Engineering polymer-enhanced bimetallic cooperative interactions in the hydrolytic kinetic resolution of epoxides

Article abstract of DOI:10.1002/adsc.200700339

Through systematic variations of the length of oligo(ethylene glycol)-based linkers and the catalyst density of poly(styrene)-supported cobalt-salen catalysts, we have elucidated an optimal catalyst flexibility and density of polymeric Co-salen catalysts for the hydrolytic kinetic resolution (HKR) of racemic terminal epoxides that follows a bimetallic cooperative pathway. The optimized polymeric catalyst brings the two cooperative Co-salen units to a favorable proximity efficiently and hence displays significantly improved catalytic performance in the HKR compared with its monomeric small molecule analogue. Complex Co(5b), representing the most active poly(styrene)-supported HKR catalyst known so far, can effect the resolution of a variety of epoxides to reach ≥ 98 % ee in 6-24 h with a low cobalt loading of 0.01-0.1 mol%.

Full text of DOI:10.1002/adsc.200700339

FULL PAPERS
DOI: 10.1002/adsc.200700339
Engineering Polymer-Enhanced Bimetallic Cooperative Interac-
tions in the Hydrolytic Kinetic Resolution of Epoxides
Xiaolai Zheng,a Christopher W. Jones,a,b and Marcus Wecka,c,*
a
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
Molecular Design Institute and Department of Chemistry, New York University, New York, NY 10003, USA
b
c
Fax : (+1)-212-995-4895; e-mail: marcus.weck@nyu.edu
Received: July 10, 2007; Revised: November 6, 2007; Published online: January 4, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Through systematic variations of the significantly improved catalytic performance in the
length of oligo(ethylene glycol)-based linkers and HKR compared with its monomeric small molecule
the catalyst density of poly
cobalt-salen catalysts, we have elucidated an optimal active poly
ACHTREUNG
AHCTREUNG
catalyst flexibility and density of polymeric Co-salen so far, can effect the resolution of a variety of epox-
catalysts for the hydrolytic kinetic resolution (HKR) ides to reach ꢀ98% ee in 6–24 h with a low cobalt
of racemic terminal epoxides that follows a bimetal- loading of 0.01–0.1 mol%.
lic cooperative pathway. The optimized polymeric
catalyst brings the two cooperative Co-salen units to Keywords: asymmetric catalysis; cobalt; hydrolytic
a favorable proximity efficiently and hence displays kinetic resolution; poly(styrene); salen ligands
G
Introduction
The hydrolytic kinetic resolution (HKR) of racemic
terminal epoxides with Co
(III)-salen catalysts,[5,6] first
AHCTREUNG
The immobilization of homogeneous catalysts onto in- studied by Jacobsen,[7] represents a pertinent example
soluble or soluble supports has been practiced inten- of such a dual activation pathway (Figure 1). During
sively in the past two decades, leading to a promising the catalytic transformation, one cobalt center acti-
avenue for the separation and recycling of oftentimes vates an epoxide whereas the other binds to the hy-
expensive transition metal-containing catalysts.[1,2] droxide. A nucleophilic attack of the hydroxide to the
While the relationship between catalytic properties less sterically hindered a-carbon of the epoxide af-
and support structures has been investigated for a fords the key bimetallic intermediate that undergoes
spectrum of reactions involving a single catalytic hydrolysis to regenerate the active catalytic species.
site,[1,2] approaches to immobilized catalysts tailored This cooperative bimetallic mechanism has been sup-
for transformations operating via a bimetallic or bi- ported by the observation of a second-order depend-
molecular cooperative mechanism are largely absent ence of the reaction rate on the Co-salen species.[8] In-
in the literature. This is important since a wide variety corporation of Co-salen units into oligomeric,[9,10]
of catalytic transformations have been found to pro-
ceed through a dual activation pathway, namely, the
activation of two substrates (e.g., an electrophile and
a nucleophile) simultaneously by two catalytic species
in the transition state of the rate-determining step.[3,4]
Besides allowing for facile removal of the usually
toxic metal species as well as the possibility for recy-
cling, immobilization of a dual activation catalyst
holds the potential of providing a favorable proximity
of the two cooperative catalytic species that may sub-
stantially promote the activity and/or selectivity of
the resulting catalyst in comparison with its non-sup-
ported small molecule analogue.
