2
K. G. Lalwani, A. Sudalai / Tetrahedron Letters xxx (2015) xxx–xxx
OH
OBn
OBn
OBn
iii
i
vi
O
N
OR
, R = H
13, R = Ms
NHR
N
R
N3
R
R'
1
3
, R = Me
, R, R' = H
4
ent- , R = H
14
10
12
[(-)-ephedrine]
[(+)-amphetamine]
[(-)-metamphetamine]
6, R = propargyl
[(-)-selegiline]
ii
iv
2, R = H
4, R = Me, R' = H
[(-)-norephedrine] [(+)-metamphetamine]
5, R = Me, R' = Bn
OBn
OH
ix
[(+)-benzphetamine]
.HCl
x
N
N
R
R
Cbz
NH3Cl
Figure 1. Sympathomimetic drugs of non-catecholamine class.
4, R = H
(as HCl salt)
2
15
, R = H
vii
v
16, R = Me
epoxide 9 was achieved from 7 by following a modified procedure
involving essentially two-step reaction sequence of NBS-
5, R = Bn
a
viii
bromination in the presence of benzyl alcohol to give bromo
benzyloxy alcohol 8 regioselectively, followed by treatment with
powdered NaOH in THF to form ( )-9 in 84% yield. The HKR of race-
mic epoxide 9 was performed using (S,S)-salenCo(III)OAc as the
catalyst and water as the nucleophile (0.5 equiv) that produced
the corresponding (1R,2R)-benzyloxy epoxide 10 (45% yield; 98%
ee) and (1S,2S)-benzyloxy diol 11 (44% yield; 98% ee) in high
optical purity. Epoxide 10 was readily separated from diol 11 by
a simple chromatographic purification.
NH3Cl
OH
3
NH2Cl
1
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, 0 °C, 3 h, 92%; (ii) MsCl, Et3N,
CH2Cl2, 1 h; (iii) NaN3, DMF, 80 °C, 82%; (iv) (a) 10% Pd/C, H2 (1 atm), MeOH, 25 °C,
4 h; (b) methanolic HCl, quantitative yield over 2 steps; (v) 10% Pd/C, H2 (60 psi),
methanolic HCl, 25 °C, 20 h, 70%; (vi) (a) LiAlH4, THF, 0 °C, 3 h; (b) CbzCl, Et3N,
CH2Cl2, 2 h, 90% over two steps; (vii) MeI, NaH, 60 °C, DMF, 6 h, 75%; (viii) (a) 10%
Pd/C, H2 (1 atm), MeOH, 25 °C, 4 h; (b) methanolic HCl, quantitative yield over 2
steps; (ix) 10% Pd/C, H2 (60 psi), methanolic HCl, 25 °C, 20 h, 77%; (x) (a) PhCHO,
NaOAc, 1,2-dichloroethane, 4 Å molecular sieves, 25 °C, 4 h; (b) NaCNBH3, MeOH,
0 °C, overnight, 88% over two steps.
Regiospecific reductive ring opening of epoxide 10 with LiAlH4
was carried out to give benzyloxy alcohol 12 (92% yield). Alcohol
12 was mesylated quantitatively to give mesylate 13, which was
subjected to SN2 displacement with NaN3 to provide azide 14 with
complete inversion (82% yield over two steps).21 Catalytic hydro-
genation of azide 14 [10% Pd/C, H2 (1 atm), MeOH, 25 °C] followed
by its treatment with methanolic HCl furnished (1R,2S)-norephe-
drine hydrochloride 2 in quantitative yield and high optical purity
(98% ee).22 Further, catalytic hydrogenolysis of hydrochloride 2
over 10% Pd/C in the presence of methanolic HCl gave (S)-am-
phetamine hydrochloride 3 in 70% yield and 98% ee.23 Further,
LiAlH4 reduction of azide 14 gave the corresponding free amine
in situ which was immediately protected as its benzyl carbamate
15 (90% over two steps). N-methylation of 15 (CH3I, NaH, DMF)
gave 16 (75% yield), which was again subjected to catalytic hydro-
genation [10% Pd/C, H2 (1 atm), MeOH, 25 °C] followed by its treat-
ment with methanolic HCl produced (1R, 2S)-ephedrine
hydrochloride 1 in quantitative yield over 2 steps.24 Compound
16 on catalytic hydrogenation in the presence of methanolic HCl
gave (S)-methamphetamine hydrochloride 425 which was con-
densed with benzaldehyde to form the corresponding imine
in situ, NaCNBH3 reduction of which furnished (S)-benzphetamine
5 in free state (88% yield, 98% ee)26 (Scheme 2).
OBn
OBn
6 steps
ii
OH
i
O
N
OH
, R = H
R
ent - 10
11
ent - 4, R = H
(as HCl salt)
iii
17, R = Ts
6, R = propargyl
Scheme 3. Reactions and conditions: (i) TsCl, Et3N, Bu2SnO, CH2Cl2, 0 °C, 2 h, 98%;
(ii) K2CO3, MeOH, 0 °C, 1 h, 94%; (iii) propargyl bromide, anhydrous K2CO3, CH3CN,
25 °C, 85%.
to give 17 (98% yield); (ii) treatment of tosylate 17 with K2CO3 in
MeOH to produce ent-10 (94% yield). A similar sequence of
reactions was carried out on ent-10 as described in Scheme 1
(LiAlH4 reduction, mesylation, azidation, reduction of azide group,
methylation, catalytic hydrogenolysis) that produced (R)-metam-
For the synthesis of (R)-metamphetamine ent-4 and (R)-selegi-
line 6, chiral diol 11 was chosen as the starting material, which was
smoothly converted to benzyloxy epoxide ent-10 in two steps: (i)
selective protection of primary alcohol in the presence of Bu2SnO
phetamine hydrochloride ent-4 in 45% yield over
6
steps.24
Compound ent-4 was finally propargylated to give (R)-selegiline
6 in 85% yield (98% ee)27 (Scheme 3).
Conclusion
OBn
OBn
In conclusion, we have provided an effective procedure for the
enantioselective synthesis of (1R,2S)-ephedrine 1, (1R,2S)-norephe-
drine 2, (S)-amphetamine 3, (S)-metamphetamine 4, (S)-ben-
zphetamine 5, (R)-metamphetamine ent-4 and (R)-selegiline 6
from commercially available cinnamyl alcohol. In this approach,
the key intermediates (10 and 11) were readily prepared in high dia-
stereo- and enantioselectivity from the racemic syn-benzyloxy
epoxide 9 by employing hydrolytic kinetic resolution reaction. The
present catalytic synthesis is efficient and involves simple reagents
with high yielding steps providing for large scale production of
these biologically promising compounds. To the best of our
knowledge, this is the first synthetic strategy for accessing
ii
OH
i
OH
O
Br
7
9
( ) -
8
( ) -
OBn
OBn
iii
OH
O
OH
10
, (45% yield, 98% ee) 11
, (44% yield, 98% ee)
Scheme 1. Reagents and conditions: (i) NBS, BnOH, CH3CN, 25 °C, 3 h, 85%; (ii)
NaOH powder, THF, 0 °C, 2 h, 84%; (iii) (S,S)-(salen)Co(III)OAc complex (0.5 mol %),
H2O (0.5 equiv), THF, 23 °C, 14 h.