Synthesis of novel well-defined chain-end-functionalized polystyrenes with dendritic chiral ephedrine moieties and their applications as highly enantioselective diethylzinc addition to N-diphenylphosphinoyl arylimines

Article abstract of DOI:10.1016/j.tet.2007.08.093

A series of novel well-defined chain-end-functionalized polystyrenes having 2, 4, 8, and 16 chiral ephedrine moieties dendritically distributed at their hyperbranched chain-ends were quantitatively synthesized. Their well-defined architectures were fully

Full text of DOI:10.1016/j.tet.2007.08.093

Tetrahedron 63 (2007) 11754–11762
Synthesis of novel well-defined chain-end-functionalized
polystyrenes with dendritic chiral ephedrine moieties and their
applications as highly enantioselective diethylzinc addition
to N-diphenylphosphinoyl arylimines
,y
*
Ashraf A. El-Shehawy
Organic and Polymeric Materials Department, Graduate School of Science and Engineering, Tokyo Institute of Technology,
2-12-1, Ohokayama, Meguro-ku, Tokyo 152-8552, Japan
Received 18 July 2007; revised 26 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract—A series of novel well-defined chain-end-functionalized polystyrenes having 2, 4, 8, and 16 chiral ephedrine moieties dendritically
distributed at their hyperbranched chain-ends were quantitatively synthesized. Their well-defined architectures were fully confirmed by
elemental analysis, FTIR, SEC as well as by 1H and 13C NMR spectroscopies. These polymers were precisely controlled in the molecular
weight and molecular weight distribution as well as well-defined in chain-end-functionalities. These dendritic chiral polymers serve as highly
enantioselective chiral ligands in the enantioselective addition of diethylzinc to a series of N-diphenylphosphinoyl arylimines. Among them,
chiral dendrimer having eight ephedrine moieties at the chain-ends afforded the corresponding enantiomerically enriched phosphinoylamides
in good to high yields with enantioselectivities up to 93% ee. The obtained enantioselectivities are comparable with those obtained by using
N-benzylephedrine and its corresponding copolymer as chiral ligands.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ones using chiral b-amino alcohols derived from nore-
phedrine,6a and their corresponding copolymers,6b in the
presence of Lewis acids as activators. The addition
products 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-
1,2,4-triazin-5-ones were obtained in high yields with
enantioselectivities up to 92% ee.6 Subsequent reductive
cleavage of the 1,2,4-triazinyl heterocyclic ring led
smoothly to the corresponding free amines without any
significant loss of enantiomeric purity.6
The synthetic usefulness of enantiomerically pure amines1
has stimulated great interest in developing methods for their
asymmetric preparation.2 The addition of organometallics to
imines is a powerful method for the asymmetric synthesis of
chiral amines.3 We have previously reported on the enantio-
selective addition of allylmetal reagents to imines using var-
ious chiral ligands including chiral amino alcohols and their
corresponding copolymers, which afforded the enantioen-
riched homoallylic amines in quantitative yields with enan-
tioselectivities up to 96% ee4. Diastereoselective allylation
of chiral imines activated by Lewis acids has been also re-
ported by us and the corresponding optically active second-
ary homoallylic amines with perfect diastereoselectivities
were obtained.5 Moreover, very recently, we have reported
on an efficient dual catalytic enantioselective diethylzinc
addition to the exocyclic C]N double bond of some
4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-
Since Soai and co-workers reported on the MOPEP (an
ephedrine derivative)-mediated addition of diethylzinc to
N-diphenylphosphinoyl imine,7 enantioselective alkylations
of N-diphenylphosphinoyl imines with dialkylzinc reagents
that employ chiral amino alcohols,8 polymeric chiral amino
alcohols,9 and chiral dendrimers10 as chiral ligands have
been described.
Meanwhile, dendrimers represent a new and fascinating
class of regular highly branched and well-defined macro-
molecules.11 When the well-designed chiral functionalities
are loaded in the core or at the chain-ends of the dendrimers,
these functionalities are expected to be positioned on the sur-
face and they are expected to act as chiral ligands in asym-
metric synthesis.10,12,13 However, the dendrimer backbone
structure may cause unfavorable interactions with the chiral
Keywords: Chiral dendrimers; Hyperbranched polymers; N-Diphenylphos-
phinoyl arylimines; Enantioselective addition reactions; Dialkylzinc re-
agents; Chiral b-amino alcohols.
* Tel./fax: +20 47 3223415; e-mail addresses: elshehawy2@yahoo.com;
ashraf@polymer.titech.ac.jp
Permanent address: Department of Chemistry, Faculty of Education, Kafr
y
El-Sheikh University, Kafr El-Sheikh, PO Box 33516, Egypt.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.093

A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
11755
sites and consequently may reduce the enantioselectivity.
Thus, highly enantioselective synthesis utilizing chiral
dendrimers has been a challenge.
2. Results and discussion
As mentioned in the preceding section, we have recently de-
veloped an iterative methodology based on a divergent ap-
proach, by which chain-end-functionalized polystyrenes
with a definite number of BnBr functionalities dendritically
distributed at their chain ends were prepared.15 Since these
polymers have reactive BnBr functionalities at their chain
ends, it may be possible to introduce new chiral functional-
ities at the chain ends by the reaction with suitable chiral
reagents. For this purpose, chain-end-functionalized
polystyrenes having a definite number of 2, 4, 8, and 16
BnBr moieties at their chain-ends, PS(BnBr)2–
PS(BnBr)16, respectively, were first synthesized by the pre-
viously reported method (Fig. 1).14b–d,15 Thus, the utility of
attaching a chiral moiety via the reactive benzyl bromide
functionalities in the BnBr-end-functionalized polystyrenes
was examined.
However, Hirao and co-workers recently developed an
attractive iterative methodology based on a divergent appro-
ach, by which well-defined chain-end-functionalized poly-
styrenes with a definite number of benzyl bromide (BnBr)
functionalities dendritically distributed at their chain ends
were prepared.11e,i,j,14,15 These BnBr-end-functionalized
polystyrenes were found to be a new class of functionalized
polymers, which can be utilized as an interesting precursory
polymers leading to novel special-shaped polymers with
branched architecture. Based on the above-mentioned
methodology, we have recently reported on the successful
synthesis of novel well-defined chain-end-functionalized
polystyrenes with a definite number of perfluorooctyl
(C8F17) groups dendritically distributed or linearly aligned
in a double line at the chain-ends, by various addition reac-
tions of polystyryllithium to specially designed 1,1-diphe-
nylethylene derivatives, followed by introduction of the
C8F17 groups, and examined their surface segregation
behaviors of C8F17 groups.15
From literature survey on the dialkylzinc addition to N-di-
phenylphosphinoyl imines using chiral N-alkyl-N-benzyl-
norephedrines as chiral ligands, N-benzylephedrine was
found to be the most highly enantioselective chiral
ligand.9,10 Therefore, the chiral ephedrine moiety was cho-
sen to be introduced at the functional dendrimer. Thus,
the reaction of chain-end-functionalized polystyrenes
PS(BnBr)2–PS(BnBr)16 that have two–sixteen BnBr moie-
ties, respectively, at their chain ends with ephedrine 1 was
examined (Scheme 1). The anchoring reaction proceeded
virtually quantitatively affording the corresponding chain-
end-functionalized polystyrenes having the same number
of ephedrine moieties, PS(Ephed)2–PS(Ephed)16, respec-
tively, at their chain-ends. The resulting chiral dendrimers
were all readily purified by reprecipitation from their THF
solutions to methanol and isolated in quantitative yields.
