Cheap and long-life reusable polymer for asymmetric organozinc catalysis based on camphor-derived hydroxyamides

Article abstract of DOI:10.1002/chir.22061

Polystyrene grafted with a chiral zinc-complexing camphor-derived N,N-disubstituted hydroxyamide is proposed as a new type of functional polymer of high reusability for the development of sustainable organozinc-catalyzed asymmetric reactions. The main goal of this new functional polymer is the ease of the hydroxyamide-moiety preparation (cheap chiral ligand obtained straightforwardly from an enantiopure starting material coming from the chiral pool), as well as its chemical robustness when compared with other related zinc-complexing functional groups. The latter allows the polymer to be active after multiple applications, without significant loss of its catalytic activity. This fact is exemplified by the design and preparation of a polymer functionalized with a bis(hydroxyamide) proved previously as active in the homogeneous enantioselective addition of diethylzinc to aldehydes. The result is a cheap functional polymer with a very high reusability (the enantioselectivity and chemical yield are maintained practically constant after 20 applications). Additionally, a methodology for the multicycle use of these functional polymers is presented. Copyright

Full text of DOI:10.1002/chir.22061

CHIRALITY (2012)
Cheap and Long-Life Reusable Polymer for Asymmetric Organozinc
Catalysis Based on Camphor-Derived Hydroxyamides
TOMÁS DE LAS CASAS ENGEL,1 ESTHER M. SÁNCHEZ-CARNERERO,1 EKATERINA SOKOLOVSKAYA,2
CLAUDIO M. GALLARDO-ARAYA,1 FLORENCIO MORENO JIMÉNEZ,1 BEATRIZ LORA MAROTO,1 AND
1
*
SANTIAGO DE LA MOYA CERERO
1Departamento de Química Orgánica I, Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Ciudad Universitaria s/n, Madrid, Spain
2Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, Karlsruhe, Germany
ABSTRACT
Polystyrene grafted with a chiral zinc-complexing camphor-derived N,N-
disubstituted hydroxyamide is proposed as a new type of functional polymer of high reusability
for the development of sustainable organozinc-catalyzed asymmetric reactions. The main goal of
this new functional polymer is the ease of the hydroxyamide-moiety preparation (cheap chiral
ligand obtained straightforwardly from an enantiopure starting material coming from the chiral
pool), as well as its chemical robustness when compared with other related zinc-complexing func-
tional groups. The latter allows the polymer to be active after multiple applications, without signifi-
cant loss of its catalytic activity. This fact is exemplified by the design and preparation of a polymer
functionalized with a bis(hydroxyamide) proved previously as active in the homogeneous enantio-
selective addition of diethylzinc to aldehydes. The result is a cheap functional polymer with a very
high reusability (the enantioselectivity and chemical yield are maintained practically constant after
20 applications). Additionally, a methodology for the multicycle use of these functional polymers is
presented. Chirality 00:000 –000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric catalysis; diethylzinc reaction; sustainable chemistry; ketopinic acid;
hydroxyamides
INTRODUCTION
loss of activity, have been reported for titanium catalysts
instead of zinc ones,14–19 probably because of a higher
chemical robustness of the chiral ligands involved in such
titanium catalysts. Thus, Seebach has reported some heteroge-
neous BINOL- and TADDOL-based titanium catalysts, which
can be recycled and reused in, at least, 20 consecutive applica-
tions without any significant loss of activity.28–30
Chiral organometallic catalysts based on zinc have found
broad application in asymmetric organic synthesis.1–13 In
some cases, these catalysts could be efficiently recycled
from the reaction media and reused several times in new
reactions.14–20 This possibility is very interesting for sustain-
able organozinc-catalyzed processes, especially when they
must be performed at the industrial multikilogram level.
Supporting the chiral-ligand moiety in a polymeric solid
matrix (i.e., polystyrene (PS)) is usually the best option for
designing reusable functional polymers that can be recov-
ered by simple filtration.21–25 However, the development of
a heterogeneous supported catalyst is not trivial, and in
many cases, the catalytic activity can be negatively affected
by the supporting matrix.14–25 Moreover, it is well known that
the successive recovering–recycling–reusing cycles used to
decrease the catalyst activity,14–25 which can be overridden
by enhancing the chemical robustness of the active ligand in
some cases.26
One of the most studied asymmetric reactions promoted
by organozinc catalysts is the enantioselective addition of
organometallic reagents (mainly organozinc ones) to
aldehydes.1–3,5–7,11–13 In this line, many recyclable catalysts
based in the immobilization of the most successful homoge-
neous ligands (i.e., b-amino alcohols) have been described
for this valuable asymmetric C-C bond-forming reaction.14–19
This strategy (ligand heterogenization) has also given good
results for the development of interesting continuous-flow
reactors, which can be also used in multiple applications.27
Despite this huge effort, the higher numbers of consecutive
applications of a heterogenized ligand, without significant
© 2012 Wiley Periodicals, Inc.
