Chemoenzymatic synthesis of rivastigmine via dynamic kinetic resolution as a key step.
ABSTRACT A practical and efficient procedure for the synthesis of rivastigmine was developed. This procedure includes dynamic kinetic resolution using a polymer-bound ruthenium complex and a lipase in combination as a key step. Enantiopure (-)-rivastigmine was obtained from commercially available 3'-hydroxyacetophenone via five steps in overall 57% yield.
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ABSTRACT: Secondary alcohols having bulky substituents on both sides of the hydroxy group are inherently poor substrates for most lipases. In view of this weakness, we redesigned a Burkholderia cepacia lipase to create a variant with improved enzymatic characteristics. The I287F/I290A double mutant showed a high conversion and a high E value (>200) for a poor substrate for which the wild-type enzyme showed a low conversion and a low E value (5). This enhancement of catalytic activity and enantioselectivity of the variant resulted from the cooperative action of two mutations: Phe287 contributed to both enhancement of the (R)-enantiomer reactivity and suppression of the (S)-enantiomer reactivity, while Ala290 created a space to facilitate the acylation of the (R)-enantiomer. The kinetic constants indicated that the mutations effectively altered the transition state. Substrate mapping analysis strongly suggested that the CH/π interaction partly enhanced the (R)-enantiomer reactivity, the estimated energy of the CH/π interaction being -0.4 kcal mol(-1). The substrate scope of the I287F/I290A double mutant was broad. This biocatalyst was useful for the dynamic kinetic resolution of a variety of bulky secondary alcohols for which the wild-type enzyme shows little or no activity.Organic & Biomolecular Chemistry 06/2012; 10(31):6299-308. · 3.57 Impact Factor
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ABSTRACT: Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipase B and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transformed into homoallylic acrylates after hydrolysis of the ester function and subsequent DMAP-catalyzed esterification with acryloyl chloride. After ring-closing metathesis 5,6-dihydropyran-2-ones were obtained in good yields. Selective hydrogenation of the carboncarbon double bond afforded the corresponding δ-lactones without loss of chiral information.Chemistry - A European Journal 08/2013; · 5.93 Impact Factor
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ABSTRACT: A highly efficient and convenient procedure for the enantioselective synthesis of (S)-Rivastigmine, a cho-linergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson’s disease, is accomplished by the treatment of versatile, readily accessible (S)-(-)-2-methyl- 2-propanesulfinamide with 3-hydroxyacetophenone. This protocol provides high yield and excellent enan-tiomeric excess in short step synthesis.International Journal of Organic Chemistry. 01/2011; 1:30-36.
r2010 American Chemical Society
Published on Web 03/26/2010
J. Org. Chem. 2010, 75, 3105–3108 3105
Chemoenzymatic Synthesis of Rivastigmine via
Dynamic Kinetic Resolution as a Key Step
Kiwon Han, Cheolwoo Kim, Jaiwook Park,* and
Department of Chemistry and Bionanotechnology Center,
Pohang University of Science and Technology,
San-31 Hyojadong, Pohang 790-784, Korea
Received December 31, 2009
A practical and efficient procedure for the synthesis of
rivastigmine was developed. This procedure includes
dynamic kinetic resolution using apolymer-boundruthe-
nium complex and a lipase in combination as a key step.
Enantiopure (-)-rivastigmine was obtained from com-
in overall 57% yield.
Rivastigmine (1) is anacetylcholinesterase inhibitorof the
a long duration of action.1It improves cognition, participa-
tion indaily activities,andglobal evaluation ofpatients with
mild to moderate Alzheimer’s disease.2In addition, it is
supposed to be effective in the treatment of dementia caused
by Parkinson’s disease3and Lewy body.4Now, its tartrate
first synthesized by resolution of the racemic rivastigmine
using (þ)-di-O,O0-p-toluoyl tartaric acid monohydrate in
1987.5Later, asymmetric syntheses of rivastigmine were
reported.6Herein, we wish to report an alternative asym-
metric synthetic procedure for rivastigmine, which includes
the dynamic kinetic resolution of a secondary alcohol inter-
mediate as a key step.
