Modular chiral dendritic monodentate phosphoramidite ligands for Rh(II)-catalyzed asymmetric hydrogenation: Unprecedented enhancement of enantioselectivity

Article abstract of DOI:10.1039/b815380a

Modular chiral dendrimers with monodentate phosphoramidite ligands located at the core were synthesized and applied in the Rh-catalyzed asymmetric hydrogenations, afforded unprecedented enhancement of enantioselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b815380a

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Modular chiral dendritic monodentate phosphoramidite ligands
for Rh(II)-catalyzed asymmetric hydrogenation: unprecedented
enhancement of enantioselectivityw
Feng Zhang,ab Yong Li,a Zhi-Wei Li,a Yan-Mei He,a Shou-Fei Zhu,c
Qing-Hua Fan*a and Qi-Lin Zhou*c
Received (in College Station, MA, USA) 3rd September 2008, Accepted 30th September 2008
First published as an Advance Article on the web 15th October 2008
DOI: 10.1039/b815380a
Modular chiral dendrimers with monodentate phosphoramidite
ligands located at the core were synthesized and applied in
the Rh-catalyzed asymmetric hydrogenations, afforded
unprecedented enhancement of enantioselectivity.
which consist of structurally tunable chiral backbone and
sterically demanding polyether dendritic wedges.
Monodentate chiral phosphorus ligands have recently
attracted considerable attention because of their excellent
performance, relatively simple synthesis and good stability.10
To achieve facile catalyst separation, monodentate phos-
phorus ligands and/or their metallic complexes have been
successfully immobilized onto organic or inorganic supports
via chemical bonds or noncovalent interactions.11 Chiral
dendritic monodentate phosphoramidite ligands were also
developed recently by us and Reek’s group,12 but evident
dendrimer effects were not observed and the recycling of
catalyst was not explored. In this present study, we synthesized
a new kind of modular chiral dendritic monodentate phos-
phoramidite ligands through substitution of the dimethyl-
The search for ideal chiral catalysts which combine the
advantages of both homogeneous and heterogeneous catalysis
is the center of many present investigations on the transition
metal catalyzed asymmetric synthesis.1,2 Due to the well-
defined and tunable molecular architectures as well as
nano-scale size, metallodendrimers have been emerging as a
promising class of catalysts as demonstrated in the pioneering
work by van Koten in 1994.3 So far, a number of organo-
metallic dendrimers with catalytic sites at the core or at the
periphery have been reported.4 Among them, however, exam-
ples of positive dendrimer effect, in which the dendrimer
played an active role in enhancing catalytic reactivity and/or
selectivity, are still limited.5–8 For asymmetric catalysts, subtle
conformational changes may significantly influence their
enantioselectivity because the catalytic reaction is governed
by small increments of free enthalpy of activation.9 Thus,
attachment of chiral catalyst onto the well-defined dendrimer
framework is expected to provide a unique tool for fine-tuning
catalytic performance through adjusting their microenviron-
ment. To the best of our knowledge, however, only two
groups reported successful study which afforded obviously
better enantioselectivity with higher generation dendritic
catalysts.7b,c Most recently, we have reported dendrimers with
a chiral diphosphine unit, BINAP (2,20-bis(diphenylphosphino)-
1,10-binaphthyl) at their core, and found that the iridium
catalysts with these dendritic BINAP exhibited significantly
higher catalytic activity than the parent Ir-catalyst.8e As an
extension of our research,8 here we report a new kind of chiral
dendrimers with a monodentate phosphoramidite at the core,
amino moiety by the Frechet-type dendritic wedges and
´
applied them in the Rh-catalyzed asymmetric hydrogenation
of a-dehydroamino acid esters and enamides. Unprecedented
positive dendrimer effect on enantioselectivity was observed in
both catalytic reactions for the first time.
The synthesis of chiral dendritic monodentate phosphor-
amidite ligands 1–4 is outlined in Scheme 1. Frechet-type
´
dendrimer was chosen as the support due to its inertness to
a Beijing National Laboratory for Molecular Sciences, Center for
Chemical Biology, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, 100190, P. R. China
b Graduate School of the Chinese Academy of Sciences, Beijing,
100080, P. R. China
c State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin, 300071, P. R. China.
