Dendritic MonoPhos: synthesis and application in Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2006.01.013

A new class of dendritic monodentate phosphoramidite ligands were synthesized through substitution of the dimethylamino moiety in MonoPhos by the Frechet-type dendritic wedge and applied in the asymmetric hydrogenation of α-dehydroamino acid esters and di

Full text of DOI:10.1016/j.tetasy.2006.01.013

Tetrahedron: Asymmetry 17 (2006) 536–543
Dendritic MonoPhos: synthesis and application in
Rh-catalyzed asymmetric hydrogenation
Wei-Jun Tang,ꢀ Yi-Yong Huang, Yan-Mei He and Qing-Hua Fan*
Laboratory of Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, PR China
Received 20 November 2005; accepted 5 January 2006
Available online 20 February 2006
Dedicated to Professor Jack Halpern on the occasion of his 80th birthday
Abstract—A new class of dendritic monodentate phosphoramidite ligands were synthesized through substitution of the dimethyl-
´
amino moiety in MonoPhos by the Frechet-type dendritic wedge and applied in the asymmetric hydrogenation of a-dehydroamino
acid esters and dimethyl itaconate. High enantioselectivities (up to 97.9% ee) and catalytic activities (up to 4850 hꢀ1 TOF) were
achieved, which are better or comparable to those obtained from MonoPhos. The third generation dendrimer catalyst gave the
slightly lower catalytic activity relative to the lower generation ones. The steric shielding by the dendrimer could stabilize the
rhodium complex against decomposition caused by hydrolysis in a protic solvent. The inactive catalysts (RhL3 and RhL4) were
activated by addition of a free metal precursor Rh(COD)2BF4, and showed high enantioselectivities and catalytic activities.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
dritic ligands for asymmetric catalysis through the incor-
poration of BINAP4 or BINOL5 into the core of the
´
Dendrimers are highly branched macromolecules, which
have precisely defined molecular structures with nano-
scale size. Since the pioneering work of van Koten
et al. reported in 1994,1 dendritic catalysts have become
a subject of intensive research.2 Compared to the linear
soluble polymeric chiral catalysts, the dendrimer archi-
tecture might offer better control of the disposition of
the catalytic species than soluble polymer-based cata-
lysts. Thus, it is possible to fine-tune the catalytic prop-
erties of the dendritic catalysts through the adjustment
of their structure, size, shape, and solubility. Although
a number of organometallic dendrimers with catalytic
sites at the core or at the periphery, have been reported,
only a few dendrimer catalysts have shown different
properties from those of small molecule analogues.3 In
the case of the core-functionalized dendrimers, it is
expected that the steric shielding or blocking effect of
the specific microenvironment created by the dendritic
structure could modulate the catalytic behavior of the
core.3e Recently, we developed two types of chiral den-
Frechet-type dendrimers, respectively. In both cases, it
was found that the size of the dendritic wedges influ-
enced the reactivity and/or the enantioselectivity of
the dendritic catalysts. As an extension of our
research,3e,4–6 herein we report the synthesis of dendritic
chiral monodentate phosphoramide ligands through the
´
attachment of MonoPhos onto the focal point of Fre-
chet’s polyether dendrimers and their applications in
the Rh-catalyzed asymmetric hydrogenation of a-dehyd-
roamino acid esters and dimethyl itaconate.
After being neglected for about 30 years, the monoden-
tate phosphorus ligands7 are gaining more and more
attention. Pioneering studies from the groups of Pringle,
Reetz, Feringa, and others8 have shown that the use of
a conformationally rigid symmetric bidentate ligand
is not essential to obtain good stereo-discrimination.
Chiral monodentate phosphonite, phosphoramidite, or
phosphites have proven to be able to induce excellent
enantioselectivity in rhodium-catalyzed asymmetric
hydrogenation reactions, comparable to or better than
those obtained by diphosphine ligands.8,9 So far, a num-
ber of monodentate phosphorus ligands have been
designed and reported. Three outstanding examples
are listed in Scheme 1. The easy synthesis and modular
structure of monodentate phosphoramidites in general
*
Corresponding author. Tel.: +86 10 62554472; fax: +86 10
62554449; e-mail: fanqh@iccas.ac.cn
ꢀ Present address: The Hong Kong Polytechnic University, Hong
Kong, China.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.013

W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
537
R
N
'
R
R
R
R
R
O
O
O
O
O
O
P
N
P
N
P
N
O
'
R
N
R
2
SpiroPhos
3
DpenPhos
1
MonoPhos
Scheme 1. Examples of phosphoramidite.
