Synthesis of a neonicotinoide pesticide derivative via chemoenzymatic dynamic kinetic resolution

Article abstract of DOI:10.1021/jo9014276

(Chemical Equation Presented) Chemoenzymatic dynamic kinetic resolution (DKR) via combined ruthenium and enzyme catalysis was used in the key step of a synthesis of a neonicotinoid pesticide derivative (S)-3. The DKR was carried out under mild conditions

Full text of DOI:10.1021/jo9014276

pubs.acs.org/joc
Synthesis of a Neonicotinoide Pesticide Derivative via Chemoenzymatic
Dynamic Kinetic Resolution
†
‡
,†
Patrik Krumlinde, Kriszti ꢀa n Bog ꢀa r, and Jan-E. B €a ckvall*
†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden, and Medicinal Chemistry, Discovery, AstraZeneca R&D S o€ dert a€ lje, SE-151 85 S o€ dert a€ lje, Sweden
‡
jeb@organ.su.se
Received July 8, 2009
Chemoenzymatic dynamic kinetic resolution (DKR) via combined ruthenium and enzyme catalysis
was used in the key step of a synthesis of a neonicotinoid pesticide derivative (S)-3. The DKR was
carried out under mild conditions with low catalyst loading. The method gives (S)-3 in high
enantiomeric excess (98%).
5
Introduction
primary alcohols has in recent years proved to be an
efficient route to enantiopure compounds. This method
relies on a catalytic in situ racemization of the remaining
substrate, thereby enabling 100% yield of enantiomerically
pure product.
As a result of the chiral environment in biological systems,
the two enantiomers of a chemical compound will in many
cases have different biological activity. Therefore it is desir-
able to have access to enantiomerically pure pharmaceuti-
cals, pesticides, perfumes, and flavors, and during the past
three decades asymmetric synthesis has emerged as one of the
Several different racemization catalysts have been ex-
plored, and in our group we have focused on the ruthenium
catalysts shown in Figure 1.
1
most important research areas in organic chemistry.
In industry, resolution of enantiomers is still the predo-
minant method for producing enantiomerically pure com-
pounds. However, resolution is limited to give a maxi-
mum theoretical yield of 50% of the enantiomerically pure
product, and furthermore, the product has to be separated
from the starting material. Combined enzyme- and transi-
2
tion metal-catalyzed dynamic kinetic resolution (DKR) of
3
secondary alcohols and primary amines as well as of
4
FIGURE 1. Ruthenium-based racemization catalysts.
Ever since Bayer released imidacloprid onto the market in
991, neonicotinoid insecticides have been the fastest grow-
(
1) (a) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
1
New York, 2000. (b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
6
ing family of insecticides. The in vivo action of this type of
compounds is similar to that of epibatidine and nicotine
(Figure 2), and the common target is the nicotinic acetylcho-
(
(
2) P ꢁa mies, O.; B €a ckvall, J. -E. Chem. Rev. 2003, 3247–3262.
3) (a) Martı
n-Matute, B.; Edin, M.; Bog ꢀa r, K.; Kaynak, F. B.; B €a ckvall,
´
J.-E. J. Am. Chem. Soc. 2005, 127, 8817–8825. (b) Choi, J. H.; Choi, Y. K.;
Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J. Org. Chem. 2004,
7
line receptor (nAChR).
6
2
9, 1972–1977. (c) Martı
007, 11, 226–232.
4) (a) Paetzold, J.; B €a ckvall, J. -E. J. Am. Chem. Soc. 2005, 127, 17620–
7621. (b) Thal ꢀe n, L. K.; Zhao, D.; Sortais, J. B.; Paetzold, J.; Hoben, C.;
´
n-Matute, B.; B €a ckvall, J.-E. Curr. Opin. Chem. Biol.
(
(5) Str u€ bing, D.; Krumlinde, P.; B €a ckvall, J. -E. Adv. Synth. Catal. 2007,
349, 1577–1581.
1
B €a ckvall, J. -E. Chem.;Eur. J. 2009, 15, 3403–3410. (c) Reetz, M. T.;
Schimossek, K. Chimia 1996, 50, 668–669. (d) Choi, Y. K.; Kim, M. J.;
Ahn, Y.; Kim, M. J. Org. Lett. 2001, 3, 4099–4101.
(6) Jeschkel, P.; Nauen, R. Pest Manage. Sci. 2008, 64, 1084–1098.
