Supramolecular chiral phosphorous ligands based on a [2]pseudorotaxane complex for asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2008.03.039

A new type of supramolecular chiral phosphorus-based ligands was prepared from easily available monodentate ligands through complexation between dibenzylammonium salt and dibenzo[24]crown-8 macrocycle. Rhodium complexes with these supramolecular ligands w

Full text of DOI:10.1016/j.tetlet.2008.03.039

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2878–2881
Supramolecular chiral phosphorous ligands based on a
[2]pseudorotaxane complex for asymmetric hydrogenation
Yong Li a,b, Yu Feng a,b, Yan-Mei He a, Fei Chen a, Jie Pan a, Qing-Hua Fan a,*
a Beijing National Laboratory of Molecular Sciences, Center for Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100080, PR China
Received 22 November 2007; revised 5 March 2008; accepted 7 March 2008
Available online 18 March 2008
Abstract
A new type of supramolecular chiral phosphorus-based ligands was prepared from easily available monodentate ligands through
complexation between dibenzylammonium salt and dibenzo[24]crown-8 macrocycle. Rhodium complexes with these supramolecular
ligands were prepared, and the supramolecular bidentate ligand-containing catalyst has demonstrated better catalytic activity for all
substrates, and higher enantioselectivity except for the ortho-substituted substrates than those obtained from the parent monodentate
ligand in the asymmetric hydrogenation of a-dehydroamino acid esters.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chiral phosphorous ligands; Pseudorotaxane; Self-assembly; Asymmetric hydrogenation
The development of new effective ligands is a continuous
challenge in the transition-metal-catalyzed asymmetric
hydrogenation. Over the past decades, a number of
excellent chiral diphosphine ligands, such as BINAP [2,2-
bis(diphenylphosphino)-1,10-binaphthyl] and DuPHOS
[1,2-bis(phospholano)benzene], have been reported for
highly enantioselective hydrogenation reactions.1 However,
the preparation and modification of these classical biden-
tate ligands often require complicated multistep synthesis.
Recently, a supramolecular approach to prepare the chela-
ting bidentate ligands for homogeneous catalysis has proven
to be a particularly intriguing alternative to the conven-
tional method.2–4 For example, Breit and co-workers
recently reported the libraries of the defined heterodimeric
bidentate ligands by the self-assembly of the easily
available monodentate ligands through complementary
hydrogen-bonding.2a,3a–f Reek and co-workers recently
introduced a novel class of bidentate ligands through coor-
dinative bonding.2b,c,4a–e They used the zinc(II)porphyrin–
pyridyl interaction as an assembly motif to generate biden-
tate phosphorus-based ligands for hydroformylations and
asymmetric hydrogenations. In most cases, these supramo-
lecular bidentate ligands have shown superior selectivity
and/or catalytic activity to those obtained by simply mix-
ing two monodentate phosphorus ligands. Furthermore,
such a noncovalent synthetic strategy allows the spontane-
ous, selective formation of stable bidentate ligands with
modular architectures and consequently offers the possibi-
lity of easily constructing the libraries of enantioselective
catalysts.3e,4e Despite these efforts, the successful catalytic
applications of supramolecular ligands are still limited,
even fewer in asymmetric catalysis.3e–i,4d–f Therefore, it
would be highly desirable to develop new types of supra-
molecular chiral ligands for homogeneous asymmetric
catalysis.
The complexation between secondary ammonium salts
and crown ethers, such as dibenzo[24]crown-8 (DB24C8)
macrocycle, has been extensively used as a recognition
motif for the construction of pseudorotaxanes, rotaxanes
and catananes.5,6 By mixing such two complementary
*
Corresponding author. Tel.: +86 10 62554472; fax: +86 10 62554449.
E-mail address: fanqh@iccas.ac.cn (Q.-H. Fan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.039

Y. Li et al. / Tetrahedron Letters 49 (2008) 2878–2881
2879
PPh2
PPh2
O
O
O
O
O
O
P
P
P
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H2N
H2N
O
O
PF6
PF6
1
2
Fig. 1. Structure of supramolecular chiral phosphorous ligands based on a [2]pseudorotaxane complex.
components together in a 1:1 molar ratio, it results in the
formation of a pseudorotaxane complex held by strong
[N+–Hꢀ ꢀ ꢀO] hydrogen bonds between the acidic NH2þ pro-
tons and the oxygen atoms in the DB24C8 macrocycle.
