
%
Enantiomeric excess measured by GC using a Chiraldex G-TA column.
d Ligand/Rh = 2. e Substrate/Rh = 1000. f At 5 °C.
Scheme 1 Synthesis of ligands 1–4.
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Chem. Commun., 2001, 2702–2703
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b109043g

The rest of the ligands were compared under ‘standard’
conditions i.e. dichloromethane as a solvent, 5 bar of hydrogen
pressure, a ligand-to-rhodium ratio of 1 and at room tem-
perature. Using ligand 2, with methoxy groups instead of the
tert-butyl groups in para positions of the biphenol moieties,
resulted in slightly lower activity and enantioselectivity (entry 3
vs. 8). Ligands 3 and 4 whose configuration of carbon atom C-3
is opposite to those of ligands 1 and 2, respectively, produced a
lower reaction rate and enantioselectivity (entry 3 and 8 vs. 9
and 10).
The results clearly show that the enantiomeric excesses and
activities depend strongly on the absolute configuration of the
C3 stereocenter of the carbohydrate backbone and the sub-
stituents in the biphenyl moities. Therefore, enantioselectivities
and activities were best using ligand 1 with a S configuration at
C-3 and tert-butyl groups in the ortho- and para-positions of the
biphenyl moieties.
further structural diversity is easy to achieve, so enantioselectiv-
ity and catalyst performance can be maximized for each new
substrate as required. Studies of this kind, as well as mechanistic
studies, are currently under way.
We thank the Spanish Ministerio de Educación, Cultura y
Deporte and the Generalitat de Catalunya (CIRIT) for their
financial support (PB97-0407-CO5-01).
Notes and references
We subsequently applied these new highly efficient phos-
phite–phosphoroamidite ligands 1–4 in the Rh-catalyzed hydro-
genation of other benchmark dehydroaminoacid derivatives
(Table 2). The results followed the same trend as for substrate 7.
The absolute configuration of the hydrogenated products 10 and
12 is opposite that of the hydrogenated product 8, but they have
the same spatial arrangement.15 The catalyst precursor with
ligand 1 produced the highest enantiomeric excess (98%, entries
5 and 10).
1 (a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994; (b) Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley,
New York, 2000; (c) Comprehensive Asymmetric Catalysis, ed. E. N.
Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, vol. 1; (d)
H. Brunner and W. Zettlmeier, Handbook of Enantioselective Catalysis,
VCH, Weinheim, 1993.
2 (a) U. Nettekoven, P. C. J. Kamer, P. W. N. M. van Leeuwen, M.
Widhalm, A. L. Speck and M. Lutz, J. Org. Chem., 1999, 64, 3996; (b)
U. Barens, M. J. Burk, A. Gerlach and W. Hems, Angew. Chem., Int.
Ed., 2000, 39, 1981.
It is remarkable that these phosphite–phosphoroamidite
ligands showed a much higher degree of enantioselectivity and
higher reaction rates than their corresponding diphosphite
analogues under similar reaction conditions (entries 1–4 vs. 11
and 12).13,16
3 (a) A. S. C. Chan, W. Hu, C.-C. Pai and C.-P. Lau, J. Am. Chem. Soc.,
1997, 119, 9570; (b) T. A. Ayers and T. V. RajanBabu, Process Chem.
Pharm. Ind., 1999, 327; (c) R. Selke, J. Organomet. Chem., 1989, 370,
249.
4 K. Inoguhi, S. Sakuraba and K. Achiwa, Synlett, 1992, 169.
5 O. Pàmies, M. Diéguez, G. Net, A. Ruiz and C. Claver, Chem.
Commun., 2000, 2383.
6 (a) M. T. Reetz and T. Neugebauer, Angew. Chem., Int. Ed., 1999, 38,
179; (b) M. T. Reetz and G. Mehler, Angew. Chem., Int. Ed., 2000, 39,
3889.
In summary, we have described the first application of
phosphite–phosphoroamite ligands in the asymmetric hydro-
genation reaction. These ligands can be easily prepared in a few
steps from commercial -(+)-xylose as an inexpensive natural
D
chiral source. Regarding both good activity and the excellent
enantioselectivity (up to > 99% ee) obtained in simple un-
optimised asymmetric hydrogenation of a series of a,b-
unsaturated carboxylic acid derivatives, we feel that a promis-
ing new class of ligands—the phosphite–phosphoro-
amidite—has been disclosed for enantioselective Rh-catalyzed
asymmetric hydrogenation. Moreover, because of the modular
construction of these phosphite–phosphoroamidite ligands,
7 (a) M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van Esch,
A. H. M. de Vries, J. G. de Vries and B. L. Feringa, J. Am. Chem. Soc.,
2000, 122, 11 539; (b) G. Franciò, F. Faraone and W. Leitner, Angew.