is an attractive strategy to obtain enantiomerically enriched
products from racemic substrates with high yields and
excellent enantiomeric excesses, both approaching 100%.7
Several groups including ours have developed racemization
catalysts that are compatible with the enzymatic systems
are soluble in the reaction medium so that recovering them
is not easy after the reaction is complete. Recently, we
reported the use of a polymer-bound racemization catalyst
(2) in the DKR of alcohols (Figure 1).9,10In this work, we
used its modified analogue 3 which was more practical to
The polymer-bound racemization catalyst 3 was prepared
by heating a mixture of polystyrene-attached benzoyl chlor-
ide (4) and [Ph4(η4-C4CO)]Ru(CO)3(5) in toluene for 1 d
in the racemization of optically active 1-phenylethanol ((S)-6,
>99%ee) (Table1). The racemization of (S)-6 in the presence
(1) Polinsky, R. J. Clin. Ther. 1998, 20, 634–647.
(2) Rosler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.;
Dal-Bianco, P.; Stahelin, H. B.; Hartman, R.; Gharabawi, M. Brit. Med. J.
1999, 318, 633–638.
(3) Reading, P. J.; Luce, A. K.; McKeith, I. G. Movement Disord. 2001,
Cicin-Sain, A.; Ferrara, R.; Spiegel, R. Lancet 2000, 356, 2031–2036.
(5) Enz, A. GB 2203040A, 1987.
(6) (a) Boezio, A. A.;Pytkowicz, J.; C^ ot? e, A.; Charette,A. B.J. Am. Chem.
Soc. 2003, 125, 14260–14261. (b) Mangas-S? anchez, J.; Rodrı´guez-Mata,
M.; Busto, E.; Gotor-Fern? andez, V.; Gotor, V. J. Org. Chem. 2009, 74, 5304–
5310. (c) Hu, M.; Zhang, F.-L.; Xie, M.-H. Synth. Commun. 2009, 39, 1527–
587. (b) Pamies, O.; B€ ackvall, J.-E. Chem. Rev. 2003, 103, 3247–3262.
(c) Kim, M.-J.; Ahn, Y.; Park, J. Bull. Korean Chem. Soc. 2005, 26, 515–
522. (d) Kim, M.-J.; Park, J.; Ahn, Y. In Biocatalysis in the Pharmaceutical and
Biotechnology Industries; Patel, R. N., Ed.; CRC Press: Boca Raton, 2007; pp
249-272. (e) Martín-Matute, B.; B€ ackvall, J.-E. Curr. Opin. Chem. Biol. 2007,
(8) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park,
J. Angew. Chem., Int. Ed. 2002, 41, 2373–2376. (b) Kim, M.-J.; Chung, Y. I.;
Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am. Chem. Soc. 2003, 125,
11494–11495. (c) Martı´n-Matute, B.; Edin, M.; Bog? ar, K.; B€ ackvall, J.-E.
Angew. Chem., Int. Ed. 2004, 43, 6535–6539. (d) Kim, M.-J.; Kim, H. M.;
Kim, D. H.; Park, J. Green Chem. 2004, 6, 471–474. (e) Martı´n-Matute, B.;
Edin, M.; Bog? ar, K.; Kaynak, F. B.; B€ ackvall, J.-E. J. Am. Chem. Soc. 2005,
127, 8817–8825. (f) Hilker, I.; Rabani, G.; Verzijl, G. K. M.; Palmans,
A. R. A.; Heise, A. Angew. Chem., Int. Ed. 2006, 45, 2130–2132. (g) Akai, S.;
Tanimoto, K.; Kanao, Y.; Egi, M.; Yanamoto, T.; Kita, Y. Angew. Chem.,
Int. Ed.2006,45, 2592–2595. (h)Eckert, M.;Brethon,A.; Li,Y.X.; Sheldon,
R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2007, 349, 2603–2609. (i) Ko
S.-B.; Baburaj, B.; Kim, M.-J.; Park, J. J. Org. Chem. 2007, 72, 6860–6864.
(j) Kim, M.-J.; Lee, H. K.; Park, J. Bull. Korean Chem. Soc. 2007, 28, 2096–
2098. (k) Bog? ar, K.; Vidal, P. H.; Le? on, A. R. A.; B€ ackvall, J.-E. Org. Lett.