Figure 1. Jacobsen Co-salen catalysts (A) and key bimetallic
intermediates in the HKR of epoxides (B).
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255

Xiaolai Zheng et al.
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Results and Discussion
The styryl-substituted salen ligands 4a–d were pre-
pared from inexpensive starting materials as de-
scribed in Scheme 1. Etherifications of styrene precur-
sors 1a–d and 3-tert-butyl-5-chloromethyl-2-hydroxy-
benzaldehyde were effected by a weak base, sodium
bicarbonate, under solvent-free conditions to give oli-
go(ethylene glycol)-bridged styrenic salicyl aldehydes
2a–d. A one-pot protocol, developed in our group[15]
for the synthesis of unsymmetrical salen ligands, was
employed to condense the HCl-protected diamine
315[15,16] with 3,5-di-tert-butyl-2-hydroxybenzaldehyde
and 2a–d sequentially, affording 4a–d with various
lengths of oligo(ethylene glycol) linkers (m=0–3) in
72–78% overall yields.
Figure 2. A working model of supported Co-salen catalysts.
polymeric,[11,12] and dendritic frameworks[13] has led to
Free radical polymerizations of 4a–d were per-
enhanced catalytic performances in terms of both ac- formed at 808C for 24 h in the presence of 2.5 mol%
tivity and enantioselectivity. 2,2ꢁ-azobis(isobutyronitrile) as initiator. Homopoly-
However, general design criteria that can guide the mers 5a–d (Scheme 2) were obtained in 85–93% iso-
immobilization of dual activation catalysts have not lated yields after repeated precipitations from metha-
been developed, limiting the rational design of sup- nol. To elucidate the effect of salen density along the
ported catalysts that follow a bimetallic cooperative poly(styrene) support on the catalytic performance,
G
pathway. Whereas it is obvious that site-isolation[14] is copolymerization of 4b and styrene in a molar ratio
not a key variable, the role of parameters such as of 1/4 was carried out to yield copolymer 6. The co-
linker length and flexibility as well as catalyst density polymerization process was monitored by 1H NMR
remains unclear. In this contribution, we employ poly- spectroscopy. During the copolymerization, conver-
A
ferent lengths of oligo(ethylene glycol) linkers as ing a statistically randomly distributed nature of the
model catalysts in an approach to achieve optimal bi- resulting copolymer. Gel-permeation chromatography
metallic cooperative interactions in HKR reactions (GPC) showed that homopolymers 5a–d have number
(Figure 2). The goal is to establish structure-property average molecular weights (Mn) ranging from 14,100
relationships between catalysts, supports and linkers. to 18,400 whereas copolymer 6 has an Mn of 7,400
Poly(styrene) was the support of choice for this study (Table 1). The GPC traces of all polymers exhibited a
U
because it is highly stable and readily accessible.[2c] typical unimodal character with polydispersity indices
The oligo(ethylene glycol) derivatives were chosen as (PDI) ranging from 2.32 to 2.80.
linkers as a result of their flexibility, stability and hy-
The salen polymers 5a–d and 6 were metallated
drophilicity, as well as tunable lengths of the oxyethy- with cobalt(II) acetate tetrahydrate under nitrogen to
lene repeating unit.
give the corresponding Co(II)-(salen) complexes as
Scheme 1. Synthesis of styryl-substituted salen ligands.
256
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Scheme 2. Synthesis of poly(styrene)-supported Co(II)-(salen) complexes.
