Asymmetric synthesis of l-DOPA and (R)-selegiline via, OsO 4-catalyzed asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tetasy.2004.08.007

A simple and effective procedure for the enantioselective synthesis of two important neurotransmitter drugs, that is, (S)-3,4-dihydroxyphenylalanine (l-DOPA) and (R)-N,α-dimethyl-N-2-propynylbenzeneethaneamine [(R)-selegiline], is described by employing the Sharpless asymmetric dihydroxylation (AD) as a key step to introduce chirality.

Full text of DOI:10.1016/j.tetasy.2004.08.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3111–3116
Asymmetric synthesis of L-DOPA and (R)-selegiline via,
OsO4-catalyzed asymmetric dihydroxylation
Iliyas Ali Sayyed and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 24 June 2004; accepted 4 August 2004
Abstract—A simple and effective procedure for the enantioselective synthesis of two important neurotransmitter drugs, that is,
(S)-3,4-dihydroxyphenylalanine (L-DOPA) and (R)-N,a-dimethyl-N-2-propynylbenzeneethaneamine [(R)-selegiline], is described
by employing the Sharpless asymmetric dihydroxylation (AD) as a key step to introduce chirality.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and the use of expensive chiral catalysts. Herein we re-
port a short and effective procedure for the synthesis
of L-DOPA 1 and (R)-selegiline 2 in a high enantiomeric
excess from easily available starting materials.
(S)-3,4-Dihydroxyphenylalanine 1 (L-DOPA) is a potent
neurotransmitter normally administered to patients
suffering from ParkinsonÕs disease.1 Additionally,
(R)-N,a-dimethyl-N-2-propynylbenzeneethaneamine
2
(selegiline), a selective, irreversible inhibitor of monoam-
ineoxidase-B, is widely used, along with L-DOPA, in the
treatment of ParkinsonÕs disease as well as AlzheimerÕs
disease2 (Fig. 1). Subsequent studies have shown that
(R)-selegiline 2 is quite effective in the treatment of Par-
kinsonÕs disease as well as AlzheimerÕs disease when
compared to racemic selegiline.3 While several methods
are available for the synthesis of racemic selegiline,4
scant attention5 has been given to the enantioselective
synthesis of (R)-selegiline 2.
2. Results and discussion
Since no practical methods are available for the catalytic
asymmetric aziridination of olefins, chiral aziridines
have often been made from chiral pool materials involv-
ing several steps.9 Furthermore, the ring opening of chi-
ral aziridines with nucleophiles constitutes a general
method for the synthesis of optically active amines.10
Recently, the catalytic asymmetric dihydroxylation
(AD) reaction of olefins using dihydroquinidine or
dihydroquinine derivatives as ligands has emerged as a
useful and reliable transformation in organic synthe-
sis.11 We employed the AD reaction in our strategy, cou-
pled with a reductive ring opening of aziridines for the
synthesis of L-DOPA 1 and (R)-seligiline 2 (Schemes 1
and 2). Accordingly, the key intermediates, 3-phenylaz-
iridine-2-carboxylic ester 7, and (2R,3R)-2-methyl-3-
phenylaziridine 12 were prepared from the correspond-
ing olefins by employing an AD reaction. Thus,
b-methyl styrene and a,b-unsaturated ester 3 were sub-
jected to an AD reaction in the presence of catalytic
amount of OsO4 and hydroquinine-1,4-phthalazinediyl
diether [(DHQ)2–PHAL] as the chiral ligand to give chi-
ral diols 4 and 9 in excellent enantiomeric excess. The
vicinal diols 4 and 9 on treatment with SOCl2 in pres-
ence of Et3N in CH2Cl2 at 0ꢁC gave the corresponding
cyclic sulfites 5 and 10, respectively, as diastereomeric
mixtures in a 1:1 ratio. Several attempts to oxidize
CO2H
NH2
HO
HO
NMe
2
1
Figure 1.