They have been fully characterized by elemental analysis,
Thus, in continuous to our interest in the attractive charac-
teristics of dendrimers, we wish to report herein on the
successful synthesis of a novel series of chain-end-function-
alized polystyrenes with a definite number of chiral ephed-
rine moieties dendritically distributed at their chain-ends,
by attractive iterative methodology based on a divergent
approach, by which well-defined chain-end-functionalized
polystyrenes with a definite number of BnBr functionalities
were prepared, followed by introduction of the ephedrine
moieties. The preliminary application of these chiral
polymers as a highly enantioselective diethylzinc addition
to a series of N-diphenylphosphinoyl arylimines was also
reported.
1
FTIR, SEC as well as by H and 13C NMR spectroscopies.
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
n
Br
n
n
n
Br
Br
Br
Br
PS(BnBr)2
Br
Br
Br
PS(BnBr)4
Br
Br
Br
Br
Br
Br
BnBr = Benzyl bromide
PS(BnBr)8
Br
PS(BnBr)16
Figure 1. .Structure of the chain-end-functionalized polystyrenes having 2, 4, 8, and 16 benzyl bromide moieties PS(BnBr)n.

11756
A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
Ph
OH
Me
*
Ph
Me
N
*
Me
N
Br
Br
H
OH
PS
1
Me
PS
PS
K2CO3/ DMF, 50 °C, 24 h
Me
OH
(1R,2S)-PS(Ephed)2
1a: (1R,2S)-Ephedrine
1b: (1S,2R)-Ephedrine
N
Me
*
*
Ph
Ph
OH
N
*
*
PS
PS
PS
Me
Me
(1R,2S)-PS(Ephed)8a
(1S,2R)-PS(Ephed)8b
(1R,2S)-PS(Ephed)4
(1R,2S)-PS(Ephed)16
Scheme 1. .General pathway for the synthesis of chain-end-functionalized polystyrenes with a definite number of chiral ephedrine moieties PS(Ephed)n.
The analytical results of the resulting chiral dendrimers
PS(Ephed)2–PS(Ephed)16 in comparison with their precur-
sory polymers are summarized in Table 1.
disappeared and new resonance peaks were observed at
3.69–3.91 ppm attributed for the methylene protons of the
benzylephedrine moieties, in addition to the resonance
peaks assigned for the other protons of ephedrine moieties
(see Supplementary data). The degree of ephedrine-end-
functionalization was determined by comparing the relative
intensities of the 1H NMR resonance peak at 3.69–3.91 ppm
with that assigned for methylene protons of the benzylephe-
drine moiety with those observed at 0.17–0.84 ppm attrib-
uted for the methyl protons of the sec-butyl groups
Quantitative degree of ephedrine-end-functionalization was
confirmed by FTIR and 1H NMR analyses, both of which in-
dicated that the bromomethyl groups in the starting poly-
mers PS(BnBr)2–PS(BnBr)16 had quantitatively reacted
with ephedrine. The FTIR absorption band attributed for
the C–Br bond of the BnBr moiety that should appear at
1208 cmꢀ1 had completely disappeared after the reaction
and a new absorption band at 3345 cmꢀ1 attributed for the
hydroxyl group of the ephedrine moiety clearly appeared.
1
(initiator fragment). The integral values of the H NMR
resonance peaks attributed for the other protons of ephedrine
moieties were also taken into consideration. The end func-
tionalities of chiral ephedrine moieties thus determined
were found to be in quite agreement with those predicted
(Table 1).
1
Moreover, H NMR analysis showed that the resonance
peaks attributed for the methylene protons of the BnBr moi-
eties (in the range of 4.32–4.40 ppm) had completely
Interestingly, the SEC profile of the resulting dendritic chiral
polymers showed also sharp and symmetric monomodal dis-
tributions (Mw/Mn being less than 1.04) similar to that of the
corresponding BnBr-end-functionalized polymers before the
end-functionalization reaction. Neither shoulder nor tailing
was observed. As expected, the Mn values that determined
Table 1. Synthesis of chain-end-functionalized polystyrenes with a definite
number of chiral ephedrine moieties PS(Ephed)n in compared with their
precursory polymersa
Entry Polymer
Mn (kg/mol)b
Mw/Mn Functionalityc
SEC
Calcd SEC 1H NMR
Calcd 1H NMR
1
by each of SEC and H NMR analyses agreed quite well
1
2
3
4
PS(BnBr)2
PS(BnBr)4
PS(BnBr)8
PS(BnBr)16 24.48 24.28 24.43
PS(Ephed)2 19.84 19.86 20.00
PS(Ephed)4 20.70 20.75 20.82
PS(Ephed)8a 22.40 22.39 22.44
PS(Ephed)8b 22.40 22.41 22.45
PS(Ephed)16 25.82 25.83 25.89
19.67 19.63 19.81
20.36 20.22 20.39
21.73 21.93 21.71
1.02
1.03
1.03
1.03
1.03
1.04
1.03
1.04
1.03
2
4
8
16
2
4
8
8
16
1.98
3.99
8.00
15.99
1.99
4.00
7.99
8.00
15.98
with those predicted (Table 1). Thus, the anchoring reaction
of chiral ephedrine moiety proceeded quantitatively as it
was desired within analytical limits. It is interesting to note
that in this polymer series, the molecular weight of polysty-
rene main chain remained unchanged (Mn w19.3 kg/mol),
while the dendritic branched chain-end that includes the
chiral moiety increases in both size and molecular weight
as the reaction sequence was repeated.
5d
6d
7d
8d
9d
a
In all cases, the isolated yields after reprecipitation were ca. 100%.
In all cases, the Mn values of polystyrene main chains determined by SEC
were alwaysw19.3 kg/mol.
Functionality of benzyl bromide and chiral ephedrine moieties.
In all cases, (1R,2S)-ephedrine was used except for entry 8 in which
(1S,2R)-ephedrine was used as chiral moiety.
b
As stated in literature, when chiral dendrimers with hetero-
atoms in the dendrimer backbones are used as chiral ligands
in the dialkylzinc addition to each of aldehydes10d,16 and
imines,10 the heteroatoms in the backbones may cause
c
d

A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
11757
Table 2. Enantioselective diethylzinc addition to N-diphenylphosphinoyl
imine 2a using chiral dendrimers PS(Ephed)n
unfavorable coordination with the dialkylzinc reagents and
may also reduce the enantioselectivity of the addition prod-
ucts. Thus, in order to attain high enantioselectivity, it is nec-
essary to avoid any unfavorable coordination between the
dialkylzinc reagents and the framework of the dendrimer.
Therefore, we have devised the above-mentioned chiral
dendrimers PS(Ephed)n with hydrocarbon backbone struc-
ture (Scheme 1). In this case, the backbone hardly co-
ordinates with the diethylzinc and each chiral site of the
dendritic ligands is expected to work independently of other
chiral sites.
a
Entry Dendritic
chiral ligand time (h) (%)
Reaction Yieldb
eec
(%)
Config.d
1
2
3
4
5
6
7a
8
PS(Ephed)2 48
PS(Ephed)2 90
PS(Ephed)4 48
PS(Ephed)4 72
PS(Ephed)8a 48
PS(Ephed)16 48
PS(Ephed)16 48
PS(Ephed)8b 48
53
85
71
90
81
83
84
85
R
R
R
R
R
R
R
S
92 (91)e(74)f 90 (92)e(89)f
78
93
91
79
80
90
a
All reactions were performed in toluene at room temperature using
3.0 molar equiv of diethylzinc and equimolar amounts of chiral polymer
(based on the total number of ephedrine moieties against the imine) and
imine 2a, except for entry 7, which was performed using 1.5 molar equiv
of chiral polymer.