(7) Matsuda, K.; Buckingham, S. D.; Kleier, D.; Rauh, J. J.; Grauso, M.;
Sattelle, D. B. Trends Pharmacol. Sci. 2001, 22, 573–580.
DOI: 10.1021/jo9014276
r 2009 American Chemical Society
Published on Web 09/02/2009
J. Org. Chem. 2009, 74, 7407–7410 7407

Krumlinde et al.
JOCArticle
SCHEME 2. DKR of 6
a
TABLE 1. Screening of Conditions for the DKR of 6
Ru-2
scale (mol Na
CALB (mg/
mmol [6] time conv yield ee
entry (mmol) %) (mol %) substrate) (M) (h) (%) (%) (%)
2
CO
3
b
1
2
3
4
5
a
0.2
0.2
6
10
10
5
5
0.5
0.25
0.5
100
100
100
20
25
25
10
2
0.2 48
90 ND 95
0.2 15 100 ND 98
0.5 40 100 86 98
0.5 41 >99 96 >99
0.5 36 100 91 >99
FIGURE 2. Compounds known to act on the nicotinic acetylcho-
line receptor (nAChR).
20
2
Reaction conditions: unless otherwise noted the reaction was carried
SCHEME 1. Synthesis of 6 on 100 mmol Scale
out at 50 °C in toluene with 1.5 equiv of isopropenyl acetate and an
equimolar amount of t-BuOK to ruthenium catalyst 2 loading. The
reaction was carried out at room temperature.
b
Candida antarctica lipase B (CALB) has been shown to
have an excellent enantioselectivity for the 1-phenyl ethanol
motif, and DKR has been carried out on a large number of
derivatives. As expected the enantioselectivity in the trans-
1
1
esterification of 6 in toluene was excellent, both at room
temperature and at 50 °C. DKR using Ru-catalyst 2 is often
performed at room temperature, but sometimes the tempera-
ture has to be elevated when electron-deficient substrates are
employed.
The DKR of 6 was carried out with the enzyme CALB and
ruthenium catalyst 2 in toluene using isopropenyl acetate as
acyl donor (Scheme 2). Reaction at room temperature was
slow and gave 90% conversion and 95% ee after 45 h
The release of imidacloprid to the market stimulated the
development of different derivatives of the neonicotinoid
motif. Recently, Kagabu et al. presented a racemic synthesis
8
of a chiral chloronicotinyl insecticide, Me-imidacloprid (3).
(Table 1, entry 1). Increasing the temperature to 50 °C
The biological activity of this compound is slightly lower
than that of imidacloprid; however, (S)-3 has a higher
potency compared with that of (R)-3. In this paper we
present an easy and efficient synthesis of enantiopure (S)-3
using DKR in the key step.
greatly enhanced the rate of the reaction and also the
enantioselectivity (Table 1, entry 2). The improved enantios-
electivity is due to the faster racemization at higher tempera-
tures, which makes the balance between the acylation rate
and racemization better. In an attempt to make the process
more cost-effective, the catalyst loading was decreased from
Results and Discussion
5
to 0.5 mol % (entry 3 compared to 1 and 2).
The amount of CALB was also decreased from 25 to 10 mg
Alcohol 6 (Scheme 1) is a key intermediate in the synthesis
of (S)-3 using our approach. Racemic 6 was expected to work
as substrate in a DKR reaction, and hence enantiopure (R)-6
would be readily accessible. The synthesis of alcohol 6 was
changed compared to the previously described route
because the new route (Scheme 1) was thought to be easier
in a scale-up procedure. Ketone 5 was synthesized according
9
to the method developed by Kuo.
of 5 yielded 6 in 68% total yield over 3 steps on a 100 mmol
scale. This corresponds to an average yield of 88% in each
step. Alcohol 6 was then employed in the subsequent DKR
without further purification.
CALB/mmol substrate to keep the acylation rate relatively
low compared to racemization. Because of the low catalyst
loading the reaction time had to be extended, and after 40 h
complete conversion had been obtained. In an attempt to
decrease the catalyst loading even further (0.25 mol %, entry
7
4
), the CALB loading was also decreased to 2 mg/mmol
,10
substrate to keep the racemization and resolution rates
balanced. The result was a slower reaction, but with excellent
yield and enantiomeric excess. To ensure complete conver-
sion within a reasonable reaction time the Ru-catalyst load-
ing was again increased to 0.5 mol %, and this time the
reaction was finished within 36 h with >99% ee (entry 5).
