Chemoenzymatic synthesis of the non-tricyclic antidepressants Fluoxetine, Tomoxetine and Nisoxetine

Article abstract of DOI:10.1039/b000846j

3-Chloro-1-phenylpropan-1-ol and the corresponding butanoate, 3-chloro-1-phenyl-1-propyl butanoate, were kinetically resolved using lipase B from Candida antarctica catalysis by transesterification and hydrolysis respectively. The resulting chiral building blocks (S)- and (R)-3-chloro-1-phenylpropanol were converted into both enantiomers of the antidepressant drugs, Fluoxetine, Tomoxetine and Nisoxetine. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b000846j

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Chemoenzymatic synthesis of the non-tricyclic antidepressants
Fluoxetine, Tomoxetine and Nisoxetine
Hui-Ling Liu, Bård Helge Hoff and Thorleif Anthonsen*
1
chirality by kinetic resolution using lipase catalysis. Although
resolutions only give a maximum yield of 50%, lipase catalysis
has several advantages. Enzymes are mild catalysts, they are
easily recovered after termination of the process, and can be
reused several times. Moreover, high enantiomeric excess (ee)
may be obtained even in cases when the important kinetic
parameter, the enantiomeric ratio E, is moderate provided
lower yield is acceptable. It is also possible to obtain 100%
of one single enantiomer by combination of lipase-catalyzed
resolution and Mitsunobu esterification-inversion in one
pot.9 Moreover, dynamic resolution, in which the unreacted
substrate is continuously racemized also gives only one
enantiomer starting from a racemic mixture. However, for
biological testing single enantiomers of both forms may be
needed.
Department of Chemistry, Norwegian University of Science and Technology,
N-7491 Trondheim, Norway. Tel: ϩ47 73596206; Fax: ϩ47 73596255;
E-mail: Thorleif.Anthonsen@chembio.ntnu.no
Received (in Lund, Sweden) 27th January 2000, Accepted 5th April 2000
Published on the Web 4th May 2000
3-Chloro-1-phenylpropan-1-ol and the corresponding butanoate, 3-chloro-1-phenyl-1-propyl butanoate, were
kinetically resolved using lipase B from Candida antarctica catalysis by transesterification and hydrolysis
respectively. The resulting chiral building blocks (S)- and (R)-3-chloro-1-phenylpropanol were converted into
both enantiomers of the antidepressant drugs, Fluoxetine, Tomoxetine and Nisoxetine.
Introduction
Fluoxetine (1), Tomoxetine (2), Nisoxetine (3) and Duloxetine
(4) belong to the group of non-tricyclic antidepressants which
Racemic 3-chloro-1-phenylpropan-1-ol (6) was obtained by
reduction of 3-chloro-1-phenylpropan-1-one (7) with sodium
borohydride. It was kinetically resolved by transesterification in
n-hexane using vinyl butanoate as acyl donor, and lipase B from
Candida antarctica (CALB) as catalyst. The resolution pro-
ceeded with an exceptionally high E-value of 1000, which
implies that the enantiomers will be perfectly separable by this
method. Gram-scale resolution was performed and optical
rotation values7 confirmed that the (R)-enantiomer was the
faster reacting enantiomer, as expected based on the stereo-
preference of CALB.10
Racemic 3-chloro-1-phenylpropyl butanoate (8) was kinetic-
ally resolved by CALB-catalysed hydrolysis in phosphate
buffer. The resolution proceeded excellently with an E-value of
923 and the (R)-butanoate was the faster reacting enantiomer.
The isolated (S)-(6) after transesterification and (R)-(6) after
hydrolysis, were reacted with three differently substituted
phenols in the presence of triphenylphosphine and diethyl
azodicarboxylate and inversion of configuration took place at
the secondary center (Mitsunobu conditions9). Treatment of
the obtained chloro ethers, 9, 10 and 11, with excess aqueous
methylamine in ethanol afforded both enantiomers of the
target products Fluoxetine (1), Tomoxetine (2) and Nisoxetine
(3).
act by inhibiting the uptake of norepinephrine and serotonin.1
A chemoenzymatic synthesis of Duloxetine has been reported.2
Fluoxetine hydrochloride is sold as the racemate (Prozac, Eli
Lilly Co.), but recently interest has been shown for marketing
the more active (R)-enantiomer as a so-called “Improved
Chemical Entity” version of the drug.3 Tomoxetine (2) was
the first norepinephrine reuptake inhibiting antidepressant
to be reported, and the (R)-enantiomer is nine times more
potent than the (S)-enantiomer.4 Nisoxetine (3) is also a potent
inhibitor. The drugs are derivatives of 3-methylamino-1-
phenylpropan-1-ol (5) which contains a stereocenter, and retro-
synthetic analysis reveals that enantiopure (R)-3-chloro-1-
phenylpropan-1-ol (6) should be a suitable chiral building
block.
