Enhanced cooperativity in hydrolytic kinetic resolution of epoxides using poly(styrene) resin-supported dendronized co-(salen) catalysts

Article abstract of DOI:10.1002/adsc.200800175

Excellent enantioselectivities and isolated yields have been achieved for the hydrolytic kinetic resolution of epoxides using a resin-supported dendronized R,R-(salen)Co catalyst with catalyst loadings as low as 0.04 mol%, the lowest metal loadings of any heterogeneous resin-supported (salen)Co catalyst reported to date. In addition, the supported catalysts can be recycled and reused with comparable enantioselectivities. It is hypothesized that the high catalytic activity can be attributed to the flexible linker and the dendronized framework supporting the (salen)Co moieties on the resin thereby promoting cooperativity between two metal centers. This work opens up new opportunities for the design of highly active resin-supported catalysts that catalyze transformations through a bimetallic pathway.

Full text of DOI:10.1002/adsc.200800175

FULL PAPERS
DOI: 10.1002/adsc.200800175
Enhanced Cooperativity in Hydrolytic Kinetic Resolution of
Epoxides using Poly(styrene) Resin-Supported Dendronized
G
Co-(Salen) Catalysts
Poorva Goyal,a,b Xiaolai Zheng,b and Marcus Wecka,b,*
a
Department of Chemistry and Molecular Design Institute, New York University, New York, NY 10003-6688, USA
Fax : (+1)-212-260-7905; phone: (+1)-212-992-7968; e-mail: marcus.weck@nyu.edu
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA
b
Received: March 22, 2008; Published online: July 28, 2008
Abstract: Excellent enantioselectivities and isolated linker and the dendronized framework supporting
yields have been achieved for the hydrolytic kinetic the (salen)Co moieties on the resin thereby promot-
resolution of epoxides using
a resin-supported ing cooperativity between two metal centers. This
dendronized R,R-(salen)Co catalyst with catalyst work opens up new opportunities for the design of
loadings as low as 0.04 mol%, the lowest metal load- highly active resin-supported catalysts that catalyze
ings of any heterogeneous resin-supported (salen)Co transformations through a bimetallic pathway.
catalyst reported to date. In addition, the supported
catalysts can be recycled and reused with comparable
enantioselectivities. It is hypothesized that the high Keywords: asymmetric catalysis; cobalt; epoxides;
catalytic activity can be attributed to the flexible hydrolytic kinetic resolution; salen ligand
Introduction
this manuscript we present such a strategy and de-
scribe a recyclable and resin supported (salen)Co cat-
Recent years have seen a tremendous growth in the alyst system that is highly active and selective for the
development of methods for heterogenizing homoge- hydrolytic kinetic resolution of epoxides with signifi-
neous catalysts in an attempt to combine the advan- cantly lower (up to 80%) catalyst loadings.
tages of both homogeneous and heterogeneous cata-
Chiral metallosalen catalysts discovered by Jacob-
lysts.[1–7] This is mainly motivated by the need of the sen and Katsuki[15–19] have emerged as a powerful and
industry for libraries of enantiomerically pure com- ubiquitous family of catalysts for numerous asymmet-
pounds as potential leads in drug discovery and to ric organic transformations including the epoxidation
reduce metal contamination in products and the of olefins,[20,21] the hydrolytic kinetic resolution of ep-
waste stream.[8] Among the methods of choice for het- oxides,[22–28] other epoxide ring-opening reactions,[29]
erogenizing homogeneous catalysts is the covalent at- hetero Diels–Alder reactions,[30] and conjugate addi-
tachment of catalysts to insoluble organic polymers or tion reactions.[31,32] Among these reactions, the hydro-
resins.[1,9] The advantages of using insoluble polymer lytic kinetic resolution (HKR) of racemic epoxides by
supports include easy separation of the metal catalysts (salen)Co catalysts is of particular interest, since
from the products, easy recyclability of the oftentimes enantiopure epoxides are versatile intermediates for
expensive metal catalysts by simple filtration, as well asymmetric organic syntheses in the pharmaceutical
as the potential use of resin-supported catalysts in and fine chemical industries. A variety of groups have
continuous flow processes.[5,10] One major limitation reported the immobilization of (salen)Co catalysts on
to the use of resin-supported catalysts is the limited polymer supports or membranes,[25–28,33–46] but only
tunability of the resin-supported materials in regard two reports[45,46] describe the use of insoluble polymer
to activity and selectivity. In most cases, resin-support- resins as supports. However, these resin-supported
ed catalysts are less active and selective than their ho- catalysts require high catalyst loadings in HKR when
mogeneous counterparts.[11–14] Therefore, new strat- compared to soluble and optimized polymer-support-
egies to immobilize catalysts on insoluble polymer ed catalysts.[26,40]
supports that allow for the tuning of catalytic activity
It has been postulated that the HKR of epoxides
and enantioselectivity as well as for easy recyclability using (salen)Co catalysts follows a bimetallic pathway
of the catalyst for repeated re-use are warranted. In where two catalytic centers with proper proximity are
1816
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1816 – 1822

Enhanced Cooperativity in Hydrolytic Kinetic Resolution of Epoxides
FULL PAPERS
Figure 1. Schematic representation of the resin-supported catalyst design and structure.
