DNA-based hydrolytic kinetic resolution of epoxides

Article abstract of DOI:10.1016/j.tetasy.2008.10.004

DNA-bound copper(II) complexes serve as catalysts for the hydrolytic kinetic resolution of 2-pyridyloxiranes in water. Selectivity factors of up to 2.7 were achieved, indicating a chirality transfer of DNA to epoxides via a coordinated metal ion.

Full text of DOI:10.1016/j.tetasy.2008.10.004

Tetrahedron: Asymmetry 19 (2008) 2374–2377
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
DNA-based hydrolytic kinetic resolution of epoxides
*
*
Ewold W. Dijk, Ben L. Feringa , Gerard Roelfes
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
DNA-bound copper(II) complexes serve as catalysts for the hydrolytic kinetic resolution of 2-pyridyloxir-
anes in water. Selectivity factors of up to 2.7 were achieved, indicating a chirality transfer of DNA to epox-
ides via a coordinated metal ion.
Received 15 August 2008
Accepted 9 October 2008
Available online 19 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
Water is increasingly recognised as a special solvent for asym-
metric catalysis.1 Many catalysts not only tolerate the presence
of water, but also in many cases water is beneficial for the rate
and enantioselectivity of the catalysed reactions.2 The use of
R
(±)
1a R = H
1b R = Ph (trans)
1c R = Ph (cis)
1d R = 4-MeO-C6H4
1e R = Me (trans)
hybrid catalysts represents
a powerful, emerging approach
towards aqueous phase catalysis. A hybrid catalyst is created by
incorporation of a catalytically active transition metal complex
into a protein3 or oligonucleotide4 host. The well-defined chiral
environment provided by the host is used to induce enantioselec-
tivity in the catalysed reaction.
Cu2+
H2O
HO
OH
O
We have introduced the concept of DNA-based asymmetric
catalysis, in which DNA is used as a chiral scaffold.5 Using a nonco-
valently bound metal–ligand complex as a cofactor, the chirality of
DNA was transferred to the copper(II) catalysed Diels–Alder reac-
tion in water. Two generations of catalyst have been developed;
the first contains an acridine-based intercalator moiety that is
connected via a spacer to a metal-binding domain. The ligands of
the second generation are based on simple polyaromatic or bipyr-
idine-type molecules that combine the DNA- and metal-binding
properties into a single moiety (Fig. 1). The latter DNA–metal
0conjugate catalysts yielded the Diels–Alder product in excellent
diastereoselectivity and enantioselectivity.5b In addition to the
Diels–Alder reaction, DNA-based asymmetric catalysis has also
been successfully applied in enantioselective Michael additions6
and electrophilic fluorination7 reactions.
Kinetic resolution is a powerful method for obtaining enantio-
merically enriched chiral compounds.8 By virtue of the unequal
reactivity of both enantiomers in a racemic mixture with a chiral
reagent or catalyst, kinetic resolution results in enantiomeric
enrichment in the slow-reacting compound. A variety of enzymes
and synthetic catalysts have been developed for the kinetic resolu-
tion of many classes of compounds.9 In this regard, the hydrolytic
kinetic resolution (HKR) of epoxides is particularly useful, since it
N
N
R
R
+
(enriched)
2a-e
= achiral ligand L1-L3
N
N
N
N
N
HN
N
2
N
L3
L2
L1
Figure 1. Schematic representation of the DNA-based hydrolytic kinetic resolution
of 2-pyridyloxiranes 1a–e.
results in enantiomerically pure epoxides, which represent very
attractive building blocks for organic synthesis. A very efficient
and stereoselective catalyst for the HKR of terminal epoxides was
reported by Jacobsen et al.10 By using chiral cobalt–salen com-
* Corresponding authors. Tel.: +31 50 3634235; fax: +31 50 363 4296 (G.R.).
E-mail addresses: b.l.feringa@rug.nl (B.L. Feringa), j.g.roelfes@rug.nl (G. Roelfes).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.004

E. W. Dijk et al. / Tetrahedron: Asymmetry 19 (2008) 2374–2377
2375
plexes, S values of up to >400 were obtained by reaction with
0.55 equiv of water. Alternatively, highly selective enzymatic cata-
lysts have been developed for the HKR of epoxides in aqueous
environments.11,12
Herein, we report the first examples of DNA-based kinetic reso-
lution, that is the hydrolytic kinetic resolution of epoxides (Fig. 1).
