Polymer-supported l-prolinol-based catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines

Article abstract of DOI:10.1016/j.tetasy.2012.12.007

l-Prolinol-based ligands anchored to Merrifield or Wang-type resins have been shown to form efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines. The enantioselectivity achieved with the polymeric catalyst (ee up to 88%) is slightly lower than the one obtained with the homogeneous ligand N-benzyl-l-prolinol, but the polymer-supported ligand presents the advantage of its recyclability: it can be recovered and used in up to six consecutive catalytic cycles with only a slight decrease in the enantiomeric excess. The phosphinamides obtained as addition products can be transformed into the corresponding enantiomerically enriched α-branched primary amines under mild acidic conditions.

Full text of DOI:10.1016/j.tetasy.2012.12.007

Tetrahedron: Asymmetry 24 (2013) 116–120
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Tetrahedron: Asymmetry
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Polymer-supported L-prolinol-based catalysts for the enantioselective
addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines
⇑
⇑
Raquel Almansa, Juan F. Collados, David Guijarro , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 November 2012
Accepted 19 December 2012
L
-Prolinol-based ligands anchored to Merrifield or Wang-type resins have been shown to form efficient
catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines.
The enantioselectivity achieved with the polymeric catalyst (ee up to 88%) is slightly lower than the
one obtained with the homogeneous ligand N-benzyl-L-prolinol, but the polymer-supported ligand pre-
sents the advantage of its recyclability: it can be recovered and used in up to six consecutive catalytic
cycles with only a slight decrease in the enantiomeric excess. The phosphinamides obtained as addition
Dedicated to the memory of Professor
Balbino Mancheño Magán
products can be transformed into the corresponding enantiomerically enriched
amines under mild acidic conditions.
a-branched primary
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
catalyst is the use of ligands immobilized on solid supports. There
are several examples in the literature of addition reactions of dial-
kylzinc reagents to aldehydes14 and imines6b,15 promoted by sup-
ported aminoalcohols. The most popular supports that have been
used are polymers,14,15a,b,d although other supports have proved
to be efficient, such as dendrimers,14c–e,15c,e–g silica gel,14c–e molec-
ular sieves14c and zirconium phosphates.14d The immobilization of
the chiral ligand onto an insoluble polymeric chain, such as poly-
styrene, is still one of the best options, since it allows the recovery
of the ligand by simple filtration. In a continuation of our studies
on the addition of dialkylzinc reagents to N-(diphenylphos-
The enantioselective addition of dialkylzinc reagents to N-
(diphenylphosphinyl)imines is one of the most reliable methods
for the asymmetric synthesis of amines.1,2 Chiral phosphinamides
that are obtained as the addition products can be easily trans-
formed into the corresponding primary amines by simple acidic
treatment without any loss of enantiomeric purity.3 Dialkylzinc re-
agents4 are very interesting nucleophiles since they tolerate sev-
eral functional groups,5 allowing the preparation of
polyfunctionalised organic compounds. However, the reaction of
N-phosphinylimines with dialkylzincs is very slow and low yields
of the addition products are obtained over long reaction times un-
less an additive is used to facilitate the reaction.6–12 b-Aminoalco-
hols are among the most efficient promoters for these addition
reactions. A variety of them have been shown to induce excellent
enantioselectivities, but, in most cases, the use of a stoichiometric
amount of the aminoalcohol ligand is necessary.6 A few years ago,
phinyl)imines, we have developed L-prolinol-based ligands an-
chored to Merrifield or Wang-type resins and herein we report
the results of our research activities.