Chirality has previously been introduced by applying
Sharpless-asymmetric epoxidation,5 by asymmetric reduction
of 3-chloro-1-phenylpropan-1-one (7) catalyzed by diisopino-
campheylchloroborane,6 by borane in the presence of
oxazaborolidine catalyst (chemzyme)7 or by bakers’ yeast.8
Experimental
General
Immobilized CALB (Novozyme 435, Novo-Nordisk A/S) had
an activity of 7000 PLU (palm oil lipase units) gϪ1, and a water
content of 1–2% w/w. Solvents were dried over molecular sieves,
column chromatography was performed using silica gel 60 from
Results and discussion
We have developed an alternative strategy for introduction of
DOI: 10.1039/b000846j
J. Chem. Soc., Perkin Trans. 1, 2000, 1767–1769
This journal is © The Royal Society of Chemistry 2000
1767

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Fluka and enzymatic reactions were performed in a shaker
incubator (New Brunswick, Edison, NJ, USA).
each, m, -CH2Cl), 5.94 (1 H, dd, J = 5.5 and 8.2, CH), 7.25–7.35
(5 H, m, phenyl). 13C NMR: 39.2 and 40.7 (-CH2CH2-),
72.9 (-CHOR), 126.3 and 128.6 (both 2 Ph-C), 128.2 (Ph C-4),
139.7 (Ph C-1), 172.6, 36.3, 18.4 and 13.6 (butanoyl). TLC
(n-hexane–acetone, 4:1), Rf = 0.52.
Analyses
Optical rotations were determined using an Optical Activity
Ltd. AA-10 automatic polarimeter, and are given in 10Ϫ1 deg
cm2 gϪ1; concentrations are given in g 100 mLϪ1. Chiral analyses
were performed using Varian 3300 and 3400 gas chromato-
graphs equipped with CP-Chirasil-dex CB columns from
Chrompack (25 m, 0.25 mm, 0.25 or 0.32 µm film thickness) at
7.5 psi, split ratio 60 mL minϪ1, with an outlet pressure of 3 bar.
The alcohol and ester were analyzed using temperature pro-
grammes: 100–120, 2 ЊC minϪ1; 120–140, 0.5 ЊC minϪ1; 140–180,
15 ЊC minϪ1, 1, t1 (R): 48.35, t2 (S): 49.22, Rs (resolution): 3.8, 2,
t1 (S): 44.664, t2 (R): 45.786, Rs: 1.9. TLC: Al sheets, 20 × 20
cm, silica gel 60 F 254, Merck. NMR spectra were recorded in
CDCl3 solutions, using Bruker DPX 300 and 400 instruments,
operating at 300 and 400 MHz for 1H and 75 and 100 MHz for
13C, respectively. Chemical shifts are in ppm relative to TMS
and coupling constants in Hz. Enantiomeric ratios, E were
calculated using the computer program E & K calculator version
2.03.11
(S)-3-Chloro-1-phenylpropan-1-ol [(S)-6] and (R)-3-chloro-1-
phenylpropyl butanoate [(R)-8]
Racemic 6 (1.0 g, 5.9 mmol) and vinyl butanoate (3.4 g, 29.4
mmol) were dissolved in n-hexane (80 mL). Immobilized CALB
(130 mg) was added, and the reaction mixture was shaken at
30 ЊC for 8 days until 50% conversion was reached. The enzyme
was filtered off, and the reaction mixture concentrated in vacuo.
The unreacted alcohol and the produced ester were separated
by column chromatography (n-hexane–acetone, 4:1), to give
(S)-6, yield 0.33 g, 1.93 mmol (33%), ee = 96%, [α]D22 = Ϫ23
(c = 1, CHCl3), and (R)-8, yield 0.44 g, 1.83 mmol (31%), ee =
1
97%, [α]D22 = ϩ33 (c = 1, CHCl3). H NMR corresponded with
racemic 6 and 8 respectively.
