111

C H A P T E R 2





Asymmetric synthesis of (S)-Dapoxetine and (R)-Selegiline using
Sharpless asymmetric epoxidation strategy
112
SECTION-I
Asymmetric synthesis of selective serotonin reuptake inhibitor (S)-
Dapoxetine

2.1.1 Introduction
Premature ejaculation (PE) is the most common form of male sexual dysfunction.
1

Globally, between 20% and 40% of men, at some point in their lives, have reported
symptoms of PE or a complaint of PE,
1-3
which may be classified as lifelong or acquired.
4

Lifelong PE is characterized by early ejaculation in the majority of intercourse attempts
with nearly every partner from the first sexual encounter onwards, whereas acquired PE
develops at some point in a mans life after he has previously experienced normal
ejaculation and may be linked to urological or psychological problems.
4
Current treatments
Historically, PE was considered a psychosomatic problem.
5, 6
Therefore,
behavioral, cognitive, and sex/relationship therapies have been a key component of PE
management. Behavioral approaches have generally focused on the physical aspect of
PE, including the squeeze technique as first described by Masters and Johnson in 1970
7

and the stop-start method described by Semans in 1956.
8

A number of pharmacologic therapies have been employed in the management of
PE. A topical cream containing local anesthetics lidocaine 1 and prilocaine 2 was
effective for PE (Figure 1).
9, 10
H
N
O
N
H
H
N
O
N
Lidocaine 1 Prilocaine 2

Figure 1. Local anesthetics agent.
113
In addition, topical treatments can be messy and inconvenient to use.
Alternatively, Selective serotonin reuptake inhibitors (SSRIs), commonly used in the
treatment of depression, are often used to treat PE. A key limitation of therapy for PE
with currently available SSRIs is that in addition to delaying ejaculation, this class of
drugs has been associated with a number of unwanted side effect have been observed
following treatment with citalopram 3, fluvoxamine 4, fluoxetine 5, paroxetine 6,
sertraline 7 (Figure 2).
11, 12

O
F
N
NC
CF
3
N
O
O
H
2
N
NHMe
O
F
3
C
(R)-Fluoxetine 5
N
H
O
O
O
Cl
Cl
NHMe
(R,S)-Paroxetine 6
(S,S)-Sertraline 7
(R)-Citalopram 3
Fluvoxamine 4

Figure 2. Selective serotonin reuptake inhibitors (SSRIs)

N
H
N
N
H
O
O
O
O
Me
N
S
Me O
N
H
N
N
N
Me
O
O
O
N
S
O
N
H
N
N
N
Me
O
O
O
Sildenafil 8
Vardenafil 9
Tadalafil 10
Figure 3. Phosphodiesterase-5 (PDE-5) inhibitors

114
Other systemic treatments that have been evaluated for the management of PE include the
phosphodiesterase-5 (PDE-5) inhibitors such as Sildenafil 8, Tadalafil 9, and Vardenafil
10, currently licensed for the treatment of Erectile Dysfunction (ED) (Figure 3).
Dapoxetine
Presently, no pharmacologic agent is approved by any regulatory agency
specifically for the treatment of PE, which may contribute to under treatment of the
condition. Dapoxetine is a novel short-acting SSRI for the treatment of PE. In preclinical
models, dapoxetine has been statistically shown to significantly inhibitory ejaculatory
expulsion reflexes, acting at a supraspinal level.
13, 14
Similar to other SSRIs, dapoxetine
exerts its effects primarily through the inhibition of the serotonin reuptake transporter,
with minimal inhibitory activity at the norepinephrine and dopamine reuptake
transporters.
15
However, unlike long-acting SSRIs, which are typically administered in a
chronic (daily) fashion and may take days or weeks to reach steady-state plasma
concentrations,
16
dapoxetine is a short-acting SSRI, which may be better suited to the
treatment of PE.
17
O
N
Me Me
O
N
Me Me
O
N
Me Me
()-Dapoxetine 11
(R)-Dapoxetine 11a (S)-Dapoxetine 11b

Figure 4. Structure of racemic and enantiomers of Dapoxetine

(S)-(+)-Dapoxetine 11b hydrochloride ((S)-(+)-N,N-dimethyl-[3-(naphthalen-1-yloxy)-1-
phenylpropyl]amine; Priligy),
18
a potent SSRI with a short half-life has been developed
specifically for the treatment of PE. The (S)-Dapoxetine 11b is 3.5 times more potent
19

115
than is (R)-Dapoxetine 11a (Figure 4).

This substance was first launched in 2009 in
Europe where it is used for the oral, on-demand treatment of PE in men between 18 and
64 years of age.
2.1.2 Review of Literature
The synthetic methods available in the literature for (S)-Dapoxetine are as follows
OBannon approach (1992)
20
OBannon et al have reported three different approaches for the synthesis of (S)-
Dapoxetine 11b, first method describes resolution of racemic dapoxetine 11 with D-
tartaric acid (Scheme 1). Racemic dapoxetine 11 was synthesized by Knoevenagel
condensation of benzaldehyde 12 with malonic acid in the presence of ammonium acetate
produced the beta-aminoacid 13.
CHO
NH
2
OH
O N
OH
Me Me
O
N
OEt
Me Me
O
OEt
O N
OH
Me Me
N
O
Me Me
O
N
Me Me
i
ii
iii
iv
v
vi
vii
12
13
14
16 15 17
11
(S)-11b
()-

Scheme 1. Reagents and condition: i) Malonic acid, NH
4
OAc, EtOH, reflux; ii) Pd-C, H
2
,
HCHO; iii) EtOH, HCl (gas), reflux; iv) dimethyl amine; v) LiAlH
4
, THF (or) Red-Al in
toluene; vi) NaOH, 1-fluoronaphthol, DMA, 100

C; vii) (R,R)-tartaric acid.

116
Reductive alkylation of the amino group of 13 with formaldehyde produced the
dimethylamine 14. Then, Fischer esterification of 14 with ethanolic HCl furnished the
intermediate amino ester 16. Amino ester 16 was alternatively obtained by Michael
addition of dimethylamine to ethyl cinnamate 15. Reduction of the ester functionality in
16 provided amino alcohol (S)-17. The sodium alkoxide of 17 was then coupled with 1-
fluoronaphthalene to produce the racemic Dapoxetine 11, which was finally resolved into
enantiomers by (R,R)-tartaric acid.
Second approach of same group, the (S)-Dapoxetine 11b was synthesized from
unnatural amino acid (R)-Phenyl glycine 18 as a starting material which illustrated in the
Scheme 2. (R)-Phenyl glycine 18 protected with (Boc)
2
O to afford N-Boc-(R)-phenyl
glycine 19.
CO
2
H
NH
2
CO
2
H
NHBoc
NHBoc
OH
NHBoc
OMs
NHBoc
CN
NH
2
OH
O
NH
2
OH
N
OH
O
N
i
ii iii
iv
v
vi
vii
viii
(R)-Phenyl glycine 18
19
20
21
22
(S)-13b (S)-23b
(S)-17b
(S)-11b

Scheme 2. Reagents and condition: i) aq.NaHCO
3
, (Boc)
2
O, DCM; ii) BH
3
.THF, 0

C; iii)
MsCl, pyridine, DCM; iv) NaCN, DMSO, 60

C; v) dil.H
2
SO
4
, reflux; vi) BH
3
.THF, 0

C; vii)
HCHO, HCO
2
H, reflux; viii) 1-Fluoronaphthalene, NaH, DME.
Borane reduction of 19 provided the N-Boc amino alcohol 20, which was
activated as the mesylate 21 by reaction with methanesulfonyl chloride in pyridine,
117
yielding 21. Displacement of the mesylate group of 21 with NaCN furnished the Boc-
aminonitrile 22. Hydrolysis of the nitrile group with concomitant N-Boc deprotection
under the acidic condition to afford amino acid (S)-13b. This was reduced to amino
alcohol 23b using borane in THF. Eschweiler-Clarke methylation of aminoalcohol 23b
yielded the dimethyl amine (S)-17b. This was finally condensed with 1-
fluoronaphthalene to produce the (S)-Dapoxetine 11b.
Third approach of same group, the synthesis of
14
C-labeled compound 11b was
reported as shown in Scheme 3. The selective tosylation of the primary hydroxyl of (R)-
1-phenyl-1,3-propanediol 24 provided 25. From this, naphthyl ether 26 was prepared by
Williamsons synthesis with the sodium alkoxide of 1-naphthol. The secondary hydroxyl
group in 26 was then converted to mesylate 27 upon treatment with methanesulfonyl
chloride and catalytic amount of DMAP. Subsequent displacement with methylamine in a
sealed vessel afforded the secondary amine 28. This was finally alkylated with
14
CH
3
I to
yield the target
14
C-labeled compound (S)-11b.
OH
OH
OTs
OH
O
OH
O
NH
O
OMs
i ii
iv
iii
O
N
H
3
14
C CH
3
v
24
25
26
27 28
14
C-labled (S)-Dapoxetine 11b

Scheme 3. Reagents and condition: i) TsCl, Et
3
N, DCM; ii) 1-naphthol, NaOH, DMF; iii)
MsCl, cat. DMAP, Et
3
N, DME, 0

C; iv) MeNH
2
, sealed tube, heat; v)
11
CH
3
I.

118
Gotor approach (2006)
21
Gotor et al have reported the enzymatic resolution of 3-amino-3-phenylpropane-
1-ol derivative ()-29 has been studied through N-acylation in the presence of candida
antarctica lipase A (CAL-A) as a biocatalyst (Scheme 4). Racemic 3-amino-3-
phenylpropan-1-ol ()-23 was synthesized from benzaldehyde 12, a process which
involves two steps: formation of 3-amino-3-phenylpropionic acid ()-13 followed by
reduction to afford the corresponding amino alcohol ()-23.
CHO
NH
2
OH
O
NH
2
OH
NH
2
OTBDMS
O
O
O
HN
OTBDMS
O
O
NH
2
OTBDMS
NH
2
OH
N
OH
Me Me
N
O
Me Me
93% ee
i
ii
iii
v
vi
vii
12
13 23 ()- ()-
29 ()-
(R)-29a
30
31
(S)-23b
(S)-17b
(S)-11b
iv

Scheme 4. Reagents and condition: i) Malonic acid, NH
4
OAc, EtOH, reflux, 12 h, 68%; ii)
LiAlH
4
, THF, reflux, 3 h, 77%; iii) TBDMCl, imidazole, DCM, rt, 95%; iv) CAL-A, TBME, 30

C, 250 rpm; v) 6 M HCl, 50

C, 84%; vi) (CH

2
O)
n
, HCO
2
H, reflux, 83%; vii) 1-naphthol, Ph
3
P,
DEAD, THF, rt, 72%.

The alcohol was protected with TBDMSCl thus obtaining ()-29. At this point to
resolve ()-29 by direct enzymatic (Candida antarctica lipase A (CAL-A)) N-acylation of
in the presence of activated ester such as ethyl methoxyacetate 30, as acyl donor. The
119
compound 31 was hydrolyzed with aq. 6M HCl to the corresponding amino alcohol (S)-
23b followed by in situ deprotection of the silyl ether. Later dimethylation of the amino
group in 23b led to the formation of (S)-17b. Finally, the nucleophilic substitution of (S)-
17b under the Mitsunobu reaction condition with 1-naphthol afforded the (S)-Dapoxetine.
Sirivasan approach (2007)
22
Sirivasan et al have developed two different methods for asymmetric synthesis of
(S)-Dapoxetine. The first approach of the Srinivasan consists of Sharpless asymmetric
dihydroxylation as a key reaction to induce the chirality as shown in the Scheme 5.
OMe
O
OMe
O OH
OH
O
S
O
O
O OMe
OMe
O N
3
OH
OMe
O NH
OH
O
Bu
t
O
OMe
O NH
O
O
Bu
t
O
S
SMe
OH
NH
2
OH
N
Me Me
O
N
Me Me
OH
NHBoc
OMe
O NH
O
Bu
t
O
i ii
iii
iv
v
vi
vii
viii
ix
32
33
34
35 36
37
37
38
39
(S)-23b
(S)-17b
(S)-11b

Scheme 5. Reagents and conditions: (i) (DHQ)
2
PHAL (5 mol%), OsO
4
, NMO, t-BuOH: H
2
O,
0

C, 16 h; (ii) SOCl
2
, Et
3
N, DCM, 0

C to rt, 1 h; (iii) NaN

3
(5 equiv.), DMF, rt, 48 h; iv) H
2
,
Pd-C, EtOAc, rt, 24 h, (Boc)
2
O, Et
3
N; (v) MeI, CS
2
, MsCl, Et
3
N, DCM, 0

C to rt, 12 h; (vi) n-
Bu
3
SnH, AIBN, toluene, reflux, 75% two steps; (vii) LiAlH
4
, THF, rt, 12 h; (viii) TFA, DCM,
rt, (ix) HCHO, HCO
2
H, reflux; (x) 1-Naphthol, Ph
3
P, DEAD, THF, rt.