2. Results and discussion
Since N-benzyl-L-prolinol has been shown to efficiently catalyse
the addition of dialkylzincs to N-(diphenylphosphinyl)imines,13 we
decided to prepare several polymers bearing the prolinol frame-
work bonded to the polymeric chain through the benzylic substitu-
ent on the nitrogen atom. The supported aminoalcohols were
we found out that N-benzyl-L-prolinol was a very efficient ligand
for the addition of dialkylzinc reagents to N-(diphenylphos-
phinyl)imines, obtaining ee’s in up to 94% with 0.5 equiv of the
aminoalcohol.13 However, the amount of ligand used was still rel-
atively high and we thought that the productivity of the catalyst
could be increased if it could be easily recovered and reused sev-
eral times. Moreover, reuse of the catalyst would reduce the
amount of waste material and make the process more environ-
mentally friendly, with potential applications in the chemical
industry. One interesting way to achieve the recovery of the
synthesised from
or Wang-type resins, both containing benzylic halide moieties that
could be used as electrophiles to benzylate the nitrogen atom of
prolinol. The commercial polymers and -prolinol were stirred in
L-prolinol and commercially available Merrifield
L-
L
DMF at room temperature for 90 h (Scheme 1). By using Merrifield
resins with different chloride contents and changing the
aminoalcohol load, polymers 1a–f with different levels of prolinol
incorporation were obtained (Table 1, entries 1–6). In order to
study the effect on the enantioselectivity of the presence of a linker
⇑
Corresponding authors. Fax: +34 965903549.
E-mail addresses: dguijarro@ua.es (D. Guijarro), yus@ua.es (M. Yus).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.12.007

R. Almansa et al. / Tetrahedron: Asymmetry 24 (2013) 116–120
117
N
X
OH
i-iii
+
N
H
OH
O
Merrifield resin: no linker; X = Cl
Wang-type resin: linker=
1
; X = Br
Scheme 1. Reagents and conditions: (i) DMF, 25 °C, 90 h; (ii) filtration; (iii) successive washing with DMF, EtOH, THF, THF/H2O (1:1), MeOH, acetone and Et2O.
Table 2
separating the polymeric chain from the prolinol moiety, Wang-
type resin 1g was also prepared (Table 1, entry 7). In all cases,
the amount of aminoalcohol present in the polymeric ligands
was calculated by determining the nitrogen content of the poly-
mers by elemental analysis.
Enantioselective addition of diethylzinc to imine 2a in the presence of supported
prolinols 1a
Entry
Ligand
Product 3aa
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
N-Benzyl-
L-prolinol
79
84
71
72
84
78
62
80
92
82
84
52
62
74
50
70
Table 1
1a
1b
1c
1d
1e
1f
Preparation of the polymer-supported prolinols
Entry
Commercial resin
X
Polymeric ligand
Linker
mmol X/g No. mmol Prolinol/ga
1
2
3
4
5
6
—
—
—
—
—
—
Cl 1.0
1a
1b
1c
1d
1e
1f
0.61
0.87
0.93
1.09
1.48
3.10
1g
Cl 4.3
Cl 1.5
Cl 1.5
Cl 1.7
Cl 4.3
a
All reactions were performed by the dropwise addition of diethylzinc (6 equiv)
over ca. 10 min to a stirred suspension of the polymeric ligand 1 (1 equiv) in a
solution of imine 2a (0.25 mmol) in anhydrous toluene (3.5 mL) under argon at
room temperature and stirring was continued for 2 days.
b
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate)
O
based on the starting imine 2a. Isolated compound 3aa was always P95% pure
7
Br 0.5-1.5
1g
1.00
(300 MHz 1H NMR).
c
Enantiomeric excess determined by HPLC using a ChiralCel OD-H column. The
(R)-enantiomer was the major one in all cases.
a
Determined by elemental analysis of nitrogen.
d
Results previously reported by us.13b
Polymeric ligands 1 were evaluated as promoters of the addi-
tion of diethylzinc to N-(diphenylphosphinyl)benzaldimine 2a as
a model reaction (Scheme 2) and the results were compared with
those previously obtained with N-benzyl-L-prolinol as a homoge-
lectivities. Ligand 1g, derived from a Wang-type resin, gave an ee
of 70%, which was only slightly higher than the ee achieved with
the Merrifield-type ligand 1d with similar prolinol content (com-
pare entries 5 and 8 in Table 2). Therefore, it seems that the possi-
ble beneficial effect of having a linker between the polymeric
support and the prolinol moiety is not very pronounced in this
case.