To avoid purification between steps, direct hydrolysis of
product 7to (R)-6 in the crude reaction mixture was investigated.
The NaBH reduction
4
(8) Kagabu, S.; Kiriyama, K.; Nishiwaki, H.; Kumamoto, Y.; Tada, T.;
Nishimura, K. Biosci. Biotechnol. Biochem. 2003, 67, 980–988.
(
(
9) Kuo, D. L. Tetrahedron 1992, 48, 9233–9236.
10) For a scale-up synthesis of 5 to 100 g with this method, see: Lee,
(11) For transesterification in organic solvents, see: (a) Faber, K. Bio-
transformations in Organic Chemistry, 5th ed.; Springer: Berlin, 2004. (b)
Bornscheuer, U. T., Kazlauskas, R. J. Hydrolases in Organic Synthesis, 2nd
ed.; Wiley-VCH: Weinheim, 2005.
C. -H.; Jiang, M.; Cowart, M.; Gfesser, G.; Perner, R.; Kim, K. H.; Gu,
Y. G.; Williams, M.; Jarvis, M. F.; Kowaluk, E. A.; Stewart, A. O.; Bhagwat,
S. S. J. Med. Chem. 2001, 44, 2133–2138.
7
408 J. Org. Chem. Vol. 74, No. 19, 2009

Krumlinde et al.
JOCArticle
SCHEME 3. Hydrolysis of (R)-7
SCHEME 4. Mesylation of (R)-6
Hydrolysis under alkaline conditions (NaOH in MeOH)
resulted in racemization of the product, most probably catalyzed
by remaining ruthenium species. The hydrolysis of 7 was there-
SCHEME 5. SN2 Substitution of Mesylate (R)-8 by Nitrogua-
nidine 9 To Yield the Final Product (S)-3
12
fore carried out with CALB in a phosphate buffer (pH 7.2),
which leads to very mild reaction conditions (Scheme 3). An
additional benefit of using CALB for the hydrolysis is that a
second resolution is introduced, thereby yielding a mixture
consisting of traces of the (S)-enantiomer of 7 and the enantio-
pure (R)-6as the major component. This poses no problem in the
following reactions since the acetate 7 is more or less unreactive
to those reaction conditions and is easily removed in the final
purification. Attempts to perform the S 2 substitution directly
N
on (R)-7 (DMSO, K CO (2 equiv) 90 °C, 16 h) with nitrogua-
2
3
nidine derivative 9(see Scheme 5 for the structure) as nucleophile
were unsuccessful and gave only a hydrolysis product (6) insmall
amounts.
TABLE 2. Screening of Conditions for the Substitution of (R)-8
entry
a
solvent
temp (°C) concn (M) time (h) yield (%) ee (%)
1
MeCN
reflux
50
90
0.1
0.1
0.1
0.2
0.2
0.1
0.1
14
50
4
40
34
53
51
58
63
69
85
91
94
98
98
92
96
8
a,d
In the article by Kagabu et al. alcohol 6 was transformed
2
MeCN
1,4-dioxane
THF
THF
DMSO
DMSO
a
3
to the tosylate to provide a good leaving group for the final
SN2 substitution. All efforts to reproduce the tosylation
procedure were unsuccessful, since the tosylate was found
to be unstable and difficult to purify. We therefore turned
our attention to the mesylate group, a good alternative to the
tosylate group. Even though mesylate 8 was more stable than
the corresponding tosylate, 8 is still rather unstable. If it is
stored at room temperature, it decomposes within weeks,
where one of the decomposition products is the vinyl com-
pound. Mesylate 8 also racemizes at room temperature,
probably via elimination and readdition of the mesylate
group. After 2 days at room temperature, the ee drops from
b
4
50
50
50
25
20
16
1
c
5
c
6
c
7
3
a
b
2 3
Base: K CO (2 equiv), 9 (1 equiv). Base: NaH (1 equiv), 9 (1 equiv).
d
Base: NaH (3 equiv), 9 (3 equiv). Full conversion was not obtained.
c
on the reactant and the reaction conditions, this can in many
15
cases be the dominating pathway. With electron-deficient
substrates the cationic intermediate is destabilized and the
reaction is more likely to proceed according to the S 2 model.
N
In the case of nucleophilic substitutions in the pyridylmethyl
position, which is positionally equivalent to a benzylic position
but electron-deficient, the S 2 pathway should be followed.