120
As indicated in the Scheme 5, the trans-cinnamyl ester 32 upon Sharpless
asymmetric dihydroxylation afforded (2R,3S)-methyl-2,3-dihydroxy-3-phenylpropanoate
33 in 80% yield with 99% ee. The vicinal diol on treatment with thionyl chloride gave the
corresponding cyclic sulfite 34 as a diastereomeric mixture in a 1:1 ratio. The cyclic
sulfite reacted with NaN
3
to furnish azido alcohol 35 in 85% yield. The azide reduction
followed by Boc protection of the amine functionality resulted in the formation of
compound 36. The deoxygenation of the secondary alcohol 36, under the Barton
McCombie protocol gave the product 38 in 75% yield. The ester functionality in 38 was
reduced to intermediate 39 by LAH. The Boc group in 39 was subsequently deprotected
by TFA to give (S)-23b. The amine (S)-23b was alkylated using the Clarke-Eschweiler
condition to afford (S)-17b in 83% yield. Mitsunobu reaction conditions, which gave (+)-
(S)-dapoxetine 11b in 72% yield.

Another approach of same group, the trans-cinnamyl alcohol 40 was subjected to
SAE conditions

to give the epoxide 41 in 88% yield with 98% ee is represented in the
Scheme 6.

Regioselective opening of the epoxide 41 with NaN
3

gave the azido diol 42 in
97% yield. The azido diol 42 was converted into the mono-TBS protected azido alcohol
43 in 96% yield, which on reduction with 5% Palladium on Charcoal in EtOAc followed
by treatment of the amine with (Boc)
2
O afforded the N-Boc protected alcohol 44 in 88%
yield. The secondary alcohol 44 was converted into its xanthate ester 45 under standard
reaction condition followed by a deoxygenation under the Barton-McCombie

protocol
affording the protected amino alcohol 46, which was further treated with TFA to give the
121
amino alcohol (S)-23b in 81% yield in two steps. The amino alcohol (S)-23b was
converted in to (S)-dapoxetine 11b using literature procedure.
OH OH
O
OH
N
3
OH
OTBS
N
3
OH
OTBS
NHBoc
OH
OH
NH
2
O
N
Me Me
OTBS
NHBoc
OTBS
NHBoc
O
S
SMe
i
ii
iii iv v
vi
vii
40
41b
42
43
44
45
46
(S)-23b
(S)-11b

Scheme 6. Reagents and conditions: i) (R,R)-(+)-DET, Ti(O
i
Pr)
4
, TBHP, 4

MS, DCM, -20

C, 3 h, 88%; ii) NaN

3
, MeOH: H
2
O (8 : 1), 65
o
C, 4 h, 97%; iii) TBSCl, DCM, imidazole, 0

C-rt, 6 h, 96%; iv) H

2
, Pd-C, (Boc)
2
, EtOAc, rt, 12 h, 88%; v) CS
2
, NaH, MeI, THF, 0
o
C-rt,
overnight, 84%; vi) n-Bu
3
SnH, AIBN, toluene, reflux, 6 h; vii) TFA, DCM, 0

C-rt, 5 h, 81%
two steps.

Benjamin List approach (2008)
23

Benjamin list et al have reported formal synthesis of (S)-Dapoxetine 11b through
Mannich reaction catalyzed by organocatalyst as shown in the Scheme 7.
N
Boc
H
O
NHBoc
CHO
NHBoc
OH
i
ii
47 48
49
50
(S)-Dapoxetine 11b

Scheme 7. Reagents and conditions: i) (S)-Proline (20 mol %), CH
3
CN, 0

C, 2-3 h, 54%; ii)

NaBH
4
, MeOH.

Proline-catalysed Mannich reaction of acetaldehyde 48 with N-tert-
butoxycarbonyl (N-Boc)-imine 47 yields amino aldehyde 49. Further, aldehyde 49 was
122
reduced to alcohol 50. Finally, the synthesis of (S)-Dapoxetine 11b was completed
according to literature procedure.

Deshmukh approach (2009)
24
Deshmukh et al have reported formal synthesis of (S)-Dapoxetine 11b from
enantiopure 3-hydroxy azetidin-2-one 57. The intermediate (S)-3-(dimethyl amino)-3-
phenylpropan-1-ol (S)-17b was synthesized in enantiopure form starting with 3-hydroxy
azetidin-2-one 57, which was synthesized from diethyl tartrate 51. Diethyl L-tartrate 51
was protected as its acetonide 52 using a reported protocol (Scheme 8). Compound 52
was subjected to partial hydrolysis to afford mono acid, which was further converted to
its acid chloride 53. This acid chloride 53 was used as such for Staudinger cycloaddition
reaction with the imine derived from benzaldehyde and p-anisidine, to furnish
diastereomeric mixture (60:40) of -lactams 54a and 54b. The required diastereomer 54b
was obtained by column chromatography. Spiro -lactam 54b was then subjected to the
deprotection of acetonide using ferric chloride to obtain diol 55, which on periodate
oxidative cleavage yielded azetidin-2,3-dione 56. Stereoselective reduction of the keto
group of azetidin-2,3-dione 56 was achieved using sodium borohydride to get 3-hydroxy
b-lactam 57. The 3-hydroxy b-lactam 57 was converted to its xanthate derivative 58,
which was further subjected to deoxygenation under the Barton-McCombie

protocol to
furnish -lactam 59. It was then subjected to oxidative removal of the p-methoxy-phenyl
group on the lactam nitrogen using ceric ammonium nitrate (CAN) to obtain compound
60 in 60% yield.

123

HO CO
2
Et
CO
2
Et HO
CO
2
Et
CO
2
Et
O
O
N
O
CO
2
Et
H
O
PMP
N
H Ph
O
O
CO
2
Et
H
O
PMP
O
H Ph
N
O
CO
2
Et
H
O
PMP
O
H Ph
N
OH
CO
2
Et
H
OH
PMP
O
H Ph
N PMP
O
H Ph
O
N
O
Ph
PMP
HO
N
O
Ph
PMP
O
S
MeS
N
O
Ph
PMP
NH
O
Ph
N
O
Ph
Boc
NHBoc
OH
CO
2
Et
COCl
O
O
i
ii
iii
iv
v
vi
vii viii ix
x
xi
NH
2
OH
xii
51
52
53
54a
54b
+
54b
55
56
57
58 59
60
61
39
(S)-23b
N
OH
(S)-17b
Me Me

Scheme 8. Reagents and conditions: i) 2,2-dimethoxy propane, PhH, PTSA, reflux, 5 h; ii) a)
NaOH, THF/H
2
O, rt, 4-6 h, b) (COCl)
2
, DCM, reflux, 5 h; iii) PMP-N=CH-Ph, Et
3
N, DCM, -
40

C, to rt, 15 h; iv) FeCl

3
, DCM, rt, 2 h; v) NaIO
4
, acetone/water, rt, 6-8 h; vi) NaBH
4
,
MeOH, 0

C, 2 h; vii) NaH, CS
2
, MeI, THF, 0

C-rt, 6 h; viii) n-Bu

3
SnH, AIBN, toluene, reflux,
3-4 h; ix) CN, CH
3
CN/H
2
O, 0

C, 1 h; x) LAH, THF, 0

C to rt, 4 h; xi) TFA, DCM, 0

C to rt,
2 h; HCHO, NaCNBH
3
, AcOH, CH
3
CN, rt, 2 h.

The Lactam 60 was then protected as its carbamate derivative with (Boc)
2
O obtains 61. It
was further reduced by LAH to get Boc protected amino alcohol 39. Intermediate 39 was
further subjected to Boc deprotection with TFA to get amino alcohol (S)-23b. The
methylation of (S)-23b using formaldehyde and sodium cyanoborohydride afforded the
desired N-bismethylated amino alcohol (S)-17b.
124

Lee approach (2010)
25
Lee et al have reported enantiomers of Dapoxetine employing Du Bois
asymmetric C-H amination reaction of the prochiral sulfamate ester 63, catalyzed by a
chiral valerolactam-derived, dirhodium (II) complex which illustrated in the Scheme 9.
OH
O
i
S
H
2
N
O O
O
S
HN
O O
ii
O
S
N
O O
iii
iv
NH
O
v
N
O
N
O
Rh
Rh N
O N
N
Ts
Ts
H
H
2
2
Rh
2
(R-nap)
4
62
63 64
65
28
(S)-11b

Scheme 9. Reagents and conditions: i) ClSO
2
NH
2
, DMA, 0

C to rt; ii) 2 mol% Rh

2
(R-nap)
4
,
PhI=O, 4 MS, DCM, rt; iii) MeI, K
2
CO
3
, cat. TBAI, DMF, 0

C to rt; iv) NaH, i-Naphthol,

DMF then 5 M HCl, rt; v) HCHO, HCO
2
H, reflux.

3-phenyl-1-propanol 62 was converted to sulfamate ester 63. Treatment of the prochiral
sulfamate ester 63 with Iodosobenzene in the presence of Rh
2
(R-nap)
4
catalyst afforded
the cyclic sulfamate ester 64. The methylation of (S)-sulfamate ester 64 with methyl
iodide afford the cyclic N-methyl-sulfamate ester 65 (83% yield, 91.1% ee). Subsequent
reaction of 65 with 1-naphthol in the presence of base produced N-methyl-[3-
(naphthalen-1-yloxy)-1-phenylpropyl]amine 28 in yield 87%. Finally, reductive
amination of 28, under Eschweiler-Clarke conditions with formaldehyde and formic acid
as the hydrogen source, gave dapoxetine 11b in 79%.

125

2.1.3 Present work
2.1.3.1 Objective
Literature search revealed that several reports are available for the synthesis of
(S)-Dapoxetine. Previously, to best of our knowledge the (S)-Dapoxetine was prepared
from a racemic mixture of dapoxetine by resolution with tartaric acid. An alternative
synthesis of (S)-dapoxetine, starting from (R)-1-phenyl-1,3-propandiol and selective
displacement of the secondary alcohol moiety with dimethylamine, was described.
Another route for the preparation of (S)-Dapoxetine, beginning with chiral 1,3-amino
alcohols that are obtained by enzyme-catalyzed resolution of racemic 1,3-amino alcohols,
has also been reported. However, each of the reported methods for the synthesis of (S)-
Dapoxetine have the intrinsic disadvantage that the undesired (R)-enantiomer is discarded
or recycled after racemization. Consequently, the development of an efficient and
enantioselective synthesis of (S)-dapoxetine is highly desirable. Only a few strategies are
currently available for the asymmetric synthesis of (S)-Dapoxetine. The first asymmetric
synthesis of (S)-Dapoxetine hydrochloride and its
14
C-isotop, beginning with unnatural
amino acid (R)-N-Boc-phenylglycine, was described. Recently, stereoselective syntheses
of (S)-Dapoxetine from trans-methyl cinnamate and cinnamyl alcohol, employing
respective Sharpless asymmetric dihydroxylation and epoxidation processes in key steps,
were developed. Unfortunately, both of these routes are long (9 to 10 steps) and they
require a radical deoxygenation step to remove the undesired hydroxyl functionality. A
formal synthesis of (S)-Dapoxetine from enantiopure 3-hydroxyazetidine-2-one was
described. However, this route also required radical deoxygenation. Recently, Lee et al
126
have reported the synthesis of (S)-Dapoxetine using Du Bois asymmetric C-H amination
reaction catalyzed by a chiral valerolactam-derived, dirhodium (II) complex. However,
this route also suffers low enantiomeric excess and use of expensive chiral catalyst.
However, there is need to bring the refinement in the synthetic strategy of the (S)-
dapoxetine in order to avoid the use of multiple steps, lengthy procedures and costly
reagents. In this section, we described improved procedure for the synthesis of (S)-
Dapoxetine using Sharpless asymmetric epoxidation as a key step and source of chirality.