Next, we performed a recyclability study with the two ligands
that gave the highest enantioselectivities, 1a and 1b. When the
addition reaction of diethylzinc to imine 2a was complete, stirring
was stopped and the polymer was allowed to settle at the bottom
of the flask, after which the liquid layer was separated with the aid
of a syringe. The polymeric ligand was then washed three times
with anhydrous toluene under argon and then used directly as a
promoter of the next addition reaction. The results obtained with
both ligands in the different cycles are collected in Table 3 and
represented in Figure 1. In all the reactions, a small amount of
by-product resulting from the reduction of imine 2a was also
observed; however, this could be separated from the desired addi-
tion product by column chromatography. We assume that the
reduction process took place via a b-hydride transfer from diethyl-
zinc to the imine carbon atom.
neous ligand.13 Diethylzinc (6 equiv) was added dropwise to a sus-
pension of the polymeric ligand 1 (1 equiv) in a solution of imine
2a in toluene at room temperature over ca. 10 min. After stirring
for 2 days at the same temperature, the liquid phase was separated
from the polymer by syringe and the solution was hydrolysed, to
afford, after work-up, the expected phosphinamide 3aa in the
yields and ee’s indicated in Table 2.
O
P
O
P
Ph
Ph
Ph
Ph
N
HN
i-iii
+
Et2Zn
H
2a
3aa
Scheme 2. Reagents and conditions: (i) polymeric ligand 1 (1 equiv), toluene, 25 °C,
2 days; (ii) separation; (iii) NH4Cl (aq).
Both ligands gave yields in the range of 60–80% in all the cycles.
However, ligand 1a showed a much better recyclability than ligand
1b. As can be seen in Fig. 1, the ee obtained with ligand 1b de-
creased considerably in the third cycle, whereas in the reactions
promoted by ligand 1a, the ee value remained practically constant
during the first five cycles, decreased slightly in the sixth cycle and
We found that polymeric ligands 1a and 1b gave slightly lower
ee’s than those obtained with the homogeneous ligand (compare
entries 1–3 in Table 2). However, the enantioselectivity decreased
with the other ligands derived from Merrifield resins, 1c–f (Table 2,
entries 4–7). According to these results, it seems that a low prolinol
incorporation in the polymeric catalyst leads to higher enantiose-

118
R. Almansa et al. / Tetrahedron: Asymmetry 24 (2013) 116–120
Table 3
polymeric ligand 1a was used, the fact that it could be quantita-
tively recovered by a simple separation procedure and reused in
five more cycles without a significant loss of chiral induction im-
proves its catalytic efficiency.
Recyclability study performed with ligands 1a and 1b. Yields and ee’s obtained for the
addition of diethylzinc to imine 2aa.
Cycle
Ligand 1a
Yieldb (%)
Ligand 1b
Yieldb (%)
eec (%)
eec (%)
Once we had established that 1a was the ligand of choice, we
decided to investigate the scope of this reaction by testing some
other dialkylzinc reagents and imines (Scheme 3 and Table 4). As
stated above, the addition of diethylzinc to imine 2a gave product
3aa in 84% yield and 80% ee (Table 4, entry 1). With the idea of
reducing the reaction time and increasing the yield, this reaction
was repeated with heating in a microwave reactor at 50°C (70 W,
0.8 bar) for 1 h,16 which improved the yield to 95%, but caused
the ee to decrease to 62% (Table 4, entry 2). As previously repor-
ted,3,6c dimethylzinc turned out to be much less reactive than
diethylzinc and no addition product was formed after stirring the
reaction for 2 days at room temperature. The addition of diisopro-
pylzinc to imine 2a gave product 3ab in good yield and enantiose-
lectivity (Table 4, entry 4). Dibutylzinc was as efficient as
diethylzinc, and afforded the addition product 3ac in 80% yield
and 86% ee (Table 4, entry 6). We also tried to prepare compounds
3aa–ac by the reaction of the corresponding dialkylzinc reagent
1
2
3
4
5
6
7
8
9
77
74
74
73
68
74
61
68
74
82
78
78
78
76
70
56
50
42
60
67
58
66
68
58
—
84
72
50
52
46
38
—
—
—
—
—
a
All reactions were performed by the dropwise addition of diethylzinc (6 equiv)
over ca. 10 min to a stirred suspension of polymeric ligand 1 (1 equiv) in a solution
of imine 2a (0.25 mmol) in anhydrous toluene (3.5 mL) under argon at room tem-
perature and stirring was continued for 2 days. After completion of the reaction, the
polymeric ligand was separated from the liquid layer, washed three times with
anhydrous toluene and used directly in the next cycle.