In a previous paper, we have described that the piperazine-
based bis(hydroxyamide) 1, a robust and cheap chiral ligand
straightforwardly obtained from renewable camphor-derived
(1S)-ketopinic acid (sustainable ligand),31 is able to promote
the enantioselective ethylation of benzaldehyde in the absence
of titanium by formation of a C2-symmetric zinc-chelate
catalyst.32 Recently, we have discovered that analogue 1,4-
diazepane-based 2 also promotes efficiently the same
reaction, although through a non-C2-symmetric zinc-chelate
catalyst.33 The latter is highly interesting because it opens
the way to the design of active immobilized ligands based
of those bis(hydroxyamides), which irremissibly will gener-
ate non-C2-symmetric zinc-chelate catalytic centers because
of the covalent joint of the active ligand structure to the
This article is dedicated to Prof. Enrique Teso on the occasion of his 60th
birthday.
Contract grant sponsor: Spain Government (grant CTQ2010-18076) and UCM
(grant to research group GR35/10-A-910107).
*Correspondence to: Santiago de la Moya Cerero, Departamento de Química
Orgánica I, Universidad Complutense de Madrid, Facultad de Ciencias
Químicas, Ciudad Universitaria s/n, 28040-Madrid, Spain.
E-mail: santmoya@quim.ucm.es
Received for publication 20 February 2012; Accepted 28 March 2012
DOI 10.1002/chir.22061
Published online in Wiley Online Library
(wileyonlinelibrary.com).

LAS CASAS ENGEL ET AL.
supporting matrix. This observation prompted us to investi-
(CH), 27.9 (CH2), 27.6 (CH2), 27.1 (CH2), 27.0 (CH2), 21.26 (CH3),
21.12 (CH3), 20.9 (CH3), 20.7 ppm (CH3); FTIR: n = 3404 (w), 1738 (s),
1622 (s); MS (ESI-neg): m/z (%): 443 (64), 479 (100); HRMS (ESI-neg-
FTMS): m/z: calculated for C25H35N2O5: 443.2546; found: 443.2609.
Second step. A two-neck round-bottom flask provided with a magnetic
stirrer and a water condenser was charged with 1,4-bis{[(1S)-7,7-dimethyl-2-
oxonorborn-1-yl]carbonyl}-1,4-diazepan-6-ol (0.89 g, 2.0mmol), NaBH4
(0.61g, 16.0mmol), and methanol (50 ml). The mixture was refluxed for
24h under argon. Then, the mixture was cooled down and concentrated
under reduced pressure. The residue was diluted with ethyl acetate
(50 ml), and water (50 ml) was added. The layers were separated, and the
aqueous layer was extracted with ethyl acetate (3Â 25 ml). The combined
organic layers were dried over anhydrous MgSO4. The mixture was filtered
and the solvent evaporated under reduced pressure. The crude was purified
by flash column chromatography (ethyl acetate) to obtain 4 (0.81 g, 90%
yield) as a white solid. M.p.: decomposes at 220ꢀC; [a]D20 À219.2 (c 0.75,
CHCl3); 1H NMR (700 MHz, CDCl3) (as a mixture of 1:1 rotamers):
d = 5.77–5.16 (br s, 2H), 4.70 (dd, J = 15.0, 3.7 Hz, 1H), 4.50 (ddd, J = 12.0,
12.0, 6.3 Hz, 1H), 4.40 (dd, J = 14.3, 6.3 Hz, 1H), 4.35–4.29 (m, 2H), 4.18
(br s, 1H), 4.13 (dd, J= 8.3, 3.7 Hz, 1H), 3.28 (br s, 1H), 3.21 (dd, J = 12.0,
5.4 Hz, 1H), 3.10 (d, J = 15.0 Hz, 1H), 3.06–2.99 (m, 1H), 2.87 (ddd, J = 14.3,
12.0, 5.4Hz, 1H), 1.99–1.91 (m, 2H), 1.89–1.81 (m, 2H), 1.81–1.65 (m, 4H),
1.64–1.48 (m, 4H), 1.40 (s, 3H), 1.38 (s, 3H), 1.18–1.01 (m, 2H), 1.07
