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 man’s 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 19707

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

HN

ONH

HN

ON

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

CF3

N

O

O

H2N

NHMe

O

F3C

(R)-Fluoxetine 5

NH

O O

O

ClCl

NHMe

(R,S)-Paroxetine 6(S,S)-Sertraline 7

(R)-Citalopram 3Fluvoxamine 4

Figure 2. Selective serotonin reuptake inhibitors (SSRIs)

NH

NN

H

OO

O

O

Me

N

S

Me O

NH

NN

NMeO

O O

N

S

O

NH

NN

N

MeO

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

NMe Me

O

NMe Me

O

NMe 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 potent19

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

O’Bannon approach (1992)20

O’Bannon 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.

CHONH2

OH

O N

OH

MeMeO

N

OEt

MeMeO

OEt

O N

OH

MeMe

N

O

MeMe

O

NMeMe

i ii

iii

iv v

vi vii

12 13 14

1615 17

11 (S)-11b(±)- Scheme 1. Reagents and condition: i) Malonic acid, NH4OAc, EtOH, reflux; ii) Pd-C, H2, HCHO; iii) EtOH, HCl (gas), reflux; iv) dimethyl amine; v) LiAlH4, 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)2O to afford N-Boc-(R)-phenyl

glycine 19.

CO2H

NH2

CO2H

NHBoc NHBocOH

NHBocOMs

NHBocCN

NH2

OH

O NH2

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.NaHCO3, (Boc)2O, DCM; ii) BH3.THF, 0 °C; iii) MsCl, pyridine, DCM; iv) NaCN, DMSO, 60 °C; v) dil.H2SO4, reflux; vi) BH3.THF, 0 °C; vii) HCHO, HCO2H, 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 14C-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

Williamson’s 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 14CH3I to

yield the target 14C-labeled compound (S)-11b.

OH

OH

OTs

OH

O

OH

O

NH

O

OMs

i ii

iv

iii

O

NH3

14C CH3

v

24 2526

27 2814C-labled (S)-Dapoxetine 11b

Scheme 3. Reagents and condition: i) TsCl, Et3N, DCM; ii) 1-naphthol, NaOH, DMF; iii) MsCl, cat. DMAP, Et3N, DME, 0 °C; iv) MeNH2, sealed tube, heat; v) 11CH3I.

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.

CHONH2

OH

O NH2

OH

NH2

OTBDMS

OO

O

HN

OTBDMS

OO

NH2

OTBDMSNH2

OH

N

OH

MeMe N

O

MeMe

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, NH4OAc, EtOH, reflux, 12 h, 68%; ii) LiAlH4, 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) (CH2O)n, HCO2H, reflux, 83%; vii) 1-naphthol, Ph3P, 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

OOH

OH

OSO

O

O OMe

OMe

ON3

OHOMe

ONH

OH

O

ButO

OMe

ONH

O

O

ButO

S

SMe

OH

NH2

OH

NMe Me

O

NMe Me

OH

NHBoc

OMe

ONH

O

ButO

i ii

iii iv

v vi

vii viii ix

32 33 34

35 36 37

3738 39

(S)-23b (S)-17b(S)-11b

Scheme 5. Reagents and conditions: (i) (DHQ)2PHAL (5 mol%), OsO4, NMO, t-BuOH: H2O, 0 °C, 16 h; (ii) SOCl2, Et3N, DCM, 0 °C to rt, 1 h; (iii) NaN3(5 equiv.), DMF, rt, 48 h; iv) H2, Pd-C, EtOAc, rt, 24 h, (Boc)2O, Et3N; (v) MeI, CS2, MsCl, Et3N, DCM, 0 °C to rt, 12 h; (vi) n-Bu3SnH, AIBN, toluene, reflux, 75% two steps; (vii) LiAlH4, THF, rt, 12 h; (viii) TFA, DCM, rt, (ix) HCHO, HCO2H, reflux; (x) 1-Naphthol, Ph3P, 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 NaN3 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 NaN3

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)2O 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 OHO

OH

N3

OH

OTBS

N3

OHOTBS

NHBoc

OH

OH

NH2

O

NMe 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(OiPr)4, TBHP, 4 Å MS, DCM, -20 °C, 3 h, 88%; ii) NaN3, MeOH: H2O (8 : 1), 65 oC, 4 h, 97%; iii) TBSCl, DCM, imidazole, 0 °C-rt, 6 h, 96%; iv) H2, Pd-C, (Boc)2, EtOAc, rt, 12 h, 88%; v) CS2, NaH, MeI, THF, 0 oC-rt, overnight, 84%; vi) n-Bu3SnH, 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.