2007, 9, 3401–3404. (l) Kim, M.-J.; Choi, Y. K.; Kim, S.; Kim, D.; Han, K.;
F.; Jerphagnon, T.; Gayet, A. J. A.; Tarabiono, C.; Postema, C. P; Ritleng,
J. Am. Chem. Soc. 2008, 130, 13508–13509.
(10) For the DKRs of secondary alcohols using other heterogeneous
racemization catalysts, see: (a) Wuyts, S.; De Temmerman, K.; De Vos,
Jacobs, P. A.; De Vos, D. E. Green Chem. 2007, 9, 1104–1108. (c) Zhu,
(11) The synthesis of 2 required a long reaction time (5 days), while the
synthesis of 3 was complete within 1 day because the polymer-attached
benzoyl chloride (4) was more reactive than its benzyl chloride counterpart.
3106 J. Org. Chem. Vol. 75, No. 9, 2010
Han et al.
complete within 8 h. The racemization activity remains unal-
tered even after five repeated use of 3 and K2CO3.
We then explored the DKR of racemic 6 with recycling 3
and a commercial lipase (Candida antarctica lipase B im-
mobilized on polyacrylic resin; trade name, Novozym-435).
containing isopropenyl acetate (1.5 equiv) as acyl donor,
3 (4 mol %), Novozym-435 (10 mg/mmol of substrate), and
potassium carbonate (1 equiv) in toluene at room tempera-
turefor1 day(Scheme 2).ThefirstDKRreactionproceeded
smoothly toafford theacetate7in goodisolatedyield(96%)
and high optical purity (99% ee). Then, the DKR reaction
was repeated four times with the recycling of both 3 and
lipase. After each run, the solid mixture containing catalysts
3 times with dry toluene, and then reused. In the fourth run,
the conversion was only 61% after 1 day, but the catalytic
activity was resumed by the addition of 1 equiv of fresh
potassium carbonate in the fifth run (Table 2). These results
several times without losing their activities.12
The application of DKR using 3 in the synthesis of
rivastigmine is described in Scheme 3. Alcohol intermediate
10 for DKR was prepared in two steps from commercially
available starting material 8. The reaction of 8 with N-ethyl-
N-methylcarbamoyl chloride afforded 9 (85% yield) which
in turn was reduced with NaBH4to give 10 quantitatively.13
Before the DKR of 10, its enzymatic kinetic resolution
enantioselectivity. The EKR of 10 (0.3 mmol) was carried
out in the presence of isopropenyl acetate as acyl donor with
Novozym-435 (30 mg/mmol ofsubstrate) in toluene atroom
temperature. The reaction proceeded to 50% completion in
FIGURE 1. Polymer-supported ruthenium catalysts.
TABLE 1.Recycling of 3 in the Racemization of (S)-6a
run reaction time (h)% ee of 6b
aReaction condition: (S)-6 (0.15 mmol), 3 (4 mol % Ru), K2CO3
(1 equiv), toluene (0.5 mL), rt.bDetermined by HPLC.
Preparation of Polymer-Bound Ruthenium
DKR of 6
Recycling of Catalysts in the DKR of 6a
aReaction conditions: 6 (0.50 mmol), 3 (4 mol % Ru), Novozym-435
(0.5 mL), rt, 1 d.bMeasured by1H NMR.cMeasured by HPLC with a
chiral column.d1 equiv of fresh K2CO3was added.
Asymmetric Synthesis of Rivastigminea
Cl2(0.3 M), rt, 4 h, 85%; (ii) NaBH4(1 equiv), MeOH (1 M), 0 ?C,
10 min, 99%; (iii) 3 (4 mol % Ru), Novozym-435 (30 mg/mmol),
isopropenyl acetate (1.5 equiv), K2CO3(1 equiv), toluene (0.3 M), rt, 1 d,
92%, 99% ee; (v) MeSO2Cl (1.3 equiv), Et3N (3 equiv), CH2Cl2(0.2
M), 0 ?C, 30 min, and then Me2NH in THF (4 equiv), rt, 2 d, 77%.
(12) The removal of potassium carbonate from the polymer-attached
catalysts and the separation between the latter were not tried because they
were not readily separable.