Furthermore, additional [C–Hꢀ ꢀ ꢀO] and p–p stacking inter-
actions, as well as ion–dipole interactions, also contribute
to the stability of the resulting pseudorotaxane. Specifi-
cally, based on the formation of the stable complex
between dibenzylammonium salt and DB24C8, as well as
inspired by the pioneering work of Breit,2a we envisaged
the use of such pseudorotaxane complex for the construc-
tion of chiral bidentate or tridentate phosphorus-based
ligands (Fig. 1) for asymmetric catalysis.7
The synthesis of crown ether-based chiral phosphite
ligands 3a and 3b is summarized in Scheme 1. The reduc-
tion of the corresponding esters (4a8 and 4b9) with LiAlH4
in THF gave alcohols 5a and 5b in high yield, respectively.
The chiral phosphite ligands (3a and 3b) were then readily
prepared by the reaction of the resulting alcohols 5a and 5b
with (S)-2,20-bisnaphthol phosphorochloridite10 in good
yields, respectively. The secondary ammonium salt con-
taining phosphine ligand 6 was prepared in 69% overall
yield by the substitution of benzyl amine with 4-(diphenyl-
phosphino oxide)benzyl bromide and then reduction with
HSiCl3–NEt3, followed by the protonation of the resulting
amine with HPF6 solution (Scheme 2). All the three ligands
were well characterized by 1H, 13C and 31P NMR as well as
by HRMS spectroscopy. All the results are in full agree-
ment with the compounds synthesized.
With these complementary phosphorous ligands in
hand, we first investigated the formation of the complex
between 3a and 6 in solution. When an equal amount of
3a and 6 was mixed in CDCl3 at room temperature, three
peaks at ca. 140 ppm in the 31P NMR spectrum were
observed. In addition to the peak at 140.4 ppm of free
ligand 3a, two new peaks at 139.6 and 139.5 ppm of the
supramolecular bidentate ligand 1 were observed, indicat-
ing that a mixture of two diastereoisomers was formed.
This was probably due to the generation of planar chiral-
ity.11 The formation of complex 1 was further confirmed
by mass spectrometry using the electrospray ionization
1
(ESI) technique (1174.3 for [MꢁPF6]+). The result of H
O
O
O
O
R1
R2
O
O
O
O
R1
R2
O
O
O
O
i
O
O
O
O
4a R1 = H, R2 = CO2CH3
4b R1 = R2 = CO2CH3
5a R1 = H, R2 = CH2OH
5b R1 = R2 = CH2OH
O
3a R1 = H, R2 = H2CO
P
O
O
O
ii
R1
R2
O
O
O
O
O
O
3b R1 = R2 = H2CO
P
O
O
Scheme 1. The synthesis of dibenzo[24]crown-8 host-containing chiral phosphorous ligands 3a and 3b. Reagents and conditions: (i) H4A1Li, THF, reflux
for 2 h; (ii) 2,20-bisnaphthol phosphorochloridite, Et3N, THF, 16 h, rt.

2880
Y. Li et al. / Tetrahedron Letters 49 (2008) 2878–2881
H2
N
H
N
PF6
O
Br
i, ii
iii
Ph2P
Ph2P
Ph2P
6
Scheme 2. The synthesis of the secondary ammonium containing phosphine ligand 6. Reagents and conditions: (i) benzylamine, NaH, THF; (ii) HSiCl3,
Et3N, toluene; (iii) HPF6, CH2Cl2.
NMR was also consistent with the structure of rotaxane
skeleton. Similarly, the formation of complex 2 between
3b and 6 in solution was also confirmed by using 31P and
1H NMR as well as ESI-MS spectra (1518.5 for
[MꢁPF6]+).