(s, 3H), 0.97 ppm (s, 3H); 13C NMR (175 MHz, CDCl3) (as a 1:1mixture of
inseparable amidic rotamers): d = 178.7 (CO), 175.4 (CO), 77.5 (CH-OH),
76.6 (CH-OH), 71.5 (CH-OH), 61.6 (C), 61.4 (C), 54.3 (CH2), 50.7 (C), 50.3
(C), 48.7 (CH2), 47.4 (CH2), 46.3 (CH2), 44.9 (CH), 44.8 (CH), 41.3 (CH2),
40.0 (CH2), 29.0 (CH2), 26.9 (CH2), 26.7 (CH2), 22.2 (CH3), 21.9 (CH3),
21.6 (CH3), 21.5 ppm (CH3); FTIR: n = 3397 (w), 1607 (s); MS (ESI):
m/z (%): 447 (61), 493 (100); HRMS (ESI-FTMS): m/z: calculated for
gate the use of the robust and cheap hydroxyamides of the
type of 2 for the development of new long-life recyclable
functional polymers for the catalyzed enantioselective addi-
tion of organozinc reagents to aldehydes, as a starting model
for other organozinc-catalyzed asymmetric reactions.
EXPERIMENTAL
Materials and Methods
Common solvents were dried and distilled by standard procedures. All
starting materials and reagents were obtained commercially and used
without further purifications. Flash chromatography purifications were
performed on silica gel (230–400 mesh). Melting points (m.p.) are
uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded
at 20 ꢀC, and the residual solvent peaks were used as internal standards.
Fourier transform infrared (FTIR) spectra were obtained using the thin-
layer technique. Gas chromatography (GC) analyses were realized at
120 ꢀC in a chromatograph equipped with a capillary silicon-gum (SGL-1)
column, a flame ionization detector and using nitrogen as mobile phase.
Chiral high-performance liquid chromatography (HPLC) analyses were
realized at room temperature (r.t.) in a chromatograph equipped with a
Chiralpak-IC or Chiralpak-IA column and a diode array detector and using
hexane/isopropanol as mobile phase. Mass spectra (MS) were recorded
using the electrospray ionization (ESI) technique. high resolution mass
spectra (HRMS) were obtained by the ESI-Fourier transform mass
spectrometry (FTMS) technique. Elemental analyses (C, H, and N)
were performed by the dynamic flash combustion technique.
Synthesis of Chiral Hydroxyamide Ligands
1,4-diazepan-6-ol. The preparation of key 1,4-diazepan-6-ol is based on
a procedure reported previously by Saari et al. via 1,4-bis(p-toluenesulfonyl)-
1,4-diazepan-6-ol as key intermediate.34 We have optimized the preparation
of such key bis(p-toluenesulfonyl) intermediate as follows: N,N-ethylenebis
(p-toluenesulfonamide)34 (12.23 g, 36 mmol) was dissolved in 350ml
of absolute ethanol, and a solution of KOH (5.60g, 100 mmol) in 50ml of
absolute ethanol was added. The mixture was refluxed for 5 min with forma-
tion of a white precipitate. Then, a solution of 2,3-dibromopropan-1-ol
(7.85 g, 36 mmol) in 50 ml of ethanol was added, and the reaction mixture
refluxed for 7 h. The warm mixture was filtered, and the solvent evaporated
under vacuum. The resulting residue was recrystallized from methanol to
give 11.31g (74% yield) of 1,4-bis(p-toluenesulfonyl)-1,4-diazepan-6-ol. The
spectral data match up with those described previously in the bibliographic
reference.34
C
25H39N2O5: 447.2865; found: 447.2869.