needed for the catalysis to occur.[47–51] Examples of sized in 74% yield by reacting an aminotriester den-
promoting high local concentrations of (salen)Co for dron[52] with succinic anhydride using pyridine as the
beneficial effects on catalytic activity for HKR have solvent. This step was carried out to create a long
been shown previously on dendrimers,[38] poly- spacer between the dendron branch points and the
mers[25,26,41–44] and silica.[49] In contrast to soluble sup- resin surface thereby installing a higher degree of
ports, it is more difficult to generate cooperative acti- flexibility to the systems. Dendron linker 3 was then
vation on a solid material due to the absence of elab- reacted with pentafluorophenol and DCC to obtain
orate control over the proper proximity and relative the activated ester dendron 4 in 56% yields which
conformation of active centers on a surface, porous was then coupled with aminomethylated poly
material or insoluble polymer.[49] In this contribution, resin (1.4 mmolgÀ1 of amine loading) to obtain the
we present a new strategy to address these shortcom- dendron linker immobilized poly(styrene) resin 5. The
ings by employing a dendron to immobilize (salen)Co immobilization was also supported by appearance of
catalysts on the resin (Figure 1).
a new signal in 13C solid-state NMR spectra at
The three components of our system are a cross- 27 ppm, corresponding to the primary methyl carbons,
linked poly(styrene) resin, a dendron-based linker and at 80 ppm corresponding to the tert-butyl tertiary
and a (salen)Co catalyst. Poly(styrene) resin was an carbon. The tert-butyl ester groups on 5 were then hy-
(styrene)
AHCTREUNG
ACHTREUNG
AHCTREUNG
attractive choice for the backbone owing to its ease of drolyzed by stirring the resin in formic acid for 20 h.
commercial availability and its chemical inertness. The complete removal of protecting groups was iden-
Commercially available generation one dendron[52] ex- tified by the disappearance of the signals at 80 ppm in
hibits a branched structure and allows for the cova- the 13C solid-state NMR spectra and at 27.4 ppm cor-
lent attachment of up to three catalytic moieties responding to the primary methyl carbons. Elemental
along the dendron periphery, forcing them in close analysis of the oxygen content on 6 showed that
proximity to each other thereby promoting coopera- 0.899 mmolgÀ1 of the hydrolyzed dendron linker was
tive interactions between them. The resulting catalytic attached to the resin. Resin 6 was then coupled to
system upon activation shows high activities and salen ligand 2 using DCC and DMAP coupling condi-
enantioselectivities in the HKR of a variety of termi- tions to yield 7.
nal epoxides with catalyst loadings as low as 0.04
Formation of the product was supported by the ap-
mol% and allows for easy catalyst separation from pearance of a new signal in the 13C solid state NMR
product mixtures by simple filtration. The recovered spectrum at 119 ppm corresponding to the aromatic
À
À
catalysts are demonstrated to retain their activity and carbon next to the imine (C CH2 N=) and a broad
enantioselectivity upon recycling.