ceeded smoothly in the presence of 1 mol % of the in situ
generated Rh(I)–1 complex, furnishing methyl N-acetyl-
phenylalaninate 8a in 73% ee with quantitative conversion
after 3 h (entry 1). Increasing the hydrogen pressure led to
a remarkable decrease in the enantioselectivity of the pro-
duct under otherwise identical conditions (entries 2 and
3). The hydrogenation reaction was performed well at a
low reaction temperature while giving similar enantioselec-
tivity (entry 4). Unexpectedly, higher enantioselectivity was
observed when the catalyst loading was reduced from
1 mol % to 0.2 mol % (entry 6). Most importantly, much
lower enantioselectivity and conversion were obtained by
using the parent monodentate phosphite 3a as a ligand
under otherwise same conditions (80% vs 68% ee, 100%
vs 62% conversion). On the other hand, the catalyst
in situ generated from the mixture of 3a and PPh3 (1:1
molar ratio) with [Rh(COD)2]BF4 gave significantly low
enantioselectivity (15% ee), but affording the reduced pro-
duct in opposite configuration (entry 7). Similar phenom-
ena were previously observed by Reetz and Mehler.14 In
addition, compared with 1, the reaction using the tridentate
Both the supramolecular ligands were then employed in
the rhodium-catalyzed asymmetric hydrogenation of a-
dehydroamino acid esters.12 The catalyst was prepared
in situ by mixing cationic rhodium complex [Rh(COD)2]-
BF4 with 1 in CH2Cl2 at room temperature, giving the
quantitative formation of rhodium complex bearing a
pseudorotaxane. Notably, according to the result of 31P
NMR,13 high diastereoselectivity was observed although
the stereochemistry of these complexes was unclear at the
present time. Unlike ligand 1, the tridentate ligand 2
potentially allowed different chelating modes at the Rh
centre upon complex formation with [Rh(COD)2]BF4 in
CH2Cl2 at room temperature. Then, the hydrogenation of
methyl a-acetamidocinnamate 7a was chosen as a standard
reaction, and the preliminary results are summarized in
Table 1.
As shown in Table 1, under 1 atm of hydrogen pressure
at 20 °C in dichloromethane, the hydrogenation of 7a pro-
Table 2
Asymmetric hydrogenation of a-dehydroamino acid esters with the
supramolecular chiral catalyst 1/Rha
Table 1
Optimization of the reaction conditionsa
COOCH3
NHAc
COOCH3
NHAc
1/Rh
COOCH3
COOCH3
*
Rh catalyst
H2, CH2Cl2
*
R
R
1 atm H2, CH2Cl2
NHAc
NHAc
8
7
8a
7a
Entry
Substrate, R =
Conv. (%)
eeb (%)
Entry
Ligand
Sub/Cat Temp H2
Time eeb
(atm) (h) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
C6H5 (7a)
>99 (62)c
>99 (40)c
>99 (54)c
>99 (45)c
>99 (38)c
>99 (76)c
>99 (47)c
80 (36)c
>99 (47)c
>99 (37)c
>99 (63)c
>99 (37)c
>99 (57)c
>99 (75)c
80 (68)c
69 (76)c
79 (76)c
78 (69)c
72 (82)c
77 (69)c
77 (77)c
70 (88)c
75 (73)c
76 (70)c
77 (75)c
76 (74)c
84 (66)c
81 (75)c
(°C)
2-Cl–C6H5 (7b)
3-Cl–C6H4 (7c)
4-Cl–C6H4 (7d)
2-Br–C6H4 (7e)
4-Br–C6H4 (7f)
4-F–C6H4 (7g)
2-Me–C6H4 (7h)
3-Me–C6H4 (7i)
4-Me–C6H4 (7j)
3-MeO–C6H4 (7k)
4-MeO–C6H4 (7l)
4-NO2–C6H4 (7m)
3,4-OCH2O–C6H3 (7n)
1
2
3
4
5
6
7
8d
9d
10d
a
1
1
1
1
1
1
100
100
100
100
300
500
500
100
100
500
20
20
20
0
20
20
20
20
20
20
1
20
60
1
1
1
1
1
1
1
3
3
3
73 (R)
62 (R)
44 (R)
76 (R)
79 (R)
80 (68)c (R)
15 (S)
46 (R)
66 (R)
77 (R)
3
14
14
14
3
3
14
3a/PPh3
2
2
2
The hydrogenations were carried out with 0.1 mmol 7a in 1 mL
dichloromethane. The catalyst was generated in situ by mixing the
supramolecular ligand 1 (1.2 equiv) with [Rh(COD)2]BF4 (1.0 equiv) in
dichloromethane. Complete conversions were achieved in all the cases
except for entry 10 (90% conversion).
The hydrogenations were carried out with 0.1 mmol substrates in 1 mL
dichloromethane under the following conditions: substrate/cata-
lyst = 500:1, 1 atm H2, 20 °C, 14 h.
b
b
The ee values and conversions were determined by GC with a
The ee values and conversions were determined by GC with a
Chrompack Chirasil-L-Val column (25 m ꢂ 0.25 mm).
Chrompack Chirasil-L-Val column (25 m ꢂ 0.25 mm). All the products
c
Only ligand 3a was used, and conversion was 62% under otherwise
were in the R-configuration.
c
same conditions.
The data in the parentheses were obtained by using the parent
d
In entry 8, Rh:3b:6 = 1.5:1:1; in entries 9 and 10, Rh:3b:6 = 1:1:1.
monodentate phosphite 3a as a ligand.