Retrosynthetic analysis of (S)-Dapoxetine outline in the Scheme 10. We
envisioned (R)-1,3-diol 24 as key precursor to (S)-Dapoxetine 11b; since the dapoxetine
molecule consisting of N, N-dimethylamine and naphthyloxy moiety in its core and are
situated at 1,3-position.
O
N
Me Me
O
N
O O
OH
OH
OH
(S)-Dapoxetine 11b
91
24
40
Scheme 10. Retrosynthetic analysis of (S)-Dapoxetine

The (R)-1,3-diol 24 in turn could obtain by Sharpless asymmetric epoxidation of
cinnamyl alcohol followed by regioselective reductive ring opening of epoxide. The key
intermediate (R)-1,3-diol 24 easily converted into target molecule 11b by regioselective
intermolecular Mitsunobu etherification, Mitsunobu Phthalimide inversion and
Eschweiler-Clark reductive methylation reaction
127

A brief account of Sharpless Asymmetric Epoxidation (SAE) is given in this
section.
2.1.3.2 Sharpless Asymmetric Epoxidation
Epoxidation is one of the most useful oxidative transformations of these alkenes
and the reagents that have been developed for this process have a high degree of
selectivity for the alkenic bond. With chemo selectivity available in epoxidation reagents,
there remains challenge of achieving epoxidation with asymmetric induction. The
development of peracids as a standard method for epoxidation led to initial attempt in
1965 by Henbest to achieve asymmetric epoxidation using homochiral (enatiomerically
pure) percamphoric acid.
26
Asymmetric induction was observed but the enantiomeric
excess was a disappointing 8%.
In 1980, Katsuki and Sharpless reported that with the unique combination of a
titanium (iv) alkoxide, an optically active tartrate ester, and t-Butyl hydroperoxide, they
were able to carry out the epoxidation of a variety of allylic alcohols in good yield and
with an enantiomeric excess generally greater than 90%.
27
Subsequent improvements in
the reaction have been described
28
and the frequent use of the process as reported in the
literature attest to its wide generality and utility. Since, to date, this method provides the
most successful general solution to the problem of asymmetric epoxidation.
In general, the reaction accomplishes the efficient asymmetric synthesis of
hydroxymethyl epoxides from allylic alcohols (Scheme 11). Operationally, the catalyst is
prepared by dissolving titanium isopropoxide, diethyl or diisopropyl tartrate (DET or
DIPT, respectively), and molecular sieves in DCM at -20

C, followed by addition of
128
allylic alcohol or t-BuOOH. After a brief waiting period (presumably to allow the ligand
equilibrium to occur on titanium), the final component of the reaction is added.
R
2
R
1
R
3
":O:
-"
":O:
-"
L-(+)-diethyl tartrate
L-(-)-diethyl tartrate
t-BuOOH, Ti(Oi-Pr)
4
CH
2
Cl
2
, -20
o
C
R
2
R
1
R
3
OH
OH
CH
2
Cl
2
, -20
o
C
t-BuOOH, Ti(Oi-Pr)
4
O
R
2
R
1
R
3
OH
O
(-)-DET
(+)-DET

Scheme 11.

The virtues of the AE are obvious. In each case, the components are commercially
available cost. The availability of tartrate esters in both enantiomeric forms is especially
fortunate, allowing the synthesis of either of enantiomer of a desired product. A key
feature in this regard is the predictability of the process; no exceptions to the trend shown
in Scheme 11 have been noted in reactions using achiral substrates. And the simplicity of
standard epoxidation reactions has been effectively retained, especially considering that
the chiral catalyst system is prepared in situ. Epoxides can be easily converted into
dialcohols, amino alcohols or ethers, so formation of chiral epoxides is a very important
step in the synthetic of natural products. K. Barry Sharpless shared the 2001 Nobel Prize
in chemistry for his work on asymmetric oxidations. The prize was shared with Williams
S. Knowles and Ryoji Noyori.



129
Reaction variable for titanium tartrate catalyzed asymmetric epoxidation:
1. Stoichiometry:
Two aspect of stoichiometry are important in an asymmetric epoxidation: one is the
ratio of titanium to tartrate used for the catalyst and the other is the ration of catalyst to
substrate. With regard to the catalyst it is crucial to obtaining the highest possible
enantiomeric excess that at least a 10% excess of tartrate ester to titanium (IV) alkoxide
to be used in all asymmetric epoxidations. This is important when the reaction is being
done with either a stiochiometric or a catalytic quantity of the complex. There appears to
be no need to increase the excess of tartrate ester beyond 10-20% and, in fact, a larger
excess has been shown to slow the epoxidation reaction unnecessarily.
The second stoichiometry consideration is the ratio of catalyst to substrate. Virtually
all asymmetric epoxidations can be performed with a catalytic amount of titanium tartrate
complex if molecular sieves are added to the reaction condition. A study of catalyst-
substrate ratios in the epoxidation of cinnamyl alcohol revealed a significant loss in
enantiomeric excess (Table 1) below the level of 5 mol% catalyst. At this catalyst level,
the reaction rate also decreases with the consequence that incomplete epoxidation of the
substrate may occur. Presently, the recommended catalyst stoichiometric is from 5%
Ti/6% tartrate ester to 10% Ti/12% tartrate ester.
28
Table 1. Dependence of Enantioselectivity on Catalyst Stoichiometry
OH
O
(R,R)-41a

Ti(O-i-Pr)
4
, % (+)-DIPT, % ee, %
5.0 6.0 92
4.0 5.2 87
2.0 2.5 69
130
2. Concentration
The concentration of substrate used in the asymmetric epoxidation must be given
consideration because competing side reactions may increase with increased reagents
concentration. The use of catalytic quantities of the titanium tartrate complex has greatly
reduced this problem. The epoxidation of most substrates under catalytic conditions may
be performed at a substrate concentration up to 1M. By contrast, epoxidations using
stoichiometry amounts of complex best run at substrate concentrations of 0.1M. Even
with catalytic amounts of the complex, a concentration of 0.1M allylalcohol, which
produce sensitive epoxy alcohol products.
28
3. Preparation and Aging of the catalyst
Proper preparation of the catalyst is essential for optimal reaction rates and
enantioselectivity. The preparation and storage of stock solutions of the titanium tartrate
catalyst should not be attempted as the complex is not sufficiently stable for long term
storage. Best results are obtained when the catalyst is prepared by mixing the titanium
(IV) alkoxide and the tartrate in a solvent at -20

C, adding either TBHP (or) the allylic

alcohol, and aging the system at this temperature for 20-30 min. This aging period is
critical to the success of the reaction and must not be eliminated. On the rare occasion
that bulky titanium (IV) alkoxide such as the t-butoxide is used, the aging period should
be increased to 1 h.
29
After the aging period, the temperature is adjusted to the desired
level and the last reagent, either the allylic alcohol or the hydroperoxide, is added.
4. Variation of Oxidant
t-Butyl hydroperoxide (TBHP) is used as the oxidant for nearly all titanium-
catalyzed asymmetric epoxidations. Exceptions are for allylic alcohol and methallyl
131
alcohol, where cumyl hydroperoxide is used to advantage for the epoxidation.
28
Cumyl
hydroperoxide can be used for other epoxidations and is reported to result in slightly
faster reaction rates than TBHP.
28
Trityl hydroperoxide also can serve as an effective
replacement for TBHP. However, the product isolation is significantly easier when TBHP
used as oxidant. The most economical source of TBHP
30
is the commercially available
70% solution in water, in which case steps must be taken to obtain anhydrous material.
For smaller laboratory scale reactions, anhydrous solutions of TBHP in isooctane are
available commercially. Storage of TBHP solutions over molecular sieves is not
recommended, but brief drying over molecular Sieves (ca. 30 min) before the reaction is
recommended.
5. Oxidation solvent
The solution of TBHP in dichloromethane, dichloroethane, toluene, heptane, and
isooctane, all solvents have certain disadvantages. Dichloroethane should not be used,
and dichloromethane solutions must be stored refrigerated. Toluene solutions have on
occasion been observed to develop a contaminant which inhibits the catalytic reaction.
Except for isooctane solutions, solutions of TBHP stored at room temperature in high
density polyethylene bottles (which are preferable to glass due to the slight change of
pressurization) are titre-stable due to migration of solvent through the walls of the bottle.
One will note that most of the experiments utilize TBHP in dichloromethane. It because
of these procedures was performed before the efficacy of TBHP in isooctane was
realized. The TBHP in isooctane as the solvent of choice for most cases, with
dichloromethane or toluene as next choice.
28

132
6. Titanium Alkoxides
Titanium (IV) isopropoxide is the titanium species of choice for preparation of the
titanium tartrate complex in the asymmetric epoxidation process. The use of titanium
(IV) t-Butoxide has been recommended for those reactions in which the epoxy alcohol
product is particularly sensitive to ring opening by the alkoxide.
29
The 2-substetituted
epoxy alcohols are one such class of compounds. Ring opening by t-butoxide is much
slower than by isopropoxide. With the reduced amount of catalyst that now is needed for
all asymmetric epoxidations, the use of Ti(OBu
t
)
4
appears to be unnecessary in most
cases, but the concept is worth noting.
7. Tartrate Esters
Optically active tartrate esters are the source of chirality for the asymmetric
epoxidation process. The esters used conventionally are dimethyl (DMT), diethyl (DET)
and diisopropyl tartrate (DIPT), and with a few subtle exceptions, all are equally effective
at inducing asymmetry during the crucial epoxidation event. The minor exceptions that
have been noted include: (i) a slight improvement in enantioselectivity (from 93% to
95%) when changing from DIPT to DET in the epoxidation of (E)-monosubstituted
allylic alcohols such as (E)-2-hexen-1-ol (having only a primary alkyl chain at C-3); and
(ii) a higher product yield (but no change in enantiomeric excess) when changing from
DET to DIPT in the epoxidations of allylic alcohol.
28

The Role of Molecular sieves
The addition of activated molecular sieves to the asymmetric epoxidation condition
has the beneficial effect that virtually all reactions can be carried out with only 5-10
mol% of titanium tartrate catalyst. Without molecular sieves,
28, 30
only a few of the more
133
reactive allylic alcohols are epoxidized efficiently with less than an equivalent of the
catalyst. The role of the molecular sieves is thought to be protection of the catalyst from
adventitious water and water that may be generated in small amounts by side reactions
during the epoxidation process.
Mechanism:
A simple version of the mechanism proposed by Sharpless is given in Scheme 12.
O
O
RO
Ti
O
i-Pr-O
O-i-Pr
O
Ti
RO
2
C
CO
2
R
O
O-i-Pr
O OR
O-i-Pr
Ligand exchange;
+allylic alcohol
+t-BuOOH
- 2 i-Pr-OH
O
O
RO
Ti
O
i-Pr-O
O-i-Pr
O
Ti
RO
2
C
CO
2
R
O
O
O OR
O
O
t-Bu
R
a
R
b
R
1
O
O
RO
Ti
O
i-Pr-O
O-i-Pr
O
Ti
RO
2
C
CO
2
R
O
O
O
R
a
R
b
R
1
O
t-Bu
CO
2
R
O
O
RO
Ti
O
i-Pr-O
O-i-Pr
O
Ti
RO
2
C
CO
2
R
O
O
R
a
R
b
O
t-Bu
O
R
1
CO
2
R
Oxygen
transfer
Turn over;
-epoxy alcohol
- t-BuOH
+2 i-PrOH
Peroxide
activation

Scheme 12. Proposed mechanism for the Sharpless asymmetric epoxidation reaction of
allylic alcohols