In order to evaluate the most efficient dendrimer as chiral
ligand, the enantioselective diethylzinc addition reaction to
N-diphenylphosphinoyl benzaldimine 2a as a standard sub-
strate using chiral dendrimers PS(Ephed)2–PS(Ephed)16,
in toluene at room temperature for 48 h, was first examined
(Scheme 2). The obtained results are summarized in Table 2.
When chiral dendrimer PS(Ephed)2, bearing two chiral sites
at the chain ends, was used as chiral ligand in the enantio-
selective diethylzinc addition to the C]N double bond of
benzaldimine 2a, the corresponding enantiomerically enan-
tioenriched (R)-N-diphenylphosphinoylamide (R)-3a was
obtained in chemical yield of 53% with 81% ee (Table 2, en-
try 1). The same reaction using dendritic chiral polymer
PS(Ephed)4 that have four chiral sites afforded the addition
product (R)-3a with slightly higher enantioselectivity (84%
ee) and in an isolated yield of 71% (Table 2, entry 3). Inter-
estingly, the use of PS(Ephed)8a with eight ephedrine moi-
eties at the polystyrene chain ends afforded the addition
product (R)-3a with more higher enantioselectivity (90%
ee) and with much better chemical yield of 92% (Table 2,
entry 5). More interestingly, PS(Ephed)16, having 16 ephed-
rine moieties at the chain ends, drove the asymmetric ethyl-
ation reaction of 2a with an enantioselectivity of 79% ee
with chemical yield of 78% (Table 2, entry 6).
b
Refers to the isolated yields after flash chromatography (hexane/ethyl
acetate).
c
Determined by HPLC analysis on a chiral column (Chiralpak AD).
The absolute configuration was assigned to be R by comparing the reten-
tion time on HPLC with those reported in literature (see Section 4).
Values in parenthesis are obtained from the same reaction using 1.0 molar
equiv of (1R,2S)-N-benzylephedrine as chiral ligand.8a,10b
d
e
f
Values in parenthesis are obtained by using N-vinylbenzylephedrine copo-
lymerized with styrene and divinylbenzene as chiral ligand.9
PS(Ephed)4, but for longer reaction times (Table 1, entries
2 and 4, respectively), the addition product 3a was obtained
in higher yields with slightly higher enantioselectivities.
Although number effect of the chiral end-functional groups
on each of the reaction yield and enantioselectivity of the ad-
dition product 3a has not been clear yet, the above men-
tioned set of results was found to be in agreement with the
previous finding reported by Hirao et al.17 It has been found
that the conformation of the polystyrene main chain within
the polystyrene end-functionalized with dendritic moieties
in nonpolar solvents strongly depends on the number of
the end-functional moieties and consequently on their mo-
lecular weights. As can be seen from Table 1, the molecular
weight of the dendritically branched end chains that include
the chiral moieties are increased 6-times by repeating the
functionalization reaction sequence on going from two to
eight end-functional groups. Moreover, the volume ratio of
the dendritically branched chain-ends relative to the poly-
styrene main chain for PS(Ephed)8 is seen to be high and
comparable with the block copolymer. Therefore, the den-
dritic end-functional groups in case of chiral dendrimer
PS(Ephed)8 can act as a block copolymer in solutions. Con-
sidering the above-mentioned factors, tentatively, it is sup-
posed that the chain conformation for PS(Ephed)8 as
a chiral ligand may be more preferable for segregation of
the end-functional chiral groups from the polystyrene main
chain similar to an immiscible block copolymers.
O
P
O
P
H
H
Chiral polymer PS(Ephed)n
Ph
Ph
Ph
Ph
Et2Zn
+
N
*
Ph
N
Ph
Toluene, rt, 48 h
H
3a
2a
Scheme 2. Enantioselective diethylzinc addition to N-diphenylphosphinoyl
benzaldimine 2a in the presence of chiral dendrimers PS(Ephed)n.
As can be seen from the results that are shown in Table 2, un-
der the same reaction conditions, the enantioselectivity of
the addition product 3a obtained by using PS(Ephed)8a
(entry 5) was higher than that observed in case of using
PS(Ephed)16 (entry 6) as chiral ligand. This is probably
due to the fact that the environments of active sites at the
polystyrene chain ends of PS(Ephed)8a might have enough
space to work as a chiral ligand, while the active chiral sites
of PS(Ephed)16 interfere either with each others and/or with
the polymer backbone chains. It is interesting to note that on
performing the diethylzinc addition reaction to imine 2a in
the presence of excess amount of PS(Ephed)16 (1.5 molar
equiv, based on the total number of ephedrine moieties
against the imine 2a), the addition product 3a was obtained
in higher yield of 93% without considerable change in the
enantioselectivity (80% ee, Table 2, entry 7). More inter-
estingly, on performing the diethylzinc addition reaction
to benzaldimine 2a using each of PS(Ephed)2 and
It is worth to mention that all the dendritic chiral polymers
used in this study are soluble in toluene and worked well
as homogeneous chiral ligands during the reaction. Interest-
ingly, the enantioselectivity observed in the diethylzinc
addition reaction to imine 2a using chiral dendrimer
PS(Ephed)8a (90% ee, Table 2, entry 5) was high as those
obtained not only by using (1R,2S)-N-benzylephedrine
(92% ee, entry 5)8a,10b but also by using polystyrene
supported with the same chiral moiety (89% ee, entry 5)9

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A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
as chiral ligand. More interestingly, the enantioselectivity
thus obtained by using PS(Ephed)8a (90% ee, entry 5) was
found to be higher than that obtained from the same reaction
using the chiral dendrimer having the same chiral moiety but
with carbosilane backbone structure (86% ee).10c
As expected, chiral dendrimer PS(Ephed)8a promotes the
highly enantioselective addition of diethylzinc to all
aromatic substituted phosphinoyl imines 2a–l to afford the
corresponding enantiomerically enriched (R)-N-diphenyl-
phosphinoylamides 3a–l with yields of 83–93% and enantio-
selectivities up to 93% ee (Table 3). It is interesting to note
that phosphinoyl imines bearing para-substituents on their
phenyl groups would provide the corresponding N-phosphin-
oylamides with relatively higher enantioselectivity than
their analogues having ortho- or meta-substituted phenyl
groups. For example, the diethylzinc addition reaction to im-
ine 2d, having a para-methylphenyl group, afforded the addi-
tion product 3d with a relatively higher enantioselectivity of
93% ee (Table 3, entry 4) than that of 88 and 91% ee given by
its analogues 2b and 2c, which possessed an ortho- and meta-
methylphenyl groups, respectively (Table 3, entries 2 and 3).