>
99% to 97%. Elimination and racemization is also a severe
problem if 8 is subjected to column chromatography puri-
fication. These problems have been noticed before with
similar types of compounds and have been solved by pre-
cipitation and filtration of the salts in the mesylation proce-
N
However, the position of the nitrogen is important for the
degree of electron deficiency. Pyridyl-2-methyl and pyridyl-4-
methyl cations are destabilized both inductively and by reso-
nance, but the pyridyl-3-methyl cation is destabilized only by
induction. This can be seen in case of 1-(x-pyridyl)ethyl
methanesulfonates (x=2, 3, 4) where the 2- and 4-positioned
ethyl methanesulfonates are stable enough to enable silica gel
chromatography. However, having the substituent in 3-posi-
tion destabilizes the molecule to such a degree that not even
1
3
dure as the only purification. In the case of 8 it is possible to
make an aqueous workup with retained ee and high yield. In
this workup the inorganic salts are removed and will not
interfere in the subsequent reaction. Aqueous workup
afforded (R)-8 in 92% yield with no or a small decrease in
enantiopurity (>99% ee). This material has to be used
1
4
13
quickly or stored in a freezer.
The final step in the synthesis is an S 2 substitution of the
aqueous workup is possible.
N
In the case of mesylate 8 the chlorine in the 2-position seems
to destabilize the pyridylmethyl cation compared to the non-
halogenated pyridine since aqueous workup is possible.
Kagabu et al. obtained 9% yield of 3 in the substitution
performed in acetonitrile with K CO as base. In their case
mesylate. Substitutions in the benzylic position are known to
have a competing S 1 pathway. Depending on the substituents
N
(
12) It is important to point out that this method requires full conversion
2
3
in the DKR reaction (>99%); otherwise the nonconverted racemic alcohol
will deteriorate the ee after hydrolysis.
they used the tosylate as leaving group. As mentioned above,
we experienced this group to be less stable than the mesylate,
which could explain the low yield. Using the similar condi-
tions for reaction of mesylate 8 with 9 yielded (S)-3 in 40%
yield with an ee of 85% (entry 1, Table 2). In an attempt to
increase both the yield and ee, the temperature was lowered
to 50 °C, but the reaction did not go to completion within
50 h (entry 2). The yield was also lower, which could be
(
13) Uenishi, J.; Hamada, M.; Aburatani, S.; Matsui, K.; Yonemitsu, O.;
Tsukube, H. J. Org. Chem. 2004, 69, 6781–6789.
14) At -18 °C no loss of ee or decomposition could be detected after 1
month.
(
(15) (a) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T. J. Am.
Chem. Soc. 1985, 107, 4513–4519. (b) Richard, J. P.; Jencks, W. P. J. Am.
Chem. Soc. 1984, 106, 1383–1396. (c) Zieger, H. E.; Bright, D. A.;
Haubenstock, H. J. Org. Chem. 1986, 51, 1180–1184. (d) Lim, C.; Kim, S.
-
H.; Yoh, S. -D.; Fujio, M.; Tsuno, Y. Tetrahedron Lett. 1997, 38, 3243–3246.
J. Org. Chem. Vol. 74, No. 19, 2009 7409

Krumlinde et al.
JOCArticle
þ
explained by the interrupted reaction, but the ee was
improved to 91%. Since a large amount of nonidentified
byproducts was obtained in acetonitrile, we turned our
attention to less ionizing solvents such as dioxane and
THF. These gave indeed better results, both in terms of yield
and ee. The best result was obtained in THF (50 °C for 16 h)
using 3 equiv of 9, which had been pretreated with NaH in
situ (entry 5; Scheme 5). Lowering the temperature to 25 °C
gave a very slow reaction (not included in the table). A
HRMS (ESI) (M þ Na) : m/z calcd for C H ClNNaO
2
7
8
180.0187, obsd 180.0193. Chiral GC gradient (carrier gas H
,
flow 1.8 mL/min): 110 °C, 10 min; 1 °C/min to 135 °C, 0 min;
8
(
0 °C/min to 200 °C, 6 min. Retention times: (R)-6, 32.63 min;
S)-6, 34.11 min.
R)-1-(6-Chloropyridin-3-yl)ethyl Methanesulfonate ((R)-8).