b
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate)
based on the starting imine 2a. Isolated compound 3aa was always P95% pure
(300 MHz 1H NMR).
c
Enantiomeric excess determined by HPLC using a ChiralCel OD-H column. The
(R)-enantiomer was the major one in all cases.
Table 4
Enantioselective addition of dialkylzinc reagents to in situ generated N-(diphenyl-
phosphinyl)imines
2
in the presence of polymeric ligand 1aa. Preparation of
compounds 3.
90
84
R02Zn
Entry
Substrate
Product
ee 1a (%)
78
78
78
52
80
70
60
50
40
30
20
R0
Equiv
No.
Yieldb (%)
eec (%)
76
46
82
ee 1b (%)
70
38
1
2d
3
4
5
6
7
8
9
10
11
12
13
2a
2a
4a
2a
4a
2a
4a
4b
4c
4d
4e
4f
Et
Et
Et
i-Pr
i-Pr
n-Bu
n-Bu
Et
Et
Et
Et
Et
6
6
6
6
6
6
6
6
6
6
8
6
6
3aa
3aa
3aa
3ab
3ab
3ac
3ac
3b
3c
3d
3e
3f
84
95
86
77
88
80
82
99
61
84
82
92
80
82
62
84
76
64
86
64
78
88
74
30
32
56
72
56
50
50
42
4g
Et
3g
1
2
3
4
5
6
7
8
9
a
All reactions were performed by the dropwise addition of diethylzinc (6 equiv)
Cycle
over ca. 10 min to a stirred suspension of the polymeric ligand 1a (1 equiv) and
substrate 2 or 4 (0.25 mmol) in anhydrous toluene (3.5 mL) under argon at room
temperature and stirring was continued for 2 days.
Figure 1. Enantiomeric excesses obtained in the addition of diethylzinc to imine 2a
promoted by recovered ligands 1a and 1b.
b
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate)
based on the substrate 2 or 4. All isolated compounds 3 were P95% pure (300 MHz
1H NMR).
c
then started to greatly decrease from the seventh cycle. The
decrease in catalytic activity of these ligands with the number of
cycles could be due to the degradation of the polymeric chain after
prolonged stirring.14c Although a stoichiometric amount of the
Enantiomeric excess determined by HPLC using a ChiralCel OD-H column or a
Chiralpak AD column. The (R)-enantiomer was the major one in all cases.
d
Reaction performed under microwave irradiation at 50 °C (70 W, 0.8 bar) for
1 h.
O
P
O
O
P
P
Ph
Ph
Ph
Ph
Ph
Ph
N
HN
HN
i-iii
or
+
R'2Zn
R
H
R
SO2Tol
R
R'
2
4
3
a: R = Ph
b: R = 4-ClC6H4
c: R = 4-MeOC6H4
d: R = 2-naphthyl
e: R = PhCH2CH2
f: R = Me2CHCH2
g: R = c-C6H11
Scheme 3. Reagents and conditions: (i) polymeric ligand 1a (1 equiv), toluene, 25 °C, 2 days; (ii) separation; (iii) NH4Cl (aq).

R. Almansa et al. / Tetrahedron: Asymmetry 24 (2013) 116–120
119
with the sulfinic acid adduct 4a (Scheme 3). In these reactions,
imine 2a is generated in situ and then undergoes the addition of
the dialkylzinc reagent.17 This procedure gave slightly higher
yields for all products 3aa–ac. However, variable results were ob-
tained with regard to the enantioselectivity: a small improvement
was observed for the ethylation product 3aa, whereas lower ee’s
were obtained for compounds 3ab–ac (compare entry 1 with 3, en-
try 4 with 5 and entry 6 with 7 in Table 4).