6-(benzyloxy)-1,4-bis{[(1S,2R)-7,7-dimethyl-2-hydroxynorborn-
1-yl]carbonyl}-1,4-diazepane (7). Into a round-bottom flask provided
with a magnetic stirrer, charged with 4 (95 mg, 0.21 mmol), tetrabutyla-
monium iodide (TBAI, 78 mg, 0.21 mmol), and 18-crown-6 (56 mg,
0.21 mmol) in dry tetrahydrofuran (THF) (5 ml) under argon, NaH
(9 mg, 0.23 mmol, 60% in mineral oil) was added. The mixture was stirred
for 15 min, and then, benzyl bromide (39 mg, 0.23 mmol) was added. After
stirring the reaction mixture at r.t. for 18 h, water (15 ml) and ethyl ace-
tate (15 ml) were added. The layers were separated, and the aqueous
layer was extracted with ethyl acetate (2 Â 15 ml). The combined organic
layers were washed with brine (1 Â 15 ml) and dried over anhydrous
MgSO4. The crude was purified by flash column chromatography (ethyl
acetate) to obtain 7 (90 mg, 79%) as a white solid. M.p.: 98–99 ꢀC; [a]D20
1,4-bis{[(1S,2R)-7,7-dimethyl-2-hydroxynorborn-1-yl]carbonyl}-
1,4-diazepan-6-ol (4). First step. In a round-bottom flask provided with
a magnetic stirrer, (1S)-ketopinic acid (1.27 g, 7.0 mmol), N-[3-(dimethyla-
mino)propyl]-N-ethylcarbodiimide hydrochloride (EDCÁHCl, 1.53 g, 8.0 mmol),
4-(dimethylamino)pyridine (DMAP, 1.95g, 16.0mmol), and 1,4-diazepan-6-
ol dihydrobromide (0.97g, 3.5 mmol) were suspended in CH2Cl2 (50 ml)
and stirred at room temperature for 72h. Then, CHCl3 (50ml) and H2O
(50ml) were added. The organic layer was separated, washed successively
with 10% HCl (1 Â 50ml), H2O (1 Â 50ml), 10% NaOH (2Â 50 ml), H2O
(1 Â 50ml), and brine (1 Â 50ml), and dried over anhydrous MgSO4. The
mixture was filtered and the solvent evaporated under reduced pressure.
1,4-Bis{[(1 S)-7,7-dimethyl-2-oxonorborn-1-yl]carbonyl}-1,4-diazepan-6-ol
(1.17 g, 73% yield) was isolated as a white solid and used for the next step
without further purification. M.p.: 225–226 ꢀC; [a]D20 +0.6 (c 0.25, CHCl3);
1H NMR (300 MHz, CDCl3) (as a mixture of rotamers): d = 4.75–2.95
(m, 10H), 2.51 (d, J = 18.4 Hz, 2H), 2.40–1.83 (m, 8H), 1.89 (d,
J = 18.4 Hz, 2H), 1.54–1.38 (m, 2H), 1.30–1.11 ppm (several s, 12H); 13C
NMR (75 MHz, CDCl3) (as a mixture of rotamers, major signals are
given): d = 212.7 (CO), 170.7 (N-CO), 67.8 (CH-OH), 67.5 (C), 54.7
(CH2), 51.9 (CH2), 50.8 (C), 43.63 (CH2), 43.59 (CH2), 43.1 (CH), 43.0
1
À131.0 (c 0.155, CHCl3); H NMR (300 MHz, CDCl3) (as a mixture of in-
separable amidic rotamers): d = 7.55–7.21 (m, 5H), 5.05–2.03 (m, 15H),
2.02–1.17 (m, 18H), 1.16–0.87 ppm (m, 8H); 13C NMR (75 MHz, CDCl3)
(as a mixture of inseparable amidic rotamers; only major signals are
dated): d = 173.8 (N-CO), 172.8 (N-CO), 138.6 (CAr), 136.9 (CAr), 129.0
(CHAr), 128.2 (CHAr), 128.0 (CHAr), 77.8 (CH-O), 76.3 (CH-O), 74.9
(CH-O), 72.9 (CH-O), 71.6 (CH2-O), 71.3 (CH2-O), 61.2 (C), 59.9 (C),
54.3 (CH2), 53.6 (CH2), 50.5 (C), 50.4 (C), 48.1 (CH2), 46.3 (CH2), 45.2
(CH2), 44.9 (CH), 44.7 (CH), 42.6 (CH2), 41.9 (CH2), 40.8 (CH2), 40.3
(CH2), 29.4 (CH2), 29.2 (CH2), 26.8 (CH2), 22.0 (CH3), 21.8 (CH3),
21.7 ppm (CH3); FTIR: n = 3454 (w), 1618 (s); MS (ESI): m/z (%): 539
(4), 561 (100); HRMS (ESI-FTMS): m/z: calculated for C32H47N2O5:
539.3479; found: 539.3477.