A
Table 1. GPC data of salen polymers 5a–d and 6.
[a]
Entry
Polymer
Mn
PDI[b]
1
2
3
4
5
5a
5b
5c
5d
6
14,100
16,700
18,400
18,000
7,400
2.32
2.38
2.68
2.63
2.80
[a]
Number average molecular weight determined by GPC
methods [THF, poly(styrene) standards].
Polydispersity index.
AHCTREUNG
[b]
brick red solids in 88–95% yields (Scheme 2). The
cobalt contents were determined by ICP-MS methods
to be 1.08–1.33 mmol/g, indicating that 88–96% of the
salen units were loaded with cobalt. Monomeric
ligand 4b was also metallated accordingly to give
Co(4b), a monometallic, small metal catalyst for com-
parison to the supported version.
The catalytic performance of the poly(styrene)-sup-
G
ported Co-salen complexes was evaluated using the
HKR of racemic epichlorohydrin as a model reaction.
Prior to each resolution, the Co(II) precatalysts were
oxidized to their Co(III) acetate species in air using
N
an excessive amount of acetic acid. The catalyst load-
ing was set at 0.01 mol% on the basis of cobalt (the
concentration
of
cobalt
in
epichlorohydrin:
1.28 mmol/L) and 0.6 equivs. of water was used as the
nucleophile. The reaction kinetics were monitored by
chiral GC analysis with chlorobenzene as an internal
reference.
The effect of polymerization on the HKR reaction
is illustrated in Figure 3A. When the small molecule
standard Co(4b) was employed as the precatalyst, the
resolution proceeded to an ee of only 14% for the re-
Figure 3. The HKR of epichlorohydrin (ee vs. reaction time
plots; A: the effect of polymerization, B: the effect of the
linker length).
maining epichlorohydrin with 13% conversion in able difference in activity suggested that proper cata-
10 h. In contrast, homopolymer Co(5b) was highly lyst designs can increase the proximity of neighboring
active and enantioselective under the same conditions, catalytic units and hence enhance substantially the bi-
affording >99% ee in 51% conversion. The initial metallic cooperative interactions desired for the
turnover frequency (TOF) per cobalt for the reaction HKR. Copolymer Co(6) was also tested in the HKR
time of the first hour reaches 3300 hÀ1. This remark- of epichlorohydrin and gave an enantiomeric excess
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Xiaolai Zheng et al.
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of 89% in 10 h. An ee of 95% was reached upon ex- that more flexible linkers are desired in enhancement
tending the reaction time to 24 h. The initial TOF for of the Co-salen mediated cooperative HKR reactions.
the first hour is 2500 hÀ1 which is substantially slower
The most active catalyst Co(5b) was used in the
than that of homopolymer Co(5b). This result demon- resolution of a variety of terminal epoxides (Table 2).
strates that the copolymerization has diluted the local The majority of epoxides can be resolved with a
concentration of Co-salen units along the polymer cobalt loading of merely 0.01 mol%. For instance, the
chain, resulting in more isolated Co-salen units, there- HKR of 1,2-epoxyhexane afforded the (R)-enantio-
by making it more difficult for the bimetallic interac- mer in 44% isolated yields with>99% ee (entry 1).
tions to occur.
Racemic allyl glycidyl ether and glycidyl phenyl ether
The influence of the linker length on the HKR is were resolved in 10 h and 24 h, respectively, with
presented in Figure 3B. The systematic variation of greater than 99% ee. Even the HKR of styrene oxide
the length of oligo(ethylene glycol) linkers has eluci- was complete in 24 h with a 0.1 mol% catalyst load-
dated a clear trend. While complex Co(5b), with a ing.