allow the tuning of the catalyst to find highly effective
ligands. Substitution by the dimethylamino group was
most often used to tune the catalytic efficiency. It was
found that substituents on the nitrogen atom played
an important role on the enantioselectivity of the cata-
lyst.9e,k Although different types of substituents have
been studied, however, to the best of our knowledge,
there have been no reports on the use of dendritic wedge
as the substituent. In addition, it has proven that the
higher ligated rhodium species such as RhL3 and
RhL4 are inactive, and the structure of the catalytically
active specie is still not very clear.9b,f,h In the case of a
dendritic ligand, it is possible in principle that the steri-
cally demanding dendritic wedge can suppress the for-
mation of higher ligated rhodium species and
consequently influence the catalytic properties. To
extend the small substituents to macromolecular ones
and study the possible ‘dendritic effect’, we synthesized
a new series of dendritic phosphoramidite by choosing
Ferringa’s MonoPhos as a model ligand. This study
demonstrated that the macromolecular substituent on
the nitrogen atom did not lead to any deterioration of
the enantioselectivity.
2. Results and discussion
2.1. Synthesis of dendritic MonoPhos ligands
Ferringa’s MonoPhos was chosen as the model ligand
for our study due to its modular structure and excellent
efficiency in the asymmetric hydrogenation of a variety
O
O
1) BH3 -THF, THF
Ac2O/pyridine
O
O
O
O
2) HCl (6M), reflux
O
THF, reflux
NH2
N
O
O
98-99 %
78-90 %
H
O
O
O
O
n
n
5a~5c (n=0~2)
6a~6c (n=0~2)
O
O
O
O
O
O
O
O
P
Cl
N
P
O
O
O
8
O O
N
H
O
Et3N, THF
O
n
50-55 %
O
n
7a~7c (n=0~2)
4a (n=0 ); 4b (n=1); 4c (n=2)
Ph
PhCH2NHC2H5
O
O
O
P
N
P
Cl
O
Et3N, THF
53%
8
9
Scheme 2. Synthesis of dendritic MonoPhos 4a–4c and 9.

538
W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
of prochiral olefins.8c,9b Recently, immobilization of
MonoPhos has been reported by several research
groups.10 Doherty et al. reported the first polymer-sup-
ported Rh–MonoPhos for asymmetric hydrogenation of
methyl 2-acetamido cinnamate.10b The MonoPhos
ligand bearing a styrene moiety on the nitrogen atom
was attached onto the polymer backbone through radi-
cal copolymerization. However, the resulting supported
rhodium catalyst gave a much lower enantioselectivity
(up to 80% ee) relative to that of MonoPhos (95% ee).
This was probably due to the ligand modification and
the heterogeneous reaction conditions. In our case, sub-
stitution on the dimethylamino moiety in MonoPhos
was also used for the attachment of a dendrimer. The
synthetic routes for these new dendritic ligands are out-
lined in Scheme 2.
white powders after purification by flash column chro-
matography. For comparison, a model compound of a
small molecule 9 was also synthesized using the same
method. All these dendritic MonoPhos ligands were well
1
characterized by H, 13C, and 31P NMR spectroscopy,
elemental analyses, and/or HRMS and MALDI-TOF
mass spectrometry. All results are consistent with the
compounds synthesized.
2.2. Homogeneous rhodium-catalyzed hydrogenation of
dehydroamino acid esters and dimethyl itaconate
Firstly, the rhodium-catalyzed asymmetric hydrogena-
tion of methyl 2-acetamido cinematic 10a was used as
the model reaction to study the catalytic behavior of
the new dendritic ligands 4 and 9. The rhodium catalysts
were prepared in situ by reaction of 2 equiv of the
appropriate dendrimer ligands with [Rh(COD)2]BF4 in
dichloromethane at room temperature. Typically, the
reactions were carried out at room temperature in
dichloromethane as the solvent. The experimental re-
sults are listed in Table 1. To our delight, all catalysts
gave high enantioselectivities (up to 97.9% ee), which
are better than that (95% ee)9b obtained from Mono-
Phos 9 (entries 1–4). These results indicated that the size
of the dendritic substituents on the nitrogen atom would
not result in any negative effect on the selectivity, which
is in contrast to the results obtained with the corre-
sponding small monodentate phosphoramidite ligands
bearing different substituents on the nitrogen atom.9k
Generally, small alkyl groups on the nitrogen atom of
MonoPhos ligands are necessary for obtaining high
enantioselectivity in the asymmetric hydrogenation of
dehydroamino acid derivatives. In addition, complete
Firstly, a polyether dendrimer was chosen as the support
to ensure catalyst stability under the reaction condi-
tions.11 Dendrons 5a–5c bearing an amino group located
at the focal point were synthesized by using the conver-
12
´
gent method reported by Frechet and co-workers.
Dendrons 6a–6c were prepared quantitatively by acetyl-
ation of 5 with acetic anhydride in the presence of pyr-
idine. Then, 6 was reduced by NaBH4/I2 or BH3ÆTHF
to give the dendritic secondary amine 7a–7c in high
yields, respectively.