Subsequently, the kinetic resolution of 1a was attempted using
the first-generation ligand L1 with Ni(NO3)2 and CuSO4 under the
conditions described above. The observed conversion after 48 h,
62 1% and 20 6% for the Cu2+ and Ni2+ catalysed reactions,
respectively, (Table 2, entries 1 and 4) were significantly higher
using this ligand than using L2. With Cu2+ as the Lewis acid, the
ee of remaining epoxide 1a was determined to be 21%, leading to
an S factor of 1.5. Using Ni2+ as the Lewis acid, the ee of remaining
1a was only 5%, and because of the low activity of the Ni2+-based
catalyst, Cu2+ was the metal ion of choice in further experiments.
Finally, as a result of this preliminary screening, when using L3
as the ligand, 2-pyridyloxirane 1a could be resolved with S = 1.5,
giving 10% ee after 42 4% conversion (Table 2, entry 3).
2. Results and discussion
2-Pyridyloxiranes (2-POs) were selected as substrates for HKR,
to ensure efficient bidentate coordination of the substrate to the
metal centre. Monodentate binding oxiranes were found not to be
good substrates.13 Lewis acid-promoted ring opening of 2-pyridy-
loxiranes in water has been reported,14 making them viable
candidates for the HKR catalysed by our hybrid catalyst. 2-Pyridy-
loxiranes are readily accessible via ring closure of the correspond-
ing halohydrin15 or the Corey–Chaykovsky reaction.16 Thus,
( )-2-pyridyloxirane 1a was synthesised from 2-vinylpyridine in
reasonable yield, and b-substituted pyridyloxiranes 1b–e were syn-
thesised from 2-pyridinecarboxaldehyde and the corresponding
dimethylsulfonium ylide (Scheme 1). In this case, yields were lim-
ited due to a competing Cannizzaro reaction of the aldehyde.
Table 2
Conversions, ees and selectivity factors for the kinetic resolution of substrates 1a–ea
Entry
Substrate
Ligand
Time (h)
Conv. (%)e
ee (%)f
S
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
L1
L2
L3
L1b
L2b
L1
L2
L3
48
72
48
48
72
4.75
16
4
62
43
42
20
13
91
53
80
85
67
74
80
57
31
85
66
25
55
49
1
7
4
6
5
2
7
1
2
1
5
1
2
4
1
3
4
4
5
21
<5
10
5
1.5
n.d.g
1.5
1.6
n.d.
1.1
1.9
2.0
2.0
2.4
2.7
1.5
n.d.
1.2
n.d.
1.2
n.d.
1.3
n.d.
<5
1b
12 (S,S)
21 (S,S)
52 (S,S)
61(S,S)
45 (S,S)
63 (S,S)
32 (S,S)
<5
4
<5
7
<5
O
5
L3c
L3d
None
L2
L3
L2
L3
L1
L2
L3
2.5
2.5
1.25
22
5
11
4
47
63
47
N
N
1) NBS, dioxane/H2O 1:1
2) Na2CO3
1c
1d
1e
1a (40%)
11
<5
O
O
Br-
S+
R
N
N
a
Conditions: 1.3 mg mLꢀ1 st-DNA, 0.3 mM Cu2+/ligand complex, 3 mM substrate,
R
(20-47%)
H
20 mM MOPS buffer pH 6.5, unless noted otherwise.
b
NaOH, H2O, DCM
Ni(NO3)2 was used as the metal salt.
1.5 mM initial substrate concentration.
0.30 mM initial substrate concentration.
Determined by reversed-phase HPLC.
Ee values were reproducible within 2%.
Not determined.
1b-e
c
d
e
Scheme 1. Synthesis of epoxide substrates 1a–e.
f
g
In order to establish the optimal metal ion for the DNA-based
HKR of 2-pyridyloxirane 1a, the substrate (initial concentration
3.0 mM) was added to a buffered solution of salmon testes DNA
(st-DNA) (1.3 mg mLꢀ1), L2 (0.39 mM) and various metal ions
(0.30 mM, Table 1) at 5 °C.
Hydrolytic conversions of epoxide 1a were determined, after
72 h of continuous inversion, by rp-HPLC with caffeine as the
external standard. From the data in Table 1, it can be concluded
that of the metal ions tested, only Cu2+ and Ni2+ significantly en-
hance the rate of the hydrolysis of 1a. In both cases, however,
the ee of remaining epoxide 1a was negligible (<5%; Table 2, en-
tries 2 and 5).