Most of the literature methods for obtaining 1 and 2
involve either classical resolution of racemic DOPA,6
oxidation of L-tyrosine7 or catalytic asymmetric hydro-
genation of a-acylamidoacrylic acid.8 Furthermore,
these methods suffer from disadvantages such as low
overall yields, the need for separation of diastereomers
*
Corresponding author. Tel.: +91 020 25893300; fax: +91 020
25893359; e-mail: sudalai@dalton.ncl.res.in
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.007

3112
I. A. Sayyed, A. Sudalai / Tetrahedron: Asymmetry 15 (2004) 3111–3116
OH
CO2Et
CO2Et
O
O
O
O
a
b
OH
3
4
H
N
N3
O
O
S
CO2Et
OH
CO2Et
O
O
O
CO2Et
O
O
d
c
O
O
7
6
5
95% ee
CO2Et
O
e
f
L
-DOPA 1
85% ee
NH2
O
8
Scheme 1. Reagents and conditions: (a) cat. OsO4, (DHQ)2–PHAL, K3Fe(CN)6, K2CO3, t-BuOH–H2O, 0ꢁC, 85%; (b) SOCl2, Et3N, CH2Cl2, 0ꢁC,
88%; (c) NaN3, acetone–H2O, 80ꢁC, 82% yield, 95% ee; (d) PPh3, CH3CN, 90%; (e) 10% Pd/C, HCO2NH4, MeOH, reflux, 92%; (f) 6M HCl, PhOH,
AcOH, 130–135ꢁC, 24h, 70% yield, 85% ee.
O
OH
O
N3
S
c
a
b
OH
O
OH
11
10
9
90% ee
H
N
f
d
Me
N
NR1R2
13 a: R1, R2 = H
13 b: R1= H, R2 = CH3
12
(R)-Seligiline 2
e
80% ee
Scheme 2. Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, 0ꢁC, 85%; (b) NaN3, acetone–H2O, 80ꢁC, 82%; (c) PPh3, CH3CN, 90%; (d) Pd–C
(10%), HCO2NH4, MeOH, reflux, 88% yield, 83% ee; (e) i. ClCO2CH3, CH2Cl2, aq K2CO3, 45min, 90%, ii. LiAlH4, dry THF, 65ꢁC, 4h, 65% yield,
83% ee; (f) propargyl bromide, K2CO3, CH3CN, rt to 80ꢁC, 72% yield, 80% ee.
cyclic sulfites 5 and 10 to the corresponding cyclic sulfates
were unsuccessful, possibly due to the formation of sev-
eral by-products, which were difficult to isolate. How-
ever, when cyclic sulfites 5 and 10 were treated with
sodium azide (DMF, 80ꢁC), the corresponding azido
alcohols 6 and 11 were obtained in excellent yields.12
The enantiomeric excess of azido alcohols 6 and 11
3. Conclusion
In conclusion, we have provided an effective procedure
for the enantioselective synthesis of two important drugs
namely, L-DOPA 1 (29.4% overall yield, 85% ee) and
(R)-selegiline 2 (17.54% overall yield, 80% ee) from eas-
ily available starting materials. In this approach, the key
intermediates, chiral aziridines 7 and 12 were prepared
from the corresponding olefins by employing the asym-
metric dihydroxylation reaction.
1
was determined by H and 19F NMR of their corre-
sponding Mosher esters. Azido alcohols 6 and 11 were
then treated with triphenylphosphine in acetonitrile to
give chiral aziridines 7 and 12 in excellent yields.13 Azir-
idines 7 and 12 underwent stereospecific and regioselec-
tive ring opening at the benzylic position by subjecting
them to Pd-catalyzed reductive ring opening with
ammonium formate as the hydrogen source to produce
amines 8 and 13a in excellent yields. Finally, aminoester
8 on treatment with 6M HCl, PhOH, AcOH, 130–
135ꢁC, directly afforded L-DOPA, 1, in 70% yield and
85% ee {[a]D = ꢀ11.0 (c 1.0, 1M HCl); lit.8a
[a]D = ꢀ12.3 (c 1.0, 1M HCl)}.
4. Experimental
4.1. General information
Solvents were purified and dried by standard procedures
before use; petroleum ether of boiling range 60–80ꢁC
was used. Melting points are uncorrected. Optical rota-
tions were measured using sodium D line on a JASCO-
181 digital polarimeter. Infrared spectra were recorded
on an Shimadzu FTIR-8400 spectrometer. 1H NMR
and 13C NMR spectra were recorded on Brucker AC-
200 and MSL-300 NMR spectrometers, respectively.
Mass spectra were obtained with a Finnigan MAT-
1020 B-70 eV mass spectrometer. Elemental analyses
Similarly, 13a was transformed into (R)-selegiline 2 in
two steps by following the literature method.14 Yield
72% and ee 80% {[a]D ꢀ9.0 (c 6.5, EtOH); lit.15 [a]D
ꢀ10.8 (c 6.4, EtOH)}. The spectral data of the synthetic
materials 1 and 2 agreed well with the reported values.

I. A. Sayyed, A. Sudalai / Tetrahedron: Asymmetry 15 (2004) 3111–3116
3113
were carried on a Carlo Erba CHNS-O analyzer. Enan-
tiomeric excesses were determined by MosherÕs agent
data by using chiral shift reagents.