Phosphinoyl imines 2i and 2j with heteroatom rings (2-furyl
and 3-pyridyl, respectively) were also ethylated smoothly to
afford the corresponding enantiomerically enriched (R)-3i
and (R)-3j, respectively (Table 3, entries 9 and 10, respec-
tively). Moreover, phosphinoyl imine 2l bearing a 2-naphthyl
group provided the corresponding addition product 3l with
a much higher enantioselectivity than that observed in the
same addition reaction to imine 2k having 1-naphthyl group
(Table 3, entries 12 and 11, respectively). Thus, dendritic
chiral polymer PS(Ephed)8a also acts as a highly enantio-
selective chiral ligand for the diethylzinc addition to
N-diphenylphosphinoyl arylimines and at the best, the enan-
tioselectivity of the addition product 3d with a p-tolyl substit-
uent, obtained from the diethylzinc addition to imine 2d,
reached to 93% ee (Table 3, entry 4).
Since in asymmetric synthesis it is important that both enan-
tiomers of a given compound can be prepared, the dendritic
chiral ligand PS(Ephed)8b, prepared by the reaction of
PS(BnBr)8 with chiral monomer (1S,2R)-ephedrine 1b,
was examined in the enantioselective ethylation of phosphi-
noyl imine 2a. Chiral polymer PS(Ephed)8b worked well as
chiral polymer PS(Ephed)8a and led smoothly to the desired
secondary chiral amine 3a with almost the same chemical
yield and enantioselectivity, but with reversed stereoselec-
tivity (Table 2, entry 8).
The above-mentioned primarily results obtained from the
diethylzinc addition reaction to N-diphenylphosphinoyl ben-
zaldimine 2a prompted us to further examine the generality
of the diethylzinc addition reaction to a series of N-diphenyl-
phosphinoyl arylimines in the presence of the dendritic chi-
ral ligand PS(Ephed)8a that showed the best result, under the
optimized experimental conditions shown in Table 2, entry
5. The results of diethylzinc addition reactions to a series
of N-diphenylphosphinoyl arylimines (2a–l) displayed in
Scheme 3 are summarized in Table 3.
O
P
H
O
P
H
Ph
Ph
(1R,2S)-PS(Ephed)8a
Ph
Ph
Et2Zn
+
N
Ar
N
Ar
Toluene, rt, 48 h
H
(R)-3a-l
2a-l
Since dendritic chiral polymer PS(Ephed)8a was found to
be efficient as a chiral ligand, we examined the re-use of
the ligand in the asymmetric diethylzinc addition reaction.
The chiral polymer was easily and quantitatively recov-
ered by silica gel column chromatography followed by
reprecipitation from its THF solution to a mixture of
methanol and HCl. As shown in Table 3, the diethylzinc
addition reaction to imine 2d using the recovered polymer
PS(Ephed)8a afforded the addition product 3d (entry 13)
without any significant loss in the enantioselectivity as
in entry 4.
Scheme 3. Enantioselective diethylzinc addition to N-diphenylphosphinoyl
arylimines 2a–l using dendritic chiral ligand (1R,2S)-PS(Ephed)8a
.
Table 3. Enantioselective diethylzinc addition to N-diphenylphosphinoyl
arylimines 2a–l using chiral dendrimer (1R,2S)-PS(Ephed)8a
a
Entry Imine (Ar)
Addition Yield (%)b ee (%)c,d
product
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2d
2d
Phenyl
3a
3b
3c
3d
92
86
90
90
93
89
89
92
83
84
86
93
91
59
90
88
91
93
91
92
89
90
79
77
83
90
93
53
2-Me–C6H4
3-Me–C6H4
4-Me–C6H4
2-MeO–C6H4 3e
4-MeO–C6H4 3f
4-Cl–C6H4
4-Br–C6H4
2-Furyl
As it has been cited in literature, a stoichiometric amount
of the chiral b-amino alcohol usually is required to
assure high yield and enantioselectivity in the enantio-
selective dialkylzinc addition to N-diphenylphosphinoyl
imines.8a,b,10 Since we have used in this study an equimo-
lar amount of the dendritic chiral polymer PS(Ephed)8a,
based on the total number of the chiral sites at the periph-
ery, against imines, the obtained high yields and enantio-
selectivities of the addition products suggested that nearly
all of the chiral sites at the periphery of dendritic ligand
PS(Ephed)8a worked effectively. Thus, like in the reaction
using monomeric chiral ligands,8a the eight parts in situ
formed ethylzinc alkoxides of the amino alcohols (active
chiral sites) can operate independently and can form an
appropriate reaction field for the highly enantioselective
addition of diethylzinc to imines. It is worth to mention
that in the diethylzinc addition to imine 2d, the use of a
lesser amount of chiral dendrimer PS(Ephed)8a (0.5 molar
equiv against imine 2d) resulted in a significant decrease
3g
3h
3i
3j
3k
3l
9
10
11
12
13e
14a
3-Pyridyl
1-Naphthyl
2-Naphthyl
4-Me–C6H4
4-Me–C6H4
3d
3d
a
All reactions were performed in toluene at room temperature for 48 h us-
ing 3.0 molar equiv of diethylzinc and equimolar amounts of chiral poly-
mer (based on the total number of the ephedrine moieties against imine)
and imine 2, except for entry 14, which was performed using 0.5 molar
equiv of chiral polymer.
b
c
d
e
Refers to the isolated yields after flash chromatography (hexane/ethyl ace-
tate).
Determined by HPLC analysis on a chiral column (Chiralcel OD or
Chiralpak AD) under the conditions that is described in Section 4.
The absolute configuration was assigned by comparing the retention time
on HPLC with those reported in literature (see Section 4).
Recovered dendritic chiral polymer was used.

A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
11759
in each of the chemical yield and the enantioselectivity
of the addition product (R)-3d (Table 3, entry 14).
Elmer 341 Polarimeter in a 10-cm cell. HPLC analyses
were carried out on a chiral column (Chiralcel OD or
Chiralpak AD, 25 cm, ca. 20 ꢁC), with a 254 nm UV detector
and a flow rate of 1.0 mL/min with the eluent indicated.
To the best of our knowledge, the present method is the
first example for the synthesis of such kind of chain-end-
functionalized polystyrenes having dendritic chiral moieties
at their chain-ends and their application as chiral ligands
to the enantioselective dialkylzinc addition to imines.
4.2. Synthesis of chain-end-functionalized polystyrenes
with 2, 4, 8, and 16 chiral ephedrine moieties
PS(Ephed)n
Typical procedure for the synthesis of PS(Ephed)8 is as fol-
lows: under nitrogen atmosphere, a solution of ephedrine (1,
0.3 g, 1.8 mmol) in DMF (5 mL) was added dropwise within
5 min at 0 ꢁC to a mixture of a DMF (20 mL) solution of
chain-end-functionalized polystyrene with eight benzyl bro-
mide moieties (PS(BnBr)8 (0.5 g, Mn¼21.71ꢂ103 g/mol,
0.18 mmol, based on eight BnBr moieties) and K2CO3
(0.25 g, 1.8 mmol). The reaction mixture was allowed to
warm gradually to 50 ꢁC and stirred further for 24 h. The re-
action mixture was then allowed to return to room tempera-
ture and then poured into 1 N HCl methanolic solution
(50 mL) to precipitate the polymer. The polymer was repre-
cipitated from its THF solution to methanol 2 times more
followed by freeze-drying from its absolute benzene solu-
tion to afford the corresponding chiral polymer PS(Ephed)8.
The other dendritic chiral polymers PS(Ephed)2,
PS(Ephed)4, and PS(Ephed)16, were synthesized by the
same procedure and under the same reaction conditions.