E-mail: fanqh@iccas.ac.cn; qlzhou@nankai.edu.cn
w Electronic supplementary information (ESI) available: Procedures
for the synthesis of dendrons and chiral dendritic ligands. See DOI:
10.1039/b815380a
Scheme 1 The synthesis of modular chiral dendritic monodentate
phosphoramidite ligands (1–4).
ꢀc
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reaction,13 and dendrons 5 (5G0–5G3) bearing a secondary
amine group located at the focal point were firstly synthesized
by using the convergent method. Then, the chiral chloro-
phosphite 6A, which was generated in situ from phosphorus
trichloride and (S)-BINOL (A) in the presence of triethyl-
amine,14 reacted with dendrons 5 to give the zeroth to third
generation dendritic ligands 1 (1AGn, n = 0–3) in moderate
yields, respectively, as air-stable white powders after purifica-
tion by flash column chromatography. To demonstrate the
modularity and facility of this method, the other dendritic
ligands (2–4) were also synthesized by reacting 5 with chloro-
phosphite 6 (6B–6D) generated from the corresponding chiral
diols (B–D), respectively. All these dendritic ligands were well
characterized by 1H, 13C and 31P NMR spectroscopy as well as
MALDI-TOF mass spectrometry. All results are consistent
with the compounds synthesized.
Next, we investigated the effect of dendrimer generation on
the catalyst performance (Table 1). In sharp contrast to the
small monodentate phosphoramidite ligands,10g,h,14 in which
large groups on the nitrogen atom of the ligand led to poor
enantioselectivity, the second- and third-generation dendrimer
ligands 1AG2 and 1AG3 bearing sterically demanding groups
on the nitrogen atom gave excellent enantioselectivities
(entries 3 and 11). However, the reason of this enhancement
in enantioselectivity by introduction of large dendritic wedges
is not clear at present time.15 On the other hand, these bulk
dendrimer ligands afforded low reaction rate, which was
probably due to the encapsulation of the catalytically active
center by the dendritic wedges.8c In addition, the enantio-
selectivity induced by H8-BINOL-derived dendrimer ligand
2BG2 was found to be slightly lower than that obtained
with 1AG2 (entry 12 vs. 3). Much lower enantioselectivity
was observed with dendrimer ligand 3CG2 derived from
3,3-dimethyl-BINOL (entry 13). The dendrimer ligands
4DG0 and 4DG1 bearing 1,10-spirobiindane backbone gave
the same or slightly higher enantioselectivity as compared to
ligands 1AG0 and 1AG1 (entry 14 vs. 9, and entry 15 vs. 10).
To further demonstrate the unique positive dendritic effect
on enantioselectivity, other a-dehydroamino acid esters
(7b–7e) and enamides (9a–9d) were hydrogenated by using
dendritic ligands 1 (1AGn, n = 0–3). Generally, excellent
enantioselectivities were achieved by using the catalysts with
high-generation dendrimers. For example, among these
dendrimer catalysts, Rh/1AG2 or/and Rh/1AG3 gave the best
enantioselectivities in the asymmetric hydrogenation of sub-
strates (7b–7e) (Table 2). Similarly, in the cases of the hydro-
genation of enamides (9a–9d), it was found that the
enantioselectivity increased significantly with increasing
dendrimer generation (Table 3).
With these dendritic ligands in hand, the rhodium catalysts
were prepared in situ by reacting 2 equiv. of the appropriate
dendrimer ligands with [Rh(COD)2]BF4 in dichloromethane at
room temperature. Then, the hydrogenation of methyl
2-acetamidocinnamate (7a) as the model substrate was first
performed using 1 mol% Rh/1AG2 catalyst in different
solvents (Table 1, entries 1–3). It was found that dichloro-
methane was the best choice in terms of conversion and
enantioselectivity. Both the reaction rate and enantioselectiv-
ity were increased when the hydrogen pressure was increased
(entries 3–6). The ratio of ligand to metal has obvious influ-
ence on the enantioselectivity or the reaction rate. Unlike the
parent catalyst MonoPhos,10g the dendritic catalyst afforded
much lower enantioselectivity with a 1AG2/Rh ratio of 1
(entry 7). In contrast, similar enantioselectivity but low
conversion were observed when the ratio of 1AG2/Rh was
increased from 2 to 3 (entry 8 vs. 3).