Evidence in support of this mechanism has included extensive kinetic studies,
spectroscopy, and molecular weight determinations. A very important aspect of this
mechanism is not shown in the scheme. This is the formation of the titanium-tartrate
species from its commercially available precursors, Ti(O-i-Pr)
4
and the dialkyl tartrate.
The equilibrium in this step lies far toward the formation of the chiral complex; this is
134
critical because the enantioselectivity of the process depends on the absence of any active
achiral catalyst. Note that the complex as drawn in the upper left of Scheme 12 is
dimeric and has a C
2
axis of symmetry. This structure has not been isolated in the solid
state, but is based in part on an X-ray structure of a related tartramide complex. The
situation is undoubtedly complicated by dynamic equilibria between this form and other
species in solution. Without specifying the order of events, two isopropoxide ligands
must be replaced by one molecule of peroxide and one molecule of allylic alcohol to give
the species shown in the upper right of Scheme 12. The ease of such ligand exchange
reactions in these titanium complexes largely accounts for their utility here. The other
function of the titanium is to activate the distal oxygen of the peroxide for oxygen
transfer. At this point (lower right species of the mechanism in the Scheme 12, the
complex is fully loaded and ready for oxygen transfer to the alkene. In this mechanism,
the allylic alcohol occupies a position cis to the reactive peroxide oxygen. In the AE
reaction (R
a
= R
b
= H), the diastereofacial selectivity of the olefin in the complex results
from the avoidance of the allylic carbon and a carboxylic ester (Figure 5). After oxygen
transfer, the final step is the exchange of the reaction products, epoxy alcohol and t-
BuOH, with other ligands to give either the starting complex or some other species on the
way to load the catalyst.
RO
2
C
RO
2
C
O
O
Ti
O
Ti
O
CO
2
R
CO
2
R
R
1
O
R
a
R
b
O t-Bu
O
favored
RO
2
C
RO
2
C
O
O
Ti
O
Ti
O
CO
2
R
CO
2
R
O
O t-Bu
O
R
b
R
a (a)
(b)
R
1
Figure 5. Proposed steric interactions leadering to enantioselectivity in the Sharpless
asymmetric epoxidation reaction
135
2.1.4 Results and Discussion
As depicted in the Scheme 13, synthesis of target molecule (S)-Dapoxetine 11b
was initiated from commercially available trans-cinnamyl alcohol 40, which was
subjected to Sharpless asymmetric epoxidation
28
to afford (2S, 3S)-epoxycinnamyl
alcohol 41b in 89% yield and >98% []
25
D
= -49.3 (c 2.4, CHCl
3
) {lit.
28
[]
25
D
= -49.6 (c
2.4, CHCl
3
)}.
OH OH
O
OH
OH
O
OH
O
N
O O
O
N
Me Me
40
41b 24
26
66
i
ii iii
iv
v, vi
(S)-Dapoxetine 11b

Scheme 13: Reagents and conditions: i) (+)-DIPT, Ti(O
i
Pr)
4
, TBHP, 4 A
o
MS, DCM, -20

C,
3 h, 89%; ii) Red-Al, DME, 0 to 25

C, 3 h, 93%; iii) 1-Naphthol, Ph

3
P, DIAD, THF, 20 h, rt,
71%; iv) Phthalimide, Ph
3
P, DIAD, THF, 4 h, 82%; v) N
2
H
4
.H
2
O, EtOH, reflux, 3 h; vi)
HCHO, HCO
2
H, reflux, 6 h, 69% two steps

The
1
H NMR spectrum of 41b showed peaks 3.22-3.24
(m) and 3.92-3.93 (d) corresponding to the benzylic and methine
protons of the epoxide ring, the signal at 3.75-3.83 (m) and 4.01-4.08 (m) due to the
diastereotopic protons of the methylene (CH
2
O-) moiety respectively. Its
13
C NMR
spectrum showed typical peaks at 55.5, 61.1 and 62.4 corresponding to bezylic carbon,
methine carbon and methylene carbons. Other signals 125.6, 128.2, 128.4 and 136.5
due to the aromatic carbon respectively.
OH
O
41b
136
The enantiomeric excess of 41b was determined
through
1
H NMR spectroscopic analysis of the Moshers
ester 41c derived from (+)-MTPA chloride and 41b. The
1
H NMR of 41c showed signal at 3.59 (singlet, 3H) is corresponding to protons of the -
OMe group. In
1
H NMR spectrum the OMe group is useful to determine the
diastereomeric ratio and Moshers ester 41c present as a single diastereomer. Thereby, it
gives an idea about enantiopurity of the (2S, 3S)-epoxycinnamyl alcohol 41b and it is
found to be >98%.
The regioselective reductive ring opening of
epoxycinnamyl alcohol 41b by known procedure
31a
with Red-Al in
dimethoxyethane gave expected 1,3-diol 24 in 93% yield. The
specific rotation of the compound 24 was []
25
D
= = +66 (c 1, CHCl
3
) {lit.
31b
[]
25
D
= +65
(c 1, CHCl
3
)}. The IR spectrum of 24 showed broad band at 3392-3313 cm
-1
indicating
the presence of hydroxyl group. The
1
H-NMR spectrums of 24 showed broad singlet at
2.34 due to the hydroxyl functionality. The peaks at 1.91-2.07(m) corresponding to the
homobenzylic proton. Other peaks at 3.85-3.89 (t) and 4.95-4.99 (dd) due to the
benzylic and methylene (CH
2
O) protons respectively. Its
13
C NMR spectrum showed
typical peaks at 40.3, 61.0 and 73.8 corresponding to the homobenzylic, methylene and
benzylic carbons respectively.
The napthyloxy moiety was incorporated in the
terminal hydroxyl group in 1,3-diol 24 through
intermolecular etherification using Mitsunobu reaction
condition afforded hydroxy ether 26 in 71% yield.
33

OH
OH
24
O
OH
26
(S)
(S)
O
O
41c
(R)
O
CF
3
MeO
137
The IR spectrum of 26 showed band at 3375 cm
-1
indicating the presence of
hydroxyl group. The
1
H-NMR spectrums of 26 showed 1.66 (br s) due to hydroxy
proton. The signal at 2.15-2.25(m) and 2.35-2.47(m) corresponding to the diastereotopic
homobenzylic protons, at 3.83-3.91(m) and 3.95-4.03(m) due to methylene protons of
the ether linkage. Appearance of doublet of doublet at 5.57-5.61 (dd J = 8.7, 3.9 Hz)
due to the benzylic proton. The characteristic signal at 6.63-6.66 (d, 1H, J = 7.2 Hz)
due to the 2-position of the naphthol ring and 8.38-8.41 (m) due to Peri proton of the
naphthyl ring. Its
13
C NMR spectrum showed 41.4, 59.7 and 77.5 due to the
homobezylic, methyleneoxy and benzylic carbon respectively. The typical peaks at 106
corresponding to the 2-position of the naphthyl ring, other peaks showed 120.2, 121.8,
125.2, 125.6, 126.2, 127.5, 134.4 and 153.1 due to the naphthalene carbons.
The (S)-secondary alcohol 26 was readily transformed
into (R)-phthalimido ether 66 by stereospecific substitution of
hydroxy group with phthalimide employing a typical Mitsunobu
procedure.
34
Its IR spectrum showed absence of hydroxyl group
and appearance of characteristic band at 1707 cm
-1
confirming
the presence of carbonyl carbon of the amide. The
1
H-NMR spectrums of 66 showed
2.20-2.40 (m) and 2.50-2.69 (m) due to diastereotopic homobenzylic proton, 3.86-3.97
(m) and 4.05-4.19 (m) due to methylene proton of ether linkage respectively. The typical
peaks at 5.46-5.52 (dd) corresponding to bezylic proton. The characteristic peaks at
6.57-6.60 (d, 1H, J = 6 Hz) corresponding to 2-position of the naphthyloxy ring. Its
13
C
NMR spectrum showed characteristic signal at 168.1 corresponding to amide carbonyl
carbon. Thus, the resulting compound 66 was then subjected to hydrazonolysis
34c

O
N
O O
66
138
condition using hydrazine hydrate in ethanol refluxing for 3 hour followed by reductive
amination under Eschweiler-Clarke conditions
35
with
formaldehyde and formic acid as the hydrogen source, gave (S)-
Dapoxetine 11b in good yield (69%) its specific rotation
indicating that []
25
D
= + 65.4 (c 0.31, CHCl
3
){ref.
25
[]
28
D
= +
63 (c 0.3, CHCl
3
)}. The
1
H-NMR spectrums of Dapoxetine 11b
showed at 2.25 sharp singlet for six protons corresponding to the (-N(CH
3
)
2
two methyl
group on the nitrogen. Its
13
C NMR spectrum showed an intense peak 42.7 due to (-
N(CH
3
)
2
) methyl carbon.

2.1.5 Conclusion
In conclusion, we synthesized (S)-dapoxetine 11b in six steps from commercially
available trans-cinnamyl alcohol with an overall yield of 35%. Sharpless asymmetric
epoxidation and Mitsunobu reaction has been successfully employed to fix amine stereo
center at benzylic position in the target molecule 11b. The high yield and less number of
steps render our approach a good alternative to the known methods.






O
N
Me Me
(S)-Dapoxetine 11b
139
2.1.6 Experimental section
(2S,3S)- (3-phenyl-oxiranyl)-methanol (41b)
To a stirred solution of L-(+)-diisopropyl tartrate (0.53
mL, 2.5 mmol) in CH
2
Cl
2
(180 mL) at -20

C, 1 g of activated
powdered 4A
o
molecular sieves, Ti(O
i
Pr)
4
(0.59 mL, 2 mmol) and 5-6 M solution of
TBHP in undecane (8 mL, 40 mmol) were added sequentially. The mixture was allowed
to stir at -20 C for 1 h and then a solution of freshly distilled (E)-3-phenyl-2-propenol 40
(2.57 mL, 20 mmol) in 5 mL CH
2
Cl
2
was added dropwise over 30 min. after 3 h at -20

C, the reaction was quenched at -20

C with 10% aqueous solution of NaOH saturated

with NaCl (2 mL). After diethyl ether (30 mL) was added the cold bath was allowed to
warm to 10

C, stirring was maintained at 10

C while MgSO
4
(2 g) and Celite (500 mg)
were added. After another 15 min of stirring, the mixture was allowed to settle and clean
solution was filtered through a pad of Celite and washed with diethyl ether. Azeotropic
removal of TBHP with toluene at a reduced pressure and subjected to high vacuum gave
41b as yellow oil. Recrystallization from petroleum ether/diethyl ether gave white
crystals of 41b
Yield : 2.68 g, 89%
mp : 52-54
o
C {lit.
28
mp: 51-53

C }
[]
25
D

: - 49.3 (c 2.4, CHCl
3
) {Lit.
28
[]
25
D
= -49.6 (c 2.4, CHCl
3
)}
IR (KBr, cm
-1
) : 3446, 3032, 2922, 2870, 1606, 1462, 1400, 1222, 1074, 985,
854, 759
1
H-NMR
(300MHz, CDCl
3
)
: 1.79-1.84 (dd, J = 5.4, 5.2 Hz, 1H), 3.22-3.25 (m, 1H),
OH
O
41b
140
3.76-3.84 (m, 1H), 3.92-3.93 (d, J = 2.1 Hz, 1H), 4.01-4.09
(ddd, J =2.4, 10.5, 12.1 Hz, 1H), 7.26-7.39 (m, 5H)
13
C-NMR
(75 MHz, CDCl
3
)
: 55.5, 61.2, 62.5, 125.7, 128.3, 128.5, 136.5.

Moshers ester (41c)
To a solution of N, N-dicyclohexylcarbodiimide
(DCC) (41 mg, 0.2 mmol), and 4-dimethylaminopyridine
(2 mg, 10 mol %) in CH
2
Cl
2
(2 mL) at 0

C under argon
atmosphere, was added drop-wise a solution of alcohol 41b (28.5 mg, 0.19 mmol) in
CH
2
Cl
2
(2 mL). The reaction mixture was stirred for 10 min. and (R)--methoxy--
trifluoromethylphenyl acetic acid (46 mg, 0.19 mmol) in CH
2
Cl
2
(2 mL) was added drop-
wise, solution was stirred at 0

C for 1 h and then at 25

C for 2 h. The reaction mixture

was diluted with CH
2
Cl
2
(10 mL), washed with saturated aqueous NaHCO
3
solution (5
mL), dried over anhydrous Na
2
SO
4
and concentrated under reduced pressure to give
Mosher ester of the alcohol 41c.
Yield : 60 mg, 87%
BP : gum
1
H-NMR
(200 MHz, CDCl
3
)
: 3.27 (m, 1H), 3.59 (s, 3H), 3.78 (s, 1H), 4.34-4.44 (dd, J
=14, 6Hz, 1H), 4.67-4.74 (dd, J = 12, 2 Hz, 1H), 7.26-7.51
(m, 10H)



(S)
(S)
O
O
41c
(R)
O
CF
3
MeO
141
(R)-3-phenyl-1,3-dihydroxypropane (24)
To a solution of (2S,3S)-2,3-epoxycinnamyl alcohol 41b
(1.5 g, 10 mmol) in dimethoxyethane (50 mL) was added a 3.4 M
solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-
Al) in toluene(3.1 mL, 10.5 mmol) dropwise under nitrogen at 0