(14), 208 (4), 179 (12), 162 (100), 149 (12), 135 (85),
134 (62), 121 (5), 93 (12), 92 (10), 77 (40), 76 (35), 63
(13). Analysis: C12H12SO7 requires C, 48.00; H, 4.02;
found C, 48.05; H, 4.08%.
4.2. Preparation of ethyl (2R,3S)-2,3-dihydroxy-3-(3,4-
methylenedioxylphenyl)propionate 4
4.4. Preparation of ethyl (2R,3R)-3-azido-2-hydroxy-3-
(3,4-methylenedioxylphenyl)propionate 6
A double-walled 250mL RB flask was charged with
K3FeCN6 (8.94g, 27.2mmol), K2CO3 (3.75g,
27.2mmol), (DHQ)2–PHAL (140mg, 0.18mmol),
MeSO2NH2 (0.855g, 9.0mmol) and t-BuOH–H2O (1:1,
v/v, 90mL) and stirred for 5min at 25ꢁC. It was then
cooled to 0ꢁC and a solution of OsO4 (184lL,
0.09mmol, 0.5M solution in toluene) added followed
by cinnamate 3 (2.0g, 9.0mmol). The reaction mixture
was stirred for 24h at 25ꢁC (monitored by TLC). The
reaction was then quenched with sodium sulfite (10g)
and extracted with ethyl acetate (3 · 60mL). The organ-
ic layer was washed with brine (50mL), dried over anhy-
drous sodium sulfate and evaporated to dryness under
reduced pressure. The crude product was purified by col-
umn chromatography using EtOAc–pet. ether (1:1) as
To a stirred solution of cyclic sulfite 5 (1.85g,
6.16mmol) in DMF (5mL) was added sodium azide
(0.16g, 24.6mmol). The reaction flask was then heated
to 80ꢁC for 6h. After completion of the reaction, as
monitored by TLC, the reaction mixture was poured
into water (25mL), and then extracted with ether
(3 · 25mL). The combined organic phases were washed
with brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude azido-
alcohol was then purified with silica gel chromatography
eluted with pet. ether–EtOAc (9:1) to give azido alcohol
25
6 (1.63g). Yield: 95%; gum; ½aꢁ ¼ ꢀ65:0 (c 0.8, EtOH);
D
IR (CHCl3, cmꢀ1): 3415, 3020, 2108, 1735, 1504, 1488,
1444, 1225, 1215, 1041, 757; 1H NMR (200MHz,
CDCl3): d 1.25 (t, J = 6.0Hz, 3H), 2.45 (br s, 1H),
4.10–4.30 (q, J = 6.0Hz, 2H), 4.48 (d, J = 6.0Hz, 1H),
4.80 (d, J = 4.0Hz, 1H), 5.99 (s, 2H), 6.79 (s, 2H), 6.91
(s, 1H); 13C NMR (50MHz, CDCl3): d 14.00, 62.11,
66.89, 73.62, 101.26, 108.10, 108.28, 121.70, 128.60,
147.91, 148.01, 171.28; MS m/z (% RI): 279 (M+, 4),
176 (15), 164 (6), 149 (20), 148 (100), 135 (13), 121
(60), 105 (3), 92 (7), 90 (12), 76 (14), 65 (43), 63 (24).
Analysis: C12H13N3O5 requires C, 51.61; H, 4.68; N,
15.04; found C, 51.66; H, 4.65; N, 15.10%.
eluent to yield 1.95g of 4. Yield: 85%; gum;
25
D
½aꢁ ¼ þ4:0 (c 0.6, CHCl3), IR (CHCl3, cmꢀ1): 3552,
1
2400, 1731, 1530, 1444, 1215, 1041, 930, 757; H NMR
(200MHz, CDCl3): d 1.28 (t, J = 8.0Hz, 3H), 2.90 (br
s, 1H), 3.75 (br s, 1H), 4.21–4.33 (m, 3H), 4.90 (d,
J = 4.0Hz, 1H), 5.96 (s, 2H), 6.75–7.00 (m, 3H); 13C
NMR (50MHz, CDCl3): d 14.00, 62.00, 74.35, 74.87,
101.00, 106.99, 107.99, 119.79, 133.94, 147.69, 155.48,
172.53; MS m/z (% RI): 254 (M+, 5), 220 (4), 175 (4),
166 (10), 165 (12), 151 (100), 150 (25), 135 (6), 123
(11), 121 (10), 104 (4), 93 (45), 67 (10), 65 (28), 63
(14). Analysis: C12H14O6 requires C, 56.69; H, 5.54;
found C, 56.71; H, 5.50%.