NBoc

H

ONHBoc

CHONHBoc

OHi ii

47 48 4950

(S)-Dapoxetine 11b Scheme 7. Reagents and conditions: i) (S)-Proline (20 mol %), CH3CN, 0 °C, 2-3 h, 54%; ii) NaBH4, 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 β-lactams 54a and 54b. The required diastereomer 54b

was obtained by column chromatography. Spiro β-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 β-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 CO2Et

CO2EtHO

CO2Et

CO2Et

O

O

NO

CO2Et

HO

PMP

N

HPh

OO

CO2Et

HO

PMP

O

HPh

NO

CO2Et

HO

PMP

O

HPh

NOH

CO2Et

HOH

PMP

O

HPh

NPMP

O

HPh

O

NO

Ph

PMP

HO

NO

Ph

PMP

O

S

MeS

NO

Ph

PMPNH

O

Ph

NO

Ph

Boc

NHBoc

OH

CO2Et

COCl

O

O

i ii iii

iv v vi

vii viii ix x

xiNH2

OHxii

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/H2O, rt, 4-6 h, b) (COCl)2, DCM, reflux, 5 h; iii) PMP-N=CH-Ph, Et3N, DCM, -40 °C, to rt, 15 h; iv) FeCl3, DCM, rt, 2 h; v) NaIO4, acetone/water, rt, 6-8 h; vi) NaBH4, MeOH, 0 °C, 2 h; vii) NaH, CS2, MeI, THF, 0 °C-rt, 6 h; viii) n-Bu3SnH, AIBN, toluene, reflux, 3-4 h; ix) CN, CH3CN/H2O, 0 °C, 1 h; x) LAH, THF, 0 °C to rt, 4 h; xi) TFA, DCM, 0 °C to rt, 2 h; HCHO, NaCNBH3, AcOH, CH3CN, rt, 2 h.

The Lactam 60 was then protected as its carbamate derivative with (Boc)2O 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

SH2N

O O

OS

HN

O O

ii

OS

N

O O

iii iv

NH

O v

N

O

N

O

Rh

Rh N

O N

N

Ts

TsH

H

2 2Rh2(R-nap)462 63 64

65 28 (S)-11b

Scheme 9. Reagents and conditions: i) ClSO2NH2, DMA, 0 °C to rt; ii) 2 mol% Rh2(R-nap)4 , PhI=O, 4 Å MS, DCM, rt; iii) MeI, K2CO3, cat. TBAI, DMF, 0 °C to rt; iv) NaH, i-Naphthol, DMF then 5 M HCl, rt; v) HCHO, HCO2H, 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 Rh2(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 14C-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

NMeMe

O

NO 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 described28 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.

R2R1

R3

":O:-"

":O:-"

L-(+)-diethyl tartrate

L-(-)-diethyl tartrate

t-BuOOH, Ti(Oi-Pr)4

CH2Cl2, -20 oC

R2 R1

R3 OH

OH

CH2Cl2, -20 oC

t-BuOOH, Ti(Oi-Pr)4

O

R2 R1

R3 OHO

(-)-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

OHO

(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 TBHP30 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(OBut)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-OO-i-Pr

O

Ti

RO2C

CO2R

O

O-i-Pr

O OR

O-i-PrLigand exchange;+ allylic alcohol+ t-BuOOH- 2 i-Pr-OH

O O

RO

Ti

O

i-Pr-OO-i-Pr

O

Ti

RO2C

CO2R

O

O

O OR

O

Ot-Bu

RaRb

R1

O O

RO

Ti

O

i-Pr-OO-i-Pr

O

Ti

RO2C

CO2R

O

O

O

RaRb

R1

Ot-Bu

CO2R

O O

RO

Ti

O

i-Pr-OO-i-Pr

O

Ti

RO2C

CO2R

O

O

RaRb

Ot-Bu

O R1

CO2R

Oxygentransfer

Turn over;-epoxy alcohol- t-BuOH+ 2 i-PrOH

Peroxideactivation

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 C2 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 (Ra = Rb = 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.

RO2C

RO2C OO Ti

OTi

OCO2R

CO2R

R1

O Ra

Rb

O t-BuO

favored

RO2C

RO2C OO Ti

OTi

OCO2R

CO2R

O

O t-BuO

RbRa(a) (b)

R1

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 epoxidation28 to afford (2S, 3S)-epoxycinnamyl

alcohol 41b in 89% yield and >98% [α]25D = -49.3 (c 2.4, CHCl3) {lit.28 [α]25

D = -49.6 (c

2.4, CHCl3)}.