Another important feature of dendrimer catalysts is the easy
and reliable separation of the chiral catalysts.16 To investigate
the recyclability of the dendritic catalysts in this study, the
Rh/1AG2-catalyzed asymmetric hydrogenation of 7a was
chosen as the standard reaction. Upon the completion of the
reaction, the catalyst was quantitatively precipitated by the
addition of hexane and reused at least five times with similar
enantioselectivities before run 5 (Table 4).
Table 1 Condition optimization for the Rh-catalyzed asymmetric
hydrogenation of methyl 2-acetamido cinnamate (7a)a
Entry
Ligand
Solvent
t/h
H2/atm
eeb (%)
1
2
3
4
5
6
1AG2
1AG2
1AG2
1AG2
1AG2
1AG2
1AG2
1AG2
1AG0
1AG1
1AG3
2BG2
3CG2
4DG0
4DG1
THF
EA
12
12
12
24
24
12
12
24
3
20
20
20
1
77 (R)
94 (R)
99 (R)
94 (R)
98 (R)
99 (R)
93 (R)
99 (R)
92 (R)
91 (R)
98 (R)
95 (R)
31 (R)
92 (S)
94 (R)e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Table 2 Asymmetric hydrogenation of a-dehydroamino acid esters
catalyzed by dendritic Rh/1 catalystsa
5
50
20
20
20
20
20
20
20
20
20
7c
8d
9
10
11
12
13
14
15
a
3
ee (%)b
30
12
12
3
Entry
Ar
1AG0
1AG1
1AG2
1AG3
1
2
3
4
2-MeOC6H4 (7b)
4-BrC6H4(7c)
4-FC6H4 (7d)
83
94
92
92
93
97
93
95
99
98
97
94
94
95
97
97
3
Reaction conditions: 0.094 mmol of 7a in 1.5 mL solvent, ligand/Rh
4-MeOC6H4 (7e)
b
= 2.2 (mol/mol), substrate/catalyst = 100 (mol/mol), 25 1C. 100%
conversions were achieved in all cases except for entries 2 (28%), 8
(24%) and 13 (49%). The ee values of the reduced products were
a
Reaction conditions: 0.094 mmol of 7 in 1.5 mL CH2Cl2, (S)-1/Rh =
2.2 (mol/mol), substrate/catalyst = 100 (mol/mol), 20 atm H2, 25 1C,
3–30 h. Determined by GC analysis with chiral column. In all cases,
100% conversions were observed.
b
c
determined by GC analysis with chiral column. (S)-1AG2/Rh =
d
1.0 (mol/mol). (S)-1AG2/Rh = 3.0 (mol/mol). (R)-4DG1 was used.
e
ꢀc
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Chem. Commun., 2008, 6048–6050 | 6049

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Table
3
Asymmetric hydrogenation of enamides catalyzed by
Leeuwen, Angew. Chem., Int. Ed., 2001, 40, 1828; (b) D. Astruc and
F. Chardac, Chem. Rev., 2001, 101, 2991; (c) J. K. Kassube and
L. H. Gade, Top. Organomet. Chem., 2006, 20, 61; (d) Q. H. Fan,
G. J. Deng, Y. Feng and Y. M. He, in Handbook of Asymmetric
Heterogeneous Catalysis, eds. K. Ding and Y. Uozumi,
Wiley-VCH, Weinheim, 2008, p. 131.
dendritic Rh/1 catalystsa
5 Reviews on dendritic effect in catalytic reactions, see: (a) H.-F. Chow,
C.-F. Leung, G. Wang and Y. Y. Yang, C. R. Chim., 2003, 6, 735;
´
(b) B. Helms and J. M. J. Frechet, Adv. Synth. Catal., 2006, 348, 1125.