signal between 63–79 ppm corresponding to the over-
lap of signals of the cyclohexane carbon attached to
À À
À
À
the nitrogen ( C N) and the benzyl carbon ( CH2
O). Elemental analysis of the oxygen content corre-
sponded to an estimated[54] 90.1% of salen ligand cou-
Results and Discussion
The first step towards the synthesis of the resin-sup- pled to the terminal acid sites of the dendron on the
ported catalysts involved a one-pot synthesis of un- resin 7. Resin 7 was then metallated with cobalt(II)
symmetrical salen ligand 2, using a procedure devel- acetate tetrahydrate in methanol to yield target resin
oped by our group.[53] Resin catalyst 1 was then syn- 1. The loading of cobalt on resin 1 was determined by
thesized following the synthetic protocol outlined in elemental analysis of cobalt content to be
Scheme 1. Acid terminated dendron 3 was synthe- 0.561 mmolgÀ1.
Adv. Synth. Catal. 2008, 350, 1816 – 1822
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1817

Poorva Goyal et al.
FULL PAPERS
Scheme 1. Synthesis of poly(styrene) resin supported dendronized (salen)Co complexes.
N
With resin catalyst 1 in hand, we investigated its through the addition of excessive acetic acid. The oxi-
catalytic activity in the hydrolytic kinetic resolution dation process was followed by a color change from
(HKR) of a small library of epoxides (Table 1). Prior deep red to dark brown which is well documented in
to the catalysis, the Co(II) centers were oxidized to the literature.[25] We investigated the HKR of the fol-
the corresponding Co(III) active species under air lowing structurally diverse racemic epoxide sub-
G
Table 1. HKR of racemic terminal epoxides.
Entry
R
Catalyst Loading [mol%][a]
Time [h]
ee [%][b]
Yield [%][c]
1
2
3
4
CH2Cl
n-Bu
CH2OAllyl
Ph
0.04
0.04
0.04
0.06
3
2
7
22
>99
>99
>99
>99
46
47
45
40
[a]
Catalyst loadings are reported on a per cobalt basis relative to racemic epoxide.
Enantiomeric excess of the remaining epoxide was determined by GC analysis using a Chiraldex G-TA column.
Isolated yield based on racemic epoxides; theoretical maximum yield=50%.
[b]
[c]
1818
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1816 – 1822

Enhanced Cooperativity in Hydrolytic Kinetic Resolution of Epoxides
FULL PAPERS
Table 2. Recycling of resin catalyst 1 in the HKR of (rac)-1,2 epoxyhexane.
Cycle
Reaction Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
2
2
2
3
47
45
45
42
44
>99
>99
>99
98
3.5
98
[a]
Isolated yield based on racemic epoxides; theoretical maximum yield=50%.
Determined by GC analysis using a chiraldex G-TA column.
[b]
strates: (rac)-epichlorohydrin, (rac)-allyl glycidyl
In order to gain a better understanding of the cata-
ether, (rac)-1,2-epoxyhexane and (rac)-styrene oxide lytic properties of the activated resin catalyst 1, we in-
(Table 1). The resolution of (rac)-epichlorohydrin was vestigated the kinetics of recycling of 1 for the HKR
complete within 3 h at ambient temperature using of (rac)-1,2-epoxyhexane for the 1st, 3rd and 5th cycles.
0.04 mol% cobalt loading of 1, affording the (S)-enan- The kinetic experiments were carried out at room
tiomer in >99% ee and 46% isolated yield. Using the temperature with 0.7 equiv. of water and a catalyst
same catalyst loading, (rac)-allyl glycidyl ether was re- loading of 0.04 mol%. The kinetic plot of ee versus
solved in 7 h to give the remaining enantiomer in the reaction time is presented in Figure 2. Chiral GC
>99% ee and 45% isolated yields. The resolution of analysis showed that the reaction proceeded to com-
(rac)-1,2-epoxyhexane was complete in 2 h with the pletion in 2 h in the presence of resin-supported cata-
enantiomeric excess of the remaining epoxide higher lyst 1 for the 1st cycle. While the catalytic activity of
than 99% and 47% isolated yield. The resolution of the third recycle is comparable to the first cycle, it fell
the conjugate epoxide, (rac)-styrene oxide, took significantly for the fifth cycle. For the fifth cycle, the
nearly 22 h and a catalyst loading of 0.06 mol% for resolution took about 3.5 h to be completed with 98%
completion. While we still obtained the remaining ep- ee of the remaining epoxide. These results demon-
oxide with ees above 99% we isolated the enantiopure strate that the resin-supported catalyst can be recy-
epoxide with lower yields (40%) when compared to cled with comparable activities several times. Multiple
the other substrates (Table 1).