C. After stirring at room

temperature for 3 h, the solution was diluted with ether and quenched with 15% HCl
solution. After further stirring at room temperature for 30 min, the white precipitate
formed was removed by filtration, warm with ethyl acetate, and filtered again. The
combined organic extracts were dried with magnesium sulfate, evaporate under reduced
pressure. The residue thus obtained was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate (70:30) to afford 24.
Yield : 1.42 g, 93%
mp : 62-64
o
C (lit.
31
mp: 62-66

C)
[]
25
D

: = +66 (c 1, CHCl
3
) {lit.
31
[]
25
D
= +65 (c 1, CHCl
3
)}
IR (KBr, cm
-1
) : 3392, 3313, 2955, 2902, 1595, 1489, 1444, 1209, 1082,
1037, 972, 879, 742
1
H-NMR
(300MHz, CDCl
3
)
: 1.91-2.07 (m, 2H), 2.34 (br s, 2H), 3.86-3.89 (t, J = 5.4 Hz,
2H), 4.95-4.99 (dd, J = 3.6, 8.7 Hz, 1H), 7.26-7.37 (m, 5H).
13
C-NMR
(75 MHz, CDCl
3
)
: 40.3, 61.0, 73.8, 125.9, 127.4, 128.4, 144.2.
MS (m/z, RI %) : 152 (23)[M
+
], 134 (17), 117 (35), 107 (100)


OH
OH
24
142
(R)-3-(Naphthalen-1-yloxy)-1-pheny-propae-1-ol (26)
To a mixture of (R)-3-phenyl-1,3-dihydroxypropane
24 (456 mg, 3 mmol), 1-naphthol (576 mg, 4 mmol) and
triphenylphosphine (840 mg, 3.2 mmol) in 15 mL of
anhydrous THF under N
2
at room temperature was added a
solution of DIAD (0.63 mL, 3.2 mmol) in anhydrous THF (5 mL). The resulting mixture
was stirred until TLC indicated that the diol 24 was consumed (20 h, TLC). The solvent
was evaporated; residue was purified by flash column chromatography (silica gel (230-
400 mesh), petroleum ether/ethyl acetate (80:20) to afford 26.
Yield : 592 mg, 71%
BP : colorless oil
[]
25
D

: = +122 (c 1.3, CHCl
3
)
IR (Neat, cm
-1
) : 3375, 3053, 2935, 1590, 1388, 1253, 1078, 765
1
H-NMR
(300MHz, CDCl
3
)
: 1.66 (br s, 1H), 2.15-2.26 (m, 1H), 2.35-2.47 (m, 1H), 3.83-
3.91 (m, 1H), 3.95-4.03 (m, 1H), 5.57-5.62 (dd, J = 3.9, 8.8
Hz, 1H), 6.64-6.66 (d, J = 7.2 Hz, 1H), 7.16-7.54 (m, 9H),
7.76-7.79 (m, 1H), 8.38-8.41 (m, 1H)
13
C-NMR
(75 MHz, CDCl
3
)
: 41.4, 59.7, 77.5, 106.9, 120.3, 121.8, 125.3, 125.6, 125.7,
126.3, 127.5, 127.6, 128.7, 134.5, 141.4, 153.2
MS (m/z, RI %) : 278 (5) [M
+
], 260 (5), 144 (100)



O
OH
26
143
(S)-2-[3-(Naphthalen-1-yloxy)-1-phenyl-propyl]-isoindole-1,3-dione (66)
To a mixture of alcohol 26 (556 mg 2 mmol),
phthalimide (367 mg, 2.5 mmol) and triphenylphosphine (577
mg, 2.2 mmol) in 10 mL of anhydrous THF under N
2
at room
temperature was added a solution of DIAD (0.46 mL, 2.2
mmol) in anhydrous THF (2 mL). The resulting mixture was
stirred until TLC indicated that the alcohol was consumed. The solvent was evaporated;
the residue was subjected to chromatography on silica gel (100-200 mesh) with (95:5) pet
ether-ethyl acetate to afforded desired product 66.
Yield : 667 mg, 82%
mp : 156-158

C
[]
25
D

: = +195.6 (c 1, CHCl
3
)
IR (CHCl
3
, cm
-1
) : 3036, 2937, 1707, 1591, 1383, 1244,1084, 949
1
H-NMR
(200MHz, CDCl
3
)
: 2.20-2.40 (m, 1H), 2.50-2.69 (m, 1H), 3.86-3.97 (m, 1H),
4.05-4.19 (m, 1H), 5.46-5.52 (dd, J = 4, 8 Hz, 1H), 6.57-6.60
(d, J = 6 Hz, 1H), 7.12-7.44 (m, 9 H), 7.61-7.75 (m, 5H),
8.34-8.39 (m, 1H)
13
C-NMR
(75 MHz, CDCl
3
)
: 35.3, 37.2, 78.0, 106.6, 120.1, 121.9, 122.9, 125.0, 125.6,
126.1, 127.3, 127.6, 128.6, 131.9, 133.6, 134.3, 140.8, 152.9,
168.2
MS (m/z, RI %) : 407 (3)[M
+
], 266 (12), 264 (55), 160 (100), 144 (18)



O
N
O O
66
144
(S)-Dapoxetine 11b
To a stirred solution of 66 (407 mg, 1 mmol) in
ethanol (10 mL) was added hydrazine hydrate (80%) solution
(0.5 mL, 8 mmol) and the resulting mixture was refluxed for
3 h. The precipitated solid was filtered off, and the solvent
was removed under reduced pressure. The residue was dissolved in ether and extracted
with 2N HCl, and the aqueous phase was treated with 2N NaOH until pH >12. The
aqueous phase was extracted with ether (3x20 mL), and the combined organic phases
were dried over Na
2
SO
4
and evaporated under reduced pressure. The residue was taken
into next step.
To a solution of crude amine in 85% formic acid (227 L, 5 mmol), was added a
37% aqueous formaldehyde (220 L, 3 mmol) and the mixture heated at 95-100

C for 6
hours. After cooling the solution, acidified with 4N HCl until pH = 1 and basified with 4
N NaOH. The aqueous phase was extracted with ether (3 x 20 mL), and combined
organic phase were dried over Na
2
SO
4
and evaporated under reduced pressure. The
residue was purified by flash column chromatography (CH
2
Cl
2
/MeOH, 97:3) to afford
(S)-Dapoxetine 11b.
Yield : 210 mg, 69%
BP : pale yellow oil
[]
25
D

: = + 65.4 (c 0.31, CHCl
3
){ref.
25
[]
28
D
= + 63 (c 0.3, CHCl
3
)}
IR (Neat, cm
-1
) : 3057, 2953, 2775, 1735, 1583, 1456, 1394, 1269, 1238, 1099,
1068, 1022, 912, 850, 769
1
H-NMR : 2.25 (s, 6H), 2.26-2.29 (m, 1H), 2.58-2.69 (m, 1H), 3.58-
O
N
Me Me
(S)-Dapoxetine 11b
145
(300MHz, CDCl
3
) 3.63 (dd, J = 9.3, 5.1 Hz, 1H), 3.84-3.92 (m, 1H), 4.02-4.09
(m, 1H), 6.62-6.65 (dd, J = 7.3, 1.8 Hz, 1H), 7.23-7.79 (m,
7H), 7.43-7.50 (m, 2H), 7.76-7.79 (m, 1H), 8.21-8.25 (m,
1H)
13
C-NMR
(75 MHz, CDCl
3
)
: 32.9 , 42.7, 65.5, 67.5, 104.4, 119.9, 121.9, 124.9, 125.5,
125.7, 126.2, 127.2, 127.3, 128.1, 128.5, 134.3, 139.4, 154.5
MS (m/z, RI %) : 305 (4) [M
+
], 134 (100), 115 (12)























146















































2.1.7 Spectra
29.
1
H NMR spectrum of 41b
30.
13
C NMR spectrum of 41b
31.
1
H NMR spectrum of Moshers ester 41c
32.
1
H NMR spectrum of 24
33.
13
C NMR spectrum of 24
34.
1
H NMR spectrum of 26
35.
13
C NMR spectrum of 26
36.
1
H NMR spectrum of 66
37.
13
C NMR spectrum of 66
38.
1
H NMR spectrum of 11b
39.
1
H NMR spectrum of 11b (Expansion)
40.
13
C NMR spectrum of 11b

147














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

4
1
b
148














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

4
1
b
149














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

M
o
s
h
e
r
'
s

e
s
t
e
r

4
1
c
150














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

2
4
151














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

2
4
152














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

2
6
153














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

2
6
154














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

6
6
155














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

6
6
156














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
1
b
157














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
1
b
158














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

1
1
b
159
2.1.8 References
1. Althof, S. E. Prevalence, characteristics and implications of premature
ejaculation/rapid ejaculation. J Urol. 2006, 175, 842.
2. Porst, H.; Montorsi, F.; Rosen, R. C.; Gaynor, L.; Grupe, S.; Alexander, J. The
Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence,
comorbidities, and professional help-seeking. Eur Urol. 2007, 51, 816.
3. Carson, C.; Gunn, K. Premature ejaculation: definition and prevalence. Int J Impot
Res. 2006, 18, S5.
4. Waldinger, M. D. Recent advances in the classification, neurobiology and treatment
of premature ejaculation. Adv Psychosom Med. 2008, 29, 50.
5. Barnes, T.; Eardley, I. Premature ejaculation: the scope of the problem. J Sex Marital
Ther. 2007, 33, 151.
6. McMahon, C. The etiology and management of premature ejaculation. Nat Clin
Pract Urol. 2005, 2, 426.
7. Masters, W.; Johnson, V. Human Sexual Inadequacy. Boston, MA: Little Brown and
Co; 1970.
8. Semans, J. Premature ejaculation: a new approach. S Med J. 1956, 49, 353.
9. Atikeler, M. K.; Gecit, I.; Senol, F. A. Optimum usage of prilocaine-lidocaine cream
in premature ejaculation. Andrologia. 2002, 34, 356.
10. Busato, W.; Galindo, C. C. Topical anaesthetic use for treating premature
ejaculation: a double-blind, randomized, placebo-controlled study. BJU Int. 2004,
93, 1018.
160
11. Montejo-Gonzlez, A. L.; Llorca, G.; Izquierdo, J. A. SSRI-induced sexual
dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective,
multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997,
23, 176.
12. Montejo, A. L.; Llorca, G.; Izquierdo, J. A.; Rico-Villademoros, F. Incidence of
sexual dysfunction associated with antidepressant agents: a prospective multicenter
study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-
Related Sexual Dysfunction. J Clin Psychiatry. 2001, 62, 10.
13. Clment, P.; Bernab, J.; Gengo, P. Supraspinal site of action for the inhibition of
ejaculatory reflex by dapoxetine. Eur Urol. 2007, 51, 825.
14. Giuliano, F.; Bernabe, J.; Gengo, P.; Alexandre, L.; Clement, P. Effect of acute
dapoxetine administration on the pudendal motoneuron reflex in anesthetized rats:
comparison with paroxetine. J Urol. 2007, 177, 386.
15. Gengo, P. J.; Giuliano, F.; McKenna, K. Monoaminergic transporter binding and
inhibition profile of dapoxetine, a medication for the treatment of premature
ejaculation [abstract]. J Urol. 2005, 173, 239.
16. Hiemke, C.; Hartter, S. Pharmacokinetics of selective serotonin reuptake inhibitors.
Pharmacol Ther. 2000, 85, 11.
17. Modi, N. B.; Dresser, M. J.; Simon, M.; Lin, D.; Desai, D.; Gupta, S. Single- and
multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the
treatment of premature ejaculation. J Clin Pharmacol. 2006, 46, 301.
18. Hellstrom, W. J. G. Neuropsychiatr. Dis. Treat. 2009, 5, 37.
19. Robertson, D. W.; Wong, D. T.; Thompson, D. C. U.S. Patent 5135947, 1992.
161
20. a) Wheeler, W. J.; OBannon, D. D. J. Labelled. Compd. Radiopharm. 1992, 31,
305; b) Sarbera, L. A.; Castaner, J.; Castaner, R. M. Drugs Future 2004, 29, 1201.
21. Torre,O.; Gotor-Fernadaz, V.; Gotor, V. Tetrahedron: Asymmetry 2006, 17, 860.
22. Siddiqui, S. A.; Srivasan, K. V. Tetrahedron: Asymmetry 2007, 18, 2099; b)
Venkatesan, K.; Srinivasan, K. V. ARKIVOC 2008, xvi, 302.
23. Chincholkar, P. M.; Kale, A. S.; Gumaste, V. K.; Deshmukh, A. R. A. S.
Tetrahedron 2009, 65, 2605.
24. Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453.
25. Kang, S.; Lee, H. K. J. Org. Chem. 2010, 75, 237.
26. (a) Henbest, H. B. Chem. Sec., Spec. Publ. 1965, 19, 83. (b) Ewins, R. C.; Henbest,
H. B.; Mckervy, M. A. J. Chem. Soc., Chem. Commun., 1967, 1085.
27. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
28. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765.
29. Lu, L. D. L.; Johnson, M. G. Finn, Sharpless, K. B. J. Org. Chem. 1984, 49, 728.
30. Finn, M. G.; Sharpless, K. B., in Asymmetric synthesis, ed. J. D. Morrison,
Academic Press, New York, 1985, Vol.5, P. 247
31. (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081; (b) Chenevert, R.;
Fortier, G.; Rhlid, R. B. Tetrahedron 1992, 48, 6769.
32. (a) Bittner, S.; Assaf, Y. Chem. Ind. (London) 1975, 281; (b) Manhas, M. S.;
Hoffmann, W. H.; Lal, B.; Bose, A. K. J. Chem. Soc. Perkin Trans. 1, 1975, 461; (c)
162
Fukuyama, T.; Laud, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985, 26, 6291; (d)
Mitsunobu, O. Synthesis, 1981, 1-28; (e) Kumara Swamy, K. C.; Bhuvan Kumar, N.
N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
33. (a) Von Itzstein, M.; Jenkins, I. D. J. Chem. Soc. Perkin. Trans. 1, 1986, 436; (b)
Hughes, D. L. Org. React. 1992, 42, 335.
34. (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94, 679; (b) Wada,
M.; Sano, T.; Mitsunobu, O. Bull. Chem. Soc. Jpn. 1973, 46, 2833; (c) Huang, K.;
Ortiz-Marciales, M.; Correa, W.; Pomales, E.; Lopaz, X. Y. J. Org. Chem. 2009, 74,
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35. (a) Eschweiler, W. Ber. 1905, 38, 880; (b) Clarke, H. T.; Gillespie, H. B.;
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H. Org. Syn. 1955, Coll. Vol. 3,723.





