The optimal buffer and pH for the kinetic resolution of 1a were
determined for Cu2+/L1. Both reaction rate and selectivity showed
negligible dependence on the nature and pH of the buffer between
pH 4.0 and 7.0. For practical reasons, a 30 mM MOPS buffer at pH
6.5 was used in all further experiments.17
Next, the effect of b-substituents at the oxirane ring was
studied. trans-2-(3-Phenyloxiranyl)pyridine 1b was tested as a
substrate in the DNA-based HKR. After only 4 h with L3 as the
ligand, the reaction had proceeded to 80% conversion, with an
ee of 52% (S = 2.0, Table 2, entry 8) in the remaining substrate.
In this case, the corresponding diol formed had an ee of 16%.
To exclude Lewis acid-catalysed racemisation of the substrate
and/or the product, the reaction was allowed to proceed further.
After 5 h, the remaining substrate was present in 61% ee (85%
conversion, entry 9), and the corresponding diol had 12% ee.
Since the ee increased and the S factor stayed the same, this
demonstrates that the reaction is not reversible and racemisation
of the epoxide does not take place. The selectivity of the HKR
using L2 as the ligand was similar, but the reaction was consid-
erably slower (entry 7). Interestingly, with L1 as the ligand, the S
factor was only 1.1 (entry 6). The use of DNA from an alternative
source (calf thymus) gave identical results as with st-DNA, which
demonstrates that DNA is indeed the source of chirality in the
HKR.
Table 1
The influence of metal ions on the conversion in the HKR of 1aa
Salt
Conv. %
Sc(OTf)3
FeSO4
Co(NO3)2
Ni(NO3)2
CuSO4
<10
<10
<10
13
43
5
7
ZnSO4
None
<10
<10
In all cases, L2 was used as the ligand.
a
The product of the reaction is the corresponding diol.

2376
E. W. Dijk et al. / Tetrahedron: Asymmetry 19 (2008) 2374–2377
For the best catalyst, the substrate/catalyst ratio was lowered to
4.1. General procedure for the HKR of epoxide substrates
5:1 and 1:1 by decreasing the substrate concentration (entries 10
and 11, respectively). After 2.5 h, the conversions were slightly
lower compared to the reaction with a substrate/catalyst ratio of
10:1. However, the ee of the recovered starting material was higher
(up to 63%), resulting in S values of up to 2.7. This suggests that the
uncatalysed reaction is not negligible, and can give rise to de-
creased selectivity factors in the case of lower catalyst loadings.
Comparison of the specific rotation of the major enantiomer,18
which was resolved by preparative chiral HPLC, to the literature
value, established that the (S,S)-enantiomer of 1b remained in
excess in all cases, that is, the (R,R)-enantiomer is preferentially
hydrolysed under the influence of the DNA-based catalyst. Inter-
estingly, in the absence of a ligand for Cu2+, the reaction was
considerably faster (Table 2, entry 12). However, the observed
selectivity factor is significantly lower in this case.
Using the cis-isomer 1c instead of the trans-isomer 1b resulted
in a considerable decrease in selectivity, whereas the rate of hydro-
lysis was approximately the same (entries 13 and 14). Apparently,
the DNA-based catalyst could not discriminate efficiently between
the enantiomers of 1c. Substituents at the 2-position of the phenyl
ring (2-bromo and 2-nitro) made these substrates insoluble in the
buffer, and hence no conversion or kinetic resolution occurred,
even at elevated temperatures (data not shown). A 4-methoxy-
phenyl substituent at the oxirane 1d gave rise to a sluggish reac-
tion and many unidentified side-products. Furthermore, hardly
any enantioenrichment of the substrate was observed (entries 15
and 16). Substitution of 2-PO at the b-carbon with a methyl group
(substrate 1e) considerably decreased the resolution selectivity
(entries 17–19).
A freshly prepared 1.0 M stock solution of the epoxide in aceto-
nitrile (31.5 lL, 31.5 lmol) was added to 10.5 mL of a solution of
st-DNA (1.3 mg mLꢀ1), the metal salt (0.30 mM) and the ligand
(0.39 mM) in MOPS buffer (20 mM, pH 6.5) at 5 °C. Mixing was per-
formed by continuous inversion. After the time indicated in Table
2, a 200
with 200
After brief centrifugation (13,000 rpm), 200
was added to 200 L of a 1.50 mM caffeine solution in water and
l
l
L sample of the reaction mixture was thoroughly mixed
L of acetonitrile, leading to the precipitation of DNA.
