Chapter-1

1

1. Prostaglandins (PGs)

Prostaglandins (PGs) were discovered1 by Swedish physiologist (Nobel

laureate), Ulf von Euler in 1935 and other investigators were given the term

“Prostaglandin” anticipating the active material could be the origin from the

prostate gland. PGs were first isolated and characterized by K. Bergström

from Karolinska Institute in 1957. 2 In 1971, it was determined that

aspirin-like drugs could inhibit the synthesis of PGs.

PGs are classified among the family of eicosanoids along with

leukotrienes (LT), thromboxanes (TX) and Lipoxins (LX) (Fig 1). The PGs and

TXs are collectively identified as prostanoids. PGs exist and are synthesized

in virtually every tissues and organs of the living body.3 These are like

hormones in that they act as chemical messengers, but they are not

transported from one place to another in the body rather they are

synthesized within the cells when required. They play important

regulatory roles in many normal cellular functions, especially in relation to

inflammatory responses, regulating fat metabolism, hormones, pain, fever as

well as the cardiovascular, immune, and central nervous systems.

Chapter-1

2

α

OH

O

OH

COOH

OHOH

OH

COOH

O

OH

COOH

CH3

O

OH OH

COOH

5

13 15

(PGE2)

(LXA4)

(LT)

(TX)

Fig 1: Representative clinically relevant Eicosanoids

1.2 Structure Classification and nomenclature

The structure of PGs comprises of an oxygenated cyclopentane ring

with a heptanoic acid side chain (α-side chain) and an octene side

chain (ω-side chain) on adjacent positions of cyclopentane and such a

basic structural unit is referred to as a prostanoic acid. (Fig.2)

Chapter-1

3

HCO

2H

H

12

34

56

7

8

9

10

11

12

1314

1516

1718

1920

Fig 2: Prostanoic acid

PGs differ from the other eicosanoids in the substitution model on the

cyclopentane ring and the side-chains, and these differences are

accountable for the various biological activities of the members of the

prostaglandin family. PGs are generally classified as PGA, PGB, PGC,

PGD, PGE, PGF, PGG, and PGH referring to the different oxygen

functionalities in the cyclopentane ring substitution patterns. For each

general PG class is sub-classified based on the degree of unsaturation (i.e.,

PGE1, PGE2, and PGF2). The letters and numbers that follow the initial PG

abbreviation indicate the nature of the unsaturation and substitution.

For example, the subscript 1 in PGE1 indicates one double bond in

the side chains, while the 2 in PGE2 indicates two double bonds in the

side chains (Fig. 3)

Chapter-1

4

O

Rw

Ra

H

HO

Rw

RaO

Rw

Ra

Rw

RaH

O H

OH O

Rw

RaH

HOH

Rw

RaH

HOH

OH

Rw

RaH

HOH

OH

COOH

OH

COOH

OH

COOH

OH

A B C D E

F(alpha) F (omega)

R alpha

R omega

R alpha

R omega

R alpha

R omega

1 2 3

Fig-3: Nomenclature of prostaglandins

1.3 Biosynthesis

The production of PGs takes place immediately after the stimulus has

interacted with its receptor. The key precursor is arachidonic acid that is

biosynthesized from linoleic acid in eicosanoid biosynthetic pathways (Fig.

4), which comes from the food taken as the diet through reactions

catalyzed by a series of enzymes that comprise elongation to linolenic acid

followed by unsaturation of the fatty acids.

Chapter-1

5

O

CH3

COOH

COOH

COOH

OH

CH3

COOH

OOH

CH3

COOH

OOH

CH3

COOH

OOH

CH3

CH3

COOHO

O

OOH

CH3

COOHO

O

OH

O

OH

COOH

CH3

O

O

OH

COOH

CH3

OH

OH

O

COOH

OH

CH3

OH

OH

COOH

CH3

OH

OH

OH

COOH

CH3

OH

OH

OH

COOH

CH3

OH

O

14,15-EET

Phospholipids(Cell membranes)

12-HETE

Phospholipase A2

12-Lipoxygenase

5-LipoxygenaseArachidonic Acid

Cycloxygenase(COX1&2)

Isoprostanes (IsoPs)

5-HPETE15-HPETE

CylochromeP450

epoxygenase

Lipoxins

PGH2

PGG2

LeukotrienesLTBs,LTC's, LTDs LTEs, LTFs

TXA2

Thromboxane Synthase

Prostacyclin Synthase

TXB2

PGI2(Prostacyclin)

PGH-PGEIsomerase

Reductase PGH-PGDIsomerase

PGF2alfaPGD2

PGE2

Fig 4: Eicosanoid Biosynthetic Pathways

12-HPETE

Chapter-1

6

1.4 Limitations of natural PGs as potential drugs

In contrast to hormones, PGs do not circulate nor are they stored in the

tissue. Rather they are synthesized locally on demand, perform a

tissue-specific function and are rapidly inactivated by metabolic enzymes

afterwards. The half-life time in the body is a few minutes for PGE1 and 30

seconds for PGI2. Their pattern of action is diverse. Inspired by the

fascinating properties of the eicosanoids intensive research around the

world were made since 1960s. Major problems with the use of the natural

PGs as drugs have been encountered:

Chemical instability

Rapid metabolism

Incidence of numerous side effects.

These results triggered the chemical synthesis of PG analogues, which are

not/or less affected by the major problems, as mentioned above.