4.5. Preparation of Mosher ester of azido alcohol 6a
A two-neck 25mL flask with septum was charged with
(44mg, 0.206mmol) N,N0-dicyclohexylcarbodiimide
(DCC), catalytic amount of 4-dimethylaminopyridine
(DMAP) and CH2Cl2 (5mL) under an argon atmos-
phere. The flask was allowed to cool at 0ꢁC for 10min
and a solution of azido alcohol 6 (50mg, 0.179mmol)
in CH2Cl2 (5mL) then introduced through a syringe.
It was allowed to stir for an additional 10min, followed
by the dropwise addition of (R)-a-methoxy-a-trifluoro-
methylphenyl acetic acid (46mg, 0.196mmol) in CH2Cl2
was done. This reaction mixture was then stirred at 0ꢁC
for an additional hour and then at room temperature
overnight. The solvent was evaporated under reduced
pressure to give the crude material, which was then puri-
fied by column chromatography eluting with 5% ethyl
acetate in pet. ether to get Mosher ester of azido alcohol
6a (85mg).
4.3. Preparation of ethyl (4R,5S)-4-carbethoxy-5-(3,4-
methylenedioxylphenyl)-1,3,2-dioxathiolane-2-oxide 5
Diol 4 (1.90g, 7.48mmol) was dissolved in triethylamine
(20mL) and cooled to 0ꢁC in an ice bath under an argon
atmosphere. Freshly distilled thionyl chloride (1.33g,
0.81mL, 11.2mmol) was added dropwise and the reac-
tion mixture stirred at 0ꢁC for 45min (monitored by
TLC). After completion of the reaction, ice-cold water
(25mL) was added and extracted with ether
(3 · 25mL). The ethereal layer was washed with 10%
HCl, saturated sodium bicarbonate solution and brine,
successively. The ether extract was dried over anhydrous
sodium sulfate and evaporated under reduced pressure.
The crude product was purified by column chromato-
graphy using pet. ether–EtOAc (9:1) as eluent to furnish
sulfite 5 as light yellow oil (1.97g). Yield: 88%; brown
25
liquid; ½aꢁ ¼ ꢀ100:0 (c 2.3, EtOH); IR (CHCl3,
N3
D
CO2Et
F3C
O
cmꢀ1): 3448, 3020, 2900, 1735, 1488, 1446, 1251, 1215,
1041, 757; 1H NMR (200MHz, CDCl3): d 1.20–1.45
(m, 3H), 4.20–4.45 (m, 2H), 4.69 and 5.08 (2d,
J = 8.0Hz each, 1H), 5.18 and 5.40 (2d, J = 10.0Hz
each, 1H), 5.97–6.00 (2s, 2H), 6.38 (d, J = 10.0Hz,
1H), 6.75–7.25 (m, 2H); 13C NMR (50MHz, CDCl3):
d 13.85, 62.74, 81.30, 82.44, 83.21, 88.81, 101.26,
102.55, 115.77, 128.09, 128.90, 129.12, 132.43, 132.96,
135.52, 135.70, 166.62; MS m/z (% RI): 292 (5), 236
OMe
R
O
O
O
6a
Yield: 89%; 1H NMR (200MHz, CDCl3): d 1.23 (t,
J = 8.0Hz, 3H), 3.45 (s, 0.15H), 3.61 (s, 2.85H), 4.18

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I. A. Sayyed, A. Sudalai / Tetrahedron: Asymmetry 15 (2004) 3111–3116
(q, J = 8.0Hz, 2H), 4.93 (s, 1H), 5.42 (s, 1H), 5.96 (s,
2H), 6.55–6.70 (m, 3H), 7.15–7.60 (m, 5H).
in EtOAc and extracted with water. The aqueous layer
was adjusted to pH5 with 28% ammonia water and a
trace amount of sodium bisulfate and then cooled in
crushed ice to give L-DOPA 1 as white crystals (0.116g).