L of this mixture
l
l
the conversion of the sample was determined by rp-HPLC analysis.
Absolute amounts of remaining epoxide were determined by cor-
relation to a calibration curve. The remaining reaction mixture
was extracted with diethyl ether (5 mL, substrate 1a) or ethyl
acetate (2 ꢁ 5 mL, substrates 1b–e), the solution dried over Na2SO4
and the ee of remaining epoxide was determined by GC (1a) or
chiral HPLC (1b–e).
4.2. Synthesis of substrates and ligand L1
2-Pyridyloxirane 1a15 (Chiral GC: Chrompack CP Chirasil Dex
CB; 110 °C; He flow 1.0 mL minꢀ1, Tr = 7.1; 7.7 min; rp-HPLC:
Vydac C4 MS; MeOH/Na-phosphate 25 mM pH 2.0 30/70; flow
0.3 mL minꢀ1; Tr = 15.2 min; caffeine: Tr = 11.3 min) and ligand
L15a were synthesised following literature procedures. trans-2-(3-
Phenyl-2-oxiranyl)pyridine 1b and its diastereomer 1c were syn-
thesised by the method described by Solladié-Cavallo et al.16 and
were separated by column chromatography (SiO2, CHCl3/Et2O
4:1). Compound 1b was obtained in 30% yield from pyridine-2-car-
boxaldehyde, and had all analytical data as reported. HPLC: Daicel
Chiralpak AD; heptane/i-PrOH 95:5; flow 1.0 mL minꢀ1; Tr = 8.9;
16.8 min; rp-HPLC: Waters XTerra Phenyl; MeOH/Na-phosphate
25 mM pH 2.0 30/70; flow 0.5 mL minꢀ1; Tr = 9.5 min; caffeine:
Tr = 3.6 min. The cis-diastereomer 1c was obtained in 5% yield,
and was recrystallised from pentane, yielding colourless crystals,
mp 46–47 °C (lit.19 45–47 °C); dH (400 MHz; CDCl3) 4.45 (2H, m),
7.02–7.05 (1H, m), 7.06–7.10 (1H, m), 7.11–7.20 (3H, m), 7.20–
7.26 (2H, m), 7.41–7.47 (1H, m), 8.41–8.47 (1H, m); dC
(100.6 MHz; CDCl3) 59.64 (d), 59.99 (d), 121.13 (d), 122.40 (d),
126.79 (d), 127.55 (d), 127.76 (d), 133.81 (s), 135.61 (d), 148.87
(d), 154.56 (s). HPLC: Daicel Chiralpak AD; heptane/i-PrOH 99:1;
flow 1.0 mL minꢀ1; Tr = 16.2; 22.3 min; rp-HPLC: Waters XTerra
Phenyl; MeOH/Na-phosphate 25 mM pH 2.0 20/80; flow
0.5 mL minꢀ1 Tr = 8.8 min; caffeine: Tr = 5.5 min.
3. Conclusion
In conclusion, we have presented the first examples of DNA-
based catalytic kinetic resolution in water. Using DNA as the source
of chirality in the hydrolytic kinetic resolution of 2-pyridyloxir-
anes, S values of up to 2.7 were achieved, and the remaining epox-
ide was recovered with up to 63% ee. Although to date the
resolution selectivity is not high enough for synthetic applications
and the substrate scope is limited, these results demonstrate for
the first time that the concept of DNA-based catalysis can be
applied to achieve kinetic resolution of chiral substrates in water.
4. Experimental
Salmon testes and calf thymus DNA were purchased from
Sigma. Reagents and buffer salts were used as supplied without
further purification. 1H and 13C NMR spectra were recorded in
CDCl3 on a Varian AS400 Mercury Plus spectrometer, operating at
400 and 100.6 MHz, respectively. Chemical shifts are reported in
d units (ppm) relative to the residual solvent signals of CHCl3 (1H
NMR: 7.26 ppm; 13C NMR: 77.0 ppm), J values are given in Hertz.