Chem., Int. Ed., 2000, 39, 1428; (c) O. Huttenloch, J. Spieler and H.
Waldmann, Chem. Eur. J., 2000, 6, 671.
8 M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón and C. Claver, Chem. Eur.
J., 2001, 7, 3086.
9 A few phosphite–phosphoroamidite ligands have been described and
applied to asymmetric hydroformylation with moderate results, see for
instance: S. Naili, I. Suisse, A. Mortreux, F. Agbossou-Niedercron and
G. Nowogrocki, J. Organomet. Chem., 2001, 628, 122 and references
cited therein.
Table 2 Asymmetric hydrogenation of methyl N-acetylaminoacrylate 9 and
methyl (Z)-N-acetylaminocinnamate 11 with [Rh(cod)2]BF4/1–4a
10 The new ligands 1–4 were synthesized very efficiently in one step by
treatment of the corresponding aminoalcohols 5, easily prepared on
large scale from readily available D-(+)-xylose, with two equivalents of
the desired in situ formed phosphorochloridites 6 in the presence of
pyridine. Selected NMR data. 1: dP (CDCl3) 144.8 (br s), 145.1 (s). 2:
dP (CDCl3) 144.0 (s), 145.9 (s). 3: dP (CDCl3) 143.2 (s), 150.2 (s). 4: dP
(CDCl3) 143.5 (s), 149.3 (s).
Entry
Substrate Ligand
PH2/bar
% Conv. (t/h)b
% eec
11 (a) D. F. Ewing, G. Goethals, G. Mackenzie, P. Martin, G. Ronco, L.
Vanbaelinghem and P. Villa, J. Carbohydr. Chem., 1999, 18, 441; (b)
D. F. Ewing, G. Goethals, G. Mackenzie, P. Martin, G. Ronco, L.
Vanbaelinghem and P. Villa, Carbohydr. Res., 1999, 321, 190.
12 G. J. H. Buisman, P. C. J. Kamer and P. W. N. M. van Leeuwen,
Tetrahedron: Asymmetry, 1993, 4, 1625.
1
2
9
9
1
2
5
5
100 (8)
71 (8)
46 (8)
33 (8)
100 (12)
77 (8)
53 (8)
29 (8)
35 (8)
92 (S)
82 (S)
15 (S)
12 (S)
98 (S)
94 (S)
85 (S)
18 (S)
17 (S)
98 (S)
33 (S)
4 (R)
3
9
3
5
4
9
9
4
1
1
2
3
4
1
13
14
5
30
5
5
5
5
30
5
5d
6
13 For general hydrogenation procedure see: O. Pàmies, G. Net, A. Ruiz
and C. Claver, Eur. J. Inorg. Chem., 2000, 1287.
10
10
10
10
10
9
7
8
9
10d
11
12
14 (a) A. Pfaltz and J. M. Brown, Houben-Weyl Methods of Organic
Chemisty, ed. G. Helchem, R. W. Hoffmann, J. Mulzer and E.
Schaumann, Thieme, Stuttgart, 1995, vol. E21, D.2.5.1.2; (b) X. Zhang,
Enantiomer., 1999, 4, 541; (c) M. J. Burk and F. Bienewald, Transition
Metals For Organic Synthesis, ed. M. Beller and C. Bolm, Wiley-VCH,
Weinheim, 1998, vol. 2; ch. 1.1.2.
72 (12)
94 (20)
56 (20)
9
5
15 R. S. Cahn, C. K. Ingold and V. Prelog, Angew. Chem., Int. Ed. Engl.,
1966, 5, 385.
16 O. Pàmies, G. Net, A. Ruiz and C. Claver, Tetrahedron: Asymmetry,
2000, 11, 1097.
a [Rh(cod)2]BF4 = 0.01 mmol. Ligand/Rh = 1.1. Substrate/Rh = 100.
CH2Cl2 = 6 mL. T = 25 °C. b % Conversion measured by GC. c % ee
measured by GC using a Permabond L-Chirasil-Val column. d At 5 °C.
Chem. Commun., 2001, 2702–2703
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