spacer of six carbon/oxygen atoms between the poly-
mer backbone and the salen unit, exhibited the most
desired catalytic performance, decreasing the linker Conclusions
atom number to three in Co(5a) or even zero in
Co(7) resulted in a dramatic drop in reactivity. On In conclusion, we have employed poly(styrene)-sup-
A
the other hand, increasing the linker atom number to ported Co-salen complexes bearing different lengths
nine in Co(5c) or to twelve in Co(5d) also slowed the of oligo(ethylene glycol) linkers as model catalysts to
HKR reaction. Clearly, there is an optimal linker investigate the HKR of epoxides operating via a bi-
length when using oligo(ethylene glycol) linkers for metallic cooperative mechanism. The systematic var-
this bimetallic transformation which in our case seems iation of the linker length and the catalyst density
to be approximately six atoms.
Another variable that influences catalyst activity is following trends: (i) Using poly
within this series of catalysts elucidated clearly the
AHCTREUNG
the linker flexibility. We have reported previously porting matrix and oligo(ethylene glycol) as the
that, in the presence of a rigid phenylene linker, ho- linker, a linker of approximately six atoms represents
mopolymeric Co-salen catalysts were less active for the optimal length for promoting bimetallic coopera-
HKR in comparison with their copolymeric analogues tive interactions in the HKR. (ii) In the presence of a
due to a poor cooperative geometrical environ- flexible linker, the homopolymer-supported Co-salen
ment.[15] In comparison of this observation with the catalysts are more active than their copolymer ana-
herein described catalytic data of flexibly linked cata- logues. (iii) By means of proper linker and polymer
lysts, we can rationalize that the linker flexibility is designs, the polymer-supported catalysts can signifi-
also an important design motif. These results suggest cantly enhance the activity in the HKR obtained with
the monometallic Jacobsen-type catalysts. Currently,
the aforementioned findings are being used to guide
the design and synthesis of insoluble solid-supported
dual activation catalysts.
Table 2. The HKR of various racemic terminal epoxides.
Experimental Section
Entry R
Loading
Time
[h][b]
ee
Yield
[mol%][a]
[%][c] [%][d]
General Remarks
Reagents were purchased from Aldrich, Acros, or Alfa, and
used as received unless noted below. Dichloromethane and
THF were dried by passing through columns of activated
copper and alumina successively. Chlorobenzene was dis-
tilled over calcium dihydride and stored in a Schelenk flask
under argon. (4-Vinylphenyl)methanol (1a),[17] 2-(4-vinyl-
benzyloxy)ethanol (1b),[18] 2-[2-(4-vinylbenzyloxy)ethoxy]e-
thanol (1c),[19] 2-{2-[2-(4-vinylbenzyloxy)ethoxy]ethoxy}etha-
nol (1d),[20] (1R,2R)-1,2-diaminocyclohexane mono(hydro-
gen chloride) (3),[15,16] 3-tert-butyl-5-(chloromethyl)-2-hy-
1
2
n-Bu
CH2Cl
CH2OAllyl 0.01
CH2OPh
Ph
0.01
0.01
6
>99 44
>99 45 (49)
>99 46
8 (10)
10
24
3
4[e]
5
0.01
0.1
>99 43
24
98
45
[a]
[b]
Catalyst loadings based on cobalt.
Reaction times with (in parenthesis) or without an inter-
nal reference (0.5 mL chlorobenzene).
Determined by chiral GC or HPLC methods.
Isolated yields or GC yields (in parenthesis) based on
rac-epoxides; theoretical maximum yield=50%.
HKR was performed at room temperature for 4 h and at
358C for 20 h.