R)-6 (0.39 g, 2.5 mmol) and Et N (0.52 mL, 3.7 mmol) were
(
(
3
dissolved in CH Cl (5 mL) and cooled to 0 °C. MsCl (0.21 mL,
.7 mmol) was added dropwise to the solution upon which a
white precipitate was formed. After being stirred at 0 °C for 1 h,
10 mL of CH Cl and 10 mL of H O were added. The layers were
2
2
2
standard solvent for S 2 reactions is DMSO, and employing
N
2
2
2
it gave a very fast reaction, at both 50 and 25 °C (entry 6 and 7
respectively). The best result was obtained at 25 °C with a
yield of 69% and ee of 96%.
separated, and the aqueous layer was further extracted with
CH Cl
(2 ꢀ 10 mL). The combined organic layers were dried
over MgSO , filtered, and evaporated to yield 0.55 g of a yellow
oil that solidified upon standing. Yield 92%, ee >99%. For a
pure sample it is possible to run silica gel column chromatogra-
2
2
4
Conclusion
2 2
phy (CH Cl /EtOAc 19:1), although the majority of 8 will
In conclusion, we have presented an easy, scalable, and
highly stereoselective process (98% ee) of an imidacloprid
derivative in 32% total yield over 7 steps (85% average yield
in each step), which could be of importance for future
development of pesticides.
decompose. Compound 8 also racemized to some extent on
(ee 97%) = þ70.42 (c 1.2,
3
2
0
column chromatography. [R]
D
1
EtOAc). H NMR (400 MHz, CDCl ): δ 8.42 (1 H, app dt,
J=2.5, 0.6 Hz), 7.72 (1 H, ddd, J=8.3, 2.5, 0.4 Hz), 7.37 (1 H, dd,
J=8.3, 0.6 Hz), 5.76 (1 H, q, J=6.6 Hz), 2.91 (3 H, s), 1.72 (3 H,
13
d, J=6.6 Hz). C NMR (100 MHz, CDCl ): δ 152.2, 147.9,
1
3
þ
36.9, 134.3, 124.7, 76.8, 39.2, 23.2. HRMS (ESI) (M þ Na) : m/
Experimental Section
z calcd for C
HPLC: AS (isocratic, isohexane/isopropanol 70:30, flow
.5 mL/min). Retention times: (R)-8, 30.1 min; (S)-8, 37.0 min.
S)-Me Imidacloprid ((S)-3). Method A. Compound 9 (160
mg, 1.2 mmol) and NaH (60% suspension in mineral oil, 48 mg,
.2 mmol) were suspended in THF (2 mL). The mixture was
8 3
H10ClNNaO S 257.9962, obsd 257.9961. Chiral
(
R)-1-(6-Chloropyridin-3-yl)ethyl Acetate ((R)-7). t-BuOK
0
(0.5 M in THF, 103 μL, 0.052 mmol) was added to a flame-
dried Schlenk flask under argon. THF was removed under
vacuum, and the flask refilled with argon. Ru-catalyst 2
(
1
(
2
33 mg, 0.052 mmol), CALB (20 mg), Na
.1 mmol), and toluene (16 mL) were added, and the mixture
was stirred for 5 min at 50 °C followed by the addition of alcohol
(1.6 g, 10.3 mmol) in 5 mL of toluene. The reaction was stirred
for another 5 min at 50 °C, and then isopropenyl acetate
1.7 mL, 15.5 mmol) was charged to the flask. The reaction
2 3
CO (220 mg,
stirred for 4 h at 50 °C until the gas evolution had ceased.
Mesylate (R)-8 (94 mg, 0.40 mmol) was added in one portion,
and the reaction was stirred for an additional 16 h at 50 °C. The
solids were filtered off, the solution was evaporated onto silica,
and the product was purified by silica gel column chromato-
graphy using EtOAc as eluent. Yield 63 mg (58%), ee 98%.
