Novel phosphinobioxazines as chiral ligands in palladium-catalyzed enantioselective allylic substitution

Article abstract of DOI:10.1016/S0957-4166(99)00183-4

Novel C₂-symmetric chiral (4S,4'S)-bisphosphinobioxazine 2a, a six- membered analog of (4S,4S')bisphosphinobioxazoline (Phos-Biox, 1), and monophosphinobioxazine 2b have been synthesized and used as chiral ligands for Pd-catalyzed asymmetric al

Full text of DOI:10.1016/S0957-4166(99)00183-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1795–1802
Novel phosphinobioxazines as chiral ligands in palladium-
catalyzed enantioselective allylic substitution
Sang-gi Lee,a,∗ So Ha Lee,a Choong Eui Song a and Bong Young Chung b
aLife Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, South Korea
bDepartment of Chemistry, Korea University, 1-Anamdong, Seoul, 136-701, South Korea
Received 14 April 1999; accepted 6 May 1999
Abstract
Novel C2-symmetric chiral (4S,40S)-bisphosphinobioxazine 2a, a six-membered analog of (4S,4S0)-
bisphosphinobioxazoline (Phos-Biox, 1), and monophosphinobioxazine 2b have been synthesized and used
as chiral ligands for Pd-catalyzed asymmetric allylic substitutions of rac-1,3-diphenyl-2-propenyl acetate with
dimethyl malonate. C2-Symmetric bisphosphinobioxazine 2a exhibited moderate enantioselectivities (63–84%
ee) whereas excellent enantioselectivities (94–95% ee) were observed with monophosphinobioxazine 2b. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
The design and development of efficient chiral ligands for transition metals are essential for catalytic
asymmetric reactions and has become one of the most intense areas of investigation. In recent years,
enantiomerically pure oxazolines have received a great deal of attention through their use in various
catalytic processes. In particular, many impressive levels of enantioselectivities have been recorded in
metal-catalyzed asymmetric reactions using C2-symmetric chiral bisoxazoline1 and phosphine–oxazoline
hybrid ligands.2,3 However, in contrast with five-membered oxazolines, the chiral oxazines as ligands
have not been extensively studied to date. To the best of our knowledge, only one type of phosphino-
oxazine prepared starting from (−)-β-pinene, has been used as a chiral ligand in Pd-catalyzed allylic
substitution reactions.4
In a program directed toward the development of new C2-symmetric chiral ligands for asymmetric
catalysis,5 we recently prepared a new type of C2-symmetric phosphine–oxazoline hybrid, bisphosphino-
bioxazoline (Phos-Biox 1).5b,c The fidelity of Phos-Biox 1 as a chiral ligand holds throughout the survey
of the transition metal-catalyzed asymmetric catalysis. In Rh-catalyzed asymmetric hydrosilylations5b
∗
Corresponding author. E-mail: L3712@kistmail.kist.re.kr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00183-4

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and Pd-catalyzed allylic substitutions5c using Phos-Biox 1 as a chiral ligand, up to 97% ee has been
achieved in both asymmetric reactions. These results prompted us to investigate C2-symmetric bisphos-
phinobioxazine 2a as a potential six-membered analog of Phos-Biox 1. The six-membered bioxazine
backbone in 2a has a less planar conformation compared with the five-membered oxazoline ring in
bisphosphinobioxazoline 1. Therefore, the results using 2a as a chiral ligand may provide additional
information on the role of backbone conformation in ligand design, and might lead to further insight into
the origin of asymmetric induction. In this paper, the synthesis of phosphinobioxazines 2a,b and their
applications as chiral ligands in Pd-catalyzed asymmetric allylic substitutions are described.
2. Results and discussion
For the synthesis of 2a,b, commercially available trans-β-hydromuconic acid was chosen as a starting
material, then transformed into TBDMS ether 3 by standard methods (esterification, LiAlH4 reduction
and silylation) in a three-step synthesis (overall 70% yield).