SYNTHESIS OF HYDROXYAMIDE-GRAFTED POLYMERS 6
Synthesis of 6b (Typical Procedure). Into a round-bottom
flask provided with a magnetic stirrer, charged with 4
(0.50 g, 1.1 mmol), TBAI (0.41 g, 1.1 mmol), and 18-crown-6
(0.29 g, 1.1 mmol) in THF (50 ml) under argon, NaH
(0.05 g, 1.2 mmol, 60% in mineral oil) was added. The
Chirality DOI 10.1002/chir

CHEAP AND LONG-LIFE REUSABLE POLYMER FOR ASYMMETRIC CATALYSIS
mixture was ™stirred for 15 min and then Merrifield
StratoSpheres
(4-(chloromethyl)polystyrene,
fꢀ = 2.0 mmol gÀ1, 1% cross-linked with 1,4-divinylbenzene,
100–200 mesh, 5b) (0.56 g, 1.1 mmol) was added. After stir-
ring at r.t. for 6 days, the solvent was eliminated by filtration,
and the filtrate was washed with CH2Cl2 (50 ml), water
(50 ml), and methanol (50 ml); 6b (0.72 g) was isolated as a
white solid. 1H NMR (500 MHz, CDCl3, gel phase): d = 7.06
(m, 15H), 6.56 (m, 10H), 4.99–2.45 (m, 11H), 2.36–0.32 ppm
(m, 35H); 13C NMR (175 MHz, CDCl3, gel phase): d = 173.6,
145.7, 128.1, 71.9, 61.5, 53.5, 50.7, 48.3, 44.9, 40.5, 29.7, 27.1,
22.0 ppm. Elemental analysis: found (%): C 80.13, H 7.77, N
2.41 (f=0.86mmolgÀ1).
Synthesis of 6a. By following the same procedure used for
the synthesis of 6b, 4 (0.10 g, 0.22 mmol) was reacted wÀit1h
Merrifield resin (4-(chloromethyl)polystyrene, fꢀ =1.5–2.0 mmol g
,
1% cross-linked with 1,4-divinylbenzene, 100–200 mesh, 5a)
(0.15 g, 0.22–0.30 mmol); 6a (0.20 g) was isolated as a white
solid. Elemental analysis: found (%): C 79.05, H 7.62, N 2.28
(f = 0.82 mmol gÀ1).
Fig. 1. Reaction vessel for the multicycle process. Reaction: [a] Ar outlet,
[b] reacting mixture, [c] Ar inlet. Work up: [a] Air inlet, [b] heterogeneous
mixture to be filtered, or functional polymer to be washed or dried, [c] outlet
connected to the vacuum system.
Synthesis of 6c. Following the same procedure used for
the synthesis of 6b, 4 (0.10 g, 0.22mmol) was reacted with
Wang chlorinated resin ([4-(chloromethyl)phenoxymethyl]
polystyrene, fꢀ = 0.5–1.0 mmol gÀ1, 1% cross-linked with 1,4-
divinylbenzene, 100–200 mesh, 5c) (0.45 g, 0.22–0.44 mmol);
6c (0.41 g) was isolated as a white solid. Elemental analysis:
found (%): C 81.83, H 7.13, N 0.92 (f=0.33mmolgÀ1).
and solvent evaporation under vacuum. The obtained residue
was dissolved in HPLC-grade hexanes and submitted to anal-
ysis by GC and chiral HPLC.
The used polymer kept in the reaction vessel was then
recycled for the next reaction by washing with aqueous HCl
(3 M, 3 Â 5 ml), water (3 Â 5 ml), acetone (3 Â 5 ml), and meth-
anol (3 Â 5 ml), and final drying under vacuum.
ENANTIOSELECTIVE ETHYLATION OF ALDEHYDES
General Procedure for The Homogeneous Enantioselective
Ethylation of Aldehydes
Into an argon-purged 10-ml round-bottom flask provided
with a magnetic stirrer and a septum and containing the
ligand (0.02 mmol), diethylzinc solution (1.0 M in hexanes,
1.10 mmol) was added at room temperature. The mixture
was stirred at r.t. for 5 min. After that, the corresponding alde-
hyde (1.0 mmol) was added and the reaction mixture stirred
at r.t. for 1 h. Then, the reaction was quenched by the addi-
tion of aqueous HCl (3 M, 3 ml). The resulting mixture was
extracted with ether (3 Â 3 ml). The combined organic
layers were submitted to celite filtration and solvent evapora-
tion. The obtained residue was dissolved in HPLC-grade
hexanes and submitted to analysis by GC and chiral HPLC.