4.6. Preparation of ethyl (2S,3R)-3-(3,4-methylenedi-
oxylphenyl)aziridine-2-carboxylate 7
25
Yield: 70%; mp: 298ꢁC; lit. mp: 295ꢁC; ½aꢁ ¼ ꢀ11:0 (c
D
To a stirred solution of azido alcohol 6 (1.0g,
3.58mmol) in acetonitrile (30mL) was added PPh3
(0.937g, 3.58mmol). The reaction mixture was then stir-
red at 25ꢁC for 1h and then it was refluxed for 6h. After
completion of reaction (monitored by TLC) the solvent
was removed under reduced pressure to get crude azir-
idine. The pure product was isolated by silica gel chro-
1.0, 1M HCl); {lit.8a [a]D = ꢀ12.3 (c 1.0, 1M HCl)}; IR
(KBr, cmꢀ1): 3500, 3203, 2925, 2854, 2599, 1696, 1654,
1610, 1591, 1514, 1454, 1245, 985, 840; 1H NMR
(200MHz, D2O, DCl): d 3.20 (dd, J = 6.0Hz, 1H),
3.50 (dd, J = 6.0Hz each, 1H), 3.60 (br s, 2H) 4.45 (m,
1H), 6.80–7.05 (m, 3H), 11.8–12.6 (br s, 3H); 13C
NMR (50MHz, CDCl3):
d 39.73, 60.20, 119.05,
matography eluted with pet. ether–EtOAc (9:1) to give
120.20, 123.87, 128.09, 146.47, 147.43, 164.41. Analysis:
C9H11NO4 requires C, 54.82; H, 5.61; N, 7.10; found C,
54.80; H, 5.66; N, 7.15%.
25
D
aziridine 7 (0.757g). Yield: 90%; gum; ½aꢁ ¼ þ176:2
(c 1.0, CHCl3); IR (CHCl3, cmꢀ1): 3288, 3020, 2896,
2770, 2401, 1722, 1608, 1504, 1500, 1448, 1365, 1320,
1
1215, 1120, 1041, 939, 757, 680; H NMR (200MHz,
4.9. Preparation of (4S,5S)-4-methyl-5-phenyl-1,3,2-
dioxathiolane-2-oxide 10
CDCl3): d 1.31 (t, J = 6.0Hz, 3H), 2.16 (s, 1H), 2.50
(br s, 1H), 3.18 (br s, 1H), 4.15–4.35 (q, J = 6.0Hz,
2H), 5.93 (s, 2H), 6.65–6.85 (m, 3H); 13C NMR
(50MHz, CDCl3): d 14.07, 39.21, 40.17, 61.64, 100.97,
106.08, 108.06, 119.90, 131.81, 147.17, 147.87, 171.58;
MS m/z (% RI): 235 (M+, 30), 206 (11), 163 (6), 162
(40), 149 (8), 148 (10), 135 (48), 133 (12), 104 (20), 80
(12), 77 (15), 63 (4), 60 (5), 51 (18), 32 (100). Analysis:
C12H13NO4 requires C, 61.27; H, 5.56; N, 5.95; found
C, 61.22; H, 5.52; N, 5.98%.
Diol 9 (1.0g, 6.57mmol) was dissolved in triethylamine
(20mL) and cooled to 0ꢁC in an ice bath under an argon
atmosphere. Freshly distilled thionyl chloride (0.938g,
7.88mmol) was added dropwise and the reaction
mixture stirred at 0ꢁC for 45min (monitored by TLC).
After completion, ice-cold water (50mL) was added
and extracted with ether (3 · 25mL). The ethereal layer
was washed with 10% HCl, saturated sodium bicarbo-
nate solution and brine, successively. The ether extract
was dried over anhydrous sodium sulfate and evapo-
rated under reduced pressure. The crude product was
purified by column chromatography using pet. ether–
EtOAc (9:1) as eluent to furnish compound 10 as light
yellow oil (1.1g). Yield: 85%; gum; [a]D = ꢀ17.1 (c
1.04, CHCl3); IR (CHCl3, cmꢀ1): 3384, 3024, 2983,
4.7. Preparation of ethyl (S)-2-amino-3-(3,4-methylene-
dioxylphenyl)propionate 8
To a stirred solution of aziridine 7 (0.700g, 2.97mmol)
in methanol (10mL) was added 10% Pd/C (5wt%) and
ammonium formate (0.281g, 4.46mmol). The reaction
flask was then heated to reflux for 4h. After completion
of the reaction, the catalyst was filtered off, and the
filtrate concentrated under reduced pressure to give a
residue. The residue was then purified by silica gel
1
2935, 1612, 1456, 1382, 1215, 1049, 962, 860, 757; H
NMR (200MHz, CDCl3): d 1.48 and 1.57 (2d, J = 6.3
and 5.8Hz, 3H), 4.30–4.50 (2d, J = 9.2 and 6.4Hz,
1H), 5.44 (d, J = 9.3Hz, 1H), 7.35–7.55 (m, 5H); 13C
NMR (50MHz, CDCl3): d 14.88, 17.27, 80.82, 85.34,
85.71, 90.78, 126.99, 127.36, 128.94, 129.27, 129.60,
132.84, 133.64, 159.52; Mass (m/z, % RI): 198 (M+, 4),
154 (45), 133 (4), 126 (30), 117 (8), 106 (16), 105 (95),
91 (35), 90 (26), 90 ( 24), 78 (70), 77 (100), 65 (14), 63
(17), 57 (5). Analysis: C9H10SO3 requires C, 54.53; H,
5.07; S, 16.18; found C, 54.55; H, 5.11; S, 16.13%.