163
SECTION-II
Asymmetric synthesis of Monoamine Oxidase (MAO-B) Inhibitor (R)-
Selegiline

2.2.1 Introduction
Parkinson's disease (PD) is a degenerative disorder of the central nervous system
that often impairs the sufferer's motor skills, speech, and other functions.
1
Parkinson's
disease belongs to a group of conditions called movement disorders. It is characterized by
muscle rigidity, tremor, postural abnormalities, gait abnormalities, a slowing of physical
movement (bradykinesia) and a loss of physical movement (akinesia) in extreme cases.
The primary symptoms are the results of decreased stimulation of the motor cortex by the
basal ganglia. Normally this involves insufficient formation and thus action of dopamine
produced in the dopaminergic neurons of the midbrain (specifically the substantia nigra).
Secondary symptoms may include high level cognitive dysfunction and subtle language
problems. The disease is named after English apothecary James Parkinson, who made a
detailed description of the disease in his essay: "An Essay on the Shaking Palsy" (1817).
Alzheimer's disease
Alzheimer's disease (AD) is the most common form of dementia (taken from
Latin, originally meaning "madness"). This incurable, degenerative, and terminal disease
was first described by German psychiatrist and neuropathologist Alois Alzheimer in
1906 and was named after him.
2
Most often, it is diagnosed in people over 65 years of
age,
3
although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006,
164
there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85
people globally by 2050.
4
L-DOPA (L-3,4-Dihydroxyphenylalanine; levodopa)
Levodopa is a naturally-occurring dietary supplement and psychoactive drug
found in certain kinds of food and herbs (e.g., Mucuna pruriens, or velvet bean), and is
synthesized from the amino acid L-tyrosine (TYR) in the mammalian body and brain. L-
DOPA is the precursor to the neurotransmitters dopamine, norepinephrine
(noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines.
Aside from its natural and essential biological role, L-DOPA is also used in the clinical
treatment of Parkinson's disease (PD) and dopamine-responsive dystonia (DRD).
MeO
MeO
COOH
NHCOCH
3
MeO
MeO
COOH
NHCOCH
3
H
H
[Rh(R,R)DiPAMP, COD)BF
3
+ H
2
H
3
O
+
HO
HO
COOH
NH
2
L-DOPA (69)
67
68
Scheme 1

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson
first showed in the 1950s that administering L-DOPA to animals with Parkinsonian
symptoms would cause a reduction in their intensity. The 2001 Nobel Prize in Chemistry
was also related to L-DOPA: the Nobel Committee awarded one-fourth of the prize to
William S. Knowles for his work on chirally-catalysed hydrogenation reactions, the most
noted example of which was used for the synthesis of L-DOPA. Levodopa (or L-DOPA)
165
has been the most widely used treatment for Parkinsons disease over 30 years.
5
L-DOPA
is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase. Since
motor symptoms of PD are produced by a lack of dopamine in the substantia nigra the
administration of L-DOPA temporarily diminishes the motor symptomatology.
5
Only 5-
10% of L-DOPA crosses the blood-brain barrier. The remaining L-DOPA is often
metabolized to dopamine elsewhere, causing a wide variety of side effects including
nausea, dyskinesias and stiffness. Carbidopa and benserazide are peripheral dopa
decarboxylase inhibitors. They help to prevent the metabolism of L-DOPA before it
reaches the dopaminergic neurons and therefore reduce side effects. They are generally
given as combination with levodopa.
MAO-B inhibitors
R-(-)-Deprenyl (Selegiline 70a), Rasagiline 71a, Lazabemide 72 and Safinamide
73 are well-known selective inhibitors of MAO-B (Figure 1).
6,7
The Selegiline is quite
effective in the treatment of Parkinsons disease as well as Alzheimers disease when
used along with L-DOPA.
N
Cl
N
H
O
NH
2
F
O
N
H
Me
NH
2
O
(R)-Selegilne 70a
(R)-Rasagilne 71a
Lazabemide 72
(S)-Safinamide 73
N
HN

Figure 1. Selective Monoamine oxidase-B (MAO-B) inhibitors

166
The idea behind adding selegiline to levodopa is to decrease the dose of levodopa
and thus reduce the motor complications of levodopa therapy.
10
Comparisons of patients
on levodopa + placebo vs levodopa + selegiline showed that selegiline allowed reduction
of the levodopa dose by about 40%. Selegiline + levodopa also extended the time until
the levodopa dose had to be increased from 2.6 to 4.9 years. In addition, Selegiline has
been recently approved as transdermal patch formulation to treat major depressive
disorders. The high doses of selegiline used in such a formulation may be responsible for
MAO-A inhibition and, consequently, for the antidepressant effect.
11
N
70
N
(R)-70a
N
(S)-70b ()-

Figure 2. Racemic and enantiomers of Selegiline

Deprenyl 70 is a racemic compound (Figure 2). For the further pharmaceutical
development, the (-)-enantiomer of deprenyl 70a, which caused less hypermotility than
the opposite (+)-enantiomer 70b. This (-)-enantiomer (l-deprenyl, R-deprenyl) later has
come to be called Selegiline 70a.
12








167
2.2.2 METABOLISM OF SELEGILINE IN HUMAN
13
Nine urinary metabolites of selegiline hydrochloride were identified after administrations
to human (Scheme 2). Their identities were confirmed by comparison of the spectra from
GC/MS of peaks with those of authentic compounds.
N
Me
Me
NHMe
Me
N
H
Me
(R)-(-)-Methamphetamine 74a
N-despropynylation
(R)-(-)-Selegiline 70a
N-desmethylation
Desmethylselegiline 75a
N-despropynylation
NH
2
Me
(R)-(-)-Amphetamine 78a
p-hydroxylation
-hydroxylation
NHMe
Me
HO
(S)
(R)
NHMe
Me
OH
(1S,2R)-(+)-Ephedrine 77a
(1R,2R)-(-)-pseudoephedrine 77b
(R)
(R)
NHMe
Me
OH
-hydroxylation
p-hydroxylation
NH
2
Me
HO
(S)
(R)
NH
2
Me
OH
(1S,2R)-(+)-Norephedrine 80a
(1R,2R)-(-)-Norpseudoephedrine 80b
(R)
(R)
NHMe
Me
OH
(R)-(-)-Hydroxyamphetamine 79
(R)-(-)-Hydroxy
methamphetamine 76
Scheme 2. Metabolic pathways of selegiline in humans.

168
The following metabolites and unchanged drug (Selegiline) were detected in
urine: (R)-desmethylselegiline 75a, (R)-methamphetamine 74a, (R)-amphetamine 78a,
(1S,2R)-norephedrine 80a, (1R,2R)-norpseudoephedrine 80b, (1S,2R)-ephedrine 77a,
(1R,2R)-pseudoephedrine 77b, (R)-p-hydroxyamphetamine 79, and (R)-p-
hydroxymethamphetamine 76. The metabolites excreted 2 days after administration of
2.5-10 mg of selegiline hydrochloride amounted to 44-58% of the dose. Selegiline was
metabolized by three distinct pathways: N-dealkylation, -hydroxylation, and aromatic
ring-hydroxylation. The major metabolite was (R)-methamphetamine 74a. During
metabolism, no racemic transformation occurred and -hydroxylation showed apparently
product stereoselectivity.

2.2.3 Review of Literature
The synthetic methods available in the literature for Selegiline are as follows
Gyogys approach (1988)
14
Gyogy et al have reported the preparation of racemic selegiline 70 and 4-
fluoroselegiline 84 as given in the Scheme 3. Phenyl acetone 81 and propargylamine on
treatment with HgCl
2
-activated aluminum at 60 C gave amine 75, which on methylation
yielded racemic selegiline 70. Similarly, (4-fluorophenyl) acetone 82 gave 4-
fluoroselegiline 84.
R
O
R
HN
R
N
i
ii
R =H 81
R =F 82
R =H 75
R =F 83
R =H 70
R =F 84

Scheme 3. Reagents and conditions: (i) propargylamine, EtOH, 60

C, HgCl
2
-Al; (ii) MeI,
K
2
CO
3
, acetone.

169
Hajiceks approach (1988)
15
In this approach (R)-selegiline 70a was prepared by propargylation of
deoxyephedrine 74a with propargyl bromide. Subsequent treatment with HCl afforded
(R)-Selegiline 70a hydrochloride (Scheme 4).
NH
N N
.HCl
i
ii
74a
70a 70a. HCl

Scheme 4. Reagents and conditions: (i) propargyl bromide, K
2
CO
3
, PhH 5 C; (ii) HCl (gas)


Same group have reported the (R)-selegiline 70a hydrochloride by reaction of (R)-
deoxyephedrine 74a with HCCCH
2
OP
+
Ph
3
Cl, followed by treatment with HCl
(Scheme 5).
NH
N N
.HCl
i
ii
74a
70a
70a. HCl

Scheme 5. Reagents and conditions: (i) HCCCH
2
OP
+
Ph
3
Cl
-
, Et
3
N, CH
3
CN, 25

C, 10 h; (ii)
HCl (gas), i-PrOH, 36%.

Sterlings approach (2002)
16
Sterling et al have reported the synthesis of (R)-3-hydroxy selegiline 87,
involving classical resolution of amine 85 with D-tartaric acid to give optically pure amine
85a. Subsequent propargylation and reaction with ethyl formate gave formate derivative,
which on reduction yielded (R)-3-hydroxy selegiline 87 (Scheme 6).
NH
2
NH
2 HN N
iii ii i
85
85a
86 87 OH
OH
OH OH
()-

Scheme 6. Reagents and conditions: (i) D-tartaric acid, MeOH, reflux; then 25% NH
4
OH, 25

C; (ii) propargyl bromide, K

2
CO
3
, 25

C; (iii) HCO
2
Et, then LiAlH
4
,THF,reflux.
170
Plenevauxs approach (2002)
17

Racemic 4-[
18
F]fluoroselegiline 84 was prepared via the three step procedure: (i)
substitution by [
18
F]fluoride on 4-nitrobenzaldehyde 88 (ii) reaction with (1-chloro- 1-
(trimethylsilyl)ethyl)lithium and hydrolysis to give 4-[
18
F]flurophenylacetone 82, (iii)
reductive alkylation of ketone 82 with N-methylpropnylamine led to 84 (Scheme 7).
CHO
O
2
N
CHO
F
i
F
O
F
N
ii iii
88
89
82 84
Scheme 7. Reagents and conditions: (i) KF, 65%; (ii) 1-chloro-1-(trimethylsilyl)ethyl lithium,
hydrolysis, 50%; (iii) N-methylpropynylamine, NaBH
3
CN, 35%.

www.selegiline.com
18
In this method, (S)-phenyl alanine 90 was used as the starting material for the
preparation of (R)-selegiline 70a (Scheme 8). Methyl ester of phenyl alanine 91 on
reductive alkylation with formic acid gave N-methyl derivative 92. Propargylation and
reduction of ester 93 with LiAlH
4
yielded alcohol 94 without affecting -CC-bond, which
on subsequent reaction with thionyl chloride followed by reduction, gave (R)-selegiline
70a.
CO
2
H
NH
2
CO
2
Me
NH
2
CO
2
Me
NHMe
CO
2
Me
N N
OH
N
i ii
iii
iv
v
(S)-phenylalanine 90 91
92
93
94
70a

Scheme 8. Reagents and conditions: (i) MeOH, HCl, reflux; (ii) HCO
2
H, NaBH
4
; (iii)
propargylbromide, K
2
CO
3
; (iv) SOCl
2
; (v) LiAlH
4,
THF.