[c]
[d]
droxybenzaldehyde,[21] and poly
(styrene)-supported Co-
A
A
of polymerization: x=24)[12a] were prepared according to
[e]
published procedures. NMR spectra were acquired with a
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Varian Mercury 400 (1H, 400.0 MHz; 13C, 100.6 MHz) or a
Varian Mercury 300 (1H, 300.0 MHz; 13C, 75.5 MHz) spec-
trometer. Chemical shifts are reported in ppm and refer-
enced to the residual nuclei in the corresponding deuterated
solvents. IR and UV-vis spectra were recorded with a Shi-
madzu FTIR-8400S and a Shimadzu UV-2401PC spectrome-
ter, respectively. Mass spectra were recorded with a VG
7070 EQ-HF hybrid tandem mass spectrometer or an Ap-
plied Biosystems 4700 spectrometer. Gel-permeation chro-
matography (GPC) analyses were performed with American
Polymer Standards columns (100, 1,000, 100,000 Š linear
mixed bed) equipped with a Waters 510 or a Shimadzu LC-
nol (15 mL) was added 3,5-di-tert-butyl-2-hydroxybenzalde-
hyde (352 mg, 1.5 mmol) and activated 4 Š molecular sieve
(0.75 g). The reaction mixture was stirred at ambient tem-
perature for 3 h till the salicyl aldehyde was completely con-
sumed according to TLC analysis. A solution of styryl-sub-
stituted salicyl aldehyde 2 (1.5 mmol) in anhydrous dichloro-
methane (15 mL) was added to the reaction system, fol-
lowed by the slow addition of triethylamine (2 equiv,
3.0 mmol). After the reaction mixture was stirred at room
temperature for an additional 3 h, all solvents and the exces-
sive triethylamine were removed under vacuum. Chroma-
tography of the residue on silica gel with a mixture of ethyl
acetate and hexanes gave the desired product 4 in 72–84%
yields.
10 AD pump and a UV detector. Poly(styrene)s (Mn ranging
A
from 580 to 7,500,000) were employed as standards for cali-
bration and THF was used as a mobile phase (flow rate at
1.0 mLminÀ1). Enantiomeric excesses (ee) were determined
by capillary gas-phase chromatography (GC) analysis or by
high performance liquid-phase chromatography (HPLC).
The chiral GC analysis was performed on a Shimadzu GC
14 A instrument equipped with an FID detector as well as a
Chiraldex g-TA column (40 m”0.25 mm”0.25 mm film
thickness, Advanced Separation Technologies, Inc.) with
helium as the carrier gas. The chiral HPLC analysis was car-
ried out with a Chiracel OD column (24 cm”0.46 mm,
Chiral Technologies, Inc.; flow rate=1 mLminÀ1) using a
UV detector.
A
[(4-vinylbenzyloxy)methyl]-salicylidene}-1,2-cyclohexanedi-
amine (4a): Bright yellow solid in 84% yield after chroma-
tography on silica gel with 2/98 (v/v) ethyl acetate/hexanes.
A
[6-(4-vinylphenyl)-2,5-dioxahexyl]salicylidene}-1,2-cyclohex-
anediamine (4b): Bright yellow solid in 72% yield after
chromatography on silica gel with 5/95 (v/v) ethyl acetate/
hexanes.
A
[6-(4-vinylphenyl)-2,5-dioxahexyl]salicylidene}-1,2-cyclohex-
anediamine (4c): Viscous yellow oil in 78% yield after chro-
matography on silica gel with 10/90 (v/v) ethyl acetate/hex-
anes.
General Procedure A: Synthesis of Styryl-Substituted
Salicyl Aldehydes 2a–d
A
hydroxy-5-[12-(4-vinylphenyl)-2,5,8,11-tetraoxadodecyl]sali-
cylidene}-1,2-cyclohexanediamine (4d): Viscous yellow oil in
72% yield after chromatography on silica gel with 20/80 (v/
v) ethyl acetate/hexanes.
3-tert-Butyl-5-(chloromethyl)-2-hydroxybenzaldehyde
(1.13 g, 5.0 mmol), styryl-substituted alcohol 1 (1.5 equivs.,
7.5 mmol), and a fine powder of anhydrous sodium bicar-
bonate (4.0 equivs., 1.68 g, 20 mmol) were charged into a
Schlenk tube connected to a bubbler. The reaction mixture
was stirred as a slurry at 908C for 2 h till not further carbon
dioxide evolved from the system. Chromatography of the re-
action residue on silica gel with a mixture of ethyl acetate
and hexanes gave the desired salicyl aldehyde 2 in 70–-77%
yields.