3. Conclusion
A novel series of well-defined chain-end-functionalized
polystyrenes having 2, 4, 8, and 16 chiral ephedrine moieties
dendritically distributed at their chain ends were prepared
and evaluated as chiral ligands in the diethylzinc addition
to a series of N-diphenylphosphinoyl arylimines. Among
them, chiral dendrimer PS(Ephed)8 having eight ephedrine
moieties at the chain ends worked very well as efficient chi-
ral ligand affording the addition products in good to high
yields with enantioselectivities up to 93% ee. The obtained
enantioselectivities are comparable with those obtained by
using the corresponding N-benzylephedrine in solution sys-
tem. We believe that the results reported herein would pro-
vide guidelines for the design future of dendritic chiral
catalysts and ligands for the enantioselective asymmetric
synthesis. Further applications toward the immobilization
of other chiral ligands as well as other asymmetric reactions
are now the focus of our continuing efforts.
The degree of chiral ephedrine end-functionalization was
determined by comparing the relative intensities of the
1H NMR resonance peaks at 3.69–3.91 ppm assigned for
methylene protons of the benzylephedrine moieties, with
those at 0.17–0.84 ppm attributed for the methyl protons
4. Experimental
4.1. General
1
of the sec-butyl groups (initiator fragment). The H NMR
resonances attributed for the other protons of the chiral moi-
ety were also taken into consideration. The functionalities of
ephedrine moieties thus determined were found to be in
quite agreement to those predicted (Table 1).
All reactions were performed under a nitrogen atmosphere.
The reagents (>98% purities) were purchased from
Aldrich Co. and used as received unless otherwise stated.
DMF and toluene were freshly distilled over CaH2 under a
nitrogen atmosphere. Chain-end-functionalized polysty-
renes with benzyl bromide moieties were synthesized by
following the previously reported method.14b–d,15 N-Diphe-
nylphosphinoyl arylimines 2a–l were prepared following
literature procedures.8a,d,e,i-k,10a,18,19a The addition products
N-diphenylphosphinoylamides 3a–l are known com-
pounds.8a,c–e,f,h,j,k,m,n,9c,10a,c,d,19b–d,20 The benzyl bromide-
and ephedrine-end-functionalized polystyrenes have been
designated by PS(BnBr)n and PS(Ephed)n, and the subscript
numbers are corresponding to the number of the terminal
benzyl bromide and ephedrine moieties, respectively.
4.2.1. PS(Ephed)2. 1H NMR: d¼0.49–0.83 (br m, 6H,
CH(CH3)CH2CH3), 1.08–2.32 (br m, 578H, CH2CH+
CH3N+CH3CHN), 2.87–2.99 (br m, 2H, CH3CHN), 3.46–
3.56 (br s, 1H, ArCHAr), 3.72–3.83 (br m, 4H, ArCH2N),
4.78–4.90 (br m, 2H, CHOH), 6.30–7.25 (br m, 949H,
ArH); 13C NMR: d¼9.85, 11.34, 20.28, 20.46, 29.85, 31.18,
33.77, 38.73, 40.59, 41.92, 43.50, 45.86, 46.59, 50.37,
59.14, 63.66, 73.52, 125.68, 125.83, 126.80, 127.22, 127.56,
127.81, 128.01, 128.25, 128.67, 129.07, 129.63, 133.46,
137.18, 140.21, 142.46, 145.09, 145.28, 145.58, 146.19,
149.17; FTIR (KBr, cmꢀ1): 3345 (OH). Anal. Calcd for
C1533H1545N2O2: C, 91.97; H, 7.73; N, 0.14. Found: C,
91.75; H, 7.61; N, 0.14.
1H and 13C NMR spectra were measured on a Bruker DPX
1
(300 MHz for H and 75 MHz for 13C) in CDCl3. Size-
1
exclusion chromatograms (SEC) were measured with a TO-
SOH HLC-8020 at 40 ꢁC equipped with ultraviolet (254 nm)
and refractive index detections. THF was used as a carrier
solvent at a flow rate of 1.0 mL/min. Calibration curves
were made with standard polystyrene samples to determine
the Mn and Mw/Mn values. FTIR spectra were recorded on
a JEOL JIR-AQS20 M FTIR spectrophotometer. Flash chro-
matography was performed on deactivated silica gel (Matrix
60A, 37–70 mm) and the spots were detected with UV model
UVGL-58. Optical rotations were measured with a Perkin–
4.2.2. PS(Ephed)4. H NMR: d¼0.39–0.82 (br m, 18H,
CH(CH3)CH2CH3), 1.09–2.35 (br m, 590H, CH2CH+
CH3N+CH3CHN), 2.95–3.34 (br m, 9H, ArCHAr+(Ar)2-
CCH2Ar+CH3CHN), 3.71–3.86 (br m, 8H, ArCH2N),
4.76–4.89 (br m, 4H, CHOH), 6.16–7.27 (br m, 975H,
ArH); 13C NMR: d¼9.84, 11.36, 20.33, 20.44, 29.99,
31.37, 34.12, 38.70, 40.82, 42.06, 44.52, 45.61, 47.22,
51.12, 59.17, 63.74, 73.67, 125.66, 125.77, 126.72,
127.30, 127.63, 127.74, 128.13, 128.38, 128.45, 128.76,
129.09, 133.67, 137.39, 140.24, 142.37, 145.18, 145.39,

11760
A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
145.68, 145.80, 146.29, 149.09; FTIR (KBr, cmꢀ1): 3345
(OH). Anal. Calcd for C1590H1616N4O4: C, 91.66; H, 7.76;
N, 0.27. Found: C, 91.72; H, 7.73; N, 0.26.
4.3.1. N-(1-Phenylpropyl)-P,P-diphenylphosphinoyl-
amide 3a.8d,e,j,l,n,9c,20a,b The enantiomeric excess was deter-
mined by HPLC on a chiral stationary phase (Chiralpak AD
column, hexane/propan-2-ol 80:20); R-isomer, tR 8.77 min
and S-isomer, tR 11.83 min.
1
4.2.3. PS(Ephed)8. H NMR: d¼0.18–0.79 (br m, 42H,
CH(CH3)CH2CH3),
1.11–2.33
(br
m,
607H,
CH2CH+CH3N+CH3CHN), 2.79–3.50 (br m, 21H, ArCH-
Ar+(Ar)2CCH2Ar+CH3CHN), 3.69–3.87 (br m, 16H,
ArCH2N), 4.73–4.90 (br m, 8H, CHOH), 6.20–7.23 (br m,
1027H, ArH); 13C NMR: d¼9.91, 11.35, 20.30, 20.48,
30.17, 31.14, 33.98, 38.75, 41.18, 42.63, 44.39, 46.22,
46.97, 50.38, 59.08, 63.44, 73.59, 125.58, 125.73, 126.81,
127.39, 127.61, 127.89, 128.26, 128.35, 128.49, 128.76,
129.34, 133.59, 137.41, 140.07, 142.45, 145.33, 145.66,
145.84, 145.99, 146.31, 149.19; FTIR (KBr, cmꢀ1): 3345
(OH). Anal. Calcd for C1711H1765N8O8: C, 91.10; H, 7.83;
N, 0.50. Found: C, 91.23; H, 7.87; N, 0.49.