RESULTS AND DISCUSSION
Although the activity of ligand 2 in enantioselective ethyla-
tion of benzaldehyde has been recently reported by us,33 the
selection of this ligand, as key moiety for the construction of
the desired long-life reusable polymer, makes necessary a
comparison study of such activity in relation with the activity
of other well-known homogeneous ligands, which have been
also used in reusable polymers. Thus, we investigated the
efficiency of 233 in comparison with 3-exo-(morpholino)isobor-
neol (3), a known very active amino-alcohol ligand developed
by Nugent.35 As a test reaction, we chose the ethylation of
benzaldehyde, which was performed with a low catalyst loading
(0.5% mol eq) and a short reaction time (0.5 h) for detecting
efficiency differences (Table 1). Ligand 1,32 the first-generation
analogue of 2, was also submitted to this study to detect
possible efficiency differences when compared with 1. We
used the E (defined as E = TOFÁee, TOF being the turnover
frequency) as a convenient one for measuring the efficiency
of the tested ligands. This parameter is interesting to our pur-
pose because it weights not only enantioselectivity (ee) but also
reaction rate (TOF). On the basis of E, the efficiency of hydro-
xyamide 2 proved to be 0.72 times the efficiency of amino alco-
hol 3 (Table 1, relative-E column), which is very high, taking
into account the structural differences of the functional groups
involved in both ligands (note the higher zinc-chelating charac-
ter of an amine group when compared with an amide one).
Additionally, 2 was probed to be more efficient than 1 (see
Table 1), as it was expected because of the higher conforma-
tional flexibility of 2 when compared with 1.33
General Procedure for The Multicycle Heterogeneous
Enantioselective Ethylation of Benzaldehyde
Into the reaction vessel shown in Figure 1, with an argon
flow, provided with a magnetic stirrer and containing 6b
(0.08 mmol), toluene (2 ml) was added. The argon flow was
passed continuously through the reaction mixture from
below the fritted disc to keep the reaction mixture from falling
through the disc to the flask. The polymer was swollen by
stirring for 0.5 h. Then, diethylzinc solution (1.5 M in toluene,
3.0 mmol) was added at room temperature. The mixture was
stirred at r.t. for 5 min. After that, benzaldehyde (2.0 mmol)
was added and the reaction mixture was stirred at r.t. for
20 h. Once the reaction was finished, the argon flow was inter-
rupted and the reaction mixture filtered under vacuum. The
obtained filtrated solution was quenched by the addition of
aqueous HCl (3 M, 3 ml), and the obtained layers separated.
The aqueous layer was extracted with ether (3 Â 3 ml) and
the combined organic layers submitted to celite filtration
Chirality DOI 10.1002/chir

LAS CASAS ENGEL ET AL.
TABLE 1. Ligand efficiency in enantioselective ethylation of benzaldehydea
Ligand
Yield (%)b
ee (%)c
TOF(hÀ1
)
E
Relative E
1
2
3
50
71
98
88 (R)
92 (R)
92 (R)
200
284
392
17600
26182
36064
0.49
0.72
1.00
aBenzaldehyde, 1 mol eq; Ligand, 0.5% mol eq; Et2Zn (1 M in hexanes), 1.1 mol eq; T, real time; t, 0.5 h.
bDetermined by gas chromatography.
cDetermined by chiral high-performance liquid chromatography.
Once the good efficiency of hydroxyamide 2 is established,
we tested its versatility for the ethylation of a small battery of rep-
resentative aldehydes (Table 2). As shown in Table 2, ligand 2
was able to produce the asymmetric ethylation of aliphatic and
aromatic aldehydes with different substitution patterns.