recycling events start to lower the activity of the sup-
A key motivation to develop resin-immobilized ported catalysts. Nevertheless, even after 5 catalytic
salen complex lies in its potential for easy recovery cycles 1 does indeed retain its excellent selectivity. To
and reuse for subsequent reactions. Therefore, we in- investigate whether the lower activities are a result of
vestigated the recyclability of 1 for the HKR reaction cobalt leaching off the resin into the solvent, we mea-
of (rac)-1,2 epoxyhexane. The HKR was carried out
using the reaction conditions described above. After
complete conversion of the S-epoxide to the corre-
sponding diol, we separated and purified the resin
easily from the reaction mixture by simple filtration
and washing with dichloromethane. The collected
resin catalyst 1 was reactivated with acetic acid and
then reused under strictly identical conditions as for
the first cycle. Using this protocol, we reused 1 in five
consecutive catalyses. The results of the recycling ex-
periment are shown in Table 2. While, the enantiose-
lectivity of the reused catalyst remained almost the
same after 5 cycles, the catalytic activity fell marginal-
ly. The reaction time had to be extended to 3.5 h for
the fifth cycle to obtain an ee of 98%. This result
clearly demonstrates the high recyclability of the resin
supported dendronized catalyst 1 for the HKR of rac-
emic epoxides.
Figure 2. Plot of ee vs. reaction time in the hydrolytic kinetic
resolution of rac-1,2 epoxyhexane.
Adv. Synth. Catal. 2008, 350, 1816 – 1822
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1819

Poorva Goyal et al.
FULL PAPERS
sured the cobalt loading of the resin before the first opens new opportunity for the design of efficient in-
(cobalt loading 3.31%) and after the fifth catalytic soluble polymer-supported catalysts for reactions that
cycle (cobalt loading 3.28%) using elemental analysis. involve bimolecular transition state or cooperative in-
The resin loadings for both experiments are identical teractions between catalytic centers and might poten-
within experimental errors suggesting that cobalt tially allow for the employment of such catalysts in
leaching is not the source of the decreased catalyst ac- continuous flow reaction chambers.
tivity.
The aforementioned data sufficiently demonstrate
that the new resin catalyst 1 possesses high activity, Experimental Section
enantioselectivity and reusability in the HKR of epox-
ides. As outlined in the introduction, two earlier re- General
ports have investigated the HKR of terminal epoxides
All starting materials were obtained from commercial sup-
pliers and used without further purification unless otherwise
with resin-supported (salen)Co catalysts.[45,46] In com-
parison to these known resin-supported (salen)Co
stated. Aminomethylated poly(styrene) resin with 50–100
A
mesh and 1.4 mmolgÀ1 loading was purchased from Nova-
biochem. All air- or moisture-sensitive reactions were per-
formed using oven-dried or flame-dried glassware under an
inert atmosphere of dry argon or nitrogen. Dichloromethane
was dried by passing through columns of activated copper
and alumina successively. Chlorobenzene was distilled under
an atmosphere of argon prior to use. DMF was purchased
anhydrous and dried further using 5 Š molecular sieves. An-
alytical thin layer chromatography (TLC) was performed
using Silica XHL pre-coated (250 mm thickness) glass-
backed TLC plates from Sorbent Technologies. Compounds
were visualized using UV light or phosphomolybdic acid
stains. Flash column chromatography was performed using
silica gel 60 Š (230–400 mesh) from Sorbent Technologies.