Y. Li et al. / Tetrahedron Letters 49 (2008) 2878–2881
2881
Chem. Commun. 2007, 864; (h) Clarke, M. L.; Fuentes, J. A. Angew.
Chem., Int. Ed. 2007, 46, 930; (i) Liu, Y.; Sandoval, C. A.;
Yamaguchi, Y.; Zhang, X.; Wang, Z.; Kato, K.; Ding, K. J. Am.
Chem. Soc. 2006, 128, 14212.
ligand 2 afforded product 8a in lower enantioselectivity and
conversion (entries 8–10).
Subsequently, various a-dehydroamino acid esters were
tested in the hydrogenation reactions by using 1 as a chiral
ligand under the optimized reaction conditions. As shown
in Table 2, moderate to high enantioselectivities (69–84%
ee) were obtained. Most importantly, the supramolecular
ligand 1 gave better conversions in all the cases, and higher
enantioselectivities except for the ortho-substituted
substrates (entries 2, 5 and 8) than those obtained from
the parent monodentate phosphite 3a.
4. (a) Slagt, V. F.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M. Angew. Chem., Int. Ed. 2001, 40, 4271; (b) Slagt, V. F.; van
Leeuwen, P. W. N. M.; Reek, J. N. H. Angew. Chem., Int. Ed. 2003,
42, 5619; (c) Kuil, M.; Soltner, T.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. J. Am. Chem. Soc. 2006, 128, 11344; (d) Slagt, V. F.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M.; Reek, H. N. J. J. Am. Chem. Soc.
2004, 126, 4056; (e) Jiang, X. B.; Lefort, L.; Goudriaan, P. E.; de
Vries, A. H. M.; van Leeuwen, P. W. N. M.; de Vries, J. G.; Reek, J.
N. H. Angew. Chem., Int. Ed. 2006, 45, 1223; (f) Takacs, J. M.; Reddy,
D. S.; Moteki, S. A.; Wu, D.; Palencia, H. J. Am. Chem. Soc. 2004,
In conclusion, we have developed a new type of
supramolecular chiral phosphorus-based ligands through
complexation between dibenzylammonium salt and di-
benzo[24]crown-8 macrocycle. In most cases, the supra-
molecular bidentate ligand exhibited superior activity and
enantioselectivity to those of the parent monodentate
ligand in the rhodium-catalyzed asymmetric hydrogenation
of a-dehydroamino acid esters. These supramolecular
ligands are modular, and further studies on optimized com-
plexation of both complementary monodentate ligands and
applications to other asymmetric reactions are underway.
´
126, 4494; (g) Rivillo, D.; Gulyas, H.; Benet-Buchholz, J.; Escudero-
´
Adan, E. C.; Freixa, Z.; van Leeuwen, P. W. N. M. Angew. Chem.,
Int. Ed. 2007, 46, 7247.
5. (a) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017; (b) Ashton, P.
R.; Campbell, P. J.; Chrystal, E. J. T.; Glink, P. T.; Menzer, S.; Philp,
D.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; Williams, D. J. Angew.
Chem., Int. Ed. 1995, 34, 1865; (c) Ashton, P. R.; Fyfe, M. C. T.;
Hickingbottom, S. K.; Stoddart, J. F.; White, A. J. P.; Williams, D. J.
´
´
J. Chem. Soc., Perkin Trans. 2 1998, 2117; (d) Arico, F.; Badjic, J. D.;
Cantrill, S. J.; Flood, A. H.; Leung, K. C. F.; Liu, Y.; Stoddart, J. F.
Top. Curr. Chem. 2005, 279, 203.
6. For selected recent examples, see: (a) Horie, M.; Suzuki, Y.; Osakada,
K. J. Am. Chem. Soc. 2004, 126, 3684; (b) Oku, T.; Furusho, Y.;
Takata, T. Angew. Chem., Int. Ed. 2004, 43, 966; (c) Tachibana, Y.;
Kihara, N.; Takata, T. J. Am. Chem. Soc. 2004, 126, 3438; (d) Zhu, X.
Z.; Chen, C. F. J. Am. Chem. Soc. 2005, 127, 13158; (e) Leung, K. C.
F.; Mendes, P. M.; Magonov, S. N.; Northrop, B. H.; Kim, S.; Patel,
K.; Flood, A. H.; Tseng, H. R.; Stoddart, J. F. J. Am. Chem. Soc.