OH OHO

OH

OH

O

OH

O

N OO

O

NMe Me

40 41b 24

26 66

i ii iii

iv v, vi

(S)-Dapoxetine 11b

Scheme 13: Reagents and conditions: i) (+)-DIPT, Ti(OiPr)4, TBHP, 4 Ao MS, DCM, -20 °C, 3 h, 89%; ii) Red-Al, DME, 0 to 25 °C, 3 h, 93%; iii) 1-Naphthol, Ph3P, DIAD, THF, 20 h, rt, 71%; iv) Phthalimide, Ph3P, DIAD, THF, 4 h, 82%; v) N2H4.H2O, EtOH, reflux, 3 h; vi) HCHO, HCO2H, reflux, 6 h, 69% two steps

The 1H NMR spectrum of 41b showed peaks δ 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 δ 3.75-3.83 (m) and 4.01-4.08 (m) due to the

diastereotopic protons of the methylene (CH2O-) moiety respectively. Its 13C NMR

spectrum showed typical peaks at δ 55.5, 61.1 and 62.4 corresponding to bezylic carbon,

methine carbon and methylene carbons. Other signals δ 125.6, 128.2, 128.4 and 136.5

due to the aromatic carbon respectively.

OHO

41b

136

The enantiomeric excess of 41b was determined

through 1H NMR spectroscopic analysis of the Mosher’s

ester 41c derived from (+)-MTPA chloride and 41b. The

1H NMR of 41c showed signal at 3.59 (singlet, 3H) is corresponding to protons of the -

OMe group. In 1H NMR spectrum the –OMe group is useful to determine the

diastereomeric ratio and Mosher’s 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 procedure31a with Red-Al in

dimethoxyethane gave expected 1,3-diol 24 in 93% yield. The

specific rotation of the compound 24 was [α]25D = = +66 (c 1, CHCl3) {lit.31b [α]25

D = +65

(c 1, CHCl3)}. The IR spectrum of 24 showed broad band at 3392-3313 cm-1 indicating

the presence of hydroxyl group. The 1H-NMR spectrums of 24 showed broad singlet at δ

2.34 due to the hydroxyl functionality. The peaks at δ 1.91-2.07(m) corresponding to the

homobenzylic proton. Other peaks at δ 3.85-3.89 (t) and 4.95-4.99 (dd) due to the

benzylic and methylene (CH2O) protons respectively. Its 13C NMR spectrum showed

typical peaks at δ 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

CF3MeO

137

The IR spectrum of 26 showed band at 3375 cm-1 indicating the presence of

hydroxyl group. The 1H-NMR spectrums of 26 showed δ 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 δ 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 δ 5.57-5.61 (dd J = 8.7, 3.9 Hz)

due to the benzylic proton. The characteristic signal at δ 6.63-6.66 (d, 1H, J = 7.2 Hz)

due to the 2-position of the naphthol ring and δ 8.38-8.41 (m) due to Peri proton of the

naphthyl ring. Its 13C NMR spectrum showed δ 41.4, 59.7 and 77.5 due to the

homobezylic, methyleneoxy and benzylic carbon respectively. The typical peaks at δ 106

corresponding to the 2-position of the naphthyl ring, other peaks showed δ 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-1confirming

the presence of carbonyl carbon of the amide. The 1H-NMR spectrums of 66 showed δ

2.20-2.40 (m) and 2.50-2.69 (m) due to diastereotopic homobenzylic proton, δ 3.86-3.97

(m) and 4.05-4.19 (m) due to methylene proton of ether linkage respectively. The typical

peaks at δ 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 13C

NMR spectrum showed characteristic signal at δ 168.1 corresponding to amide carbonyl

carbon. Thus, the resulting compound 66 was then subjected to hydrazonolysis34c

O

N OO

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 [α]25D = + 65.4 (c 0.31, CHCl3){ref.25 [α]28

D = +

63 (c 0.3, CHCl3)}. The 1H-NMR spectrums of Dapoxetine 11b

showed at δ 2.25 sharp singlet for six protons corresponding to the (-N(CH3)2 two methyl

group on the nitrogen. Its 13C NMR spectrum showed an intense peak δ 42.7 due to (-

N(CH3)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

NMe 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 CH2Cl2 (180 mL) at -20 °C, 1 g of activated

powdered 4Ao molecular sieves, Ti(OiPr)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 ºC for 1 h and then a solution of freshly distilled (E)-3-phenyl-2-propenol 40

(2.57 mL, 20 mmol) in 5 mL CH2Cl2 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 MgSO4 (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 oC {lit.28 mp: 51-53 °C }

[α]25D : - 49.3 (c 2.4, CHCl3) {Lit.28 [α]25

D = -49.6 (c 2.4, CHCl3)}

IR (KBr, cm-1) : 3446, 3032, 2922, 2870, 1606, 1462, 1400, 1222, 1074, 985,

854, 759

1H-NMR (300MHz, CDCl3)

: δ 1.79-1.84 (dd, J = 5.4, 5.2 Hz, 1H), 3.22-3.25 (m, 1H),

OHO

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)

13C-NMR (75 MHz, CDCl3)

: δ 55.5, 61.2, 62.5, 125.7, 128.3, 128.5, 136.5.