chromatography eluted with EtOAc to give amine 8
25
D
(0.634g). Yield: 90%; gum; ½aꢁ ¼ þ7:5 (c 0.6, CHCl3);
IR (CHCl3, cmꢀ1): 3381, 3019, 1735, 1684, 1503, 1489,
1
1035, 910, 759; H NMR (200MHz, CDCl3): d 1.26 (t,
J = 6.0Hz, 3H), 2.35–2.70 (br s, 2H), 2.70–2.85 (dd,
J = 14.0 and 8.0Hz, 1H), 2.95–3.10 (dd, J = 16.0 and
14.0Hz, 1H), 3.60–3.75 (br s, 1H), 4.10–4.25 (q,
J = 6.0Hz, 2H), 5.92 (s, 2H), 6.60–6.80 (m, 3H); 13C
NMR (50MHz, CDCl3): d 14.14, 40.50, 55.79, 60.94,
100.86, 108.21, 109.53, 122.36, 130.78, 146.47, 147.72,
174.30; MS m/z (% RI): 237 (M+, 17), 220 (12), 206
(5), 165 (40), 164 (30), 149 (12), 136 (38), 135 (100),
121 (5), 106 (15), 102 (14), 91 (4), 77 (24), 69 (12). Anal-
ysis: C12H15NO4 requires C, 60.75; H, 6.36; N, 5.90;
found C, 60.70; H, 6.36; N, 5.92%.
4.10. Preparation of (1R,2S)-1-azido-1-phenylpropane-
2-ol 11
To a stirred solution of cyclic sulfite 10 (0.9g,
4.54mmol) in DMF (5mL) was added sodium azide
(1.18g, 18.18mmol). The reaction flask was then heated
to 80ꢁC for 6h. After completion of the reaction, as
monitored by TLC, the reaction mixture was poured
in 25mL of water, and then extracted with ether
(3 · 25mL). The combined organic phases were washed
with brine, dried over anhydrous sodium sulfate and
concentrated. The crude azidoalcohol was then purified
with silica gel chromatography eluted with pet. ether–
EtOAc (9:1) to give azido alcohol 11 (0.680g). Yield:
82%; gum; [a]D = ꢀ228.16 (c 1.2, CHCl3); IR (CHCl3,
cmꢀ1): 3019, 2855, 2106, 1600, 1525, 1430, 1215, 1120,
4.8. Preparation of (S)-2-amino-3-(3,4-dihydroxyphen-
yl)propanoic acid 1
To a 50mL flask was added amine 8 (0.200g,
0.84mmol), phenol (0.236g, 2.52mmol), glacial acetic
acid (0.151g, 2.52mmol) and 6M HCl (10mL). The
reaction mixture was heated to reflux for 36h and then
concentrated to give a residue. The residue was dissolved

I. A. Sayyed, A. Sudalai / Tetrahedron: Asymmetry 15 (2004) 3111–3116
3115
1
1065, 930, 669; H NMR (200MHz, CDCl3): d 1.18 (d,
J = 6.4Hz, 3H), 1.65–1.90 (br s, 1H), 3.90–4.05 (m, 1H),
4.47 (d, J = 5.4Hz, 1H), 7.30–7.50 (m, 5H); 13C NMR
4.13. Preparation of (R)-2-amino-1-phenylpropane 13a
To a stirred solution of aziridine 12, (0.400g, 3.0mmol)
in 10mL of methanol was added Pd–C (10%) and
ammonium formate (0.378g, 6.00mmol). The reaction
flask was then heated to reflux for 4h. After completion
of the reaction, the catalyst was filtered off, and the
filtrate concentrated under reduced pressure to give a
residue. The residue was then purified by silica gel
chromatography eluted with EtOAc to give amine 13a
(0.336g).
(50MHz, CDCl3):
d 18.30, 70.35, 71.27, 127.65,
128.35, 128.57, 136.18; Mass (m/z, % RI): 177 (M+, 4),
159 (15), 131 (13), 115 (10), 105 (56), 104 (58), 103
(24), 91 (14), 77 (100), 63 (17). Analysis: C9H11N3O
requires C, 61.00; H, 6.83; N, 23.71; found C, 61.05;
H, 6.85; N, 23.68%.