4.3.2. N-[1-(2-Methylphenyl)propyl]-P,P-diphenylphos-
phinoylamide 3b.20b The enantiomeric excess was deter-
mined by HPLC on a chiral stationary phase (Chiralpak
AD column, hexane/propan-2-ol 90:10); R-isomer, tR
16.27 min and S-isomer, tR 27.35 min.
4.3.3. N-[1-(3-Methylphenyl)propyl]-P,P-diphenylphos-
phinoylamide 3c.8l–n,20a,b The enantiomeric excess was de-
termined by HPLC on a chiral stationary phase (Chiralpak
AD column, hexane/propan-2-ol 90:10); R-isomer, tR
10.78 min and S-isomer, tR 19.89 min.
4.2.4. PS(Ephed)16. 1H NMR: d¼0.17–0.84 (m, 90H,
CH(CH3)CH2CH3), 1.09–2.35 (m, 745H, CH2CH+CH3N+-
CH3CHN), 2.81–3.55 (br m, 45H, ArCHAr+(Ar)2C-
CH2Ar+CH3CHN), 3.71–3.91 (br s, 32H, ArCH2N), 4.72–
4.89 (br m, 16H, CHOH), 6.18–7.25 (br m, 1133H, ArH);
13C NMR: d¼9.89, 11.33, 20.29, 20.44, 30.22, 31.28,
34.19, 38.78, 40.88, 42.54, 43.93, 45.49, 47.14, 50.66,
59.12, 63.59, 73.44, 125.61, 125.87, 126.91, 127.34,
127.71, 127.93, 128.19, 128.37, 128.56, 128.89, 129.51,
133.75, 137.22, 139.97, 142.55, 145.29, 145.49, 145.70,
145.83, 146.28, 149.07; FTIR (KBr, cmꢀ1): 3345 (OH).
Anal. Calcd for C1953H2063N16O16: C, 90.21; H, 7.94; N,
0.86. Found: C, 89.98; H, 7.77; N, 0.85.
4.3.4. N-[1-(4-Methylphenyl)propyl]-P,P-diphenylphos-
phinoylamide 3d.8l–n,10a,c,20a,b The enantiomeric excess
was determined by HPLC on a chiral stationary phase (Chir-
alpak AD column, hexane/propan-2-ol 92:8; R-isomer),
tR 21.78 min and S-isomer, tR 27.49 min.
4.3.5. N-[1-(2-Methoxyphenyl)propyl]-P,P-diphenyl-
phosphinoylamide 3e.20a,b The enantiomeric excess was
determined by HPLC on a chiral stationary phase (Chiralpak
AD column, hexane/propan-2-ol 90:10); R-isomer, tR
21.59 min and S-isomer, tR 27.12 min.
4.3.6. N-[1-(4-Methoxyphenyl)propyl]-P,P-diphenyl-
phosphinoylamide 3f.8k,l,n,20a,b The enantiomeric excess
was determined by HPLC on a chiral stationary phase (Chir-
alpak AD column, hexane/propan-2-ol 80:20); R-isomer,
tR 11.02 min and S-isomer, tR 13.29 min.
4.3. Enantioselective diethylzinc addition to
N-diphenylphosphinoyl imines 2 using dendritic chiral
polymers PS(Ephed)n
General procedure: under nitrogen atmosphere, a toluene
solution (1 M) of diethylzinc (0.3 mmol, 0.3 mL) was added
dropwise to a mixture of dendritic chiral polymer
(0.1 mmol, based on the total number of ephedrine moie-
ties) and N-diphenylphosphinoyl imine 2 (0.1 mmol) in
toluene (5 mL) at 0 ꢁC over a period of 10 min. After the
complete addition, the reaction mixture was stirred for
48 h at room temperature followed by quenching with satu-
rated aqueous NH4Cl (5 mL). The reaction mixture was
extracted with dichloromethane (10 mLꢂ3) and the com-
bined organic extracts were washed with water and brine
and dried over anhydrous magnesium sulfate. After removal
of the solvents, the residue thus obtained was purified by
flash column chromatography (2.5% V/V triethylamine pre-
treated SiO2) eluting with hexanes/ethyl acetate mixtures of
increasing polarity (from 90:10 to 0:100) to afford first the
corresponding diphenylphosphinoylamides 3 with the
yields and enantioselectivities that are shown in Tables 2
and 3, followed by eluting the chiral polymer. The addition
products 3a–l were characterized by comparing their
physical and spectroscopic data with those reported in the
literature.8a,d,e,j,k,m,n,9c,10a,19b–d The absolute configu-
ration of the major enantiomer was assigned based on com-
paring the HPLC retention time with the literature
values.8a,c–f,h,k,l,m,n,9c,10c,d,20 Racemic samples required for
HPLC comparison were prepared by addition of EtMgBr
in THF to N-diphenylphosphinoyl imines 2.19a
4.3.7. N-[1-(4-Chlorophenyl)propyl]-P,P-diphenylphos-
phinoylamide 3g.8d,n,10c,20a,b The enantiomeric excess
was determined by HPLC on a chiral stationary phase (Chir-
alpak AD column, hexane/propan-2-ol 80:20); R-isomer,
tR 11.13 min and S-isomer, tR 12.81 min.
4.3.8. N-[1-(4-Bromophenyl)propyl]-P,P-diphenylphos-
phinoylamide 3h.8k,m,20a,b The enantiomeric excess was
determined by HPLC on a chiral stationary phase (Chiralcel
OD column, hexane/propan-2-ol 95:5); R-isomer, tR
27.56 min and S-isomer, tR 32.92 min.
4.3.9. N-[1-(2-Furyl)propyl]-P,P-diphenylphosphinoyl-
amide 3i.9c,20a,b The enantiomeric excess was determined
by HPLC on a chiral stationary phase (Chiralcel OD column,
hexane/propan-2-ol 97:3); R-isomer, tR 38.09 min and
S-isomer, tR 45.88 min.
4.3.10. N-[1-(3-Pyridyl)propyl]-P,P-diphenylphosphi-
noylamide 3j.8k The enantiomeric excess was determined
by HPLC on a chiral stationary phase (Chiralcel AD column,
hexane/propan-2-ol 90:10); R-isomer, tR 30.35 min and
S-isomer, tR 47.55 min.
4.3.11. N-[1-(1-Naphthyl)propyl]-P,P-diphenylphosphi-
noylamide 3k.9c,20a,b The enantiomeric excess was deter-
mined by HPLC on a chiral stationary phase (Chiralcel

A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
11761
R. K., Ed.; Nova Science: New York, NY, 2005; pp 1–69; (k)
Zani, L.; Bolm, C. Chem. Commun. 2006, 4263–4275; (l)
Petrini, M.; Torregiani, E. Synthesis 2007, 2, 159–186.
3. For reviews on the nucleophilic addition of organometallics to
imines, see: (a) Denmark, S. E.; Nicaise, O. J.-C. Chem.
Commun. 1996, 999–1004; (b) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895–1946; (c) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094; (d) Gung,
B. W. Org. React. 2004, 64, 1–113; (e) Connon, S. J. Angew.
Chem., Int. Ed. 2006, 45, 3909–3912; (f) Friestad, G. K.;
Mathies, A. K. Tetrahedron 2007, 63, 2541–2569.
OD column, hexane/propan-2-ol 97:3); R-isomer, tR
26.88 min and S-isomer, tR 40.93 min.