Chiral chlorophosphite 8 was prepared by the slow addi-
tion of phosphorus trichloride to (R)-BINOL and trieth-
ylamine in THF. Dropwise addition of the appropriate
dendron 7 to an ice-cooled THF solution of the resulting
chiral chlorophosphite 8 and a base gave the dendritic
chiral ligands 4a–4c in moderate yields, as air-stable
Table 1. Asymmetric hydrogenation of methyl 2-acetamido cinnamate 10a with dendritic Rh–MonoPhos catalysts
in situ catalyst
CO2CH3
NHAc
CO2CH3
NHAc
10a
Rh(COD)2BF4 + 4 or 9
Ph
Ph
CH2Cl2, r.t.
11a
Entry
Ligand
Sub./Cat.
H2 (atm)
Timea
ee (%)b (config.)
1
2
3
4
5
6
7
8
4a
4b
4c
9
100
100
100
100
100
1000
1000
1000
1000
1000
1000
1000
100
20
20
20
20
1
15
15
15
10
10
10
10
20
20
20
20
10 h
10 h
10 h
10 h
10 h
1 h
1 h
1 h
12 min (95.8%)
12 min (97.0%)
12 min (74.0%)
12 min (89.9%)
4 h
4 h
4 h
4 h
97.5 (S) (95)c
97.4 (S)
97.9 (S)
97.6 (S)
97.8 (S)
97.7 (S)
97.8 (S)
97.6 (S)
97.3 (S)
97.5 (S)
97.3 (S)
96.7 (S)
97.2 (S)
96.1 (S)
93.6 (S)
87.5 (S)
4b
4a
4c
9
9
4a
4b
4c
9
10
11
12
13d
14e
15d
16e
4b
4b
9
100
100
100
9
a Conversion is 100% unless noted otherwise.
b Determined by chiral GC analysis.
c Ee value for Rh–MonoPhos catalyst taken from Ref. 9b.
d CH2Cl2/MeOH = 2:1 (v/v) as the reaction solvent.
e CH2Cl2/MeOH = 1:1 (v/v) as the reaction solvent.

W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
539
Table 2. Asymmetric hydrogenation of a-dehydroamino acid esters
10b–10j and dimethyl itaconate 12 with dendritic Rh–MonoPhos
catalystsa
conversion and high enantioselectivities were achieved
when the reactions were carried out at either lower H2
pressure (1 atm) or with low catalyst loading (S/
C = 1000) (entries 5–8). In order to study the dendritic
effect on the reaction rate, we performed the reactions
at a substrate to catalyst ratio of 1000 at 10 atm for
12 min (entries 9–12). It was found that the first and
the second generation catalysts showed very similar cat-
alytic activity as compared to the monomer catalyst Rh–
9, albeit the third one gave slightly lower reaction rate.
The second generation catalyst 4b–Rh gave the highest
catalytic activity (up to 4850 hꢀ1 TOF). This size effect
was probably due to the encapsulation of the cataly-
tically active center by the high generation dendritic
wedges.
in situ catalyst
Rh(COD)2BF4 + 4 or 9
CO2CH3
NHAc
11b-j
CO2CH3
NHAc
10b-j
R
R
CH2Cl2, r.t., L/Rh = 2:1
S/C = 100, PH2 = 20 atm
in situ catalyst
Rh(COD)2BF4 + 4 or 9
H3C
MeOOC
12
CH2Cl2, r.t., L/Rh = 2:1 MeOOC
S/C = 100, PH2 = 20 atm
COOMe
COOMe
13
Entry
Ligand
Substrate (R)
eeb (%) (config.)
1
2
3
4
5
6
7
8
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
4c (G3)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
3-ClC6H5 (10b)
3-ClC6H5 (10b)
3-ClC6H5 (10b)
4-ClC6H5 (10c)
4-ClC6H5 (10c)
4-ClC6H5 (10c)
4-FC6H5 (10d)
4-FC6H5 (10d)
4-FC6H5 (10d)
4-BrC6H5 (10e)
4-BrC6H5 (10e)
4-BrC6H5 (10e)
4-CH3OC6H5 (10f)
4-CH3OC6H5 (10f)
4-CH3OC6H5 (10f)
4-NO2C6H5 (10gj)
4-NO2C6H5 (10g)
4-NO2C6H5 (10g)
2-CH3C6H5 (10h)
2-CH3C6H5 (10h)
2-CH3C6H5 (10h)
2-CH3C6H5 (10h)
2-CH3OC6H5 (10i)
2-CH3OC6H5 (10i)
2-CH3OC6H5 (10i)
2-ClC6H5 (10j)
2-ClC6H5 (10j)
2-ClC6H5 (10j)
12
97.8 (S)
97.6 (S)
97.1 (S)
96.0 (S)
97.3 (S)
97.6 (S)
97.4 (S)
97.1 (S)
97.6 (S)
97.5 (S)
97.0 (S)
97.3 (S)
97.7 (S)
97.7 (S)
97.9 (S)
96.2 (S)
97.0 (S)
93.9 (S)
96.3 (S)
96.2 (S)
97.3 (S)
95.1 (S)
95.6 (S)
95.0 (S)
93.8 (S)
95.6 (S)
94.6 (S)
94.1 (S)
97.7 (R) (94)c
97.0 (R)
96.8 (R)
Most importantly, this encapsulation, may stabilize the
rhodium complex against decomposition caused by
hydrolysis in the protic solvent. Thus, the second gener-
ation catalyst gave almost the same enantioselectivity
when the reaction was performed in dichloromethane/
methanol as the solvent, while the monomer catalyst
Rh–9 gave much lower enantioselectivity in the protic
solvent (entries 13–16 vs entries 2 and 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
We then applied our dendritic catalysts to the hydro-
genation of other a-dehydroamino acid ester substrates
(Table 2). As shown in Table 2, excellent enantioselectiv-
ities were also achieved in all cases, which are better or
comparable to those obtained from MonoPhos 9.