Method B. Compound 9 (160 mg, 1.2 mmol) and NaH (60%
suspension in mineral oil, 48 mg, 1.2 mmol) were suspended in
DMSO (4 mL). The mixture was stirred for 2 h at 25 °C until the
gas evolution had ceased. Mesylate (R)-8 (94 mg, 0.40 mmol)
was added in one portion, and the reaction was stirred for an
additional 3 h at 25 °C. Water and EtOAc were added, and the
layers were separated. The aqueous layer was extracted with
EtOAc (3 ꢀ 10 mL). The combined organic layers were washed
6
(
was stirred at 50 °C for 36 h. The conversion was checked by
both H NMR (>99.9%) and GC (>99.7%). The solids were
1
removed by filtration through Celite using EtOAc as eluent. The
solvent was evaporated, yielding 1.88 g of an orange liquid,
which upon standing turned green, yield 91%, ee >99%. The
product was used without further purification. A small sample
was purified by silica gel column chromatography (CH
2
Cl
2
used
=þ87.44 (c 1.4, EtOAc). H NMR
400 MHz, CDCl ): δ 8.37 (1 H, app dt, J=2.5, 0.6 Hz), 7.63 (1
2
0
1
as eluent) for analysis. [R]
(
D
3
with brine and then dried over MgSO . The solids were filtered
H, ddd, J=8.3, 2.5, 0.4 Hz), 7.30 (1 H, dd, J=8.3, 0.5 Hz), 5.85 (1
H, q, J=6.7 Hz), 2.06 (3 H, s), 1.53 (3 H, d, J=6.7 Hz). C NMR
4
1
3
off, and the solution was evaporated onto silica and purified by
silica gel column chromatography using EtOAc as eluent. Yield
(
6
C
(
1
(
100 MHz, CDCl
3
): δ 170.1, 151.0, 148.0, 136.9, 136.2, 124.3,
2
0
D
þ
63 mg (69%), ee 96%. [R]
(ee = 98%) = -130.68 (c 0.73,
9.5, 22.0, 21.2. HRMS (ESI) (M þ Na) : m/z calcd for
1
EtOAc). H NMR (400 MHz, CDCl ): δ 8.35 (1 H, app d, J=2.6
H
7 8
ClNNaO 222.0292, obsd 222.0297. Chiral GC gradient
carrier gas H
, flow 1.8 mL/min): 110 °C, 0 min; 2 °C/min to
35 °C, 0 min; 80 °C/min to 200 °C, 6 min. Retention times:
S)-7, 12.62 min; (R)-7, 12.87 min.
R)-1-(6-Chloropyridin-3-yl)ethanol ((R)-6). (R)-7 (1.9 g,
.4 mmol) and CALB (20 mg) were suspended in a mixture of
3
Hz), 8.18 (1 H, bs), 7.65 (1 H, ddd, J=8.3, 2.5, 0.4 Hz), 7.31 (1 H,
d, J=8.3 Hz), 5.50 (1 H, q, J=7.4 Hz), 3.82-3.57 (3 H, m),
2
1
3
3
MHz, CDCl
4
.25-3.18 (1 H, m), 1.58 (3 H, d, J=7.2 Hz). C NMR (100
3
): δ 160.8, 151.3, 148.4, 138.1, 133.5, 124.5, 48.9,
(
þ
1.5, 40.7, 15.8. HRMS (ESI) (M þ Na) : m/z calcd for
9
C
10
H12ClN
5 2
NaO 292.0572, obsd 292.0586. Chiral HPLC: AS
MeOH (10 mL) and phosphate buffer (pH 7.2, 10 mL). The
mixture was stirred 44 h at ambient temperature, monitored by
TLC. Water (20 mL) was added, and the mixture was extracted
with EtOAc (3 ꢀ 10 mL). The combined organic layers were
(isocratic, isohexane/isopropanol 50:50, flow 0.5 mL/min).
Retention times: (R)-3, 46.6 min; (S)-3, 57.3 min.
dried over MgSO , filtered, and evaporated to give 1.49 g of a
4
Acknowledgment. The Swedish Research Council, the
Berzelius Center EXSELENT, and K & A Wallenberg found-
ation are gratefully acknowledged for financial support.
green oil: 98 mol % of (R)-6 and 2 mol % of 7. This was used
without further purification. A small sample was purified by
silica gel column chromatography (eluent CH Cl /EtOAc 1:1)
2
2
20
1
for analysis. [R]
= þ46.05 (c 2.1, EtOAc). H NMR (400
D
MHz, CDCl
ddd, J=8.3, 2.5, 0.5 Hz), 7.27 (1 H, d, J=8.3 Hz), 4.92 (1 H, q,
3
): δ 8.28 (1 H, app dt, J=2.5, 0.8 Hz), 7.68 (1 H,
Supporting Information Available: General procedures and
1
13
copies of H and C NMR spectra and chromatograms of
compounds (R)-6, (R)-7, (R)-8, and (S)-3. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
3
J=6.5 Hz), 3.03 (1 H, s), 1.48 (3 H, d, J=6.5 Hz). C NMR (100
MHz, CDCl ): δ 150.2, 147.2, 140.3, 136.4, 124.3, 67.4, 25.4.
3
7
410 J. Org. Chem. Vol. 74, No. 19, 2009