3-tert-Butyl-2-hydroxy-5-((4-vinylbenzyloxy)methyl)ben-
zaldehyde (2a): Colorless oil in 77% yield after chromatog-
raphy on silica gel with 5/95–15/85 (v/v) ethyl acetate/hex-
anes.
3-tert-Butyl-2-hydroxy-5-[6-(4-vinylphenyl)-2,5-dioxahex-
yl]benzaldehyde (2b): Colorless solid in 70% yield after
chromatography on silica gel with 10/90–20/80 (v/v) ethyl
acetate/hexanes.
General Procedure C: Synthesis of Polymeric Salen
Ligands 5a–d and 6 via Free Radical Polymerizations
A Schlenk tube equipped with a Teflon screw cap was
charged with salen monomer 4 (0.4 mmol on the basis of
salen units) and free radical initiator AIBN (2.5 mol%,
1.6 mg, 10 mmol). The system was purged with argon three
times. Degassed chlorobenzene (1.0 mL) was injected and
the sealed reaction mixture was stirred at 808C for 24 h. The
mixture was slowly poured into methanol (10 mL) to precip-
itate the crude polymer. The suspension was stirred for
60 min and the powder was collected by centrifuge. The re-
sulting solid was dissolved in dichloromethane (0.5 mL) and
reprecipitated from methanol (10 mL). The precipitation
procedure was repeated till signals of the salen monomer
3-tert-Butyl-2-hydroxy-5-[9-(4-vinylphenyl)-2,5,8-trioxano-
nyl]benzaldehyde (2c): Pale yellow oil in 75% yield after
chromatography on silica gel with 15/85–25/75 (v/v) ethyl
acetate/hexanes.
1
were no longer detectible in the H NMR spectrum. The de-
sired polymer was obtained as a yellow powder in 81–93%
yields.
3-tert-Butyl-2-hydroxy-5-[12-(4-vinylphenyl)-2,5,8,11-tet-
raoxadodecyl]benzaldehyde (2d): Pale yellow oil in 72%
yield after chromatography on silica gel with 30/70 (v/v)
ethyl acetate/hexanes.
General Procedure D: Synthesis of Polyermic
Co(II)
G
N
In a glove box under nitrogen, a solution of Co(OAc)2·
G
4H2O (1.2 equivs., 90 mg, 0.36 mmol,) in methanol (3.0 mL)
was added slowly to a solution of the polymeric salen 5 or 6
(0.30 mmol) in dichloromethane (3.0 mL). A red slurry
formed in seconds and the reaction mixture was stirred at
ambient temperature for 20 h. Methanol (10 mL) was added
General Procedure B: Synthesis of Styryl-Substituted
Salen Ligands 4a–d
To a solution of (1R,2R)-1,2-diaminocyclohexane mono(hy-
drogen chloride) (3, 226 mg, 1.5 mmol) in anhydrous metha-
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Xiaolai Zheng et al.
FULL PAPERS
to precipitate more solid and the resulting suspension was
stirred for an additional 4 h. The solid was collected by fil-
tration, washed sequentially with 1/10 (v/v) degassed di-
chloromethane/methanol (10 mL) and methanol (2”10 mL),
and dried under vacuum to give the desired Co(II)-(salen)
complex in 88–95% yields.
3385; c) C. A. McNamara, M. J. Dixon, M. Bradley,
Chem. Rev. 2002, 102, 3275; d) C. E. Song, S.-G. Lee,
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46, 419; f) L.-X. Dai, Angew. Chem. Int. Ed. 2004, 43,
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2006, 348, 1743; h) S. J. Dolman, K. C. Hultzsch, F.