All NMR spectra were acquired on a Varian Mercury
400 MHz spectrometer (1H, 400.0 MHz; 13C, 100.6 MHz).
Chemical shifts are expressed in parts per million (d), cou-
pling constants (J) are reported in Hertz (Hz), and splitting
patterns are reported as singlet (s), doublet (d), triplet (t),
quartet (q), multiplet (m), or broad (br). Mass spectra were
recorded with a VG 7070 EQ-HF hybrid tandem mass spec-
trometer. Cross-polarization magic angle spinning (CP-
MAS) 13C solid-state NMR spectra were collected on a
Bruker DSX-500 MHz instrument. Samples were packed in
7 mm zirconia rotors and spun at 12.5 kHz. Typical 13C CP-
MAS parameters were 4000 scans, a 908 pulse length of 5ms
and a recycle time of 5 s. Enantiomeric excesses (ee) were
determined by capillary gas-phase chromatography (GC)
analysis on a Shimadzu GC 14 A instrument equipped with
an FID detector and a Chiraldex G-TA column (30 mꢂ
0.25 mm) with helium as a carrier gas.
complexes, 1 is significantly more active. Prior to this
work, the best resin supported Co-salen catalyst for
the HKR was a system reported by Jacobsen and co-
workers.[46] Their system is based on the direct immo-
bilization of Co
N
N
resins. In comparison to the reported study, the HKR
using catalyst 1 proceeds in significantly (up to 80%)
lower catalyst loadings (routinely 0.04 mol% were
used in this study while the lowest catalyst loadings
reported in the literature was 0.25 mol% catalyst) and
with shortened or equally fast resolution times for the
HKR of terminal epoxides. HKR of epichlorohydrin
took around 3 h with both the Jacobsenꢁs catalyst[46]
and our system, while the HKR of 1,2 epoxyhexane
took only 2 h with our catalyst 1 whereas the litera-
ture reported 4 h.[46] We suggest that the enhanced ac-
tivities of our resin-supported dendronized catalyst 1
as evidenced by the lower catalyst loadings and/or
shortened reaction times can be attributed to the
dendronized framework that potentially provides a fa-
vorable geometry for the two metal centers to interact
with each other by increasing the local catalyst con-
centration and facilitating the intramolecular bimetal-
lic transition state.
Conclusions
We have developed a poly(styrene) resin-supported
G
R,R-(salen)Co catalyst for the hydrolytic kinetic reso-
lution of terminal epoxides. The resin supported
dendronized catalyst shows high catalytic activities
Synthesis of Dendron 3
To a round-bottomed flask equipped with a magnetic stir
and enantioselectivities for the HKR of a library of bar was added aminotriester[52] (10 g, 0.024 mol), succinic
anhydride (3.61 g, 0.036 mol) and pyridine (48 mL). The re-
action mixture was stirred for 3 days following by the re-
moval of pyridine under vacuum. The reaction mixture was
redissolved in dichloromethane and washed with water and
brine. The collected organic layers were then dried with
MgSO4 and the solvent was removed under vacuum. The
product was purified by flash column chromatography (1:1
CH2Cl2/EtOAc) to afford the product as a white solid; yield:
9.2 g (74.1%). 1H NMR (400 MHz, CDCl3): d=1.44 (s,
27H), 1.97 (t, 6H, J=5.4 Hz), 2.22 (t, 6H, J=5.3 Hz), 2.49
terminal epoxides. Catalyst loadings as low as 0.04
mol% for the HKR resulted in ees often above 99%
with outstanding isolated yields. Such low catalyst
loadings, high ees, and excellent yields have not been
achieved before using any resin-supported (salen)Co
catalyst. We hypothesize that the high catalyst activity
stems from our unique dendron design that allows for
close proximity of two catalytic sites to each other. A
second advantage of the resin-supported catalysts is
that it can be recycled easily by filtration. This work (t, 2H, J=4.6 Hz), 2.67 (t, 2H, J=4.8 Hz), 6.63 (br s, 1H);
1820
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1816 – 1822

Enhanced Cooperativity in Hydrolytic Kinetic Resolution of Epoxides
FULL PAPERS
13C NMR (400 MHz, CDCl3): d=27.5, 29.7, 29.9, 30.2, 58.9,
Synthesis of Resin 1
80.9, 163.5, 171.9, 172.4; HR-MS (ESI+); m/z=516.31
(100.0%), calcd. for C26H45NO9 [M+1]: 515.31; anal. calcd.
for C26H45NO9: C 60.56, H 8.80, N 2.72; found: C 60.52, H
8.85, N 2.70.