Next, the addition of diethylzinc to several aromatic and ali-
phatic imines 2b–g was attempted. However, when we tried to
prepare these imines by literature procedures,18 we obtained them
in very small amounts and we could not purify them either by col-
umn chromatography on deactivated silica gel or by recrystalliza-
tion. Fortunately, imines 2b–g could be generated in situ from their
corresponding sulfinic acid adducts 4b–g (Scheme 3). All imines
derived from aromatic aldehydes gave very good ee’s, irrespective
of the electronic nature of the substituents on the aromatic ring
(Table 4, entries 8–10). It is worth noting that the addition of dib-
utylzinc to benzaldimine 2a and the reaction of diethylzinc with
adduct 4c, with a methoxy group at the para position of the ben-
zene ring, afforded products 3ac (86% ee) and 3c (88% ee), respec-
tively, with ee values that were very similar to the ones obtained
were prepared by reaction of the corresponding aldehydes with
P,P-diphenylphosphinic amide and p-toluenesulfinic acid following
a literature procedure.17 Commercially available
L-prolinol (Al-
drich, 97%), Merrifield resins (Aldrich, 1 mmol Cl/g; Aldrich,
1.5 mmol Cl/g; Fluka, 1.7 mmol Cl/g; Aldrich, 4.3 mmol Cl/g),
Wang-type resin (Aldrich, 0.5–1.5 mmol Br/g), solutions of Et2Zn
(Aldrich, 1.1 M in hexanes), (i-Pr)2Zn (Aldrich, 1.0 M in toluene)
and (n-Bu)2Zn (Acros, 1.0 M in heptane) were used as received.
Anhydrous toluene (Scharlau, 99.9%, H2O 60.017%) was used as a
solvent in all of the addition reactions. HPLC analyses were per-
formed at 25°C on a JASCO apparatus, equipped with a PU-2089
Plus pump, a MD-2010 Plus detector and an AS-2059 Plus auto-
matic injector. Elemental analyses were performed by the Techni-
cal Services of the University of Alicante.
4.2. Preparation of the polymeric ligands 1. General procedure
L-Prolinol (1.0 mL, 10.5 mmol) was added to a suspension of the
Merrifield or Wang-type resin (2.5 mmol of Cl) in DMF (25 mL) and
the mixture was stirred for 90 h at room temperature. Next, the so-
lid was filtered and washed successively with DMF, EtOH, THF,
THF/H2O (1:1), MeOH, acetone and Et2O, then dried under vacuum
for several hours until no loss of weight was observed. The number
of millimoles of prolinol per gram of the polymeric ligand was cal-
culated by determining the nitrogen content of the polymer by ele-
mental analysis; the following results were obtained: 1a (0.86% N,
0.61 mmol prolinol/g), 1b (1.22% N, 0.87 mmol prolinol/g), 1c
(1.30% N, 0.93 mmol prolinol/g), 1d (1.52% N, 1.09 mmol prolinol/
g), 1e (2.08% N, 1.48 mmol prolinol/g), 1f (4.33% N, 3.10 mmol pro-
linol/g) and 1g (1.42% N, 1.00 mmol prolinol/g).
when N-benzyl-L-prolinol was used as a homogeneous ligand to
catalyse the same reactions (90% and 92% ee, respectively).13b For
the rest of the examples of aromatic imines (Table 4, entries 3, 4,
8 and 10), an average loss of ee of 13% was observed in comparison
with the reactions catalysed by the homogeneous ligand. However,
the polymeric ligand 1a was less efficient in promoting the enan-
tioselective addition of diethylzinc to the in situ generated ali-
phatic imines 2e–g: although the isolated yields were very good
in all cases, only moderate ee values were observed in the addition
products 3e–g (30-56%, Table 4, entries 11–13).