4.11. Preparation of Mosher ester of azido alcohol 11a
A two-neck 25mL flask with septum was charged with
(44mg, 0.206mmol) N,N0-dicyclohexylcarbodiimide
(DCC), a catalytic amount of 4-dimethylaminopyridine
(DMAP) and CH2Cl2 (5mL) under an argon atmos-
phere. The flask was allowed to cool at 0ꢁC for 10min
and a solution of azido alcohol 6 (32mg, 0.180mmol)
in CH2Cl2 (5mL) introduced through syringe. It was
allowed to stir for an additional 10min, followed by
dropwise addition of (R)-a-methoxy-a-trifluoromethyl-
phenyl acetic acid (31mg, 0.196mmol) in CH2Cl2. This
reaction mixture was then stirred at 0ꢁC for an
additional hour and then at room temperature overnight.
The solvent was evaporated under reduced pressure to
give the crude material, which was then purified by col-
umn chromatography eluting with 7% ethyl acetate in
pet. ether to give the Mosher ester of azido alcohol 6a.
Yield: 88%; mp: gum; [a]D = ꢀ25.6 (c 2.0, MeOH); lit.16
[a]D = ꢀ30.2 (c 2.5, MeOH); IR (CHCl3, cmꢀ1): 3415,
3055, 3010, 2995, 1650, 1505, 1435, 1400, 1195, 1100,
1090, 870, 810, 750, 700; 1H NMR (200MHz,
CDCl3 + CD3OD): d 1.20 (d, J = 6.40Hz, 3H), 2.65–
2.80 (dd, J = 8.30 and 8.80Hz, 1H), 2.80–2.90 (br s,
2H), 2.90–3.05 (dd, J = 5.80Hz each, 1H), 3.40–3.50
(m, 1H), 7.10–7.40 (m, 5H); 13C NMR (50MHz,
CD3OD): d 18.28, 41.74, 50.37, 128.34, 129.96, 130.43,
137.20. Analysis: C9H13N requires C, 79.95; H, 9.68;
N, 10.36; found C, 79.91; H, 9.68; N, 10.39%.
4.14. Preparation of (R)-2-methylamino-1-phenylpropane
13b
A 25mL dry flask was charged with amine 13a (0.300g,
2.22mmol) in dry CH2Cl2 (8mL). To this was added
methylchloroformate (0.263g, 0.21mL, 2.77mmol) and
the reaction flask stirred vigorously. To this vigorously
stirred mixture was added K2CO3 (1.531g, 11.10mmol)
in H2O (8mL) over a period of 5min and then stirring
continued. After completion of the reaction as indicated
by the TLC, the reaction mixture was extracted with
CH2Cl2, and the solvent evaporated under reduced pres-
sure to give the crude carbamate.
N3
CH3
OMe
F3C
O
R
O
11a
Yield: 90%; 1H NMR (200MHz, CDCl3): d 1.18 (d,
J = 6.4Hz, 3H), 3.48 (s, 0.15H), 3.65 (s, 2.85H), 3.90–
4.05 (m, 1H), 4.47 (d, J = 5.4Hz, 1H), 7.25–7.55 (m,
10H).
To a solution of lithium aluminum hydride (0.126g,
3.33mmol) in dry THF (15mL) under a nitrogen atmos-
phere at room temperature was added dropwise a solu-
tion of carbamate in dry THF. The reaction flask was
then heated under reflux for 2h. After completion of
the reaction the reaction mixture was cooled to room
temperature and ethyl acetate slowly added. The reac-
tion mixture was then filtered and the filtrate evaporated
under reduced pressure to give a residue, which was
purified by column chromatography to yield 0.215g of
amine 13b. Yield: 65%; mp: 38–40ꢁC; [a]D = ꢀ8.1 (c
0.8, EtOH); lit.14 [a]D = ꢀ10.9 (c 0.8, EtOH); IR
(CHCl3, cmꢀ1): 1H NMR (200MHz, CDCl3): d 0.95
(d, J = 8.0Hz, 3H), 1.50 (s, 1H), 2.25 (s, 3H), 2.65–
2.95 (m, 3H), 7.20–7.60 (m, 5H); Mass (m/z, % RI):
149 (M+, 4), 134 (10), 119 (5), 117 (5), 91 (45), 65 (16),
58 (100). Analysis: requires C10H15N requires C, 80.49;
H, 10.12; N, 9.38; found C, 80.41; H, 10.12; N, 9.45%.