The threo diol (R,R)-4 was prepared by Sharpless asymmetric dihydroxylation (AD)6 using
(DHQD)2PHAL as a ligand in 93.5% ee. The ee of 4 was determined by HPLC analysis using a Chiralcel
OD column. The diol 4 was efficiently converted into diamine 5 in a similar manner with our previous
methods5a for 1. The diamine 5 was transformed into diamide 6 by reaction with o-fluorobenzoyl
chloride in 93% yield. After deprotection of the TBDMS group with HF/pyridine, the resulting diol
was cyclized intramolecularly using triflic anhydride to give bisfluorobioxazine 7. The reaction of
bisfluorobioxazine 7 with potassium diphenylphosphide afforded a mixture of bisphosphinobioxazine
2a and monophosphinobioxazine 2b which separated by column chromatography on silica gel to give
pure 2a (33%) and 2b (20%) (Scheme 1).
To examine the catalytic efficiency of 2a,b as chiral ligands in Pd-catalyzed allylic substitution,
the benchmark reaction between rac-1,3-diphenyl-2-propenyl acetate and dimethyl malonate has been
investigated under standard reaction conditions. The results are summarized in Table 1 in which the
results5c using Phos-Biox 1 are also included for comparison.
From the data in Table 1, it has been found that the enantioselectivity and reactivity are strongly
dependent upon the backbone ring size. The Phos-Biox ligand 1 possessing a five-membered bioxazoline
backbone exhibited excellent enantioselectivity and reactivity (entries 1–4).5c Whereas, the same allylic
substitution reactions using C2-symmetric phosphinobioxazine 2a as a chiral ligand afforded lower
reactivity and enantioselectivity. Moreover, the reactivity and enantioselectivity are largely dependent

S. Lee et al. / Tetrahedron: Asymmetry 10 (1999) 1795–1802
1797
Scheme 1. (a) (DHQD)2PHAL, OsO4/K3Fe(CN)6/K2CO3/CH3SO2HN2/t-BuOH–H2O (1/1, v/v) 0°C, 19 h, 93%; (b) (i)
MsCl/Et3N, CH2Cl2, 0°C, 1 h, 95%; (ii) NaN3, DMF, 105°C, 20 h, 88%; (iii) Pd–CaCO3/H2/EtOH, rt, 24 h, 97%; (c)
o-F-benzoylchloride/Et3N, CH2Cl2, 0°C, 5 h, 95%; (d) (i) HF/pyridine, CH3CN, rt, 2 h, 80%; (ii) Tf2O, i-Pr2NEt, −78°C to
rt, 5 h, 58%; (e) KPPh2/THF, rt, 1 h, and separation
Table 1
Pd-catalyzed enantioselective allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl
malonate using 1 and 2a,b as chiral ligands
on the solvent polarity and reaction conditions. The substitution reactions using sodium malonate
nucleophile (method A) proceeded very slowly; thus, the reactions were not completed after 26 h in either
methylene chloride or THF solvents. However, the reaction in THF afforded a higher yield (66%) than
in methylene chloride (38%) with almost the same enantioselectivities (entry 5 vs 6). A more dramatic
solvent dependency of the reactivity was observed in dimethyl malonate/BSA conditions (method B). In
methylene chloride solvent, only a tiny amount of product 8 was detected by TLC (entry 7). The reaction
rate was dramatically increased when the solvent was changed to polar THF which gave 8 in 99% yield
with 63% ee within 5 h (entry 8). The large solvent dependency of the reactivity using C2-symmetric

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bisphosphinobioxazine 2a under dimethyl malonate/BSA conditions cannot be explained simply at the
present time. Nevertheless, it seems clear that the decreased reactivity with 2a compared with Phos-Biox
1 may be related to backbone ring size. It has been found that Phos-Biox 1 formed a P,N,N,P-tetradentate
complex with Pd(II) in solid and solution states.5c Therefore, although the chelation mode of 2a with
Pd metal is not yet clear, we assume that due to the decreased ring strain of the bioxazine, the two
nitrogen atoms of the bioxazine ring could be more strongly coordinated to Pd metal than those of the
bioxazoline ring in Phos-Biox 1. Presumably, this stable P,N,N,P-tetradentate Pd-2a complex decreases
the reactivity, since the P,N,N,P-tetradentate Pd-complex requires that two of the P,N,N,P dissociate from
the Pd metal at the oxidative addition step. The results using monophosphinobioxazine 2b may provide
indirect evidence for this hypothesis. As can be seen in entries 9–12, the allylic substitutions using 2b
afforded 8 in high yields (>99%) and excellent enantioselectivities (94–95% ee).