(13) N-Ethyl-N-methylcarbamoyl chloride was prepared from triphos-
gene and ethylmethylamine in the presence of sodium bicarbonate in
J. Org. Chem. Vol. 75, No. 9, 20103107
Han et al.
enantioselectivity fortheresolutionis excellent(E=>400).
The DKR of 10 (1 mmol) was then carried out with 3
(4 mol %), Novozym-435 (30 mg/mmol), isopropenyl acetate
(1.5 equiv), and K2CO3(1 equiv) in toluene at room tem-
perature for 1 day. The acylated product 11 was obtained in
96% isolated yield and 99% ee. The DKR reaction was
repeated with 3, lipase, and K2CO3, all of which were
recovered from the first reaction, under identical conditions
to give 11 with similarly good results (94% isolated yield,
99% ee). Ester 11 was hydrolyzed under alkaline conditions
(K2CO3/MeOH/H2O) at room temperature for 2 h to give
(R)-10 (92% isolated yield, 99% ee) without loss in optical
purity. Finally, (R)-10 was transformed into target com-
pound 1 (77% isolated yield and 97% ee)14via a mesylated
intermediate according to the known procedure.15The over-
all yield was 57% from 8.
In summary, we have demonstrated a highly efficient
synthesis of rivastigmine via chemoenzymatic DKR using
This synthesis presents an illustrative application of enzyme-
metal cocatalysis for asymmetric synthesis of chiral drugs.
solution of methyl 4-hydroxybenzoate (685 mg, 4.5 mmol) in N,
N-dimethylformamide (20 mL) was added dropwise to a sus-
pension of chloromethyl polystyrene (882 mg, 3.0 mmol; sus-
bstitution: 3.4 mmol/g), cesium carbonate (1.47 g, 4.5 mmol),
and sodium iodide (135 mg, 0.9 mmol) in N,N-dimethylforma-
mide (10 mL) at room temperature. The mixture was stirred at
room temperature. After 1 day, the result solid was filtered,
washed with water (20 mL), acetone (20 mL) and CH2Cl2
30 mL) was added to solid mixture of 12 (1.23 g, 3.0 mmol) and
mixture was stirred at room temperature. After 1 day, the result
solid was filtered, washed with water (20 mL), acetone (20 mL),
and CH2Cl2(20 mL), and dried under vacuum to give polystyr-
ene containing benzoic acid (13) of pale yellow solid (1.15 g,
97% yield; FT-IR, 1723 cm-1). A solution of thionyl chloride
(436 μL, 6.0 mmol) in dry toluene (10 mL) was added dropwise
120 ?C and refluxed for 1 day. The reaction mixture was cooled
to room temperature and filtered. The result solid was washed
brown solid (1.09 g, overall 88% yield; FT-IR, 1717 cm-1).
Synthesis of Polymer-Supported Ruthenium Catalyst (3). In a
50-mL flask equipped with a grease-free high-vacuum stopcock
were placed 4 (414 mg, 1.0 mmol), η4-(C4Ph4CO)(CO)3Ru (5)
(570 mg, 1.0 mmol), and dry toluene (20 mL) under argon
atmosphere. The mixture was stirred at 130 ?C for 1 day. The
reaction mixture was cooled to room temperature and filtered.
The result solid was washed with acetone (10 mL) and CH2Cl2
(10 mL) and dried under vacuum to give 3 of orange solid
identified by ICP mass. The product’s molecular weight was
2381 g/mol in accordance with the result of ICP mass. FT-IR
(cm-1): 2043, 1990, 1715.
General Procedure for Recycling of 3 in the Racemization of
Optically Active 1-Phenylethanol ((S)-6). A suspension contain-
ing K2CO3(21 mg, 0.15 mmol), 3 (14 mg, 6 μmol), and (S)-6
(17 μL, 0.15 mmol) in dry and degassed toluene (500 μL) was
Immediately, 1-phenylethanol (17 μL, 0.15 mmol) and toluene
(500 μL) were added, and the mixture was stirred for 8 h. These
procedures were repeated four times.
acetate (83 μL, 0.75 mmol), and 6 (55 μL, 0.5 mmol) in dry and
degassed toluene (1.7 mL) was stirred at room temperature under
was purified by column chromatography on silica gel to give
(R)-ester (7) (96% yield, 99% ee).