Mosher’s ester (41c)

To a solution of N, N’-dicyclohexylcarbodiimide

(DCC) (41 mg, 0.2 mmol), and 4-dimethylaminopyridine

(2 mg, 10 mol %) in CH2Cl2 (2 mL) at 0 °C under argon

atmosphere, was added drop-wise a solution of alcohol 41b (28.5 mg, 0.19 mmol) in

CH2Cl2 (2 mL). The reaction mixture was stirred for 10 min. and (R)-α-methoxy-α-

trifluoromethylphenyl acetic acid (46 mg, 0.19 mmol) in CH2Cl2 (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 CH2Cl2 (10 mL), washed with saturated aqueous NaHCO3 solution (5

mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give

Mosher ester of the alcohol 41c.

Yield : 60 mg, 87%

BP : gum

1H-NMR (200 MHz, CDCl3)

: δ 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

CF3MeO

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 oC (lit.31 mp: 62-66 °C)

[α]25D : = +66 (c 1, CHCl3) {lit.31 [α]25

D = +65 (c 1, CHCl3)}

IR (KBr, cm-1) : 3392, 3313, 2955, 2902, 1595, 1489, 1444, 1209, 1082,

1037, 972, 879, 742

1H-NMR (300MHz, CDCl3)

: δ 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).

13C-NMR

(75 MHz, CDCl3)

: δ 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 N2 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

[α]25D : = +122 (c 1.3, CHCl3)

IR (Neat, cm-1) : 3375, 3053, 2935, 1590, 1388, 1253, 1078, 765

1H-NMR (300MHz, CDCl3)

: δ 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)

13C-NMR (75 MHz, CDCl3)

: δ 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 N2 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

[α]25D : = +195.6 (c 1, CHCl3)

IR (CHCl3, cm-1) : 3036, 2937, 1707, 1591, 1383, 1244,1084, 949

1H-NMR (200MHz, CDCl3)

: δ 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)

13C-NMR (75 MHz, CDCl3)

: δ 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 OO

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 Na2SO4 and evaporated under reduced pressure. The residue was taken

into next step.

To a solution of crude amine in 85% formic acid (227 µL, 5 mmol), was added a

37% aqueous formaldehyde (220 µL, 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 Na2SO4 and evaporated under reduced pressure. The

residue was purified by flash column chromatography (CH2Cl2/MeOH, 97:3) to afford

(S)-Dapoxetine 11b.

Yield : 210 mg, 69%

BP : pale yellow oil

[α]25D : = + 65.4 (c 0.31, CHCl3){ref.25 [α]28

D = + 63 (c 0.3, CHCl3)}

IR (Neat, cm-1) : 3057, 2953, 2775, 1735, 1583, 1456, 1394, 1269, 1238, 1099,

1068, 1022, 912, 850, 769

1H-NMR : δ 2.25 (s, 6H), 2.26-2.29 (m, 1H), 2.58-2.69 (m, 1H), 3.58-

O

NMe Me

(S)-Dapoxetine 11b

145

(300MHz, CDCl3) 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)

13C-NMR

(75 MHz, CDCl3)

: δ 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. 1H NMR spectrum of 41b

30. 13C NMR spectrum of 41b

31. 1H NMR spectrum of Mosher’s ester 41c

32. 1H NMR spectrum of 24

33. 13C NMR spectrum of 24

34. 1H NMR spectrum of 26

35. 13C NMR spectrum of 26

36. 1H NMR spectrum of 66

37. 13C NMR spectrum of 66

38. 1H NMR spectrum of 11b

39. 1H NMR spectrum of 11b (Expansion)

40. 13C NMR spectrum of 11b

147

1 H N

MR

Spe

ctru

m o

f 41b

148

13C

NM

R S

pect

rum

of 4

1b

149

1 H N

MR

Spe

ctru

m o

f Mos

her'

s est

er 4

1c

150

1 H N

MR

Spe

ctru

m o

f 24

151

13C

NM

R S

pect

rum

of 2

4

152

1 H N

MR

Spe

ctru

m o

f 26

153

13C

NM

R S

pect

rum

of 2

6

154

1 H N

MR

Spe

ctru

m o

f 66

155

13C

NM

R S

pect

rum

of 6

6

156

1 H N

MR

Spe

ctru

m o

f 11b

157

1 H N

MR

Spe

ctru

m o

f 11b

158

13C

NM

R S

pect

rum

of 1

1b

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-González, 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. Clément, P.; Bernabé, 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.; O’Bannon, 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,

4195.