3. Conclusion
Novel C2-symmetric bisphosphinobioxazine 2a, a six-membered analog of bisphosphinobioxazoline
1, and monophosphinobioxazine 2b have been successfully synthesized, and their catalytic efficiency
for Pd-catalyzed allylic substitutions of rac-1,3-diphenyl-2-propenyl acetate have been examined. Our
results demonstrated how the reactivity and enantioselectivity of Pd-catalyzed allylic substitutions can
be changed by modification of the backbone ring size of the ligand. The concepts used for the design
of ligands 2a,b may serve as a guideline for the development of new ligands for asymmetric catalysis.
Current efforts are directed toward elucidation of the coordination mode and application of these new
chiral phosphinobioxazines to other metal-catalyzed asymmetric catalysis reactions.
4. Experimental
4.1. General procedures
1H NMR and 13C NMR spectra were recorded on a Varian Gemini 300 MHz spectrometer with TMS
as internal reference. IR spectra were recorded on a MIDAC 101025 FT-IR spectrometer and optical
rotations were measured with an Autopol® polarimeter. Melting points were taken on a Thomas–Hoover
capillary melting point apparatus and are uncorrected. Chemical analyses were carried out by the
Advanced Analysis Center at the Korea Institute of Science and Technology. HRMS (FAB) analysis was
carried out by the Mass Spectrometry Analysis Group at the Korea Basic Science Institute. All solvents
were distilled prior to use. Column chromatography was performed on Kieselgel 60 (230–400 mesh) and
TLC was carried out using glass sheets precoated with silica gel 60F 254 purchased from Merck.
4.2. (3R,4R)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-dihydroxyhexane 4
In a double jacketed reaction flask attached to a cooling system was placed a mixture of
(DHQD)2PHAL (2.26 g, 2.9 mmol), K3Fe(CN)6 (28.7 g, 87.1 mmol), K2CO3 (12.03 g, 87.1
mmol), methanesulfonamide (2.76 g, 29.0 mmol) in tert-butanol:water (70:70 mL). The mixture was
stirred at 0°C for 1 h. Osmium tetroxide (1.85 mL, 0.29 mmol, 4% OsO4 in water) was added. After
30 min stirring, trans-1,6-bis(tert-butyldimethylsilyloxy)-3-hexene (10.0 g, 29.0 mmol) was added, and
then stirred for a further 19 h. The reaction was quenched with sodium metabisulfite. After stirring for

S. Lee et al. / Tetrahedron: Asymmetry 10 (1999) 1795–1802
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an additional 2 h at room temperature, the organic layer was extracted with ethyl acetate, dried, filtered,
and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-
hexane=1:4, v/v) giving 4 (10.2 g, 93%) with 93.5% ee. The enantiomeric excess was determined by
HPLC analysis of the corresponding (3R,4R)-1,6-bis(tert-butyldiphenylsilyloxy)-3,4-dihydroxyhexane
(in order to use the UV detector, the TBDMS group was converted to the TBDPS group) using a
Chiralcel OD chiral column [eluent: n-hexane:i-propanol=97:3; flow rate: 0.8 mL/min; retention times
(3S,4S)-isomer: 10.9 min, (3R,4R)-isomer: 14.2 min]. Rf 0.2; [α]D=+19.4 (c 1.05, CH3OH); mp
32–33°C; 1H NMR (300 MHz, CDCl3) δ 3.87 (m, 4H), 3.72 (m, 2H), 3.41 (d, J=3.2 Hz, 2H), 1.74 (m,
4H), 0.90 (s, 18H), 0.08 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 72.77, 61.12, 35.48, 25.81, 18.04,
−5.56; IR (KBr) 3424, 1472, 1256, 1094, 836 cm−1.