(R)-3-Chloro-1-phenylpropan-1-ol [(R)-6]
Racemic 8 (1.21 g, 5.0 mmol) was suspended in buffer (180 mL,
0.1 M, pH = 7). Immobilized CALB (303 mg) was added, and
the reaction mixture was shaken at 30 ЊC for 12 days until 50%
conversion was reached. The enzyme was filtered off, the reac-
tion mixture was extracted with Et2O (3 × 80 mL), dried over
MgSO4 and concentrated in vacuo. The produced alcohol and
the remaining ester were separated by column chromatography
(n-hexane–acetone, 4:1) to afford (R)-6, yield 0.35 g, 2.1 mmol
(42%), ee = 95%, [α]D22 = ϩ24 (c = 1, CHCl3), lit.7 ϩ24. 1H NMR
corresponded with racemic 6.
Small scale transesterifications
Substrate alcohol (37.5 mg, 2.2 × 10Ϫ4 mol) was dissolved in
n-hexane (3 mL), vinyl butanoate (5 equivalents) was added
and the reaction was started by adding immobilized CALB (39
mg) to the reaction mixture at 30 ЊC. Chiral GLC analysis gave
Ϫ
)
the enantiomeric excess of substrate (eesϪ) and product (eep
from which conversion, c, was calculated [c = ees/(ees ϩ eep)].
In control experiments without enzyme, no acylation was
observed using vinyl butanoate as acyl donor.
(R)-4-(3-Chloro-1-phenylpropoxy)-1-trifluoromethylbenzene
[(R)-9]
Small scale hydrolyses
Substrate ester (26.6 mg, 1.11 × 10Ϫ4 mol) was dispersed in
phosphate buffer (30 mL, 0.1 M, pH = 7). The reaction was
started when immobilized CALB (34 mg) was added to the
reaction mixture.
Triphenylphosphine (0.51 g, 1.93 mmol), and diethyl azodicarb-
oxylate (0.3 mL, 0.34 g, 1.93 mmol) were added to a solution
of (S)-6 (0.33 g, 1.93 mmol) and trifluoromethyl-p-cresol (0.31
g, 1.93 mmol) in THF (5 mL). The mixture was stirred at room
temp. overnight until the reaction was completed (TLC). THF
was removed in vacuo and the residue was triturated with pen-
tane (3 × 5 mL). The combined pentane fractions were concen-
trated, and the residue was purified by flash chromatography
(pentane–Et2O, 4:1) to give (R)-9 as a thick liquid, yield 0.28 g,
0.89 mmol (46%). 1H NMR: 2.25 and 2.48 (1 H each, m,
-CH2-), 3.59 and 3.78 (1 H each, m, -CH2Cl), 5.43 (1 H, dd,
J = 4.6 and 8.5, CH), 6.91 and 7.43 (2 H each, AAЈXXЈ-system
of p-disubstituted benzene), 7.24–7.36 (5 H, m, phenyl). 13C
NMR: 41.1 and 41.2, (-CH2CH2-), 77.0 (-CHOR), 125.9 and
129.0 (both 2 Ph-C), 128.2 (Ph C-4), 134.0 (Ph C-1),
p-trifluoromethyl phenoxy part: 160.3 (C-1), 115.9 (2 C-2),
3-Chloro-1-phenylpropan-1-ol (6)
3-Chloro-1-phenylpropan-1-one (7) (4.22 g, 0.025 mol) was dis-
solved in EtOH (50 mL) at room temp. NaBH4 (0.5 equiv.) was
added, and the reaction mixture was stirred for 2 h. The reac-
tion was stopped by slow addition of 0.1 M HCl (100 mL)
and stirred for an additional 30 min. The mixture was extracted
with Et2O (3 × 40 mL), dried over MgSO4 and concentrated
in vacuo. The residue was purified by flash chromatography
(silica gel, CH2Cl2–EtOAc, 10:1) to give racemic 6, yield 3.75 g,
0.02 mol (88%). 1H NMR: 2.00 and 2.12 (2 H, m, -CH2-), 2.75
(1 H, s, OH), 3.48 and 3.66 (1 H each, m, CH2Cl), 4.86 (1 H, t,
CH, J = 5.5), 7.23–7.35 (5 H, m, aromatic). 13C NMR: 41.4
and 41.7 (-CH2CH2-), 71.1 (-CHOH), 125.8 and 128.6 (both 2
Ph-C), 127.8 (Ph C-4), 143.7 (Ph C-1). TLC: (CH2Cl2–EtOAc,
10:1), Rf = 0.53.