Resin 7 (66.5 mg) was dissolved in CH2Cl2 (2 mL) in a vial
and stirred under an argon atmosphere (in glove box). A so-
lution of cobalt(II) acetate tetrahydrate (15.69 mg,
0.063 mmol) in methanol (2 mL) was added to the mixture
and the reaction mixture was stirred at room temperature
for 2–3 days. The color of the resin changed from yellow to
deep red. The reaction mixture was then diluted with meth-
anol, stirred for 4–5 mins and suction filtered on a frit wash-
ing continuously with methanol. The washed red resin mate-
rial was collected in a vial and dried over high vacuum to
give resin 1. Elemental analysis of cobalt showed that
0.561 mmolgÀ1 Co was loaded on the resin.
Synthesis of Dendron 4
To a round-bottomed flask equipped with a magnetic stir
bar and a reflux condenser was added 3 (2 g, 0.0038 mol),
DCC (1.03 g, 0.0050 mol) and pentafluorophenol (1.71 g,
0.0093 mol) in DMF (30 mL). The reaction mixture was
stirred at room temperature for 16 h, during which a precipi-
tate formed. The precipitate was filtered off and the DMF
was removed under vacuum at 558C to afford a crude mix-
ture. The product was then subjected to flash column chro-
matography (9:1 hexane/EtOAc) to afford 4 as a white
solid; yield: 1.50 g (56.8%). 1H NMR (400 MHz, CDCl3):
d=1.44 (s, 27H), 1.97 (t, 6H, J=5.4 Hz), 2.22 (t, 6H, J=
5.7 Hz), 2.56 (t, 2H, J=4.5 Hz), 3.10 (t, 2H, J=4.8 Hz), 6.23
(s, 1H); 13C NMR (400 MHz, CDCl3): d=27.5, 29.7, 29.9,
30.2, 58.9, 80.9, 138.1, 140.1, 142.4, 143.4, 163.5, 171.9, 172.4;
HR-MS (ESI+): m/z=682.30 (100.0%), calcd. for
C32H44F5NO9 [M+1]: 681.29; anal. calcd. for C32H44F5NO9:
C 56.38, H 6.51, N 2.05; found: C 56.42, H 6.49, N 2.01.
General Procedure for HKRof Terminal Epoxides
Resin catalyst 1 (3.56 mg, 0.002 mmol on basis of cobalt,
0.04 mol%) was dissolved in CH2Cl2 (1 mL) in a vial and
stirred. To this, 0.1 mL glacial acetic acid was added to acti-
vate the catalyst and the reaction mixture was stirred in
open air for 30 min. The reaction mixture was then evacuat-
ed under vacuum to remove excess acetic acid and dichloro-
methane and then pumped on high vacuum for 5 min. To
the resulting resin, the desired racemic epoxide (5 mmol)
was added along with chlorobenzene (50 mL, internal stan-
dard) and the vial was immersed in a water bath at room
temperature. Water (0.7 equiv., 63 mL) was then injected to
start the reaction. Samples (4 mL) were removed from the
reaction mixture at each designated time interval and dilut-
ed with anhydrous diethyl ether (3 mL) and passed through
a plug of silica gel in a pasteur pipet to remove water and
the resin catalyst. The conversion and the enantiomeric ex-
cesses were calculated by the GC analysis.
Synthesis of Resin 6
Aminomethylated
poly
A
HL
(Novabiochem,
1.4 mmolgÀ1, 300 mg, 0.42 mmol), 4 (572.2 mg, 0.84 mmol)
and anhydrous DMF (10 mL) were charged to a Schlenk
flask and stirred at 1008C in an argon atmosphere for 20 h.
Filtration and rinsing with anhydrous DMF and CH2Cl2 fol-
lowed by drying under high vacuum overnight yielded the
orange-colored resin 5. Resin 5 (378 mg) was suspended in
95% HCOOH (12 mL) and stirred at room temperature for
20 h. The reaction mixture was then filtered though a frit
and washed with DMF and CH2Cl2. The solid was dried on
high vacuum to yield the orange resin 6. Elemental analysis
of oxygen showed that 0.899 mmolgÀ1 hydrolyzed linker was
immobilized on the resin.
General Procedure for Recycling of Resin Catalyst 1
The used resin catalyst 1 was separated and purified from
the reaction mixture by filtration over a fine frit and repeat-
ed washing with dichloromethane (5–10 mL). The collected
resin catalyst 1 was then reused for HKR under strictly
identical conditions as for the first cycle.