4.3. (3R,4R)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-[O,O0-di(methanesulfonyl)]dihydroxyhexane
To a stirred solution of triethylamine (7.2 mL, 5.5 mmol) and dihydroxyhexane 4 (8.47 g, 22.4 mmol)
in dry methylene chloride (130 mL) was added methanesulfonyl chloride (3.64 mL, 43.0 mmol) in
a dropwise manner using a syringe at −76°C for 1 h and the mixture was stirred for 16 h at room
temperature. The reaction mixture was diluted with ethyl ether, and washed with saturated NH4Cl
solution. The organic layer was dried (MgSO4), and concentrated. The residue was solidified in n-hexane,
then purified by recrystallization with n-hexane:ethyl acetate (2:1, v/v) to give dimesylate (11.4 g, 95%)
as a white crystal. Rf 0.5; [α]D=+4.1 (c 1.01, CH3OH); mp 99–100°C; 1H NMR (300 MHz, CDCl3) δ
5.07 (m, 2H), 3.78 (m, 4H), 3.07 (s, 6H), 1.95 (m, 4H), 0.88 (s, 18H), 0.06 (s, 12H); 13C NMR (75 MHz,
CDCl3) δ 78.18, 57.96, 38.26, 33.27, 25.69, 18.18, −5.47; IR (KBr) 2958, 1348, 1184, 1098, 938, 832,
774, 538 cm−1; HRMS (FAB, m-nitrobenzyl alcohol matrix) calcd for C20H47O8S2Si2: [M+H]+ (base
peak): 535.2251. Found: 535.2245.
4.4. (3S,4S)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-diazidohexane
A stirred mixture of dimesylate (3R,4R)-1,6-bis(tert-butyldimethylsilyloxy)-3,4-[O,O0 -di(methane-
sulfonyl)]dihydroxyhexane (7.82 g, 14.6 mmol) and NaN3 (4.75 g, 73.1 mmol) in DMF (40 mL) was
reacted at 100–105°C for 20 h. The reaction mixture was allowed to cool to room temperature and
diluted with ethyl ether. The precipitated white solid was removed by filtration and the filtrate was
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel (ethyl acetate:n-hexane=1:20) to afford diazide (5.5 g, 88%) as a colorless oil. Rf 0.8; [α]D=−53.1 (c
1.26, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.76 (t, J=5.9 Hz, 4H), 3.61 (m, 2H), 1.84 (m, 4H), 0.90 (s,
18H), 0.08 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 62.24, 59.19, 34.21, 25.73, 18.23, −5.49; IR (KBr)
2956, 2108, 1472, 1258, 1106, 838 cm−1.
4.5. (3S,4S)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-diaminohexane 5
To a solution of diazide (3S,4S)-1,6-bis(tert-butyldimethylsilyloxy)-3,4-diazidohexane (2.91 g, 6.8
mmol) in ethanol (45 mL) was added the Lindlar catalyst (2 g, 5% Pd/CaCO3). The mixture was
hydrogenated under atmosphere pressure at room temperature for 5 h. The catalyst was then removed
by filtration over Celite, and the filtrate was evaporated under reduced pressure to afford diamine 5 (2.5
1
g, 97%). [α]D=−10.9 (c 1.1, CH3OH); H NMR (300 MHz, CDCl3) δ 3.75 (m, 4H), 2.83 (m, 2H),
2.17 (s, 2H), 1.70 (m, 2H), 1.56 (m, 2H), 0.89 (s, 18H), 0.057 (s, 12H); 13C NMR (75 MHz, CDCl3)

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S. Lee et al. / Tetrahedron: Asymmetry 10 (1999) 1795–1802
δ 60.85, 53.27, 37.13, 26.24, 18.07, −5.47; IR (KBr) 2954, 1471, 1255 1096, 836 cm−1; HRMS (FAB,
PEG matrix) calcd for C18H45N2O2Si2: [M+H]+ (base peak): 377.3023. Found: 377.3020.