Once the election of 2 is supported as key moiety for
designing the desired recyclable (easily filterable) functional
polymers, we proceeded to obtain such polymers. For this
purpose, we decided to graft 2 onto polystyrene (PS), on
the basis of the known good swollen properties of this poly-
mer by the action of several organic solvents used in organo-
zinc reactions (i.e., toluene). The polymer swelling factor is a
key parameter in catalyst heterogenization because a good
swelling factor reduces the undesired diffusion effect
produced by the heterogenization.30 For grafting 2 onto PS, we
prepared 4 as a conveniently functionalized analogue of 2. This
ligand could be easily and selectively linked to different
chloromethylated PS (5), by a Williamson reaction involving
its less-hindered central hydroxyl group, to generate 6
(Scheme 1). Moreover, the central location of such reacting hy-
droxyl group of 4, as well as its remote disposition from the cat-
alytic region (zinc-dialkoxide complex),32,33 makes it possible
to keep the basic structural characteristics of the homogeneous
parent ligand 2 after the immobilization (tail-tied-ligand
strategy).36
Ligand 4 was straightforwardly obtained from (1S)-ketopinic
acid and 1,4-diazepan-6-ol following the two-step synthetic
strategy we described previously for the preparation of its
analogue 2,33 using 1,4-diazepan-6-ol34,37 instead of 1,4-diaze-
pan. The preparation of starting 1,4-diazepan-6-ol was opti-
mized as previously commented in the Experimental section.
Before preparing 6, the effect of the benzyloxyl linkers on
the catalytic activity of the hydroxyamide-based centers was
tested. For this purpose, we prepared ligand 7, as a homogenous
model of 6, to be compared with its non-benzyloxylated analogue
2. The preparation of 7 was also realized from 4 via a Williamson
reaction as shown in Scheme 1. As expected, the etherification
was highly selective, involving only the central less-hindered
hydroxyl group of 4, and other possible ethers being
undetected. Benzaldehyde ethylation was used as a test
reaction for the comparison study between 2 and 7. Gratifyingly,
the measured activity of 7 (97% yield and 93% ee, by using
2% mol eq of ligand, 1.1 mol eq of Et2Zn, r.t. and 1 h of
TABLE 2. Activity of homogeneous ligand 2 in enantioselective
ethylation of aldehydesa
Aldehyde
Yield (%)b
ee (%)c
benzaldehyde
98d
91
94
83
81
97
95
89
93d
92
93
92
92
92
74f
80f
2-chlorobenzaldehyde
4-chlorobenzaldehyde
2-methylbenzaldehyde
4-methylbenzaldehyde
2-methoxybenzaldehyde
hexanalf
cyclohexanecarbaldehydef
aAldehyde (RCHO), 1.0 mol eq; 2, 2% mol eq; Et2Zn (1 M in hexanes): 1.1 mol
eq; T, real time; t, 1 h.
bDetermined by gas chromatography.
cDetermined by chiral high-performance liquid chromatography (major enan-
tiomer: R in all cases).
dData from Ref. 11.
e2, 5% mol eq; t, 2 h.
Scheme 1. Preparation of functionalized polymers 6 based on (polysty-
rene) PS and homogeneous benzoyloxylated analogue 7.
fAnalysis of the corresponding alcohol benzoates.
Chirality DOI 10.1002/chir

CHEAP AND LONG-LIFE REUSABLE POLYMER FOR ASYMMETRIC CATALYSIS
reaction) resulted practically identical to the activity of 2 under
To validate the heterogenization of ligand 2 as polymer 6b,
we proceeded to realize a comparison study on the scope of
both in enantioselective ethylation of aldehydes. Satisfyingly,
no noticeable differences between 2 and 6b, beyond the
logical reaction rate decreasing for the grafted polymer, were
found (cf., Table 4 and 2).
Once 6b was confirmed as a functional polymer based on a
chemically robust chiral hydroxyamide, we proceeded to test
its stability in an asymmetric multicycle process. The chosen
test reaction was the ethylation of benzaldehyde. In each
cycle, the reaction was finalized by standard acid quenching
(diluted HCl) and the functional polymer recovered by simple
filtration (see Experimental section).
the same conditions.33
The preparation of hydroxyamide-grafted polymers of the
type of 6 was optimized to improve the level of ligand loading
(f) in relation with the polymer activity (Table 3). As starting
chloromethylated PS 5, we used a Merrifield resin with a
chlorine loading (fꢀ) of 1.5–2.0 mmol gÀ1 (5a), Merrifield
StratoSpheres™ with fꢀ = 2.0 mmol gÀ1 (5b), and a Wang resin
with fꢀ = 0.5–1.0 mmol gÀ1 (5c).