Recycling of the Catalytic System in DKR of 6. A suspension
containing K2CO3(21 mg, 0.15 mmol), 3 (14 mg, 6 μmol),
Novozym-435 (1.5 mg, 10 mg/mmol), isopropenyl acetate (25 μL,
(500 μL) was stirred at room temperature under argon in a 25 mL
Schlenk flask. After 24 h, the solution was removed, and the
solid residue was washed with dry and degassed toluene (3 ?
(25 μL, 0.23 mmol), and toluene (500 μL) were added, and
5 times. In the fifth recycling reaction, 1 equiv of fresh K2CO3
was added before 6, isopropenyl acetate, and toluene were
Synthesis of 3-Acetylphenyl Ethyl(methyl)carbamates (9). To
a suspension containing 30-hydroxyacetophenone (8, 1.12 g,
8.3 mmol) in dry CH2Cl2(15 mL) were added NaH (60%,
dispersion in mineral oil, 660 mg, 16.6 mmol) and N-ethyl-
atmosphere, and the resultant mixture was stirred for 4 h. The
reaction was quenched by addition of H2O (5 mL). The reaction
mixture was extracted with CH2Cl2/H2O, and the organic layer
product. The residue was purified with column chromatography
(silica gel, MeOH/CH2Cl2= 1/10) to provide oily 9 (1.55 g, 85%
yield):1H NMR (CDCl3, 300 MHz, ppm) δ 7.81-7.77 (m, 1H),
2H), 3.05 (d, J = 25.12 Hz, 3H), 2.60 (s, 3H), 1.29-1.18 (m, 3H);
13C NMR (CDCl3, 75 MHz, ppm) δ 197.3, 154.3, 151.8, 138.4,
129.4, 126.7, 125.1, 121.7, 44.2, 34.3, 33.9, 26.7, 13.3, 12.4; HRMS
(EI) C12H15NO3calcd 221.1052 (Mþ), found 221.1050.
Synthesis of 3-(1-Hydroxyethyl)phenyl Ethyl(methyl)carba-
mates (10). To a solution of 9 (1 g, 4.52 mmol) in dry methanol
at 0 ?C under argon atmosphere. The reaction mixture was
stirred at 0 ?C for 10 min. After completion of the reaction was
confirmed by TLC, the reaction was quenched by careful
addition of H2O (1 mL), and methanol was evaporated. The
residue was extracted with CH2Cl2/H2O, and the organic layers
were combined and dried over MgSO4. The solvent was evapo-
99% yield):1H NMR (CDCl3, 300 MHz, ppm) δ 7.33 (t, J =
(q, J = 6.48 Hz, 1H), 3.51-3.38 (m, 2H), 3.03 (d, J = 23.25 Hz,
3H), 1.49 (d, J = 6.45 Hz, 3H), 1.27-1.17 (m, 3H);13C NMR
(CDCl3, 75 MHz, ppm) δ 154.7, 151.7, 147.6, 129.2, 122.2,
literature: Srinivasu, M. K.; Rao, B. M.; Reddy, B. S.; Kumar, P. R.;
Chandrasekhar, K. B.; Mohakhud, P. K. J. Pharm. Biom. Anal. 2005, 38,
(15) Fieldhouse, R. PCT WO 2005/058804 A1, 2005. In this reference,
mesyl anhydride was used as mesylating agent. In our case, we employed
mesyl chloride instead of mesyl anhydride.
3108J. Org. Chem. Vol. 75, No. 9, 2010
Han et al.
120.6, 118.8, 69.9, 44.1, 34.2, 33.8, 25.0, 13.2, 12.5; HPLC
(Chiracel-OD, n-hexane/2-propanol =95/5, flow rate =1.0 mL/
min, UV 217 nm) (S)-10 = 17.27 min, (R)-10 = 20.13 min;
HRMS (EI) C12H17NO3calcd 223.1208 (Mþ), found 223.1206.
anhydrous toluene (300 μL, 0.3 M) was added Novozym-435
stirred at room temperature for 12 h. The enzyme was removed
from the reaction mixture by filtration through a Celite. The sol-
vent was evaporated under reduced pressure to give an oily mix-
was dissolved in 2-propanol without further purification and then
UV 217 nm (R)-11=10.70 min, (S)-11=12.64 min, (S)-10=
17.27 min, (R)-10 = 20.13 min.).