3
126.8 (q, JCF = 3.7 Hz, 2 C-3), 123.2 (q (2JCF = 32.7 Hz, C-4),
124.3 (q, JCF = 271.6 Hz, -CF3). [α]D22 = Ϫ1.3 (c = 5.2, CHCl3).
1
TLC: (n-pentane–Et2O, 4:1), Rf = 0.60.
(S)-4-(3-Chloro-1-phenylpropoxy)-1-trifluoromethylbenzene
[(S)-9]
3-Chloro-1-phenylpropyl butanoate (8)
Using the same procedure as for (R)-9, (S)-9 was synthesized
starting with (R)-6. Workup gave (S)-9 (0.23 g, 0.73 mmol),
Racemic 6 (2.24 g, 13 mmol), butanoic anhydride (2.28 g, 14
mmol) and pyridine (1.11 g, 14 mmol) were dissolved in CH2Cl2
(50 mL), cooled to 0 ЊC and DMAP (25 mg) was added. The
mixture was stirred for 20 min at 0 ЊC and then at room temp.
overnight. The reaction mixture was washed with 0.1 M HCl
(10 × 25 mL), then with saturated NaHCO3 (3 × 25 mL), dried
over MgSO4 and concentrated in vacuo. The residue was puri-
fied by column chromatography (n-hexane–acetone, 4:1) to
yield 54%, [α]D22 = ϩ 1.0 (c = 5.1, CHCl3). H and 13C NMR
1
spectra were identical with those of (R)-9.
(R)-Fluoxetine [(R)-1] [(R)-4-(3-methylamino-1-phenylpropoxy)-
1-trifluoromethylbenzene]
The chloro ether (R)-9 (0.28 g, 0.89 mmol) and aqueous
MeNH2 (40%, 3 mL) were dissolved in EtOH (5 mL). The solu-
tion was refluxed at 130 ЊC for 6 h, cooled to room temp. and
poured into water (40 mL). The mixture was extracted by Et2O
1
give racemic 8, yield 3.0 g, 12.5 mmol (93%). H NMR: 0.92
(3 H, t, J = 7.4, -CH3), 1.65 (2 H, sextet, -CH2-), 2.16 (2 H, t,
-CH2-), 2.20 and 2.33 (1 H each, m, -CH2-), 3.43 and 3.54 (1 H
1768
J. Chem. Soc., Perkin Trans. 1, 2000, 1767–1769

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(3 × 20 mL). The Et2O extract was washed with water and
aqueous NaCl, dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography (CH2Cl2–
MeOH–NH4OH, 40:10:1) to afford (R)-1, yield 0.17 g, 0.55
(R)-2-(3-Chloro-1-phenylpropoxy)-1-methoxybenzene [(R)-11]
(R)-11 was synthesized using a similar procedure as for (R)-9,
using (S)-6 (0.53 g, 3.1 mmol), guaiacol (0.39 g, 3.1 mmol),
Ph3P (0.81 g, 3.1 mmol) and diethyl azodicarboxylate (0.54 g,
0.48 mL, 3.1 mmol) in dry THF (7 mL) at room temp. Workup
and chromatography gave (R)-11, yield 0.35 g, 1.3 mmol (42%)
as a thick liquid, [α]D22 = ϩ26 (c = 2, CHCl3). 1H NMR: 2.21 and
2.55 (1 H each, m, -CH2-), 3.64 and 3.88 (1 H each, m, -CH2Cl),
5.33 (1 H, dd, J = 4.3 and 8.8, CH), 7.22–7.41 (5 H, m, phenyl),
o-methoxyphenoxy part: 3.86 (3 H, s, -OCH3), 6.71 (2 H, m,
H-3,6), 6.86 (2 H, m, H-4,5). 13C NMR: 41.4 and 41.6, (-CH2-
CH2-), 78.5 (-CHOR), 125.8 and 128.6 (both 2 Ph-C), 127.8 (Ph
C-4), 141.0 (Ph C-1), o-methoxyphenoxy part: 55.9 (-OCH3),
150.2 (C-1), 147.4 (C-2), 116.6 (C-3), 120.7 (C-4), 121.8 (C-5),
112.0 (C-6). TLC (n-pentane–Et2O, 4:1), Rf = 0.51.