4.12. Preparation of (2R,3R)-2-methyl-3-phenylaziridine
12
To a stirred solution of azido alcohol 11 (0.650g,
3.67mmol) in 25mL of acetonitrile was added PPh3
(0.962g, 3.67mmol). The reaction mixture was then stir-
red at room temperature for 1h and then refluxed for
6h. After completion of the reaction as monitored by
TLC, the solvent was removed under reduced pressure
to give crude aziridine. The pure product was then iso-
lated by silica gel chromatography eluted with pet.
ether–EtOAc (9:1) to give aziridine 12 (0.440g). Yield:
90%; gum; [a]D = +58.5 (c 0.8, CHCl3); IR (CHCl3,
cmꢀ1): 3285, 2890, 2395, 1608, 1504, 1500, 1470, 1380,
1320, 1215, 1120, 1041, 939, 790, 680; 1H NMR
(200MHz, CDCl3): d 1.24 (d, J = 5.4Hz, 3H), 1.90–
2.15 (m, 2H), 2.54 (d, J = 2.9Hz, 1H), 7.00–7.40 (m,
5H); 13C NMR (50MHz, CDCl3): d 19.36, 36.82,
40.28, 125.37, 126.73, 128.24, 140.26. Analysis:
C9H11N requires C, 81.16; H, 8.31; N, 10.51; found C,
81.20; H, 8.35; N, 10.51%.
4.15. Preparation of (R)-N,a-dimethyl-N-2-propynylbenz-
eneethaneamine; (R)-selegiline 2
To a stirred solution of (R)-2-(methylamino)-1-phenyl-
propane 13b, (0.200g, 1.34mmol) in acetonitrile
(10mL) was added K2CO3 (0.277g, 2.01mmol) and

3116
I. A. Sayyed, A. Sudalai / Tetrahedron: Asymmetry 15 (2004) 3111–3116
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5. (a) Josef, H. Chem. Abstr. 113: 590e; (b) Josef, H. Chem.
Abstr. 117: 150680; (c) Ott-Dombrowski, S.; Richard, C.;
Jeorge, S.; Hans, W. Chem. Abstr. 124: 288969x.
6. (a) Chen, C.; Zhu, Y.-F.; Wilcoxen, K. J. Org. Chem.
2000, 65, 2574; (b) Deng, W. P.; Wong, K. A.; Kirk, K. L.
Tetrahedron: Asymmetry 2002, 13, 1135; (c) Ooi, T.;
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7. (a) Klibanov, A. M.; Berman, Z.; Alberti, B. N. J. Am.
Chem. Soc. 1981, 103, 6263; (b) Boger, D. L.; Yohannes,
D. J. Org. Chem. 1987, 52, 5283; (c) Jung, M. E.;
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Wolsche, U. Helv. Chim. Acta 1973, 56, 2857.
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Weinkauff, D. J. J. Am. Chem. Soc. 1975, 97, 2567; (b)
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propargyl bromide (0.478g, 0.36mL, 4.02mmol). The
reaction mixture was then allowed to stir at room
temperature overnight until all the starting material
had disappeared. The reaction mixture was then
extracted with 5% HCl (5 · 10mL), made alkaline to
give an oil, to give 0.215g of I-selegiline 1b in 72% yield.
Yield: 72%; gum; [a]D = ꢀ9.0 (c 6.5, EtOH); lit.15
[a]D = ꢀ10.8 (c 6.48, EtOH); IR (CHCl3, cmꢀ1): 1H
NMR (200MHz, CDCl3): d 0.95 (d, J = 6.0Hz, 3H),
2.25 (t, J = 2.0Hz, 1H), 2.35 (s, 1H), 2.40–2.55 (m,
3H), 2.80–3.10 (m, 2H), 3.40 (d, J = 2.0Hz, 2H), 7.00–
7.50 (m, 5H); 13C NMR (50MHz, CDCl3): d 21.1,
31.4, 46.8, 51.90, 60.8, 68.1, 82.2, 125.6, 128.3, 128.6,
140.2; Mass (m/z, % RI): analysis: requires C13H17N re-
quires C, 83.37; H, 9.14; N, 7.47; found C, 83.34; H,
9.11; N, 7.53%.
Acknowledgements
9. Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000,
39, 4518.
Author I.A.S thanks the CSIR, New Delhi, for the
award of senior research fellowship. The authors would
also like to thank Dr. B. D. Kulkarni, Head, CE-PD
Division, for his constant encouragement and support.
10. (a) Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Pergamon: Oxford, 1989; (b) Kasai, M.; Kono, M.
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R. W. Tetrahedron Lett. 1991, 32, 3807; (e) Moran, E. J.;
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