Thin layer chromatography was performed on Merck Silica gel 60
TLC plates, flash column chromatography was performed on Silicy-
cle Silia P 60 Å silica gel. Mass spectra were recorded on a Jeol
JMS-600H mass spectrometer. Reversed-phase and normal-phase
HPLC analyses were performed on Shimadzu LC-10AD-VP HPLC
instruments equipped with a Shimadzu SPD-M10A-VP diode array
detector. Conversions were determined on a Vydac C4 MS or
Waters Xterra Phenyl column using methanol/Na-phosphate
(25 mM, pH 2.0 or 6.5) as an eluent. Chiral HPLC analyses were per-
formed on a Daicel Chiralpak AD column using heptane/2-propanol
as eluent. Chiral GC analysis was performed on a HP-6890 chro-
matograph using a flame ionisation detector. Optical rotations
4.3. trans-2-[3-(4-Methoxyphenyl)-2-oxiranyl]pyridine 1d
To a cooled (0 °C) suspension of 4-methoxybenzyldimethyl-
sulfonium hydrogen sulfate20 (8.16 g, 22.6 mmol) in dichlorometh-
ane (36 mL) were added tetrabutylammonium hydrogen sulfate
(384 mg, 1.13 mmol, 0.05 equiv) and freshly distilled pyridine-2-
carboxaldehyde (2.8 mL, 29.5 mmol, 1.3 equiv). A 50% aqueous
solution of sodium hydroxide (22 mL) was added dropwise over
15 min. The reaction mixture was slowly warmed to room temper-
ature and stirring was continued overnight. The reaction mixture
was diluted with water and ethyl acetate, the layers separated
and the aqueous phase extracted with ethyl acetate (3 ꢁ 50 mL).
The combined organic layers were dried over Na2SO4, filtered
and the solvent was evaporated. Crude yield: (4.55 g, 20 mmol,
89%) of a brownish oil. The diastereomers were separated by flash
column chromatography (SiO2, pentane/diethyl ether 1:2). The
trans-isomer (Rf 0.34) was isolated as an off-white solid (1.01 g,
4.4 mmol, 20%), mp 52–53 °C (lit.21: 51–53 °C); dH (400 MHz;
CDCl3) 3.80 (3 H, s), 4.00 (1H, d, J 1.8), 4.05 (1H, d, J 1.8), 6.88–
6.92 (2H, m), 7.21–7.33 (4H, m), 7.67–7.71 (1H, m), 8.57–8.59
were determined on
polarimeter.
a Schmidt + Haensch Polartronic MH8

E. W. Dijk et al. / Tetrahedron: Asymmetry 19 (2008) 2374–2377
2377
2. Reviews: (a) Pan, C.; Wang, Z. Coord. Chem. Rev. 2008, 252, 736–750; (b)
Lindström, U. M. Chem. Rev. 2002, 102, 2751–2772; (c) Kobayashi, S.; Manabe,
K. Acc. Chem. Res. 2002, 35, 209–217.
(1H, m); dC (100.6 MHz; CDCl3) 55.19 (q), 61.67 (d), 62.52 (d),
113.91 (d), 119.87 (d), 123.02 (d), 126.99 (d), 128.49(s), 136.65
(d), 149.40 (d), 156.50 (s), 159.77 (s); m/z (EI) 227 (22, M+),
198(100), 121(74); HRMS for C14H13NO2: calcd 227.0952, found
227.0946. HPLC: Daicel Chiralpak AD; heptane/i-PrOH 9:1; flow
1.0 mL minꢀ1; Tr = 9.7; 18.1 min; rp-HPLC: Waters XTerra Phenyl;
3. Selected examples include: (a) Wilson, M. E.; Whitesides, G. M. J. Am. Chem. Soc.
1978, 100, 306–307; (b) Ohashi, M.; Koshiyama, T.; Ueno, T.; Yanase, M.; Fujii,
H.; Watanabe, Y. Angew. Chem., Int. Ed. 2003, 42, 1005–1008; (c) Collot, J.;
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H. K.; Abramite, J. A.; Wang, Z.; Guo, Z.; Lu, Y. J. Am. Chem. Soc. 2004, 126,
10812–10813; (e) Reetz, M. T.; Jiao, N. Angew. Chem., Int. Ed. 2006, 45, 2416–
2419; (f) Pierron, J.; Malan, C.; Creus, M.; Gradinaru, J.; Hafner, I.; Ivanova, A.;
Sardo, A.; Ward, T. R. Angew. Chem., Int. Ed. 2008, 47, 701–705; For a review see
(g) Steinreiber, J.; Ward, T. R. Coord. Chem. Rev. 2008, 252, 751–766.
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M.; Slawin, A. M. Z.; Kamer, P. C. J. Chem. Commun. 2007, 1556–1558; For a
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Roelfes, G.; Boersma, A. J.; Feringa, B. L. Chem. Commun. 2006, 635–637; (c)
Boersma, A. J.; Feringa, B. L.; Roelfes, G. Org. Lett. 2007, 9, 3647–3650.