ee (%)b
Entry
Ar
1AG0
1AG1
1AG2
1AG3
6 Selected examples of achiral dendrimer catalysts with positive
dendrimer effect, see: (a) C. Muller, L. J. Ackerman, J. N. H. Reek,
¨
1
2
3
4
a
C6H5 (9a)
60
60
61
47
78
71
73
60
86
78
78
78
90
94
94
92
P. C. J. Kamer and P. W. N. M. van Leeuwen, J. Am. Chem. Soc.,
2004, 126, 14960; (b) M. Ooe, M. Murata, T. Mizugaki, K. Ebitani
and K. Kaneda, J. Am. Chem. Soc., 2004, 126, 1604; (c) T. Fujihara,
Y. Obora, M. Tokunaga, H. Sato and Y. Tsuji, Chem. Commun.,
2005, 4526; (d) A. Ouali, R. Laurent, A. M. Caminade, J. P. Majoral
and M. Taillefer, J. Am. Chem. Soc., 2006, 128, 15990.
7 Selected examples of chiral dendrimer catalysts with positive
dendrimer effect, see: (a) R. Breinbauer and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2000, 39, 3604; (b) Y. Ribourdouille,
G. D. Engel, M. Richard-Plouet and L. H. Gade, Chem. Commun.,
4-ClC6H4 (9b)
4-BrC6H4 (9c)
4-MeC6H4 (9d)
Reaction conditions: 0.094 mmol of 9 in 1.5 mL CH2Cl2, (S)-1/Rh =
2.2 (mol/mol), substrate/catalyst = 100 (mol/mol), 20 atm H2, 25 1C,
3–35 h. Determined by GC analysis with chiral column. In all cases,
100% conversions were observed.
b
2003, 1228; (c) A. Gissibl, C. Padie, M. Hager, F. Jaroschik,
´
R. Rasappan, E. Cuevas-Yanez, C. O. Turrin, A. M. Caminade,
J. P. Majoral and O. Reiser, Org. Lett., 2007, 9, 2895.
Table 4 Catalyst recycling in the asymmetric hydrogenation of 7a
catalyzed by dendritic Rh/1AG2 catalysta
8 (a) Q. H. Fan, Y. M. Chen, X. M. Chen, D. Z. Jiang, F. Xi and
A. S. C. Chan, Chem. Commun., 2000, 789; (b) G. J. Deng, Q. H. Fan,
X. M. Chen, D. Liu and A. S. C. Chan, Chem. Commun., 2002,
1570; (c) B. Yi, Q. H. Fan, G. J. Deng, Y. M. Li, L. Q. Qiu and
A. S. C. Chan, Org. Lett., 2004, 6, 1361; (d) L. Wu, B. L. Li,
Y. Y. Huang, H. F. Zhou, Y. M. He and Q. H. Fan, Org. Lett.,
2006, 8, 3605; (e) Z. J. Wang, G. J. Deng, Y. Li, Y. M. He,
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Cycle
Run 1
Run 2
Run 3
Run 4
Run 5
Conv. (%)
ee (%)
100
98
100
98
100
98
100
98
100
91
a
See Table 1.
In summary, we have demonstrated for the first time the
importance of the dendritic wedges on enantioselectivity in the
Rh-catalyzed asymmetric hydrogenation of functionalized ole-
fins, such as a-dehydroamino acid derivatives and enamides.
Higher enantioselectivities were achieved as the dendritic
wedges on the N-atom of the phosphoramidite ligand became
bigger. Such dendritic enhancement of enantioselectivity is
rarely observed in the field of dendrimer chemistry.7b,c Current
work is aiming at the detailed insight of the nature of this
strong dendrimer effect and the exploration of these dendritic
monodentate phosphoramidites in other asymmetric reactions.
We are grateful to the financial support from the National
Natural Science Foundation of China (20532010 and
20772128) and Chinese Academy of Sciences.
9 R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008.
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Notes and references
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observed. For details, see ESIw.
4 Selected reviews on organometallic dendrimer catalysts, see: (a) G.
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ꢀc
This journal is The Royal Society of Chemistry 2008
6050 | Chem. Commun., 2008, 6048–6050