2006, 128, 10707; (f) Huang, F. H.; Nagvekar, D. S.; Zhou, X. C.;
Gibson, H. W. Macromolecules 2007, 40, 3561.
7. During the course of preparing this Letter, analogous chiral bidentate
ligands based on a pseudoratanane skeleton have been independently
developed by Nishibayashi, see: Hattori, G.; Hori, T.; Miyake, Y.;
Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 12930.
Acknowledgements
We are grateful to the financial support from the Na-
tional Natural Science Foundation of China (20325209,
20532010 and 20772128), the Chinese Academy of Sciences
and the Major State Basic Research Development Program
of China (2005CCA06600).
Supplementary data
8. Yamaguchi, N.; Gibson, H. W. Angew. Chem., Int. Ed. 1999, 38,
143.
Supplementary data (Experimental procedures and
characterization) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.03.039.
9. Gibson, H. W.; Wang, H.; Bonrad, K.; Jones, J. W.; Slebodnick, C.;
Zackharov, L. N.; Rheingold, A. L.; Habenicht, B.; Lobue, P.; Ratliff,
A. E. Org. Biomol. Chem. 2005, 3, 2114.
10. Korostylev, A.; Gridnev, I.; Brown, J. M. J. Organomet. Chem. 2003,
680, 329.
11. (a) Makita, Y.; Kihara, N.; Nakakoji, N.; Takata, T.; Inagaki, S.;
Yamamoto, C.; Okamoto, Y. Chem. Lett. 2007, 36, 162; (b) Mobian,
P.; Banerji, N.; Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006,
4, 224.
References and notes
1. For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994; (b) Ojima, I. Catalytic Asymmetric
Synthesis, 2nd ed.; Wiley: New York, 2000; (c) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 2; (d) Lin, G. Q.; Li, Y. M.; Chan,
A. S. C. Principles and Applications of Asymmetric Synthesis; Wiley-
Interscience: New York, 2001; (e) Blaser, H. U.; Malan, C.; Pugin, B.;
Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103;
(f) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
12. For selected recent examples, see: (a) You, J. S.; Drexler, H.; Zhang,
S. L.; Fischer, C.; Heller, D. Angew. Chem., Int. Ed. 2003, 42, 913; (b)
Tang, W. J.; Wu, S. L.; Zhang, X. M. J. Am. Chem. Soc. 2003, 125,
9570; (c) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito,
E.; Wang, F.; Sun, Y. K.; Armstrong, J. D., III; Grabowski, E. J. J.;
Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126,
9918; (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) Togni, A.; Breutel, C.;
Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A. J. Am. Chem. Soc.
1994, 116, 4062.
2. For reviews, see: (a) Breit, B. Angew. Chem., Int. Ed. 2005, 44, 6816;
(b) Sandee, A. J.; Reek, J. N. H. Dalton Trans. 2006, 3385; (c) Kleij,
A. W.; Reek, J. N. H. Chem. Eur. J. 2006, 12, 4218.
13. 31P NMR of complex Rh(I)–1 in situ generated by the mixing of 1
with [Rh(COD)2]BF4 in CDCl3: d 120.4 (dd, JRh–P = 265.7 Hz,
3. (a) Breit, B.; Seiche, W. J. Am. Chem. Soc. 2003, 125, 6608; (b) Breit,
B.; Seiche, W. Angew. Chem., Int. Ed. 2005, 44, 1640; (c) Chevallier,
F.; Breit, B. Angew. Chem., Int. Ed. 2006, 45, 1599; (d) Waloch, C.;
Wieland, J.; Keller, M.; Breit, B. Angew. Chem., Int. Ed. 2007, 46,
3037; (e) Weis, M.; Waloch, C.; Seiche, W.; Breit, B. J. Am. Chem.
Soc. 2006, 128, 4188; (f) Birkholz, M. N.; Dubrovina, N. V.; Jiao, H.;
Michalik, D.; Holz, J.; Paciello, R.; Breit, B.; Bo¨ner, A. Chem. Eur. J.
2007, 13, 5896; (g) Sandee, A. J.; van der Burg, A. M.; Reek, J. N. H.
JP–P = 34.8 Hz, major) and 120.2 ppm (dd, JRh–P = 265.8 Hz, JP–P
=
35.2 Hz, minor) for the phosphite moiety; 31.5 (dd, JRh–P = 144.2 Hz,
JP–P = 35.6 Hz, minor) and 30.9 ppm (dd, JRh–P = 145.8 Hz,
JP–P = 35.6 Hz, major) for the phosphine moiety (for details, see
Supplementary data).
14. Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593.