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Chemistry: A Textbook, 4th ed.; Springer: Berlin, 2000.
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936–938; (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
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13. Monodentate epoxide substrates, such as styrene oxide, could not be resolved
using our approach. Enantiomeric enrichment of styrene oxide was not
observed upon submission to the reaction conditions. Presumably, styrene
oxide can not successfully compete with water in the coordination to the DNA-
bound metal ion. See also Ref. 5c.
MeOH/Na-phosphate 25 mM pH 6.5 40/60; flow 0.5 mL minꢀ1
;
Tr = 15.9 min; caffeine: Tr = 2.9 min.
4.4. trans-2-(3-Methyl-2-oxiranyl)pyridine 1e
To a cooled (0 °C) suspension of triethylsulfonium bromide22
(1.45 g, 7.28 mmol) in dichloromethane (12 mL) were added tetra-
butylammonium hydrogen sulfate (124 mg, 0.364 mmol) and
freshly distilled pyridine-2-carboxaldehyde (0.77 mL, 8.0 mmol).
A 50% aqueous solution of sodium hydroxide (7 mL) was added
dropwise over 15 min. The reaction mixture was slowly warmed
to room temperature and stirring was continued overnight. The
reaction mixture was diluted with water and ethyl acetate, the lay-
ers separated and the aqueous phase extracted with ethyl acetate
(3 ꢁ 25 mL). The combined organic layers were dried over Na2SO4,
filtered and the solvent was evaporated. Crude yield: (856 mg,
6.3 mmol, 87%) of a dark brown oil. The diastereomers were sepa-
rated by flash column chromatography (SiO2; pentane/diethyl
ether 1:1). The trans-isomer was obtained as a pale yellow oil
(136 mg, 1.0 mmol, 14%). dH (400 MHz; CDCl3) 1.47 (3H, d, J 5.1),
3.12–3.16 (1H, m), 3.74 (1H, d, J 2.2), 7.18–7.21 (2H, m), 7.63–
7.67 (1H, m), 8.53–8.55 (1H, m); dC (100.6 MHz; CDCl3) 17.64 (q),
58.26 (d), 59.67 (d), 119.40 (d), 122.77 (d), 136.60 (d), 149.09 (d),
157.26 (s); m/z (EI) 135 (3.8, M+), 120 (27), 79 (100); HRMS for
C8H9NO: calcd 135.0684, found 135.0681. HPLC: Daicel Chiralpak
AD; heptane/i-PrOH 99:1; flow 1.0 mL minꢀ1; Tr = 11.8; 16.5 min;
rp-HPLC: Vydac C4 MS; MeOH/Na-phosphate 25 mM pH 7.0
30/70; flow 0.5 mL minꢀ1; Tr = 12.8 min; caffeine: Tr = 9.8 min.
14. Hanzlik, R. P.; Hamburg, A. J. Am. Chem. Soc. 1978, 100, 1745–1749.
15. Hanzlik, R. P.; Edelman, M.; Michaely, W. J.; Scott, G. J. Am. Chem. Soc. 1976, 98,
1952–1955.
16. Solladié-Cavallo, A.; Lupattelli, P.; Marsol, C.; Isarno, T.; Bonini, C.; Caruso, L.;
Maiorella, A. Eur. J. Org. Chem. 2002, 1439–1444.
Acknowledgements
17. Copper was shown not to bind MOPS; see: Mash, H. E.; Chin, Y.-P.; Sigg, L.; Hari,
We are grateful to Nanoned and NWO-CW for the financial sup-
port. Mrs. T. Tiemersma-Wegman is acknowledged for technical
assistance with HPLC separations.
R.; Xue, H. Anal. Chem. 2003, 75, 671–677.
18.
½
a 2D0
ꢂ
¼ ꢀ275 (>95% ee, c 3 ꢁ 10ꢀ3, EtOH); Lit.: Solladié-Cavallo, A.; Roje, M.;
Isarno, T.; Sunjic, V.; Vinkovic, V. Eur. J. Org. Chem. 2000, 1077–1080.
½ ꢂ ¼ þ285 (c 1, EtOH).
a 2D2
19. Berti, G.; Bottari, F.; Macchia, B.; Nuti, V. Ann. Chim. (Rome) 1964, 54, 1253–
1265.
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