Hydrogenation of substrates with electron donating
and withdrawing meta- (entries 1–3) or para-substituents
(entries 4–18) on the phenyl group gave slightly higher
ee values as compared to the ortho-substituted sub-
strates (entries 19–28). It was noted that the dendritic
catalysts showed slightly higher enantioselectivities for
all ortho-substituted substrates than those obtained
from the monomer ligand 9 (entries 19–28). Hydrogena-
tion of dimethyl itaconate 12 also gave excellent enantio-
selectivities, which are better than those of MonoPhos
(entries 29–31).9b
4a (G1)
4b (G2)
9 (G0)
4a (G1)
4b (G2)
9 (G0)
Feringa9b and Zhou9f reported that the L/Rh ratio sig-
nificantly influenced the catalytic activity. For example,
when the L/Rh ratio was increased to 3 and 4, catalytic
activity ceased. In order to investigate the possible differ-
ent catalytic performance of the dendritic catalysts, we
performed the reactions with L/Rh ratio from 1:2 to
4.2:1 in dichloromethane as the solvent (Table 3). As
shown in Table 3, the reactions with 2.1:1 and 1:1 L/
Rh ratio gave exactly the same ee values, but the latter
showed slightly higher activity (entries 1 and 2). This re-
sults are in agreement with those observed by Mono-
Phos.9b Even more interesting was the finding that a
similar ee value was also observed when the L/Rh ratio
was lowered to 1:2 (entry 3). Due to the strong binding
between the ligand and Rh, the reactions with a L/Rh
ratio between 3.0:1 and 4.2:1 was much slower even at
high H2 pressure when the low generation dendritic cat-
alysts were used (entries 4–8, 10, and 12). Most interest-
ingly, when the third generation catalyst Rh–4c was
used with L/Rh of 4.2:1 (entry 9), the catalytic system
remained partially active and gave very similar ee values.
12
12
a Conversion is 100% in all cases.
b Determined by chiral GC analysis.
c Ee value for Rh–MonoPhos catalyst taken from Ref. 9b.
This result indicated that the catalytically active center
could be encapsulated by the dendritic wedges,3e which
consequently suppressed, to some extent, the formation
of unwanted higher ligated rhodium species at higher
L/Rh ratio during the hydrogenation.
Feringa9b used electrospray mass spectrometry to inves-
tigate the rhodium species at 2:1 L/Rh ratio that are
present during hydrogenation. Different species includ-
ing complexes containing 1, 2, or 3 ligands and 1 sub-
strate molecule were observed. Their study showed
that some of higher ligated rhodium species were
formed during the hydrogenation, which could not be

540
W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
Table 3. Effect of L/Rh ratio on asymmetric hydrogenation of methyl 2-acetamido cinnamate 10a
in situ catalyst
CO2CH3
NHAc
11a
CO2CH3
NHAc
10a
Rh(COD)2BF4 + 4 or 9
Ph
Ph
CH2Cl2, rt. S/C=100
Entry
Ligand (L/Rh)
H2 (atm)
Time (h)
Conv. (%)a
ee (%)a
1
2
3
4
5
6
7
8
4b (2.1:1)
4b (1:1)
4b (1:2)
4b (3.0:1)
4b (4.0:1)
4b (4.2:1)
9 (4.2:1)
1
1
1
1
1
20
20
20
20
1
3
3
3
3
3
5
5
5
5
4
4
4
4
88.0
98.7
100
4.4
1.4
5.7
3.0
4.0
46.6
4.0
97.6
3.7
97.9
97.8
94.5
nd
nd
nd
nd
nd
97.0
nd
97.2
nd
4a (4.2:1)
4c (4.2:1)
4b (3.5:1)
4b (3.5:1!2.0:1)b
9 (3.5:1)
9
10
11
12
13
1
1
1
9 (3.5:1!2.0:1)b
92.0
95.6
a Determined by chiral GC.