4.3.12. N-[1-(2-Naphthyl)propyl]-P,P-diphenylphosphi-
noylamide 3l.9c,10c,20a,b The enantiomeric excess was deter-
mined by HPLC on a chiral stationary phase (Chiralpak OD
column, hexane/propan-2-ol 97:3); R-isomer, tR 27.22 min
and S-isomer, tR 44.71 min.
4.4. Recovery of the dendritic chiral polymer
4. (a) Itsuno, S.; Watanabe, K.; Ito, K.; El-Shehawy, A. A.;
Sarhan, A. A. Angew. Chem., Int. Ed. 1997, 36, 109–110; (b)
El-Shehawy, A. A.; Abdelaal, M. Y.; Watanabe, K.; Ito, K.;
Itsuno, S. Tetrahedron: Asymmetry 1997, 8, 1731–1734; (c)
Itsuno, S.; Watanabe, K.; Matsumoto, T.; Kuroda, S.; Yokoi,
A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999,
2011–2016; (d) Itsuno, S.; Watanabe, K.; El-Shehawy, A. A.
Adv. Synth. Catal. 2001, 343, 89–94.
5. (a) El-Shehawy, A. A.; Omara, M. A.; Ito, K.; Itsuno, S. Synlett
1998, 367–368; (b) Itsuno, S.; El-Shehawy, A. A.; Abdelaal,
M. Y.; Ito, K. New J. Chem. 1998, 22, 775–777; (c) Itsuno,
S.; El-Shehawy, A. A. Polym. Adv. Technol. 2001, 12, 670–679.
6. (a) El-Shehawy, A. A. Tetrahedron: Asymmetry 2006, 17,
2617–2624; (b) El-Shehawy, A. A. Tetrahedron 2007, 63,
5490–5500.
The recovered dendritic chiral polymer thus obtained after
the diethylzinc addition reaction through the column chro-
matography was precipitated from its THF solution in
a 4:1 mixture of methanol 2 M HCl followed by stirring
for 4 h. The polymer was then reprecipitated again from
its THF solution to methanol and after being freeze dried
from its absolute benzene solution for 24 h, the recycled den-
dritic chiral polymer was used again in the enantioselective
addition of diethylzinc to imines.
Acknowledgements
The author would like to give great thanks to Prof. Akira
Hirao at Tokyo Institute of Technology, Japan, for his kind
assistance during the development of this work as well as
for synthesizing the starting polymers at his laboratory.
7. For recent reviews on the use of N-phosphinoyl imines in
stereoselective synthesis, see: (a) Weinreb, S. M.; Orr, R. K.
Synthesis 2005, 1205–1227; (b) Charette, A. B.; Boezio,
ˆ
A. A.; Cote, A.; Moreau, E.; Pytkowicz, J.; Desrosiers, J.-N.;
Legault, C. Pure Appl. Chem. 2005, 77, 1259–1267.
ꢀ
Supplementary data
8. (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem.
Commun. 1992, 1097–1098; (b) Hayase, T.; Inoue, Y.; Shibata,
T.; Soai, K. Tetrahedron: Asymmetry 1996, 7, 2509–2510; (c)
Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727–
728; (d) Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem.
1997, 62, 7364–7375; (e) Guijarro, D.; Pinho, P.; Andersson,
P. G. J. Org. Chem. 1998, 63, 2530–2535; (f) Brandt, P.;
Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson, P. G.
Chem.—Eur. J. 1999, 5, 1692–1699; (g) Jimeno, C.; Vidal-
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.08.093.
References and notes
1. For the importance of optically active amines, see: (a) Jacques,
J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and
Resolution; John Wiley & Sons: New York, NY, 1981; (b)
Moser, H.; Rihs, G.; Santer, H. Z. Naturforsch 1982, 376,
451–462; (c) Whitesell, J. K. Chem. Rev. 1989, 89, 1581–
1590; (d) Koga, K.; Odashima, K. Yakugaku Zasshi 1997,
117, 800–816; (e) Federsel, H.-J.; Collins, A. N.; Sheldrake,
G. N.; Crosby, J. Chirality Industry II; John Wiley and Sons:
Chichester, UK, 1997; pp 225–244; (f) Maruoka, K.; Ooi, T.;
Kano, T. Chem. Commun. 2007, 1487–1495.
2. For the asymmetric synthesis of amines, see: (a) Johansson, A.
Contemp. Org. Synth. 1995, 2, 393–407; (b) Burk, M. J.; Wang,
Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142–5143; (c)
Bloch, R. Chem. Rev. 1998, 98, 1407–1438; (d) Burk, M. J.;
Gasy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084–
6085; (e) Denamrk, S. E.; Nizaise, O. J.-C. Comprehensive
Asymmetric Catalysis; Jacobson, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 924–958; (f)
Ding, H.; Friestad, G. K. Synthesis 2005, 2815–2829; (g)
Friestad, G. K. Eur. J. Org. Chem. 2005, 3157–3172; (h)
Chelucci, G. Tetrahedron: Asymmetry 2005, 16, 2353–2383;
(i) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr.
Org. Chem. 2005, 9, 1315–1392; (j) El-Shehawy, A. A.;
Itsuno, S. Preparation of Immobilized Chiral Ligands onto
Polymer Supports and their Application to Asymmetric
Synthesis. In Current Topics in Polymer Research; Bregg,
ꢁ
Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1999, 40, 777–780; (h) Jimeno, C.; Reddy,
ꢁ
ꢁ
K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Org.
Lett. 2000, 2, 3157–3159; (i) Sato, I.; Kodaka, R.; Soai, K.
J. Chem. Soc., Perkin Trans. 1 2001, 2912–2914; (j) Zhang,
X.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.;
Chan, A. S. C. Tetrahedron Lett. 2001, 42, 6369–6372; (k)
Pinho, P.; Anderson, P. G. Tetrahedron 2001, 57, 1615–1618;
(l) Zhang, H.-L.; Zhang, X.-M.; Gong, L.-Z.; Mi, A.-Q.; Cui,
X.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett.
2002, 4, 1399–1402; (m) Zhang, X. M.; Zhang, H. L.; Lin,
W. Q.; Gong, L. Z.; Mi, A. Q.; Cui, X.; Jiang, Y. Z.; Yu,
K. B. J. Org. Chem. 2003, 68, 4322–4329; (n) Zhang, H.-L.;
Jiang, F.; Zhang, X.-M.; Gong, L.-Z.; Mi, A.-Q.; Cui, X.;
Jiang, Y.-Z.; Wu, Y. D. Chem.—Eur. J. 2004, 10, 1481–1492;
(o) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2007, 18, 896–899.
9. (a) Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem.
Commun. 1994, 317–318; (b) Suzuki, T.; Narisada, N.;
Shibata, T.; Soai, K. Tetrahedron: Asymmetry 1996, 7, 2519–
2522; (c) Suzuki, T.; Shibata, T.; Soai, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 2757–2760; (d) Suzuki, T.; Narisada,
N.; Shibata, T.; Soai, K. Polym. Adv. Technol. 1999, 10, 30–38.

11762
A. A. El-Shehawy / Tetrahedron 63 (2007) 11754–11762
10. (a) Suzuki, T.; Hirokawa, Y.; Ohtake, K.; Shibata, T.; Soai, K.
Tetrahedron: Asymmetry 1997, 8, 4033–4040; (b) Sato, I.;
Kodaka, R.; Shibata, T.; Hirokawa, Y.; Shirai, N.; Ohtake, K.;
Soai, K. Tetrahedron: Asymmetry 2000, 11, 2271–2275; (c)
Sato, I.; Hosoi, K.; Kodaka, R.; Soai, K. Eur. J. Org. Chem.