A moderate 4 loading (f) in polymer 6, obtained by using a
stoichiometric amount of sodium hydride for the grafting
reaction, was enough to reach a good activity (see entries 3
and 12 of Table 3). A higher ligand loading, achieved by rising
the grafting time, improved the polymer activity (cf., entries
4 and 3). On the other hand, higher loadings, obtained by
using an excess of sodium hydride, diminished noticeably the
activity of the corresponding 6 (cf., entries 2 and 3). This fact
can be explained by a loss of highly active catalytic moieties
involving the key bis(hydroxyamide)-chelated zinc-dialkoxyde
structure32,33 because of an extra grafting of some ligand
moieties onto the polymer by more than one hydroxyl function.
Therefore, the use of a stoichiometric amount of base for the
Williamson grafting reaction is a key parameter for achieving
a good highly loaded active polymer.
Thus, the optimized polymer 6b, with a ligand loading of
0.86 mmol gÀ1, was employed in 20 consecutive enantioselec-
tive additions of diethylzinc to benzaldehyde (Fig. 2). The
TABLE 4. Activity of 6b in enantioselective ethylation of aldehydesa
Aldehyde
Yield (%)b
ee (%)c
benzaldehyde
97
91
82
81
82
92
96
92
93
92
90
90
89
84
76d
76d
Optimization of the asymmetric-reaction conditions was car-
ried out for the highest-loaded polymer 6a (f = 0.82 mmol gÀ1
)
2-chlorobenzaldehyde
4-chlorobenzaldehyde
2-methylbenzaldehyde
4-methylbenzaldehyde
2-methoxybenzaldehyde
hexanal
(Table 3, entries 4–9). The highest chemical yield and enantios-
electivity were reached when 1.5 mol eq of diethylzinc and
4% mol eq of supported ligand were used (entry 8). The optimi-
zation was followed by a study on the influence of the polymeric
matrix on both ligand grafting and catalytic activity (entries 8,
10, and 12). This study lets us choose grafted polymer 6b
(f = 0.72 mmol gÀ1) as the most privileged (entry 10). Finally, a
higher ligand loading in 6b (f = 0.86g molÀ1), which optimizes
the mass of polymer to be used in the asymmetric reaction,
was achieved by increasing the grafting time (cf., entries 11
and 10).
cyclohexanecarbaldehyde
aAldehyde (RCHO), 1.0 mol eq; 6b (f = 0.86 mmol gÀ1), 4% mol eq; Et2Zn (1.5 M
in toluene), 1.5 mol eq; T: room temperature; t, 20 h.
bDetermined by gas chromatography.
cDetermined by chiral high-performance liquid chromatography (major enantio-
mer: R in all cases).
dDetermined by analysis of the corresponding alcohol benzoates.
TABLE 3. Optimization of 6 preparation in function of its activity in enantioselective ethylation of benzaldehyde (see reaction in
Table 1, ligand = 6)
6 preparationa
Benzaldehyde ethylationb
Et2Zn (mol eq)
c
Entry
Starting 5
NaH (mol eq)
t (d)
f (mmol gÀ1
)
6 typology (% mol eq)
Yield (%)d
ee (%)e
1f
2
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5c
3.0
3.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
6
3
2
4
4
4
4
4
4
4
6
4
0.20
0.69
0.44
0.82
0.82
0.82
0.82
0.82
0.82
0.72
0.86
0.33
6a (2)
6a (2)
6a (2)
6a (2)
6a (1)
6a (4)
6a (8)
6a (4)
6a (4)
6b (4)
6b (4)
6c (4)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
2.0
1.5
1.5
1.5
18
23
83
95
82
95
85
97
97
97
97
97
63
57
93
90
87
90
90
93
92
94
93
90
3
4
5
6
7
8
9
10
11
12
a4, 1.0 mol eq; 5, 1.0 mol eq (for calculating the amount of 5a and 5c, the lowest value of the fꢀ interval was considered); tetrabutylammonium iodide (TBAI), 1.0 mol
eq; 18-Crown-6, 1.0 mol eq; solvent, tetrahydrofuran; T, room temperature.
b1.5 M Et2Zn in toluene. T, room temperature; t, 20 h.
cDetermined by elemental analysis.
dDetermined by gas chromatography.
eDetermined by chiral high-performance liquid chromatography (major enantiomer: R in all cases).
fWithout adding TBAI/18-crown-6.
Chirality DOI 10.1002/chir

LAS CASAS ENGEL ET AL.
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Chirality DOI 10.1002/chir