b The in situ prepared Rh complexes (4a/Rh or 9/Rh = 3.5:1) was added Rh(COD)2BF4, giving the catalyst mixtures with L/Rh = 2.0:1.
transferred to the active species again under the reaction
conditions. In order to test the possibility of dissociation
of these inactive catalysts (RhL3 and RhL4) during
hydrogenation, we used the mixtures of the preformed
inactive complexes with a 3.5:1 L/Rh ratio and
metal precursor Rh(COD)2BF4 as the catalysts (totally
L/Rh = 2:1) for hydrogenation of 10a at 1 atm H2 pres-
sure for 4 h. Interestingly, a similar enantioselectivity
and conversion were achieved as compared to those
obtained from the preformed catalyst with a 2:1 L/Rh
ratio (entry 10 vs 11 and entry 12 vs 13). In addition,
we determined the dependency of conversion versus time
to further demonstrate this finding (Fig. 1). Obviously,
the catalyst mixtures showed very similar reaction rates
to those of the preformed catalyst. This showed that the
inactive catalysts could be activated by addition of free
metal precursor Rh(COD)2BF4, and similar active spe-
cies were probably formed during hydrogenation.
3. Conclusion
We have developed a new class of dendritic monoden-
tate phosphoramidite ligands through substitution of
´
dimethylamino moiety in MonoPhos by the Frechet-
type dendritic wedge. These dendrimer catalysts were
successfully applied in the asymmetric hydrogenation
of a-dehydroamino acid esters and dimethyl itaconate.
Higher or comparable enantioselectivities were achieved
as compared to that obtained from MonoPhos. The
steric shielding by the dendrimer could stabilize the
rhodium complex against decomposition caused by
the hydrolysis in protic solvent. The third generation
dendrimer catalyst gave slightly lower catalytic activity
relative to the lower generation ones due to the
encapsulation of the catalytically active center by the
dendritic wedge. This encapsulation effect could also
suppress, to some extent, the formation of unwanted
higher ligated inactive rhodium species at higher L/Rh
ratio during the hydrogenation. It was demonstrated
that the inactive catalysts (RhL3 and RhL4) could be
activated by addition of free metal precursor
Rh(COD)2-BF4, and similar active species was probably
formed during hydrogenation. We are currently study-
ing the synthesis of more rigid dendritic monodentate
phosphorus ligands and their applications in different
catalytic asymmetric transformations.
100
80
60
40
B
C
A
20
0
0
50
100
150
200
250
300
4. Experimental
Time (min)
4.1. Materials and equipment
Figure 1. Dependency of conversion versus time (T = 10 ꢁC, PH
=
2
1 atm, [9a] = 0.025 M, [Rh] = 0.25 mM). Curve A: 4a/Rh = 4:1; Curve
B: 4a/Rh = 1:1; Curve C: catalyst A + 3 equiv Rh(COD)2BF4 (totally
L/Rh = 1:1).
All solvents were dried using standard, published meth-
ods and were distilled under nitrogen atmosphere before

W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
541
use. Except as specified, commercial reagents were used
4.3. General procedure for synthesis of dendritic
N-ethyl amine compounds 7a and 7b
as received without further purification. Dendrimers 5a–
5c were synthesized according to the published
method.12
To
a 250 mL three-necked round-bottomed flask
equipped with a magnetic stirrer, a dropping funnel
and a reflux condenser, compound 6 (6a or 6b)
(12 mmol), NaBH4 (36 mmol), and dry THF (80 mL)
was added. After a solution of iodine (36 mmol) in
10 mL THF was added dropwise over 30 min at 0 ꢁC,
the mixture was heated to reflux for 24 h. When the
reaction mixture was cooled to 0 ꢁC and quenched by
saturated NH4Cl solution (10 mL), the pH was adjusted
to 12 with 20% aqueous NaOH solution. THF was
removed, and the residue was extracted with CH2Cl2
(100 mL · 3). The organic layer was washed with brine
and evaporated to give an oily product. This oil was
added to a 50 mL round-bottomed flask charged with
30 mL THF and 6 M hydrochloric acid (10 mL). After
the mixture was stirred at refluxing temperature for
6 h, it was cooled to 0 ꢁC and the pH was adjusted to
12 again followed by evaporation, extraction, and con-
centration. The crude product was purified by silica
gel column chromatography (eluent: dichloromethane/
methanol 10:1) to afford a yellow oil.
NMR spectra were recorded on a BRUKER Model
ADVANCE DPX 300 spectrometer (300 MHz H and
1
122 MHz 31P) using tetramethylsilane for 1H as an
internal standard, 85% of H3PO4 in D2O for 31P as an
external standard. All signals are reported in parts per
million unit. MALDI-TOF-MS were recorded on a
Bruker Biflex spectrometer with a-cyano-4-hydroxycin-
namic acid (CCA) as a matrix. Elemental analysis was
performed with a Carlo Erba 1106 Elemental Analyzer.