4.3. Recyclability study performed with polymeric ligands 1a
and 1b
As described above, ligand 1a is an efficient and recyclable cat-
alyst for the addition of dialkylzinc reagents to N-(diphenylphos-
phinyl)aldimines. Since the phosphinyl group can be easily
removed from the addition products under acidic conditions,3 this
methodology represents an interesting procedure for synthesizing
A suspension of imine 2a (0.25 mmol) and ligand 1a or 1b
(0.25 mmol of N) in anhydrous toluene (3.5 mL) under argon was
prepared in
a centrifuge tube. Next, diethylzinc (1.5 mmol,
a
-branched primary amines with high enantiomeric purities. It is
1.4 mL of a 1.0 M solution in toluene) was added dropwise over
ca. 10 min to that stirred suspension at room temperature. After
stirring for two days at the same temperature, the tube was centri-
fuged and the liquid layer was carefully extracted with a syringe
trying to avoid the extraction of the solid particles. Anhydrous tol-
uene (3.0 mL) was then added to the solid, after which the mixture
was stirred for 5 min, the tube was again centrifuged and the liquid
phase was extracted with a syringe. This washing process was per-
formed three times. The combined organic layers were hydrolysed
with an aqueous saturated solution of NH4Cl (10 mL) and work-up
was performed as described in Section 4.4.
Solid imine 2a (0.25 mmol) was quickly added to the centri-
fuge tube containing the polymeric ligand 1a or 1b from the pre-
vious reaction and an inert atmosphere was created inside the
tube by carrying out several vacuum-argon cycles. Anhydrous tol-
uene (3.5 mL) was added to the solid mixture and then diethyl-
zinc (1.5 mmol, 1.4 mL of a 1.0 M solution in toluene) was
added dropwise over ca. 10 min to the stirred resulting suspen-
sion at room temperature and the reaction was stirred for
two days at the same temperature. Following this procedure,
ligands 1a and 1b were used in 9 and 6 consecutive reactions,
respectively.
worth noting that -prolinol is also commercially available and
D
could be used to prepare other polymeric ligands with enantio-
meric aminoalcohol moieties, which would provide the opportu-
nity of preparing the enantiomers of the final amine products.
3. Conclusions
In conclusion, we have reported that N-benzyl-L-prolinol an-
chored to a polymeric support is an efficient promoter for the addi-
tion of dialkylzinc reagents to N-(diphenylphosphinyl)imines. By
the appropriate choice of the prolinol content, a polymeric ligand
was prepared that could be recovered and used in up to six con-
secutive cycles without a significant loss of enantioselectivity.
The enantiomeric excesses achieved with the supported catalyst
were slightly lower than those obtained with N-benzyl-L-prolinol
as an homogeneous ligand, but the former has the advantage of
its recyclability. This methodology is very useful for the prepara-
tion of enantiomerically enriched protected amines from aromatic
N-(diphenylphosphinyl)imines, but is less effective when imines
bearing aliphatic substituents are used as substrates.
4. Experimental
4.1. General
4.4. Addition of dialkylzinc reagents to imines 2 catalysed by
ligand 1a. Preparation of compounds 3. General procedure
The dialkylzinc reagent (1.5 mmol) was added dropwise over ca.
10 min to a stirred suspension of imine 2a or adduct 4 (0.25 mmol)
and ligand 1a (0.25 mmol of N) in anhydrous toluene (3.5 mL) un-
For general experimental information, see reference.11 Imine 2a
was prepared according to a literature procedure.9h,18 Adducts 4

120
R. Almansa et al. / Tetrahedron: Asymmetry 24 (2013) 116–120
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Knochel, P. Synlett 1995, 393–403; (d) Vettel, S.; Vaupel, A.; Knochel, P.
Tetrahedron Lett. 1995, 36, 1023–1026; (e) Vettel, S.; Vaupel, A.; Knochel, P. J.