1
mmol (62%), [α]D22 = ϩ2.0 (c = 1, CHCl3). H NMR: 2.11 and
2.27 (1 H each, m, -CH2-), 2.46 (3 H, s, -CH3), 2.82 (2 H, br t,
-CH2N), 5.33 (1 H, dd, J = 4.7 and 8.3, CH), 6.90 and 7.42 (2 H
each, AAЈXXЈ-system of p-disubstituted benzene), 7.25–7.38
(5 H, m, phenyl). 13C NMR: 37.8 and 51.51, (-CH2CH2-), 78.3
(-CHOR), 35.7 (-NCH3), 125.8 and 128.9 (both 2 Ph-C), 128.0
(Ph C-4), 140.6 (Ph C-1), p-trifluoromethylphenoxy part: 160.4
3
(C-1), 115.8 (2 C-2), 126.8 (q, JCF = 3.7 Hz, 2 C-3), 123.2 (q,
1
2JCF = 32.7 Hz, C-4), 124.8 (q, JCF = 271.2 Hz, -CF3). TLC
(CH2Cl2–MeOH–NH4OH, 40:10:1), Rf = 0.60.
(S)-Fluoxetine [(S)-1)] [(S)-4-(3-methylamino-1-phenyl-
propoxy)-1-trifluoromethylbenzene]
(R)-Nisoxetine [(R)-3] [(R)-2-(3-methylamino-1-phenyl-
propoxy)-1-methoxybenzene]
(S)-Fluoxetine [(S)-1] was prepared in the same way as (R)-1
using (S)-9. Workup gave (S)-1 (0.14 g, 0.46 mmol), yield 63%,
[α]D22 = Ϫ3.0 (c = 1, CHCl3). 1H and 13C NMR spectra were
identical with those of (R)-1.
(R)-Nisoxetine was synthesized like (R)-Fluoxetine [(R)-1],
using the chloro ether (R)-11 (0.22 g, 0.80 mmol) and excess
aqueous MeNH2 (40%, 3 mL) in EtOH (7 mL) at 130 for 6 h.
Workup gave (R)-3, yield 0.12 g, 0.44 mmol (55%), [α]D30 = ϩ35
(R)-2-(3-Chloro-1-phenylpropoxy)-1-methylbenzene [(R)-10]
1
(c = 1, CHCl3). H NMR: 1.88 (1 H, br s, NH), 2.03 and 2.26
(R)-10 was synthesized using the same procedure as for syn-
thesis of (R)-9 using (S)-6 (0.31 g, 1.8 mmol), o-cresol (0.20 g,
1.8 mmol), triphenylphosphine (0.47 g, 1.8 mmol) and diethyl
azodicarboxylate (0.31 g, 1.8 mmol, 0.28 mL) in dry THF
(8 mL) at room temp. Workup and purification afforded (R)-10
as a thick liquid, yield 0.27 g, 1.03 mmol (57%), [α]D22 = Ϫ10.8
(c = 3.4, CHCl3). 1H NMR: 2.23 and 2.48 (1 H each, m, -CH2-),
3.61 and 3.79 (1 H each, m, -CH2Cl), 5.38 (1 H, dd, J = 4.4 and
8.5, CH), 7.23–7.37 (5 H, m, phenyl), o-methylphenoxy part:
2.31 (3 H, s, -CH3), 6.62 (1 H, d, J = 8.2, H-6), 6.78 (1 H, t, H-5),
6.96 (1 H, m, H-4), 7.12 (1 H, d, J = 7.5, H-3). 13C NMR: 41.4
and 41.5, (-CH2CH2-), 77.2 (-CHOR), 125.8 and 128.7 (both 2
Ph-C), 127.8 (Ph C-4), 141.0 (Ph C-1), o-methylphenoxy part:
16.6 (-CH3), 155.7 (C-1), 127.0 (C-2), 130.7 (C-3), 120.5 (C-4),
126.6 (C-5), 112.8 (C-6). TLC (n-pentane–Et2O, 4:1), Rf = 0.71.