4.6. (3S,4S)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-[N,N0 -di(o-fluorobenzoyl)]diaminohexane 6
A solution of (3S,4S)-1,6-bis(tert-butyldimethylsilyloxy)-3,4-diaminohexane 5 (3.38 g, 9.0 mmol) and
triethylamine (3.2 mL, 122.6 mmol) in dry methylene chloride was cooled to −76°C under nitrogen. o-
Fluorobenzoyl chloride (3.57 g, 22.5 mmol) was added dropwise over 30 min, then the reaction mixture
was allowed to warm to room temperature. After stirring for 12 h at room temperature, the reaction was
quenched by addition of saturated aqueous NaHCO3 solution. The organic layer was separated and dried
with MgSO4. After evaporation of the solvent, the residue was purified by column chromatography on
silica gel (ethyl acetate:n-hexane=1:4) to give the white solid (5.3 g, 95%). [α]D=−36.3 (c 1.0, CHCl3);
mp 64–65°C; 1H NMR (300 MHz, CDCl3) δ 7.83 (m, 2H), 7.37 (m, 2H), 7.21–6.99 (m, 6H), 4.46 (m,
2H), 3.76 (t, J=5.8 Hz, 4H), 2.03 (m, 2H), 1.85 (m, 2H), 0.83 (s, 18H), 0.01 (s, 12H); 13C NMR (75
MHz, CDCl3) δ 164.01, 161.94, 158.65, 132.86, 131.54, 124.50, 121.94, 116.16, 115.82, 60.11, 51.18,
35.03, 25.92, 18.25, −5.46.
4.7. (3S,4S)-3,4-[N,N0-Bis(o-fluorobenzoyl)]diamino-1,6-hexanediol
A solution of 6 (2 g, 3.2 mmol) and HF–pyridine (30%, v/v) in CH3CN (15 mL) was stirred at room
temperature for 2 h. After completion of the reaction, the reaction mixture was poured into saturated
aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic layer was dried over
anhydrous MgSO4 and concentrated. The residue was purified by recrystallization with n-hexane to give
1
the diol (1.0 g, 80%). [α]D=−76.6 (c 1.02, CH3OH); mp 153–154°C; H NMR (300 MHz, CDCl3) δ
7.96 (m, 2H), 7.72 (m, 2H), 7.48 (m, 2H), 7.27 (t, J=8.1 Hz, 2H), 7.18 (m, 2H), 4.52 (m, 2H), 3.77 (m,
4H), 2.98 (s, 2H), 2.09 (m, 2H), 1.77 (m, 2H); 13C NMR (75 MHz, CD3COCD3) δ 165.49, 160.78 (d,
J
C–F=248.7 Hz), 133.59 (d, J=8.5 Hz), 131.58, 125.32, 124.14 (d, J=13.4 Hz), 116.83 (d, J=23.3 Hz),
59.29, 51.51, 36.01.
4.8. (4S,40S)-2,20-Bis(o-fluorophenyl)-5,50 ,6,60-tetrahydro-4,40-bi(1,3-ozazine) 7
To a stirred solution of (3S,4S)-3,4-[N,N0-bis(o-fluorobenzoyl)]diamino-1,6-hexanediol (1.88 g, 4.8
mmol) in dry methylene chloride (150 mL) was added N,N-diisopropyl ethyl amine (1.86 mL, 10.7
mmol), and the reaction temperature was cooled to −78°C. To this solution was added Tf2O (1.71 mL,
10.2 mmol) in a dropwise manner using a syringe pump for 30 min. The mixture was stirred for 4 h at the
same temperature. After stirring for an additional 5 h at room temperature, the reaction was quenched by
addition of 1% aqueous HCl solution. The organic layer was washed with saturated aqueous NaHCO3
solution, dried with MgSO4 and concentrated. The residue was purified by column chromatography on
silica gel to give bisfluorobioxazine 7 (0.99 g, 58%). [α]D=−62.9 (c 0.68, CHCl3); mp 71–72°C; 1H NMR
(300 MHz, CDCl3) δ 7.70 (t, J=7.6 Hz, 2H), 7.39 (m, 2H), 7.14 (m, 4H), 4.52 (m, 2H), 4.37 (ddd, J=3.5,
3.8, 3.2 Hz, 2H), 4.03 (m, 2H), 2.05 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 160.66 (d, JC–F=252.66
Hz), 154.35, 131.54 (d, J=9.1 Hz), 130.54, 123.73, 123.09 (d, J=11.3 Hz), 116.44 (d, J=22.4 Hz), 65.48,
56.13, 22.20.