35. (a) Eschweiler, W. Ber. 1905, 38, 880; (b) Clarke, H. T.; Gillespie, H. B.;

Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571; (c) Snyder, H. R.; Saunders, J.

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

NHCOCH3

MeO

MeO

COOH

NHCOCH3

HH

[Rh(R,R)DiPAMP, COD)BF3+ H2

H3O+

HO

HO

COOH

NH2

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 Parkinson’s 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 Parkinson’s disease as well as Alzheimer’s disease when

used along with L-DOPA.

NCl

NH

ONH2 F

O

NH

MeNH2

O

(R)-Selegilne 70a(R)-Rasagilne 71a

Lazabemide 72 (S)-Safinamide 73

NHN

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 HUMAN13

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

NH

Me

(R)-(-)-Methamphetamine 74a

N-despropynylation(R)-(-)-Selegiline 70a

N-desmethylation

Desmethylselegiline 75a

N-despropynylation

NH2

Me

(R)-(-)-Amphetamine 78a

p-hydroxylation -hydroxylationβ

NHMe

MeHO

(S)(R)

NHMe

Me

OH(1S,2R)-(+)-Ephedrine 77a

(1R,2R)-(-)-pseudoephedrine 77b

(R)(R)

NHMe

Me

OH

-hydroxylationβp-hydroxylation

NH2

MeHO

(S)(R)

NH2

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, β-hydroxylation, and aromatic

ring-hydroxylation. The major metabolite was (R)-methamphetamine 74a. During

metabolism, no racemic transformation occurred and β-hydroxylation showed apparently

product stereoselectivity.

2.2.3 Review of Literature

The synthetic methods available in the literature for Selegiline are as follows

Gyogy’s 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 HgCl2-activated aluminum at 60 °C gave amine 75, which on methylation

yielded racemic selegiline 70. Similarly, (4-fluorophenyl) acetone 82 gave 4-

fluoroselegiline 84.

RO R

HNR

N

i ii

R = H 81R = F 82

R = H 75R = F 83

R = H 70R = F 84

Scheme 3. Reagents and conditions: (i) propargylamine, EtOH, 60 °C, HgCl2-Al; (ii) MeI, K2CO3, acetone.

169

Hajicek’s 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, K2CO3, PhH 5 °C; (ii) HCl (gas)

Same group have reported the (R)-selegiline 70a hydrochloride by reaction of (R)-

deoxyephedrine 74a with HC≡CCH2OP+Ph3Cl¯, followed by treatment with HCl

(Scheme 5).

NH N N.HCl

i ii

74a 70a 70a. HCl Scheme 5. Reagents and conditions: (i) HC≡CCH2OP+Ph3Cl-, Et3N, CH3CN, 25 °C, 10 h; (ii) HCl (gas), i-PrOH, 36%.

Sterling’s 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).

NH2 NH2 HN N

iiiiii

85 85a 86 87OH OH OH OH(±)-

Scheme 6. Reagents and conditions: (i) D-tartaric acid, MeOH, reflux; then 25% NH4OH, 25 °C; (ii) propargyl bromide, K2CO3, 25 °C; (iii) HCO2Et, then LiAlH4,THF,reflux.

170

Plenevaux’s approach (2002)17

Racemic 4-[18F]fluoroselegiline 84 was prepared via the three step procedure: (i)

substitution by [18F]fluoride on 4-nitrobenzaldehyde 88 (ii) reaction with (1-chloro- 1-

(trimethylsilyl)ethyl)lithium and hydrolysis to give 4-[18F]flurophenylacetone 82, (iii)

reductive alkylation of ketone 82 with N-methylpropnylamine led to 84 (Scheme 7).

CHO

O2N

CHO

F

i

FO F

Nii 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, NaBH3CN, 35%.

www.selegiline.com18

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 LiAlH4 yielded alcohol 94 without affecting -C≡C-bond, which

on subsequent reaction with thionyl chloride followed by reduction, gave (R)-selegiline

70a.

CO2H

NH2

CO2Me

NH2

CO2Me

NHMe

CO2Me

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) HCO2H, NaBH4; (iii) propargylbromide, K2CO3; (iv) SOCl2; (v) LiAlH4, THF.