171
Sudalais approach (2004)
19

Sudalai et al have reported three different approaches for the synthesis of (R)-
Selegiline 70a. In first approach, -methyl styrene 95 was subjected to Sharpless
asymmetric dihydroxylation reaction to give chiral diol 96 which on treatment with
SOCl
2
gave the corresponding cyclic sulfite 97. Treatment of cyclic sulfite 97 with
sodium azide gave the corresponding azido alcohol 98 which on treatment with
triphenylphosphine gave chiral aziridine 99. It was under the transfer hydrogenation in
the presence of Pd-catalyst produced the amine 78a which was subsequently, converted
to (R)-selegiline 70a as per the literature procedure (Scheme 9).
OH
OH
O
S
O
O
N
3
OH
NH
NH
2
NH
N
i ii
iii
iv
v
vi
vii
95
96
97 98
99
78a 74a
70a

Scheme 9. Reagents and condition: (i) OsO
4
, (DHQ)
2
-PHAL, K
3
Fe(CN)
6
, K
2
CO
3
, t-
BuOH:H
2
O, 0

C, 82%; (ii) SOCl

2
, Et
3
N, DCM, 0

C, 85%; (iii) NaN

3
, acetone-H
2
O, 80

C,
82%; (iv) PPh
3
, CH
3
CN, 90%; (v) Pd/C (10%), HCO
2
NH
4
, MeOH, reflux, 88%; (vi) (a)
ClCO
2
CH
3
, DCM, aq. K
2
CO
3
, 45 min, 90% (b) LiAlH
4
, dry THF, 65

C, 65%; (vii) propargyl

bromide, K
2
CO
3
, CH
3
CN, 25

C, 72%.

In the second approach, -aminooxylation of 3-phenylpropanaldehyde 100 was
carried out using nitrosobenzene and catalytic amount of L-proline. The resulting
aminooxy aldehyde was reduced with NaBH
4
afforded the -aminooxy alcohol 101. It
was then reduced with molecular hydrogenation in the presence of Pd-C to the
corresponding diol 102 in 88% yield. The diol 102 upon selective tosylation of primary
172
hydroxyl functionality followed by treatment with NaH converted to the corresponding
epoxide 103. It was then subjected to selective reductive ring opening at the terminal
position with LiAlH
4
to give the secondary alcohol 104 in 92% yield. The alcohol 104
was then converted to N-methylamine 74a in a four-step reaction sequence: (i)
mesylation, substitution with azide, reduction of azide to amine, protection of amine
with (Boc)
2
O and reduction of N-Boc group using LiAlH
4
to give N-methylamine 74a.
Propargylation of amine 74a using propargyl bromide furnished (R)-selegiline 70a in
26% overall yield (Scheme10).
O OH
ONHPh
O
OH
NH
2 N
i ii
iii
v
vi
OH
OH
NH
vii
iv
100
101 102 103
104
78a
74a 70a
Scheme 10. Reagents and conditions: (i) (a) PhNO, L-proline (10 mol %), DMSO, 25 C, 20
min. then MeOH, NaBH
4
, 86%; (ii) H
2
(1atm.), 10% Pd/C, MeOH, 12 h, 88%; (iii) (a) TsCl,
Et
3
N, CH
2
Cl
2
, 0 C, 1 h, (b) NaH, DMF, 0 C, 0.5 h, 81% for 2 steps; (iv) LiAlH
4
, THF, reflux,
2 h, 92%; (v) (a) MsCl, Et
3
N, DCM, 0 C, 0.5 h, (b) NaN
3
, DMF, 80 C, 12 h, 76% for 2 steps;
(c) H
2
(1atm.), 10% Pd/C, MeOH, 2 h, 98%; (vi) (a) (Boc)
2
O, Et
3
N, 0 C, 1 h, 95%; (b)
LiAlH
4
, THF, reflux, 4 h, 90%; (vii) propargyl bromide, K
2
CO
3
, CH
3
CN, 12 h, 72%.

In the third approach, 3-phenylpropanaldehyde 126 was reacted with dibenzyl
azodicarboxylate in the presence of D-proline (10 mol %) to afford an aminoaldehyde.
Subsequently, it was reduced with NaBH
4
afforded the protected amino alcohol 131 in
95% yield (Scheme 11).
173
O
OH
N
HN Cbz
Cbz
OH
NHBoc
OTs
NHBoc
NH N
i ii
iii
iv v
100
105
106
107
74a
70a

Scheme 11. Reagents and conditions: (i) Dibenzyl azodicarboxylate , D-Proline (10 mol%), 0-
20

C, 3 h then NaBH
4
, EtOH, 95%; (ii) (a) H
2
(60 psi), Raney Ni, MeOH, AcOH, 16 h, (b)
(Boc)
2
O, Et
3
N, 0

C, 1 h, 66% for 2 steps; (iii) (a) p-TsCl, Et

3
N, DCM, 0

C, 1 h, (b) LiAlH
4
,
THF, reflux, 4 h, 81% for 2 steps; (iv) propargyl bromide, K
2
CO
3
, CH
3
CN, 12 h, 72%.

The amino alcohol 131 was then hydrogenated using Raney-nickel as catalyst to
give amino alcohol, which was converted to the corresponding carbamate 132 using
(Boc)
2
O. The primary alcohol was then tosylated to give 133, which on reduction with
LiAlH
4
gave the methylamine 99a in 81% yield. The secondary amine was propargylated
using propargyl bromide under standard conditions to give (R)-selegiline 95a in 37%
overall yield.








174
2.2.4 Present work
2.2.4.1 Objective
Literature search revealed that few reports are available for the synthesis of
Selegiline. Previously, to best of our knowledge the (R)-Selegiline 70a was prepared
from a racemic mixture through resolution by tartaric acid. Only a few strategies are
currently available for the asymmetric synthesis of (R)-Selegiline 70a. The first
asymmetric synthesis of (R)-Selegiline 70a was described from (S)-Phenyl alanine as
starting material. The stereoselective synthesis of (R)-Selegiline 70a from -methyl
styrene, employing Sharpless asymmetric dihydroxylation was developed. Unfortunately,
this method affords low optical purity (up to 83% ee). The Organocatalytic -
hydroxylation and -amination strategy also described for the synthesis of (R)-Selegiline
70a. However, these routes involved lengthy procedures and it required, Nitrosobenzene,
Dibenzylazodicarboxylate and unnatural amino acid D-proline. In this section, we
described highly enantioselective synthesis of (R)-Selegiline 70a using Sharpless
Asymmetric Epoxidation as a key step and source of chirality.
A retrosynthetic plan for the synthesis of (R)-Selegiline 70a outlined in the
Scheme 12. We envisaged (S)-secondary alcohol 104 as a key intermediate to (R)-
Selegiline. Since, (S)-secondary alcohol 104 could be easily converted into target
molecule 70a via Fukuyama-Mitsunobu reaction followed by propargylation. The key
intermediate 130 in turn could be obtained by regioselective reductive ring opening of
epoxide followed by dehalogenation of 108. Iodo compound 108 in turn could be
obtained by Sharpless asymmetric epoxidation of cinnamyl alcohol 40 followed by Apple
reaction respectively.
175
N
Me
Me
Me
OH
OH I
O
70a 104
108 40
Scheme 12. Retrosynthetic analysis of (R)-Selegiline 70a

2.2.5 Results and discussion
The (S)-secondary alcohol 104 as a key intermediate to (R)-Selegiline 70a. In
order to get (S)-secondary alcohol 104, it was considered that trans-cinnamyl alcohol 40
was the immediate precursor to 104 and accordingly, trans-cinnamyl alcohol was
subjected to Sharpless asymmetric epoxidation
20
reaction to give (2S, 3S)-epoxycinnamyl
alcohol 41b in 89% yield and >98% ee as indicated in the Scheme 13.
OH
(S)
(S)
OH
O
(S)
(R)
I
O
(S)
OH
i ii iii
(R)
N
Me
Me
Ns
(R)
N
Me
Me
H
(R)
N
Me
Me
iv v
vi
40 41b 108
104
110 74a (R)-Selegiline 70a
Scheme 13. Reagents and conditions: i) (+)-DIPT, Ti(O-i-Pr)
4
, TBHP, 4 MS, DCM, -20 C,
3 h, 89%; ii) I
2
, Ph
3
P, imidazole, Et
2
O:CH
3
CN (1:1), 0 C, 45 min, 92%; iii) H
2
(2 atm), Pd-C,
Et
3
N, EtOAc, 10 h, 94%; iii) DIAD, Ph
3
P, N Methyl-2-nitro-benzenesulfonamide 135, THF,
rt, 3 h, 86%; v) PhSH, CH
3
CN, rt, 2 h, 87%; vi) propargyl bromide, K
2
CO
3
, CH
3
CN, rt, 3 h,
76%.

Epoxycinnamyl alcohol 41b was treated with Iodine,
triphenylphosphine in the presence of imidazole under Apple
condition
21
to produce Iodo epoxide 108 in 92% yield. The
1
H NMR spectrum of 108
showed multiplet at 3.28 corresponding to methylene and methine proton, appearance
I
O
108
176
of apparent broad singlet at 3.77 corresponding to benzylic proton respectively. Its
13
C
NMR spectrum showed carbon signal at 4.4 corresponding to iodine attached to
methylene carbon and signal showed up field shift due to shielding of iodine atom. The
peaks at 61.9 and 62.4 are corresponding to methyne and benzylic carbon signal,
appearance of intense peaks at 125.5 and 1285 corresponding to -CH- carbon of the
aromatic ring, other carbon signal at 136.1 corresponding to quaternary carbon.
Subsequently, compound 108 was treated with 10% Palladium on charcoal, hydrogen (2
atm) and excess of triethylamine in ethyl acetate to give (S)-secondary alcohol 104 in
94% yield. In this transformation, the regioselective reductive ring opening of the
epoxide followed by reductive dehalogenation
22
occurred in one pot. Triethylamine was
used to neutralize the hydroiodide as a by-product in this process.
23