DKR of 10.A suspension containing K2CO3(140 mg, 1mmol),
strate), isopropenyl acetate (150 μL, 1.5 mmol), and 10 (223 mg,
1 mmol) in dry and degassed toluene (2.5 mL) was stirred at room
temperature under argon atmosphere in a 50 mL Schlenk flask.
After 24 h, the reaction mixture was filtered. The filtrate was
concentrated, and the residue was purified by column chromatog-
colorless liquid (254 mg; 96% yield, 99% ee):1H NMR (CDCl3,
300 MHz, ppm) δ 7.33 (t, J = 7.83 Hz, 1H), 7.20-7.15 (m, 2H),
3.03 (d, J = 23.25 Hz, 3H), 1.49 (d, J = 6.45 Hz, 3H), 1.27-1.17
(m, 3H);13C NMR (CDCl3, 75 MHz, ppm) δ 170.3, 154.5, 151.6,
143.0, 129.3, 122.9, 121.3, 119.5, 71.8, 44.1, 34.3, 33.8, 22.1, 21.3,
13.2, 12.5; HPLC (Chiracel-OD, n-hexane/2-propanol =95/5,
flow rate =1.0 mL/min, UV 217 nm) (R)-11 = 10.70 min,
(S)-11 = 12.64 min; [R]25D= þ68.2 (c = 1.1, CHCl3, 99% ee);
HRMS (EI) C14H19NO4calcd 265.1314 (Mþ), found 265.1310.
Hydrolysis of 11. To a solution of 11 (133 mg, 0.5 mmol) in
methanol (1.6 mL) were added potassium carbonate (138 mg,
1 mmol) and H2O (0.4 mL). The reaction mixture was stirred at
room temperature for 2 h. Methanol was removed by evapora-
tion, and the aqueous solution was extracted with CH2Cl2.
The organic layers were combined, dried over Na2SO4, and
evaporated under reduced pressure. The residue waspurified by
a column chromatography (silica gel, n-hexane/EtOAc = 1/1)
to give oily (R)-10 (101 mg; 92% yield, 99% ee).1H and13C
NMR and HRMS were that same as the data of 10: [R]24D=
þ25.3 (c = 1.1, CHCl3, 99% ee).
0.45 mmol) in dry CH2Cl2(1.6 mL) was added distilled triethy-
25 mL Schlenk flask, and the reaction solution was stirred for
10 min. Methanesulfonyl chloride dissolved in dry CH2Cl2(v/v
dropwise over 30 min at 0 ?C. The reaction solution was stirred
at 0 ?C for 1 h, dimethylamine (2 Msolution in THF, 1 mL) was
added, and the reaction mixture was stirred at room tempera-
ture for 2 d. After completion of the reaction was confirmed by
HCl. Both aqueous layers were combined and neutralized with
2 M NaOH until the pH was above 10 and then extracted with
CH2Cl2.The organic layers were combined, dried overNa2SO4,
77% yield): [R]25D= -32.8 (c = 1.3, EtOH) (lit.5[R]20D=
-32.1 (c = 5, EtOH)); HRMS (EI) C14H22N2O2calcd 250.1681
(Mþ), found 250.1683.1H and
agreement with those reported in the literature.6For determin-
ing the enantiopurity of 1, a small amount of 1 was mixed with
one equivalent of (R,R)-tartaric acid in ethanol and the resulting
mixture was then analyzed by HPLC14(Chiracel-OD, n-hexane/
2-propanol/trifluoroacetic acid =80/20/0.3, flow rate =1.5 mL/
13C NMR data are in good
Acknowledgment. This work was supported by National
Research Foundation of Korea (2009-0087801). We thank
the Korean Goverment for supporting our graduate pro-
gram (BK21 Program).
Supporting Information Available: Copies for1H and13C
NMR spectra and HPLC chromatographs of products. This
material is available free of charge via the Internet at http://