171

Sudalai’s approach (2004)19

Sudalai et al have reported three different approaches for the synthesis of (R)-

Selegiline 70a. In first approach, β-methyl styrene 95 was subjected to Sharpless

asymmetric dihydroxylation reaction to give chiral diol 96 which on treatment with

SOCl2 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

OSO

ON3

OH

NH

NH2 NH N

i ii iii iv

v vi vii

95 96 97 98

99 78a 74a 70a Scheme 9. Reagents and condition: (i) OsO4, (DHQ)2-PHAL, K3Fe(CN)6, K2CO3, t-BuOH:H2O, 0 °C, 82%; (ii) SOCl2, Et3N, DCM, 0 °C, 85%; (iii) NaN3, acetone-H2O, 80 °C, 82%; (iv) PPh3, CH3CN, 90%; (v) Pd/C (10%), HCO2NH4, MeOH, reflux, 88%; (vi) (a) ClCO2CH3, DCM, aq. K2CO3, 45 min, 90% (b) LiAlH4, dry THF, 65 °C, 65%; (vii) propargyl bromide, K2CO3, CH3CN, 25 °C, 72%.

In the second approach, α-aminooxylation of 3-phenylpropanaldehyde 100 was

carried out using nitrosobenzene and catalytic amount of L-proline. The resulting

aminooxy aldehyde was reduced with NaBH4 afforded the α-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 LiAlH4 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)2O and reduction of N-Boc group using LiAlH4 to give N-methylamine 74a.

Propargylation of amine 74a using propargyl bromide furnished (R)-selegiline 70a in

26% overall yield (Scheme10).

O OHONHPh

O

OH NH2 N

i ii iii

v vi

OHOH

NHviiiv

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, NaBH4, 86%; (ii) H2 (1atm.), 10% Pd/C, MeOH, 12 h, 88%; (iii) (a) TsCl, Et3N, CH2Cl2, 0 °C, 1 h, (b) NaH, DMF, 0 °C, 0.5 h, 81% for 2 steps; (iv) LiAlH4, THF, reflux, 2 h, 92%; (v) (a) MsCl, Et3N, DCM, 0 °C, 0.5 h, (b) NaN3, DMF, 80 °C, 12 h, 76% for 2 steps; (c) H2 (1atm.), 10% Pd/C, MeOH, 2 h, 98%; (vi) (a) (Boc)2O, Et3N, 0 °C, 1 h, 95%; (b) LiAlH4, THF, reflux, 4 h, 90%; (vii) propargyl bromide, K2CO3, CH3CN, 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 NaBH4 afforded the protected amino alcohol 131 in

95% yield (Scheme 11).

173

O OHN

HN CbzCbz

OHNHBoc

OTsNHBoc NH N

i ii

iii iv v

100105

106

107 74a 70a

Scheme 11. Reagents and conditions: (i) Dibenzyl azodicarboxylate , D-Proline (10 mol%), 0-20 °C, 3 h then NaBH4, EtOH, 95%; (ii) (a) H2 (60 psi), Raney Ni, MeOH, AcOH, 16 h, (b) (Boc)2O, Et3N, 0 °C, 1 h, 66% for 2 steps; (iii) (a) p-TsCl, Et3N, DCM, 0 °C, 1 h, (b) LiAlH4, THF, reflux, 4 h, 81% for 2 steps; (iv) propargyl bromide, K2CO3, CH3CN, 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)2O. The primary alcohol was then tosylated to give 133, which on reduction with

LiAlH4 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 β-methyl

styrene, employing Sharpless asymmetric dihydroxylation was developed. Unfortunately,

this method affords low optical purity (up to 83% ee). The Organocatalytic α-

hydroxylation and α-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

OHOHI

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 epoxidation20 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 Å MS, DCM, -20 °C, 3 h, 89%; ii) I2, Ph3P, imidazole, Et2O:CH3CN (1:1), 0 °C, 45 min, 92%; iii) H2 (2 atm), Pd-C, Et3N, EtOAc, 10 h, 94%; iii) DIAD, Ph3P, N –Methyl-2-nitro-benzenesulfonamide 135, THF, rt, 3 h, 86%; v) PhSH, CH3CN, rt, 2 h, 87%; vi) propargyl bromide, K2CO3, CH3CN, rt, 3 h, 76%.

Epoxycinnamyl alcohol 41b was treated with Iodine,

triphenylphosphine in the presence of imidazole under Apple

condition21 to produce Iodo epoxide 108 in 92% yield. The 1H NMR spectrum of 108

showed multiplet at δ 3.28 corresponding to methylene and methine proton, appearance

IO

108

176

of apparent broad singlet at δ 3.77 corresponding to benzylic proton respectively. Its 13C

NMR spectrum showed carbon signal at δ 4.4 corresponding to iodine attached to

methylene carbon and signal showed up field shift due to shielding of iodine atom. The

peaks at δ 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 dehalogenation22 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 1H

NMR spectrum showed peak at δ 1.23 appeared as a doublet confirming the presence of

methyl group, the signal at δ 2.0 (s) is due to the hydroxyl functionality, appearance of

peak at δ 2.63-2.85 as a multiplet corresponding to benzylic protons. Other signal at δ