Org. Chem. 1996, 61, 7473–7481; (f) Langer, F.; Schwink, L.; Devasagayaraj, A.;
Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229–8243; (g) Micouin, L.;
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der argon at room temperature. After stirring for two days, the
polymer was allowed to settle to the bottom of the flask and the
liquid layer was carefully extracted with a syringe while trying
to avoid extraction of the solid particles (if necessary, the mixture
was centrifuged before removing the liquid phase). Next, anhy-
drous toluene (3.0 mL) was added to the solid, the mixture was
stirred for 5 min, the polymer was again allowed to settle and
the liquid phase was extracted with a syringe. This washing pro-
cess was performed three times. The combined organic layers were
hydrolysed with an aqueous saturated solution of NH4Cl (10 mL).
Water (5 mL) was then added and the mixture was extracted with
ethyl acetate (3 ꢀ 20 mL). The combined organic layers were
washed with brine (10 mL), and then dried (MgSO4). After filtration
and evaporation of the solvents, the crude residue was purified by
column chromatography (silica gel, hexane/ethyl acetate), to give
products 3 in the yields and enantiomeric excesses indicated in Ta-
ble 4. Compounds 3aa,3 3ab,13b 3ac,11 3b,3 3c,6k 3d,13b 3e,17 3f17
and 3g17 were characterised by comparison of their physical and
spectroscopic data with the values reported in the literature. These
products were analysed by HPLC on a ChiralCel OD-H column using
a 254 nm UV detector, 10% i-PrOH in hexane as eluent and a flow
rate of 1.0 mL/min or on a Chiralpak AD column using a 254 nm
UV detector, 20% i-PrOH in hexane as eluent and a flow rate of
1.0 mL/min. The retention times were: 8.6 (R) and 12.3 (S) for
3aa (OD-H column), 8.6 (R) and 10.3 (S) for 3ab (OD-H column),
6.8 (R) and 12.8 (S) for 3ac (OD-H column), 11.9 (R) and 14.1 (S)
for 3b (AD column), 12.9 (R) and 16.0 (S) for 3c (AD column),
10.4 (R) and 14.7 (S) for 3d (AD column), 22.0 (R) and 30.7 (S) for
3e (AD column), 7.5 (S) and 10.7 (R) for 3f (AD column), 7.1 (S)
and 8.9 (R) for 3g (AD column). The absolute configuration of the
major enantiomer of 3aa was determined by its hydrolysis3 and
comparison of the specific rotation of the free amine obtained with
the reported data.3 The absolute configuration of the major enan-
tiomer of 3ab–ac was tentatively assigned according to the order
of elution of the two enantiomers in the HPLC analysis by analogy
to the product 3aa. For addition products 3b–d, the absolute con-
figuration of the major enantiomer was tentatively assigned
according to the HPLC data described in the literature for similar
compounds under the same conditions.17 The retention times of
the two enantiomers of compounds 3e–g have already been
described.17
7. For the use of iminoalcohols as additives, see Ref. 6k.
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Lin, W.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C.
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2007, 18, 2643–2648.
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10. For examples on the use of zirconium catalysts, see: (a) Porter, J. R.; Traverse, J.
F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984–985; (b)
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Yus, M. Tetrahedron 2007, 63, 1167–1174.
Acknowledgements
12. For examples on the use of a rhodium catalyst, see: Crampton, R. H.; El, H. S.;
Fox, M. E.; Woodward, S. Tetrahedron: Asymmetry 2009, 20, 2497–2503.
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A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275–3299; (c) Fan, Q.-H.; Li,
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P. M. P.; Afonso, C. A. M. Chem. Rev. 2009, 109, 418–514; (e) Somanathan, R.;
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This work was generously supported by the Spanish Ministerio
de Ciencia e Innovación (MICINN; grant no. CONSOLIDER INGENIO
2010, CSD2007-00006, CTQ2007-65218 and CTQ11-24151) and
the Generalitat Valenciana (PROMETEO/2009/039, FEDER and GV/
2007/036). R.A. thanks the Spanish Ministerio de Educación y Cien-
cia for a predoctoral fellowship. J.F.C. thanks the Instituto de Sínte-
sis Orgánica for a fellowship. We also thank MEDALCHEMY S.L. for
a gift of chemicals.
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