IR spectrum of 104 showed characteristic broad band at 3381
cm
-1
region indicating the presence of hydroxyl functionality. Its
1
H
NMR spectrum showed peak at 1.23 appeared as a doublet confirming the presence of
methyl group, the signal at 2.0 (s) is due to the hydroxyl functionality, appearance of
peak at 2.63-2.85 as a multiplet corresponding to benzylic protons. Other signal at
3.95-4.15 (m) corresponding to methine proton of the chiral center respectively. Its
13
C
NMR spectrum showed overall up field shift. The carbon signals at 22.7, 45.7 and 68.8
are corresponding to methyl, benzyl and methyne carbon respectively. The (S)-secondary
alcohol 104 was transformed into (R)-N-methyl-2-nitro-
benzenesulfonamide derivative 110 under Fukuyama-
Mitsunobu reaction condition.
24
The IR spectrum of 110
shows two very intense absorption in the 1545 cm
-1
and
OH
104
N
Me
Me
S
O
2
110
NO
2
177
1344 cm
-1
region of the spectrum due to asymmetric and symmetric stretching vibrations
of the highly polar nitrogen-oxygen bonds strongly evident the presence of -NO
2
group,
the strong bands in the 1454 cm
-1
and 1168 cm
-1
regions, due to the asymmetric and
symmetric stretching vibrations of -SO
2
- group. Its
1
H NMR spectrum showed 1.13-
1.15 (d) corresponding to terminal methyl proton, appearance of signal at 2.63-2.71 (dd,
1H, J = 8.4, 8.1 Hz), 2.81-2.87 (dd, 1H, J = 6.9, 6.6 Hz) due to diastereotopic nature of
benzylic proton, characteristic sharp singlet at 2.90 indicating the presence of methyl
group on the nitrogen and signal at 4.23-4.33 (sextet, J = 6.6 Hz) corresponding to proton
of the chiral center. Other peaks at 7.52-7.65 (m) and 7.80-7.83 (m) corresponding to
protons of the nosyl moiety respectively. Its
13
C NMR spectrum showed carbon signal at
27.9 indicating presence of methyl group on the nitrogen, peaks at 126.4, 130.6,
131.5, 133.1, 133.2 and 147.6 are corresponding to carbon signal of nosyl moiety. The
resulting sulfonamide derivative 110 was further transformed to Methamphetamine 74a
by the deprotection
25
of nosyl group with thiophenol.
Deprotection of nosyl moiety was confirmed by its IR
spectrum showed characteristic broad band 3425-3319 cm
-1
region
indicating the presence free amine. Its
1
H NMR spectrum showed
sharp intense peak around at 2.44 (s) indicating presence of methyl group on the
nitrogen. Its
13
C NMR spectrum showed overall up field shift of carbon signals. Finally,
the propargylation of the amino functionality in 74a was carried out using potassium
carbonate as a base and propargyl bromide as alkylating reagent. Thus, (R)-selegiline 70a
was obtained in 76% yield.
N
Me
Me
H
74a
178
The IR spectrum of 70a showed characteristic band
3437, 2120 and 669 cm
-1
region represent CC-H stretching,
CC stretching, and C-H bending mode indicating presence of
propargyl group. Its
1
H NMR spectrum showed characteristic singlet at 1.85
corresponding to terminal proton of acetylene moiety, typical signal at 3.43 (d)
corresponding to methylene protons of propargyl moiety respectively. Its
13
C NMR
spectrum showed peaks at 43.0, 72.6 and 80.2 corresponding to methylene, quaternary
and terminal carbon signal of propargyl moiety respectively.

2.2.6 Conclusion
In conclusion, we have developed efficient method for the synthesis of (R)-
selegiline 70a from commercially available trans-cinnamyl alcohol in a total of seven
steps with 44% overall yield. Herein, we used Sharpless asymmetric epoxidation and
Fukuyama-Mitsunobu reaction as a key step. Simple procedures, high enantioselectivity,
the ready availability of the catalyst and starting material are some of the salient features
of this approach. We envisage that this simple protocol may find application in the
pharmaceutical industry for the large scale production of (R)-selegiline 70a





N
Me
Me
(R)-Selegiline 70a
179
2.2.7 Experimental section
(S,R)-2-Iodomethyl-3-phenyloxirane (108)
To a stirred, cooled (0

C) solution of 2.5 g (16.66) of epoxy alcohol

41b, 5.24 g (20 mmol) of recrystallized triphenylphosphine, and 1.42
g (21 mmol) of imidazole in 15 mL of acetonitrile and 25 mL of ether was slowly added
5.6 g (22 mmol) of iodine resulting in a pale yellow suspension. After being stirred for 45
min, the reaction mixture was diluted with 50 mL of ether and sequentially washed with
saturated Na
2
S
2
O
3
, followed by CuSO
4
and water. The organic layer was dried briefly
over MgSO
4
, filtered, and concentrated to give iodo epoxide 108.
Yield : 4 g, 92%
BP : oil
[]
25
D
: -58 (c 2, CHCl
3
)
IR (Neat, cm
-1
) : 3063, 1604, 1495, 1458, 1406, 1248, 1171, 1073, 1018, 882.
1
H-NMR
(200 MHz, CDCl
3
)
: 3.23 (m, 3H), 3.77 (apparent s, 1H), 7.24-7.36 (m, 5H)
13
C-NMR
(50 MHz, CDCl
3
)
: 4.4, 61.9, 62.4, 125.5, 128.47, 128.53, 136.1.

(S)-1-Pheny-propane-2-ol (104)
A solution of compound 108 (3.64 g, 14 mmol) in ethyl acetate (50
ml) in the presence of triethylamine (5 ml) and 10% Pd/C catalyst (500
mg) was hydrogenated under the pressure of 2 atmosphere of hydrogen for 10 h. The
catalyst was then filtered off and the filtrate was washed with 5% aqueous hydrochloric
acid. The organic phase was dried over sodium sulfate and the solvent was evaporated.
I
O
108
OH
104
180
Residue was purified by column chromatography (silica gel 100-200 mesh, ethyl
acetate/petroleum ether 7:93) to give 104.
Yield : 1.81 g, 94%
BP : oil
[]
25
D
: + 50.2 (c 1.1 CHCl
3
), {lit.
19b
[]
25
D
= + 50.8 (c 1.1 CHCl
3
)}
IR (Neat, cm
-1
) : 3381, 2968, 2924, 1494, 1456, 1118, 1082, 941, 742
1
H-NMR
(200 MHz, CDCl
3
)
: 1.23-1.26 (d, J = 6 Hz, 3H), 2.63-2.85 (m, 2H), 3.95-4.15
(m, 1H), 7.19-7.37 (m, 5H)
13
C-NMR
(50 MHz, CDCl
3
)
: 22.8, 45.8, 68.8, 126.4, 128.5, 129.4, 138.5.

N-Methyl-2-Nitro-benzenesulfonamide (109)
Methyl amine 40% solution in water (3 mL, 35 mmol) was added
dropwise to 2-Nitro-benzenesulfonylchloride (3.32 g, 15 mmol) in DCM
(30 mL) at 0

C. The reaction mixture was stirred for 1 h followed by

washed with water (20 mL), dried over anhydrous Na
2
SO
4
and concentrated under
reduced pressure. The solid thus obtained was recrystallized from EtOAc/PE mixture to
give 109 as white solid.
Yield : 2.75 g, 85%
Mp : 109-110

C
IR (CHCl
3
, cm
-1
) : 3356, 3120, 3022, 1637, 1542, 1386, 1354, 1216, 1173, 1119,
1
H-NMR
(200 MHz, CDCl
3
)
: 2.79-2.81 (d, J = 4 Hz, 3H), 5.29 (br s, 1H), 7.72-7.90 (m,
3H), 8.10-8.18 (m, 1H)
13
C-NMR
(50 MHz, CDCl
3
)
: 29.7, 125.4, 131.4, 132.3, 132.7, 133.7, 148.10
SO
2
NHMe
NO
2
109
181
(R)-N-Methyl-N-(1-methyl-2-pheny-ethyl)-2-nitro-benzenesulfonamide (110)
A solution of DIAD (2.42 mL, 12 mmol) in dry THF
(10 mL) was added dropwise to a solution of 104 (1.49 g, 11
mmol), N-Methyl-2-Nitro-benzenesulfonamide 109 (2.37 g,
11 mmol) and triphenylphosphine (3.14 g, 12 mmol) in dry THF (30 mL) under N
2

atmosphere at room temperature. The stirring was continued until all of the alcohol 104
had been consumed (4 h, TLC). The reaction mixture was concentrated under reduced
pressure and the residue was purified by column chromatography (silica gel 100-200
mesh, petroleum ether/EtOAc, 90:10) to give 110.
Yield : 3.05 g, 82%
Mp : Low melting solid
[]
29
D
: = +17 (c 2 CHCl
3
)
IR (CHCl
3
, cm
-1
) : 2980, 2931, 1732, 1545, 1373, 1344, 1236, 1168, 1122.
1
H-NMR
(300 MHz, CDCl
3
)
: 1.13-1.15 (d, J = 6.6 Hz, 3H), 2.63-2.71 (dd, J = 8.4 and 8.1
Hz, 1H), 2.81-2.87 (dd, J = 6.9 and 6.6 Hz, 1H), 2.90 (s, 3H),
4.23-4.33 (sextet, J = 6.6 Hz, 1H), 7.10-7.21 (m, 5H), 7.52-
7.65 (m, 3H), 7.80-7.83 (m, 1H)
13
C-NMR
(75 MHz, CDCl
3
)
: 17.4, 27.9, 40.8, 54.9, 124.0, 126.4, 128.3, 129.0, 130.6,
131.5, 133.1, 133.2, 137.7, 147.6.



N
Me
Me
S
O
2
110
NO
2
182
(R)-N-Methyl-(1-methyl-2-phenyl-ethyl)-amine 74a
(1.67 g, 5 mmol) of 110 and (1.65 g, 12 mmol) of
potassium carbonate in acetonitrile (20 mL) stirred at room
temperature; thiophenol (1.03 mL, 10 mmol) was added. The
resulting solution was vigorously stirred for 2 h, the reaction mixture was filtered, solvent
was evaporated and the crude product was dissolved it in diethyl ether (40 mL), extract
with 1N HCl (2x15 mL), combined aqueous layer was basified with 1N NaOH, aqueous
layer was extract with diethyl ether (3x15 mL) combined organic layer was dried over
anhydrous Na
2
SO
4
, solvent was passed through pad of celite and evaporated under
reduced pressure to give 74a.
Yield : 650 mg, 87%
BP : pale yellow oil
[]
25
D
: = -10.5 (c 1 EtOH) {Lit.
19b
[]
25
D
= -10.87 (c 1 EtOH)}
IR (Neat, cm
-1
) : 3425, 3319, 2964, 1691, 1452, 1377, 1074, 1033,740, 702
1
H-NMR
(200 MHz, CDCl
3
)
: 1.07-1.10 (d, J = 6 Hz, 3H), 2.44 (s, 3H), 2.59-2.91 (m,
4H), 7.16-7.34 (m, 5H)
13
C-NMR
(50 MHz, CDCl
3
)
: 18.2, 32.7, 42.1, 56.5, 126.4, 128.4, 129.2, 138.3

(R)-N-Methyl-(1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine [(R)-Selegiline] (70a)
(298 mg, 2 mmol) of 74a and (552 mg, 4 mmol) of
anhydrous potassium carbonate in acetonitrile (10 mL) stirred
at room temperature, propargyl bromide (239 mg, 2.01 mmol)
was added dropwise then stirred at room temperature until disappearance of starting
N
Me
Me
(R)-Selegiline70a
N
Me
Me
H
74a
183
material (3 h, TLC), the reaction mixture was filtered off, and the solvent was evaporated
under reduced pressure to give the crude product, which was purified by column
chromatography (100-200 mesh silica gel, chloroform as a eluant) to give (R)-selegiline
70a.
Yield : 285 mg, 76%
BP : pale yellow oil
[]
25
D
: -10.3 (c 6.5 EtOH) {lit.
19b
[]
25
D
= -10.7 (c 6.5 EtOH)}
IR (Neat, cm
-1
) : 3437, 3019, 2120, 1652, 1402, 1215, 1017, 929, 669.
1
H-NMR
(200 MHz, CDCl
3
)
: 0.95-0.98 (d, J = 6 Hz, 3H), 1.85 (br s, 1H), 2.24-2.26 (t, J =
2 Hz, 1H), 2.34-2.39 (m, 1H), 2.43 (s, 3H), 2.92-3.09 (m, 2H),
3.43-3.44 (d, J = 2 Hz, 2H), 7.16-7.32 (m, 5H)
13
C-NMR
(50 MHz, CDCl
3
)
: 15.0, 37.3, 39.6, 43.0, 59.3, 72.5, 80.2, 125.8, 128.2, 129.2,
140.1
LCMS-MS : 188 (100) [M+H]
+















184















































2.2.8 Spectra
1.
1
H NMR spectrum of 108
2.
13
C NMR spectrum of 108
3.
1
H NMR spectrum of 104
4.
13
C NMR spectrum of 104
5.
1
H NMR spectrum of 109
6.
13
C NMR spectrum of 109
7.
1
H NMR spectrum of 110
8.
13
C NMR spectrum of 110
9.
1
H NMR spectrum of 74a
10.
13
C NMR spectrum of 74a
11.
1
H NMR spectrum of 70a
12.
13
C NMR spectrum of 70a

185














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
8
186














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
8
187














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
4
188














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
4
189














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
9
190














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

1
0
9
191














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

1
1
0
192














































1
3
C

N
M
R

S
p
e
c
t
r
u
m

o
f

1
1
0
193














































1
H

N
M
R

S
p
e
c
t
r
u
m

o
f

7
4
a
194














































1
3
C

N
M
R

S
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