Synthesis of Resin 7
Resin
6 (87 mg, 0.078 mmol of dendron) and CH2Cl2
(15 mL) were added under an atmosphere of argon to a
flame-dried round-bottomed flask equipped with a magnetic
stir bar. Then, the salen ligand 2[53] (306.2 mg, 0.588 mmol),
DCC (242.6 mg, 1.176 mmol) and DMAP (86.2 mg,
0.705 mmol) were added to the reaction mixture. The reac-
tion mixture was allowed to reflux for 3 days. The solvent
was removed under vacuum. The resin was suspended in
DMF and centrifuged for multiple times, each time remov-
ing the supernatant and re-suspending the resin in a fresh
DMF solution to remove the urea adducts and excess re-
agents. The resin was then filtered through a medium
coarseness frit and washed with excess dichloromethane,
DMF and methanol. The yellow solid was collected and
dried on high vacuum for 2 days to give resin material 7.
Acknowledgements
This research was supported by the U.S. DOE Office of
Basic Energy Sciences through the Catalysis Science Contract
No. DE-FG02–03ER15459. MW gratefully acknowledges a
Camille Dreyfus Teacher/Scholar Award and an Alfred P.
Sloan Fellowship.
References
[1] C. A. McNamara, M. J. Dixon, M. Bradley, Chem. Rev.
2002, 102, 3275.
[2] Q.-H. Fan, Y.-M. Li, A. S. C. Chan, Chem. Rev. 2002,
102, 3385.
[3] P. McMorn, G. J. Hutchings, Chem. Soc. Rev. 2004, 33,
108.
Adv. Synth. Catal. 2008, 350, 1816 – 1822
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1821

Poorva Goyal et al.
FULL PAPERS
[4] O. Bourrier, A. K. Kakkar, Macromol. Symp. 2004, 209,
97.
[31] G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc. 2003,
125, 4442.
[5] N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199.
[6] D. Astruc, F. Lu, J. R. Aranzaes, Angew. Chem. 2005,
117, 8062; Angew. Chem. Int. Ed. 2005, 44, 7852.
[7] N. T. S. Phan, C. S. Gill, J. V. Nguyen, Z. J. Zhang,
C. W. Jones, Angew. Chem. 2006, 118, 2267; Angew.
Chem. Int. Ed. 2006, 45, 2209.
[8] D. J. Cole-Hamilton, Science 2003, 299, 1702.
[9] N. E. Leadbeater, M. Marco, Chem. Rev. 2002, 102,
3217.
[32] N. Madhavan, M. Weck, Adv. Synth. Catal. 2008, 350,
419.
[33] B. Gigante, A. Corma, H. Garcia, M. J. Sabater, Catal.
Lett. 2000, 68, 113.
[34] J. P. Nandy, E. N. Prabhakaran, S. K. Kumar, A. C.
Kunwar, I. Javed, J. Org. Chem. 2003, 68, 1679.
[35] G.-J. Kim, J.-H. Shin, Catal. Lett. 1999, 63, 205.
[36] L. Canali, D. C. Sherrington, Chem. Soc. Rev. 1999, 28,
85.
[10] C. Duanmu, I. Saha, Y. Zheng, B. M. Goodson, Y. Gao,
Chem. Mater. 2006, 18, 5973.
[11] B. M. Choudary, T. Ramani, H. Maheswaran, L. Pra-
shant, K. V. S. Ranganath, K. V. Kumar, Adv. Synth.
Catal. 2006, 348, 493.
[37] B. C. Das, I. Javed, Tetrahedron Lett. 1997, 38, 2903.
[38] R. Breinbauer, E. N. Jacobsen, Angew. Chem. 2000,
112, 3750; Angew. Chem. Int. Ed. 2000, 39, 3604.
[39] M. Beigi, S. Roller, R. Haag, A. Liese, Eur. J. Org.
Chem. 2008, 2135–2141.
[12] Q-H. Fan, Y-W. Li, A. S. C. Chan, Chem. Rev. 2002,
102, 3385.
[13] C. Baleizao, H. Garcia, Chem. Rev. 2006, 106, 3987.