S. Lee et al. / Tetrahedron: Asymmetry 10 (1999) 1795–1802
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4.9. (4S,40S)-2,20-Bis(o-diphenylphosphinophenyl)-5,50 ,6,60-tetrahydro-4,40-bi(1,3-ozazine)2a and
(4S,40S)-2-(o-diphenylphosphinophenyl)-20 -(o-fluorophenyl)-5,50 ,6,60-tetrahydro-4,40-bi(1,3-ozazine)
2b
To a solution of bisfluorobioxazine 7 (0.68 g, 1.9 mmol) in dry THF (8 mL) was added a solution
of potassium diphenylphosphide (0.5 M in THF, 7.6 mL, 3.82 mmol) at 0°C. After 1 h stirring
at room temperature, the reaction was quenched by addition of water (25 mL), and extracted with
methylene chloride (50 mL×2). The combined organic layer was dried over anhydrous MgSO4, and
concentrated. The residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1)
to give bisphosphinobioxazine 2a (0.43 g, 33%) and monophosphinobioxazine 2b (0.2 g, 20%). 2a: Rf
0.34; [α]24 −122.6 (c 0.53, CHCl3); mp 134–135°C; 1H NMR (300 MHz, CDCl3) δ 7.75–7.69 (m, 2H),
D
7.38–7.20 (m, 24H), 6.85–6.78 (m, 2H), 4.10–4.04 (m, 2H), 3.77 (td, J=11.0, 3.8 Hz, 2H), 3.60–3.52
(m, 2H), 1.30–1.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 155.82, 139.60–128.10 (aromatic carbon
signals), 65.37, 55.84, 21.00; 31P NMR (121 MHz, CDCl3, triphenylphosphine as an external standard) δ
−2.61; HRMS (FAB) calcd for C44H39N2O2P2 [(M+H)+]: 689.2487. Found: 689.2499. 2b: Rf 0.17; [α]24
D
−104.2 (c 0.52, CHCl3); mp 64–65°C; 1H NMR (300 MHz, CDCl3) δ 7.84–7.81 (m, 1H), 7.69–7.64 (m,
1H), 7.50–7.20 (m, 13H), 7.15–7.0 (m, 2H), 6.95–6.85 (m, 1H), 4.40–4.20 (m, 2H), 3.9–3.7 (m, 2H),
1.90–1.80 (m, 1H), 1.75–1.50 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 163.32, 158.95, 156.20, 154.21,
139.54–116.28 (aromatic carbon signals), 65.70, 65.20, 56.12, 55.80, 21.68, 21.51; 31P NMR (121 MHz,
CDCl3, triphenylphosphine as an external standard) δ −2.35; HRMS (FAB) calcd for C32H29FN2O2P
[(M+H)+]: 523.1951. Found: 523.1957.
4.10. General procedure for the palladium-catalyzed allylic substitutions of rac-1,3-diphenyl-2-propenyl
acetate with dimethyl malonate
In a Schlenk tube, 4 mol of [(η3-C3H5)PdCl]2 and 10 µmol of phosphinobioxazine ligand 2 were
dissolved in solvent (1 mL) as indicated in Table 1, degassed, and then stirred for 1 h at 25°C under an
atmosphere of argon. To this solution were successively added rac-1,3-diphenyl-2-propenyl acetate (100
mg, 0.4 mmol) and a solution of nucleophile, generated in situ from dimethyl malonate (100 mg, 0.8
mmol) and base [NaH (35 mg, 0.87 mmol) or BSA (240 mg, 1.2 mmol)] in a solvent (1 mL) at 25°C.
After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL) and
poured into a cold saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with
methylene chloride (3×10 mL). The combined organic layer was dried over anhydrous MgSO4, and the
solvent was evaporated. The crude product was purified by preparative TLC (ethyl acetate:n-hexane=1:4,
1
Rf 0.4) to give the pure product. The enantiomeric purities were determined by the H NMR spectra
measured in the presence of Eu(hfc)3. When 0.8 equiv. of Eu(hfc)3 was added, one of the two methyl
ester signals appearing at δ 3.70 was split into two peaks: (R)-enantiomer at δ 3.99, (S)-enantiomer at δ
3.93. The yields and enantioselectivities are given in Table 1.
Acknowledgements
This research was supported by a grant from the Korea Institute of Science and Technology.

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(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.