Pezet, X. Teng, A. H. Hoveyda, R. R. Schrock, J. Am.
Chem. Soc. 2004, 126, 10945; i) S. Thomas, K. D. Janda,
J. Am. Chem. Soc. 2000, 122, 6929; j) P. Hodge, Chem.
Soc., Rev. 1997, 26, 417.
Synthesis of Complex Co(4b)
In a glove box under nitrogen, a mixture of salen ligand 4b
(272 mg, 0.40 mmol) and Co(OAc)2·4H2O (125 mg,
G
[3] a) J.-A. Ma, D. Cahard, Angew. Chem. Int. Ed. 2004,
43, 4566; b) M. Shibasaki, N. Yoshikawa, Chem. Rev.
2002, 102, 2187; c) E. K. van den Beuken, B. L. Feringa,
Tetrahedron 1998, 54, 12985.
0.50 mmol) in methanol (4.0 mL) was stirred at room tem-
perature for 4 h. A red powder precipitated from the reac-
tion mixture and was collected by filtration. The solid was
washed with methanol (2”10 mL) and dried under vacuum
to give the desired Co(4b) as a brick red powder; yield:
275 mg (93%).
[4] a) G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc.
2003, 125, 4442; b) G. M. Sammis, H. Danjo, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2004, 126, 9928; c) F. X.
Chen, H. Zhou, X. H. Liu, B. Qin, X. M. Feng, G. L.
Zhang, Y. Z. Jiang, Chem. Eur. J. 2004, 10, 4790;
d) S. S. Kim, D. H. Song, Eur. J. Org. Chem. 2005, 1777.
[5] For reviews on HKR, see: a) P. Kumar, V. Naidu, P.
Gupta, Tetrahedron 2007, 63, 2745; b) J. M. Keith, J. F.
Larrow, E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5.
[6] For reviews on salen chemistry, see: a) L. Canali, D. C.
Sherrington, Chem. Soc., Rev. 1999, 28, 85; b) T. Katsu-
ki, Adv. Synth. Catal. 2002, 344, 131; c) P. G. Cozzi,
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cobsen, Topics Organomet. Chem. 2004, 6, 123; e) C.
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Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen,
A. E. Gould, M. E. Furrow, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 1307.
General Procedure E: Hydrolytic Kinetic Resolutions
of Epoxide
The Co(II)-(salen) precatalyst (5.0 mmol, 0.01 mol% on the
basis of cobalt) was dissolved in dichloromethane (0.5 mL)
in a 25-mL flask. Glacial acetic acid (50 mL) was added to
the solution and the mixture was stirred in the open air for
30 min, during which time the color changed from deep red
to dark brown. After the solvent and the excessive amount
of acetic acid were roughly removed by rotary evaporation,
the residue was pumped under vacuum for 5 min to give Co-
A
G
N
vated catalyst was dissolved in the racemic epoxide
(50 mmol) (in the cases of kinetic studies, 0.5 mL chloroben-
zene was added as an internal reference for the GC analy-
sis). Deionized water (0.54 mL, 30 mmol, 0.60 equiv.) was
added to the system at room temperature to start the reac-
tion and the process of the HKR was monitored by chiral
GC or HPLC method till an ee of >98% was reached. The
remaining enantiopure epoxide, together with the unreacted
water, was vacuum-distilled into a receiving flask pre-cooled
at À788C. Water was removed by passing the recovered ep-
oxide through a plug of dry silica gel packed in a Pasteur
pipet.
[8] L. P. C. Nielsen, C. P. Stevenson, D. G. Blackmond,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 1360.
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Acknowledgements
This work is supported by the US DOE Office of Basic
Energy Sciences through the Catalysis Science Contract No.
DE-FG02–03ER15459. MW gratefully acknowledges an
Alfred P. Sloan Fellowship and a Camille Dreyfus Teacher-
Scholar Award.
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