(1 H each, m, -CH2-), 2.43 (3 H, s, NCH3), 2.77 (2 H, br m,
-CH2Cl), 5.20 (1 H, dd, J = 4.7 and 8.4, CH), 7.23–7.39 (5 H, m,
phenyl), o-methoxyphenoxy part: 3.87 (3 H, s, -OCH3), 6.68
(2 H, m, H-3,6), 6.85 (2 H, m, H-4,5). 13C NMR: 36.5 (-NCH3),
38.5 and 48.8, (-CH2CH2-), 80.6 (-CHOR), 126.0 and 128.5
(both 2 Ph-C), 127.5 (Ph C-4), 142.0 (Ph C-1), o-methoxy-
phenoxy part: 56.0 (-OCH3), 150.1 (C-1), 147.7 (C-2), 116.4 (C-
3), 120.7 (C-4), 121.4 (C-5), 112.1 (C-6). TLC (CH2Cl2–MeOH–
NH4OH, 40:10:1), Rf = 0.35.
(S)-2–(3-Chloro-1-phenylpropoxy)-1-methoxybenzene [(S)-11]
and (S)-Nisoxetine [(S)-3] [(S)-2-(3-methylamino-1-phenyl-
propoxy)-1-methoxybenzene]
[(S)-11] and (S)-Nisoxetine [(S)-3] were synthesized in the same
way as (S)-9 and (S)-1, respectively. The yield of (S)-11 was
1
0.22 g, 0.82 mmol (46.4%), [α]D22 = Ϫ26 (c = 2, CHCl3). H and
(R)-Tomoxetine [(R)-2] [(R)-2-(3-methylamino-1-phenyl-
propoxy)-1-methylbenzene]
13C NMR spectra were identical with those of (R)-11. The yield
of (S)-3 was 80 mg, 0.29 mmol (50%), [α]D22 = Ϫ30 (c = 1,
CHCl3). 1H and 13C NMR spectra were identical with those of
(R)-3.
(R)-Tomoxetine [(R)-2] was synthesized using a similar method
as for (R)-1. The chloro ether (R)-10 (0.20 g, 0.77 mmol) was
refluxed with aqueous MeNH2 (40%, 3 mL) in EtOH (5 mL)
and (R)-2 was isolated, yield 0.12 g, 0.46 mmol (60%), [α]D22 = Ϫ44
(c = 1, MeOH). 1H NMR: 1.75 (1 H, br s, NH), 2.03 and 2.19 (1
H each, m, -CH2-), 2.40 (3 H, s, -NCH3), 2.75 (2 H, m, -CH2N),
5.25 (1 H, dd, J = 4.5 and 8.2, CH), 7.19–7.35 (5 H, m, phenyl),
o-methylphenoxy part: 2.32 (3 H, s, -CH3), 6.60 (1 H, d, J = 8.1,
H-6), 6.75 (1 H, t, H-5), 6.94 (1 H, t, H-5), 7.10 (1 H, d, 7.4,
H-3). 13C NMR: 38.7 and 48.5 (-CH2CH2-), 78.1 (-CHOR),
125.7 and 128.6 (both 2 Ph-C), 127.5 (Ph C-4), 142.0 (Ph C-1),
o-methylphenoxy part: 16.6 (-CH3), 156.0 (C-1), 127.0 (C-2),
130.6 (C-3), 120.2 (C-4), 126.6 (C-5), 112.8 (C-6). TLC
(CH2Cl2–MeOH–NH4OH, 40:10:1), Rf = 0.58.
Acknowledgements
We are grateful to the Norwegian Research Council (NFR)
for financial support and to Novo-Nordisk A/S, Bagsværd,
Denmark for a gift of CALB.
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(S)-2-(3-Chloro-1-phenylpropoxy)-1-methylbenzene [(S)-10] and
(S)-Tomoxetine [(S)-2)] [(S)-2-(3-methylamino-1-phenyl-
propoxy)-1-methylbenzene]
(S)-10 and (S)-Tomoxetine [(S)-2)] were synthesized by using
the same procedures as for (S)-9 and (S)-1, respectively, (S)-10,
yield 0.21 g, 0.81 mmol (51%), [α]D22 = ϩ11.1 (c = 3.4, CHCl3). 1H
and 13C NMR spectra were identical with those of (R)-10. (S)-
2, yield 0.11 g, 0.43 mmol (53%), [α]D22 = ϩ44 (c = 1, MeOH),
1H and 13C NMR spectra were identical with those of (R)-2.
J. Chem. Soc., Perkin Trans. 1, 2000, 1767–1769
1769