2002, 3115–3118; (d) Soai, K.; Sato, I. C. R. Chim. 2003, 6,
1097–1104.
11. For reviews on the synthesis and properties of dendrimers and
hyperbranched polymers, see: (a) Kim, Y. J. Polym. Sci., Part
A: Polym. Chem. 1998, 36, 1685–1698; (b) Chow, H. F.;
Mong, T. K. K.; Nongrum, M. F.; Wan, C. W. Tetrahedron
1998, 54, 8543–8660; (c) Inoue, K. Prog. Polym. Sci. 2000,
Caminade, A.-M.; Majoral, J.-P.; Daran, J.-C.; Manoury, E.
J. Organomet. Chem. 2007, 692, 1064–1073.
14. (a) Hirao, A.; Hayashi, M. Macromolecules 1999, 32, 6450–
6460; (b) Hayashi, M.; Hirao, A. Macromol. Chem. Phys.
2001, 202, 1717–1726; (c) Hirao, A.; Haraguchi, N.
Macromolecules 2002, 35, 7224–7231; (d) Hirao, A.;
Hayashi, M.;Haraguchi, N. Macromol. Symp. 2002, 182, 11–16.
15. (a) Sugiyama, K.; Sakai, S.; El-Shehawy, A.; Hirao, A.
Macromol. Symp. 2004, 217, 1–15; (b) El-Shehawy, A. A.;
Yokoyama, H.; Sugiyama, K.; Hirao, A. Macromolecules
2005, 38, 8285–8299.
16. (a) Sato, I.; Shibata, T.; Ohtake, K.; Kodaka, K.; Hirokawa, Y.;
Shirai, N.; Soai, K. Tetrahedron Lett. 2000, 41, 3123–3126; (b)
Sato, I.; Kodaka, R.; Hosoi, K.; Soai, K. Tetrahedron:
Asymmetry 2002, 13, 805–808.
€
25, 453–571; (d) Vogtle, F.; Gestermann, S.; Hesse, R.;
Schwierz, H.; Windisch, B. Prog. Polym. Sci. 2000, 25, 987–
1041; (e) Hirao, A.; Hayashi, M.; Haraguchi, N. Macromol.
Rapid Commun. 2000, 21, 1171–1184; (f) Tomalia, D. A.
High Perform. Polym. 2001, 13, S1–S10; (g) Newkome,
17. Hayashi, M.; Loykulnant, S.; Hirao, A.; Nakahama, S.
Macromolecules 1998, 31, 2057–2063.
€
G. R.; Mooreld, C. N.; Vogtle, F. Dendrimers and Dendrons.
Concepts, Synthesis, Perspectives; VCH: Weinheim, 2001;
18. For the preparation of N-diphenylphosphinoyl imines, see also:
(a) Krzyzanowska, B.; Stec, W. J. Synthesis 1978, 521–524; (b)
Boyd, D. R.;Jennings, W. B.; McGuckin, R. M.; Rutherford, M.;
Saket, B. M. J. Chem. Soc., Chem. Commun. 1985, 582–583; (c)
Boyd, D. R.; Malone, J. F.; McGuckin, M. R.; Jennings, W. B.;
Rutherford, M.; Saket, B. M. J. Chem. Soc., Perkin Trans. 2
1988, 1145–1150; (d) Jennings, W. B.; Lovely, C. J.
Tetrahedron Lett. 1988, 29, 3725–3728; (e) Jennings, W. B.;
Lovely, C. J. Tetrahedron 1991, 47, 5561–5568; (f) Cantrill,
A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M. I.; Raphy, J.;
Sweeney, J. B. Chem. Commun. 1996, 2631–2632; (g) Hayase,
T.; Osanai, S.; Shibata, T.; Soai, K. Heterocycles 1998, 48,
139–144; (h) Hou, X. L.; Yang, X. F.; Dai, L. X.; Chen, X. F.
Chem. Commun. 1998, 747–748; (i) Yamada, K.; Harwood,
S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 3504–3506; (j) Lauzon, C.; Desrosiers, J.-N.; Charette,
A. B. J. Org. Chem. 2005, 70, 10579–10580.
19. For the spectral and analytical data for the addition products,
see also: (a) Zwierzak, A.; Slusarska, E. Synthesis 1979,
691–693; (b) Beresford, K. J. M. Tetrahedron Lett. 2004,
45, 6041–6044; (c) Yang, W.-W.; Cun, L.-F.; Zhi, Y.-G.;
Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Lett. Org. Chem.
2005, 2, 605–607; (d) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron 2007, 63, 1167–1174.
ꢀ
(h) Frechet, J. M. J.; Tomalia, D. A. Dendrimers and Other
Dendritic Polymers; Wiley: Chichester, UK, 2001; (i) Hirao,
A.; Hayashi, M.; Loykulnant, S.; Sugiyama, K.; Ryu, S. W.;
Haraguchi, N.; Matsuo, A.; Higashihara, T. Prog. Polym. Sci.
2005, 30, 111–182; (j) Hirao, A.; Sugiyama, K.; Tsunoda, Y.;
Matsuo, A.; Watanabe, A. J. Polym. Sci., Part A: Polym.
Chem. 2006, 44, 6659–6687.
12. For recent reviews on the synthesis and application of chiral
dendrimers in asymmetric synthesis, see: (a) Romagnoli, B.;
Hayes, W. J. Mater. Chem. 2002, 12, 767–799; (b)
Ribourdouille, Y.; Engel, G. D.; Gade, L. H. C. R. Chim.
2003, 6, 1087–1096.
13. For representative examples on the use of dendrimers in asym-
metric synthesis, see: (a) Brunner, H. J. Organomet. Chem.
1995, 500, 39–46; (b) Arai, T.; Sekiguti, T.; Iizuka, Y.;
Takizawa, S.; Sakamoto, S.; Yamaguchi, K.; Sasai, H.
Tetrahedron: Asymmetry 2002, 13, 2083–2087; (c)
Ribourdouille, Y.; Engel, G. D.; Richard-Plouet, M.; Gade,
L. H. Chem. Commun. 2003, 1228–1229; (d) Bellis, E.;
Kokotos, G. J. Mol. Catal. A: Chem. 2005, 241, 166–174; (e)
Laurent, R.; Caminade, A.-M.; Majoral, J.-P. Tetrahedron
Lett. 2005, 46, 6503–6506; (f) Liu, W.; Cui, X.; Cun, L.;
Zhu, J.; Deng, J. Tetrahedron: Asymmetry 2005, 16, 2525–
2530; (g) Liu, X.; Li, Y.; Wang, G.; Chai, Z.; Wu, Y.; Zhao,
G. Tetrahedron: Asymmetry 2006, 17, 750–755; (h) Wang,
G.; Zheng, C.; Zhao, G. Tetrahedron: Asymmetry 2006, 17,
2074–2081; (i) Routaboul, L.; Vincendeau, S.; Turrin, C.-O.;
20. (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
ˆ
1692–1693; (b) Boezio, A. A.; Pytkowicz, J.; Cote, A.;
Charette, A. B. J. Am. Chem. Soc. 2003, 125, 14260–14261;
ꢀ
ˆ ꢀ
(c) Cote, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5405–5410.