3.95-4.15 (m) corresponding to methine proton of the chiral center respectively. Its 13C

NMR spectrum showed overall up field shift. The carbon signals at δ 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

SO2

110

NO2

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 -NO2 group,

the strong bands in the 1454 cm-1 and 1168 cm-1 regions, due to the asymmetric and

symmetric stretching vibrations of -SO2- group. Its 1H NMR spectrum showed δ 1.13-

1.15 (d) corresponding to terminal methyl proton, appearance of signal at δ 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 δ 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 δ 7.52-7.65 (m) and 7.80-7.83 (m) corresponding to

protons of the nosyl moiety respectively. Its 13C NMR spectrum showed carbon signal at

δ 27.9 indicating presence of methyl group on the nitrogen, peaks at δ 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 deprotection25 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 1H NMR spectrum showed

sharp intense peak around at δ 2.44 (s) indicating presence of methyl group on the

nitrogen. Its 13C 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 C≡C-H stretching,

C≡C stretching, and ≡C-H bending mode indicating presence of

propargyl group. Its 1H NMR spectrum showed characteristic singlet at δ 1.85

corresponding to terminal proton of acetylene moiety, typical signal at 3.43 (d)

corresponding to methylene protons of propargyl moiety respectively. Its 13C NMR

spectrum showed peaks at δ 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 Na2S2O3, followed by CuSO4 and water. The organic layer was dried briefly

over MgSO4, filtered, and concentrated to give iodo epoxide 108.

Yield : 4 g, 92%

BP : oil

[α]25D : -58 (c 2, CHCl3)

IR (Neat, cm-1) : 3063, 1604, 1495, 1458, 1406, 1248, 1171, 1073, 1018, 882.

1H-NMR

(200 MHz, CDCl3)

: δ 3.23 (m, 3H), 3.77 (apparent s, 1H), 7.24-7.36 (m, 5H)

13C-NMR (50 MHz, CDCl3)

: δ 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.

IO

108

OH104

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

[α]25D : + 50.2 (c 1.1 CHCl3), {lit.19b [α]25

D = + 50.8 (c 1.1 CHCl3)}

IR (Neat, cm-1) : 3381, 2968, 2924, 1494, 1456, 1118, 1082, 941, 742

1H-NMR (200 MHz, CDCl3)

: δ 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)

13C-NMR (50 MHz, CDCl3)

: δ 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 Na2SO4 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 (CHCl3, cm-1) : 3356, 3120, 3022, 1637, 1542, 1386, 1354, 1216, 1173, 1119,

1H-NMR (200 MHz, CDCl3)

: δ 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)

13C-NMR (50 MHz, CDCl3)

: δ 29.7, 125.4, 131.4, 132.3, 132.7, 133.7, 148.10

SO2NHMeNO2

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 N2

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

[α]29D : = +17 (c 2 CHCl3)

IR (CHCl3, cm-1) : 2980, 2931, 1732, 1545, 1373, 1344, 1236, 1168, 1122.

1H-NMR (300 MHz, CDCl3)

: δ 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)

13C-NMR (75 MHz, CDCl3)

: δ 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

SO2

110

NO2

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 Na2SO4, solvent was passed through pad of celite and evaporated under

reduced pressure to give 74a.

Yield : 650 mg, 87%

BP : pale yellow oil

[α]25D : = -10.5 (c 1 EtOH) {Lit.19b [α]25

D = -10.87 (c 1 EtOH)}

IR (Neat, cm-1) : 3425, 3319, 2964, 1691, 1452, 1377, 1074, 1033,740, 702

1H-NMR (200 MHz, CDCl3)

: δ 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)

13C-NMR (50 MHz, CDCl3)

: δ 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

[α]25D : -10.3 (c 6.5 EtOH) {lit.19b [α]25

D = -10.7 (c 6.5 EtOH)}

IR (Neat, cm-1) : 3437, 3019, 2120, 1652, 1402, 1215, 1017, 929, 669.

1H-NMR (200 MHz, CDCl3)

: δ 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)

13C-NMR (50 MHz, CDCl3)

: δ 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. 1H NMR spectrum of 108