Optical rotations were measured with AA-10R auto-
matic polarimeter. For high-pressure hydrogenation,
50 mL stainless autoclave equipped with a glass liner
was used. The ee values were determined by chiral GC
with
column.
a 25 m · 0.25 mm Chrompack Chirasil-L-Val
4.2. General procedure for synthesis of dendritic
N-ethyl acetyl compounds 6a–6c
A 50 mL round-bottomed flask equipped with a stirrer
and a condenser, charged with the dendritic amine 5
(5a–5c) (15.0 mmol), acetic anhydride (3.0 mL), pyridine
(0.2 mL), and THF (30 mL). The reaction mixture was
refluxed for 5 h under nitrogen atmosphere. After being
cooled to room temperature, THF was evaporated
under reduced pressure. Aqueous NaOH solution
(2 M, 10 mL) was added, and the mixture was extracted
three times with CH2Cl2 (100 mL · 3). The organic layer
was washed with saturated NaHCO3 solution and brine
in turn, dried over anhydrous MgSO4, and evaporated
to give a white solid.
1
4.3.1. Compound 7a. Yield 80%; H NMR (300 MHz,
CDCl3) d 1.27–1.32 (m, 3H), 2.74–2.76 (m, 2H), 3.88
(s, 2H), 4.96 (s, 4H), 6.50 (d, J = 1.8 Hz, 1H), 6.80
(2H), 7.22–7.32 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 11.14, 40.80, 50.01, 70.12, 103.00, 108.76,
127.64, 127.93, 128.44, 132.20, 136.38, 160.19; HRMS
(ESI) for C23H25NO2 [M+1]+ calcd 348.1964, found
348.1942.
1
4.3.2. Compound 7b. Yield 78%; H NMR (300 MHz,
CDCl3) d 1.33–1.38 (m, 3H), 2.79 (br, 2H), 3.90 (s,
2H), 4.98–5.03 (s, 12H), 6.53–6.84 (m, 9H), 7.27–7.40
(m, 20H), 9.93 (br, 1H); 13C NMR (75 MHz, CDCl3)
d 11.14, 40.84, 50.02, 70.04, 101.59, 103.30, 106.50,
108.86, 127.57, 127.98, 128.56, 132.05, 136.75, 138.96,
160.08, 160.18; HRMS (ESI) for C51H49NO6 [M+1]+
calcd 772.3638, found 772.3621.
4.2.1. The first generation dendritic acetyl amine
6a. Yield 99%; H NMR (300 MHz, CDCl3) d 1.89
(s, 3H), 4.25 (d, J = 5.7 Hz, 2H), 4.91 (s, 4H), 5.77 (br,
1H), 6.43 (3H), 7.21–7.33 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 23.28, 43.75, 70.10, 100.98, 106.86,
127.58, 128.08, 128.64, 136.74, 140.72, 160.20, 169.94.
1
4.2.2. The second generation dendritic acetyl amine
6b. Yield 98%: H NMR (300 MHz, CDCl3) d 1.97
4.3.3. Compound 7c. To a solution of 1.00 M borane in
tetrahydrofuran (12 mL) in a 50 mL flask (nitrogen
atmosphere) was added 6c (3 mmol) in 30 mL THF over
30 min. The temperature was maintained at 0 ꢁC during
the addition. The colorless solution was then heated at
reflux for 24 h. The mixture was cooled to room temper-
ature and 6 M hydrochloric acid (3 mL) was added.
After refluxing for further 6 h, the final product was
obtained with the same procedure used for compound
7a (eluent: dichloromethane/methanol 20:1), yield 90%;
1H NMR (300 MHz, CDCl3) d 1.26–1.32 (m, 3H),
2.77–2.79 (br, 2H), 3.90 (s, 2H), 4.85–4.95 (m, 28H),
6.47–6.79 (m, 21H), 7.25–7.36 (m, 40H); 13C NMR
(75 MHz, CDCl3) d 11.21, 41.12, 50.22, 69.93, 70.06,
101.61, 103.22, 106.45, 106.61, 108.83, 127.54, 127.78,
127.95, 128.54, 132.27, 136.81, 139.02, 139.27, 160.00,
160.13, 160.25; HRMS (FAB) for C107H97NO14
[M+1]+ calcd 1620.6987, found 1620.6993.
1
(s, 3H), 4.32 (d, J = 5.6 Hz, 2H), 4.93 (s, 4H), 5.01 (s,
8H), 5.74 (br, 1H), 6.48–6.66 (m, 9H), 7.28–7.42 (m,
20H); 13C NMR (75 MHz, CDCl3) d 23.26, 43.77,
69.97, 70.14, 101.05, 101.56, 106.39, 106.91, 127.60,
128.05, 128.62, 136.77, 139.22, 140.68, 160.11, 160.20,
169.93.