[14] M. D. Angelino, P. E. Laibinis, Macromolecules 1998,
31, 7581.
[40] B. M. Rossbach, K. Leopold, R. Weberskirch, Angew.
Chem. 2006, 118, 1331; Angew. Chem. Int. Ed. 2006, 45,
1309.
[41] Y. Song, X. Yao, H. Chen, C. Bai, X. Hu, Z. Zheng,
Tetrahedron Lett. 2002, 43, 6625.
[15] A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc. 2005,
127, 62.
[42] J. M. Ready, E. N. Jacobsen, J. Am. Chem. Soc. 2001,
123, 2687.
[16] J. M. Ready, E. N. Jacobsen, J. Am. Chem. Soc. 2001,
123, 2687.
[17] M. S. Taylor, E. N. Jacobsen, Proc. Natl. Acad. Sci.
USA 2004, 101, 5368.
[43] S. Aerts, H. Weyten, A. Buekenhoudt, L. E. M. Gevers,
I. F. J. Vankelecom, P. A. Jacobs, Chem. Commun. 2004,
710.
[44] Y. Song, H. Chen, X. Hu, C. Bai, Z. Zheng, Tetrahe-
dron Lett. 2003, 44, 7081.
[18] R. Irie, K. Noda, Y. Ito, T. Katsuki, Tetrahedron Lett.
1991, 32, 1055.
[45] W. Solodenko, G. Jas, U. Kunz, A. Kirschning, Synthesis
[19] E. N. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker, L.
Deng, J. Am. Chem. Soc. 1991, 113, 7063.
[20] W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen,
J. Am. Chem. Soc. 1990, 112, 2801.
2007, 583.
[46] D. A. Annis, E. N. Jacobsen, J. Am. Chem. Soc. 1999,
121, 4147.
[47] G. M. Sammis, H. Danjo, E. N. Jacobsen, J. Am. Chem.
Soc. 2004, 126, 9928.
[21] R. Irie, K. Noda, Y. Ito, N. Matsumoto, T. Katsuki, Tet-
rahedron Lett. 1990, 31, 7345.
[48] J.-A. Ma, D. Cahard, Angew. Chem. 2004, 116, 4666;
Angew. Chem. Int. Ed. 2004, 43, 4566.
[49] H. Yang, L. Zhang, L. Zhong, Q. Yang, C. Li, Angew.
Chem. 2007, 119, 6985; Angew. Chem. Int. Ed. 2007, 46,
6861.
[50] K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am.
Chem. Soc. 1996, 118, 10924.
[22] S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga,
K. B. Hansen, A. E. Gould, M. E. Furrow, E. N. Jacob-
sen, J. Am. Chem. Soc. 2002, 124, 1307.
[23] J. M. Keith, J. F. Larrow, E. N. Jacobsen, Adv. Synth.
Catal. 2001, 343, 5.
[24] M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen,
Science 1997, 277, 936.
[25] X. Zheng, C. W. Jones, M. Weck, Chem. Eur. J. 2006,
12, 576.
[26] X. Zheng, C. W. Jones, M. Weck, J. Am. Chem. Soc.
2007, 129, 1105.
[51] L. P. C. Nielsen, C. P. Stevenson, D. G. Blackmond,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 1360.
[52] Available commercially from Frontier Scientific.
[53] M. Holbach, X. Zheng, C. Burd, C. W. Jones, M. Weck,
J. Org. Chem. 2006, 71, 2903.
[27] M. Holbach, M. Weck, J. Org. Chem. 2006, 71, 1825.
[28] X. Zheng, C. W. Jones, M. Weck, Adv. Synth. Catal.
2008, 350, 255.
[29] L. E. Martinez, J. L. Leighton, D. H. Carsten, E. N. Ja-
cobsen, J. Am. Chem. Soc. 1995, 117, 5897.
[30] S. E. Schaus, J. Brnalt, E. N. Jacobsen, J. Org. Chem.
1998, 63, 403.
[54] The organic loading of salen on resin was determined
from the elemental analysis of oxygen content by as-
suming two 2 unique oxygen for each salen ligand
added. The number of acid sites after hydrolysis was
determined by assuming 2 unique oxygens for each
acid present. Error range reported on elemental analy-
sis is + or À 10%.
1822
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1816 – 1822