2. 13C NMR spectrum of 108

3. 1H NMR spectrum of 104

4. 13C NMR spectrum of 104

5. 1H NMR spectrum of 109

6. 13C NMR spectrum of 109

7. 1H NMR spectrum of 110

8. 13C NMR spectrum of 110

9. 1H NMR spectrum of 74a

10. 13C NMR spectrum of 74a

11. 1H NMR spectrum of 70a

12. 13C NMR spectrum of 70a

185

1 H N

MR

Spe

ctru

m o

f 108

186

13C

NM

R S

pect

rum

of 1

08

187

1 H N

MR

Spe

ctru

m o

f 104

188

13C

NM

R S

pect

rum

of 1

04

189

1 H N

MR

Spe

ctru

m o

f 109

190

13C

NM

R S

pect

rum

of 1

09

191

1 H N

MR

Spe

ctru

m o

f 110

192

13C

NM

R S

pect

rum

of 1

10

193

1 H N

MR

Spe

ctru

m o

f 74a

194

13C

NM

R S

pect

rum

of 7

4a

195

1 H N

MR

Spe

ctru

m o

f 70a

196

13C

NM

R S

pect

rum

of 7

0a

197

2.2.9 References

1. Jankovic, J. "Parkinson's disease: clinical features and diagnosis". J. Neurol.

Neurosurg. Psychiatr. 2008, 79, 368.

2. Berchtold, N. C.; Cotman, C. W. "Evolution in the conceptualization of dementia

and Alzheimer's disease: Greco-Roman period to the 1960s". Neurobiol. Aging 1998,

19, 173.

3. Brookmeyer, R.; Gray, S.; Kawas, C. (September 1998). "Projections of Alzheimer's

disease in the United States and the public health impact of delaying disease onset".

American Journal of Public Health 1998, 88, 1337.

4. Brookmeyer, R.; Johnson, E.; Ziegler-Graham, K.; Arrighi, H. M. "Forecasting the

global burden of Alzheimer's disease". Alzheimer's and Dementia 2007, 3,186.

5. The National Collaborating Centre for Chronic Conditions, ed (2006). "Symptomatic

pharmacological therapy in Parkinson’s disease". Parkinson's Disease. London:

Royal College of Physicians. pp. 59-100.

6. Da Prada, M.; Kettler, R.; Keller, H. H.; Cesura, A. M.; Richards, J. G.; Saura Marti,

J.; Muggli-Maniglio, D.; Wyss, P. C.; Kyburz, E.; Imhof, R. From moclobemide to

Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective

MAO-A and MAO-B inhibitors. J. Neural. Transm., Suppl. 1990, 29, 279.

7. Guay, D. R. Rasagiline (TVP-1012): a new selective monoamine oxidase inhibitor

for Parkinson’s disease. Am. J. Geriatr. Pharmacother. 2006, 4, 330.

8. Riederer, P.; Lachenmayer, L.; Laux, G. "Clinical applications of MAO-inhibitors".

Curr. Med. Chem. 2004, 11, 2033.

198

9. Riederer, P.; Lachenmayer, L. "Selegiline's neuroprotective capacity revisited". J

Neural Transm 2003, 110, 1273.

10. Ives, N. J.; Stowe, R. L.; Marro, J. "Monoamine oxidase type B inhibitors in early

Parkinson's disease: meta-analysis of 17 randomized trials involving 3525 patients".

BMJ 2004, 329, 593.

11. Lee, K. C.; Chen, J. J. Transdermal Selegiline for the Treatment of Major Depressive

Disorder. Neuropsychiatr. Dis. Treat. 2007, 3, 527.

12. David, H. "The psychopharmacology of life and death. Interview with Joseph

Knoll." The Psychopharmacologists, Vol. III: Interviews. London: Arnold. 2000

pp. 81-110.

13. Shin, Ho-S. Drug Metabolism and Disposition 1997, 25, 657.

14. Gyogy, B.; Jozsef, K. CA 110: 44960g.

15. (a) Josef, H. CA 113: 590e; (b) Josef, H. CA 117: 150680.

16. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, Lerner, D.; Goldenberg, W.; 83

Miskolezi, I.; Molnar.; Rantal, F. J. Med. Chem. 2002, 45, 5260.

17. Plenevaux, A.; Flower, S. F.; Dewey, S. L.; Wolf, A. P.; Guillaume, M. Int. J.

Applications and Instrumentation Part A, Applied Radiation and Isotopes 1991, 42,

18. (S)-Phenyl alanine as a starting material. www.selegiline.com

19. Sayyed, I. A.; Sudalai, A. Tetrahedron: Asymmetry 2004, 15, 3111; (b) Talluri, S. K.;

Sudalai, A. Tetrahedron 2007, 63, 9758.

20. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.

J. Am. Chem. Soc. 1987, 109, 5765.

21. Marshall, J. A.; Cleary, D. G. J. Org. Chem. 1986, 51, 858.

199

22. Rozwadowska, M. D. Tetrahedron: Asymmetry 1993, 4, 1619.

23. Bohlmann, F.; Staffeldt, J.; Skuballa, W. Chem. Ber. 1976, 109, 1586.

24. (a) Kan, T.; Fukuyama, T. Chem. Comm., 2004, 353; (b) Hovinen, J.; Sillanpaa, R.

Tetrahedron Lett. 2005, 46, 4387.