4.2.3. The third generation dendritic acetyl amine
6c. Yield 98%: 1H NMR (300 MHz, CDCl3) d 1.96
(s, 3H), 4.28 (d, J = 5.6 Hz, 2H), 4.89–5.05 (m, 28H),
5.72 (br, 1H), 6.46–6.66 (m, 21H), 7.29–7.40 (m, 40H);
13C NMR (75 MHz, CDCl3) d 23.19, 43.66, 69.97,
70.11, 100.96, 101.59, 105.93, 106.40, 106.88, 127.14,
127.55, 127.78, 128.00, 128.17, 128.23, 128.30, 128.37,
128.57, 129.05, 136.37, 136.76, 137.14, 139.23, 140.74,
160.06, 160.16, 169.81.

542
W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
4.4. General procedure for synthesis of dendritic
phosphoramidite ligands (4a–4c and 9)
4.4.3. Compound 4c. Yield 50%; mp 69–71 ꢁC;
16
½aꢁD ¼ þ72:7 (c 0.33, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 1.02 (t, J = 7.04 Hz, 3H), 2.59–2.67 (m, 1H),
2.95–3.00 (m, 1H), 3.66–3.75 (m, 1H), 4.12–4.20 (m,
1H), 4.83–5.03 (m, 28H), 6.50–6.57 (m, 9H), 6.64–6.67
(m, 12H), 7.19–7.40 (m, 47H), 7.50–7.53 (d, J =
8.8 Hz, 1H), 7.81–7.91 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 14.24, 38.82, 39.10, 47.69, 47.91, 69.97,
70.07, 100.73, 101.57, 106.37, 106.45, 107.38, 121.70,
122.09, 122.57, 123.90, 124.54, 124.74, 126.03, 126.91,
126.96, 127.14, 127.56, 127.79, 127.99, 128.25, 128.32,
128.57, 130.04, 130.29, 130.65, 131.34, 132.52, 132.76,
136.74, 139.15, 139.29, 141.01, 149.37, 149.74, 149.81,
159.87, 160.06, 160.13; 31P NMR (122 MHz, CDCl3) d
147.13; MALDI-TOF MS for C127H108NO16P [M]+
calcd 1933.7, found 1933.6. Anal. Calcd for
C127H108NO16P: C, 78.82; H, 5.63; N, 0.72. Found C,
78.35; H, 5.50; N, 0.57.
To a solution of (R)-BINOL (0.5 g, 1.75 mmol) and tri-
ethylamine (0.5 mL) in THF (10 mL) was added drop-
wise 0.2 mL phosphorus chloride at 0 ꢁC under a
nitrogen atmosphere. After the mixture was stirred for
6 h, evaporation of excess reagent, and azeotropic distil-
lation of the residue with anhydrous toluene (5 mL)
gave the intermediate chlorophosphite in quantitative
yield. To this residue was added N-ethyl benzylamine
(2.0 mmol) and triethylamine (0.5 mL) in THF (10
mL). The mixture was stirred overnight at room temper-
ature. The crude product was purified by column chro-
matography on silica gel (eluent: dichloromethane/
petroleum ether = 1:1, v/v) to afford 9 as a white foam.
16
Yield 55%; mp 82–84 ꢁC; ½aꢁD ¼ þ315:2 (c 0.33,
1
CH2Cl2); H NMR (300 MHz, CDCl3) d 1.06 (t, J =
7.05 Hz, 3H), 2.59–2.66 (m, 1H), 2.97–3.02 (m, 1H),
3.76–3.85 (m, 1H), 4.22–4.30 (m, 1H), 7.25–7.42 (m,
12H), 7.57 (d, J = 8.8 Hz, 1H), 7.85–8.00 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 14.18, 14.21, 38.61, 38.90,
47.61, 47.87, 121.77, 122.17, 122.61, 122.63, 123.99,
124.53, 124.77, 126.04, 126.96, 127.05, 127.15, 128.23,
128.31, 129.97, 130.23, 130.70, 131.41, 132.60, 132.85,
138.34, 138.37, 149.49, 149.84, 149.90 ppm; 31P NMR
4.5. General procedure for the hydrogenation of methyl
2-acetamido cinnamate
Dendritic MonoPhos ligand (7.85 · 10ꢀ3 mmol) and
Rh(COD)2BF4 (3.74 · 10ꢀ3 mmol) in CH2Cl2 (10 mL)
were stirred at room temperature for 10 min under a
nitrogen atmosphere. Then, a 50 mL glass-lined stainless
steel reactor with a magnetic stirring bar was charged
with substrate 10a (16.4 mg, 0.0748 mmol), the in situ
prepared catalyst (2 mL, 7.74 · 10ꢀ3 mmol). The auto-
clave was closed and pressurized with hydrogen to
20 atm. The mixture was stirred at ambient temperature
for 20 h. After careful venting of hydrogen, conversion
and enantioselectivity of the reduced product was deter-
mined by chiral GC with a 25 m Chirasil-L-Val capillary
column.
(122 MHz, CDCl3)
d 147.85; HRMS (FAB) for
C29H24NO2P [M+1]+ calcd 450.1623, found 450.1611.
4.4.1. Compound 4a. The dendritic phosphoramidite
ligands were prepared using the same procedures. Yield
16
1
53%; mp 81–83 ꢁC; ½aꢁD ¼ þ254:5 (c 0.33, CH2Cl2); H
NMR (300 MHz, CDCl3) d 1.05 (t, J = 7.04 Hz, 3H),
2.61–2.68 (m, 1H), 2.97–3.02 (m, 1H), 3.66–3.74 (m,
1H), 4.12–4.19 (m, 1H), 5.03 (s, 4H), 6.49–6.51 (m,
1H), 6.57 (s, 2H), 7.25–7.43 (m, 17H), 7.53–7.56 (d,
J = 8.8 Hz, 1H), 7.85–7.99 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 14.25, 14.27, 38.84, 39.16, 47.66,
47.90, 70.07, 100.78, 107.40, 121.75, 122.12, 122.58,
123.97, 124.04, 124.56, 124.78, 126.04, 126.97, 127.04,
127.59, 127.98, 128.24, 128.32, 128.58, 130.02, 130.25,
130.69, 131.40, 132.58, 132.84, 136.87, 141.00, 149.42,
149.79, 149.85, 159.95; 31P NMR (122 MHz, CDCl3) d
147.44; HRMS (FAB) for C43H35NO4P [M+1]+ calcd
662.2460, found 662.2446.
4.6. General procedure for the measurement of conversion
time data of 4a–Rh with different L/Rh ratio
To a solution of Rh(COD)2BF4 (3.74 · 10ꢀ3 mmol) in
CH2Cl2 (7 mL) was added dropwise dendritic ligand
4a (3.74 · 10ꢀ3 mmol) in CH2Cl2 (7 mL) in 10 min.
The reaction mixture was stirred for a further 10 min
at room temperature. Then the substrate 10a (82 mg,
0.374 mmol) was added. The flask was sealed with a
plug and nitrogen was exchanged by hydrogen. The
mixture was stirred under H2 atmosphere (1 atm)
at 10 ꢁC. For sample taking, the stirrer was stopped
at distinct times, and a small quantity of the reaction
mixtures was taken with a dipping tube. The stirrer
was then restarted under the same H2 pressure.
The sample was used to determine the ee value and
conversion by using 1H NMR and GC. Data of
4a–Rh with different L/Rh ratio were obtained by the
same method.
4.4.2. Compound 4b. Yield 52%; mp 77–79 ꢁC;
16
1
½aꢁD ¼ þ151:5 (c 0.33, CH2Cl2); H NMR (300 MHz,
CDCl3) d 1.03 (t, J = 7.04 Hz, 3H), 2.62–2.67 (m, 1H),
2.95–3.00 (m, 1H), 3.67–3.76 (m, 1H), 4.13–4.21 (m,
1H), 4.97 (s, 4H), 5.00 (s, 8H), 6.48–6.68 (m, 9H),
7.22–7.39 (m, 27H), 7.52–7.55 (d, J = 8.8 Hz, 1H),
7.83–7.91 (m, 4H); 13C NMR (75 MHz, CDCl3) d
14.23, 14.26, 38.82, 39.12, 47.80, 48.06, 69.99, 70.13,
100.91, 101.64, 106.43, 107.49, 121.74, 122.12, 122.56,
122.59, 123.97, 124.54, 124.76, 126.05, 126.95, 127.02,
127.53, 127.96, 128.26, 128.32, 128.55, 130.02, 130.27,
130.70, 131.41, 132.59, 132.82, 132.83, 136.80, 139.38,
141.02, 141.04, 149.43, 149.82, 149.88, 159.90, 160.21
ppm; 31P NMR (122 MHz, CDCl3) d 147.77; MALDI-
TOF MS for C71H60NO8P [M]+ calcd 1085.4, found
1085.5; Anal. Calcd for C71H60NO8P: C, 78.51; H,
5.57; N, 1.29. Found C, 78.49; H, 5.47; N, 1.41.
Acknowledgments
Financial support from the National Natural Science
Foundation of China and Chinese Academy of Sciences

W.-J. Tang et al. / Tetrahedron: Asymmetry 17 (2006) 536–543
543
7. (a) Horner, L.; Siegel, H.; Buthe, H. Angew. Chem., Int.
¨
is greatly acknowledged. We thank Professor Qilin Zhou
for helpful discussion.
Ed. Engl. 1968, 7, 942; (b) Knowles, W. S.; Sabacky, M. J.
J. Chem. Soc., Chem. Commun. 1968, 1445.
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