1.4.1 PG-derived drug products used for various therapeutic

indications

Several clinical agents5 were developed based on prostaglandins and are

used in various therapeutic purposes and a summary of the details are

presented in the following Table No.1

Chapter-1

7

Table.1: PG derived clinical agents:

Prostaglandin based Drug Structure

No

Applications

Carboprost trometamol 4 Abortifacient

Gemeprost 11 Abortifacient

Sulprostone 12 Abortifacient

Dinoprostone (PGE2) 5 Child Birth

Alprostadil (PGE1), many

products

1 Male sexual dysfunction &

Peripheral vascular disease

Beroprost 2 Peripheral vascular disease

Iloprost 6 Peripheral vascular disease

Epoprostenol 14 Pulmonary hypertension

Treprostinil 10 Pulmonary hypertension

Misoprostol 8 Ulcers

Enoprostil 13 Ulcers

Limaprost 15 Buerger’s disease

Unoprostone isopropyl 16 Glaucoma

Latanoprost 7 Gluacoma

Travoprost 9 Glaucoma

Bimatoprost 3 Glaucoma

Chapter-1

8

O

OH

CH3

COOH

OH

O

OH

OH

OH H

HO

OH

OHOH

N

O COOH

OHCH3

OH

OH

COOH

O

OH OH

OH

H

H

OH

OOH

CH3

OH

O

OH

O

O

O

OH

OHOH

O

O

F3C

O

O

OH

HH

OH OH

OH

OH

O

O

OH

1 2

34

5

6

7 8

9

10

Chapter-1

9

O

OH

CH3

OH

O

OO

OH

O

OH

NH

O

S

O

O

O

OH OH

O

O

O

OH

CH3

OH

OOH

O

O

OH OH

OH

O

OH

OH O

O

O

11 12

13

14

1516

Chapter-1

10

1.4.2 Synthetic approaches towards natural PGs

Chemical synthesis of PGs, was necessitated based on utility of asymmetric

organic reactions along with the development of new strategies using

retrosynthetic analysis. Efficient and flexible chemical synthesis is

necessary to ensure adequate supply of natural PGs and artificial analogues.

Successful chemical synthesis has tremendous impact on the progress of

biological, physiological, and medicinal investigations. Currently, several

natural and non-natural PGs are being used as drugs.4 Although numerous

analogues have been synthesized during the past few decades and many

reside in the clinical status, only few of these are marketed. PGs are used as

antiulcer, antihypertensive, antiglaucoma drugs, etc and play an important

role in the field of fertility control.5 Among the versatile approaches for

the synthesis of cyclopentane derived PGs, major contributions and

developments were laid by E. J. Corey (Harvard university, USA, Nobel

laureate in 1990 for Chemistry), Gilbert Stork and R. Noyori (Nagoya

university, Japan and Nobel laureate in 2001) and these strategies still

remain the most elegant approaches to date.

Chapter-1

11

1.5 The Corey’s Strategy

OH

OHOH

COOH

OH

OH

CHO

CHO

COOHPh3P

O

PMeO

MeO

O

O

OH

O

OH

+

Corey's Lactone

Fig 5: Retro synthesis of Corey's strategy

The major contributions for the synthesis of PGs are from Corey group.

Although many precursors have been used for the synthesis of PGs,

the bicyclic precursor, called the Corey lactone is also used for the

industrial production of PG analogs.6 Among various PG analogs, the retro

synthetic analysis of the E and F series of PGs illustrate the widely used

Corey’s approach7, which takes notice due to the presence of the two olefinic

bonds in the side chains of PGF2α.8 The actual synthesis consists of two-fold

Wittig-type chain extension of a chiral di-aldehyde equivalent with four

defined stereogenic centers derived from cyclopentadiene via a series of

bicyclic intermediates.9

Chapter-1

12

1.5.1 The Two-Component Coupling

A second approach for the synthesis of racemic PG analogues is based

on the two component coupling pathway pioneered by Untch and Stork10

using a ω-chain unit with the Z-olefinic bond.11 Conjugate addition approach

developed by Sih12 came up with the nucleophilic addition of the E-olefinic ω

side-chain unit to the cyclopentenone in which the α-side chain is already

installed lead directly to PGE-type compounds in particular.

OH

O

OH

COOH

COOH

OH

O

I

OH

Fig 6: Retro Synthesis of the Two - Component Coupling Approach

+

1.5.2 The Three-Component Coupling

The most direct and convergent synthesis is the convergent three-

component coupling synthesis,13 developed by Noyori via consecutive

linking of the two side chains to unsubstituted 4-hydroxy-2-

cyclopentenone derivatives.14 The key step of this method is the conjugate

addition-aldol reaction connecting both the side chains in one step

Chapter-1

13

COOMe

O

OHOH

O

THPO

H

O

COOMe

I

OTHP

Fig 7: The Three-Component Coupling Approach

+

1.6 Synthesis of Key Intermediates.

1.6.1 Corey Lactone and its Derivatives.

The derivatives of the Corey lactone are highly versatile intermediates

for the synthesis of several kinds of prostaglandins. Starting from the

easily accessible C2 symmetric compound 17, an interesting lipase

catalyzed demethoxycarbonylation process has been performed, affording

the intermediate (+)-18 in good yield and in enantiomerically pure

form. In few steps, including two ozonolysis reactions, it was

transformed into the functionalized target lactone (-)-20 (Scheme 1)15

Chapter-1

14

OH

OH

HH

CO2MeMeO

2C

CO2MeMeO

2C

OH

OH

HH

MeO2C

CO2Me

OH

HH

MeO2C

CO2Me

OH

HH

O

AcO OH

O

C2-Symmetry(+)-18

(+)-19(-)-20

17

NaBH(OEt)3

94%

7 Steps

Scheme-1

Radical type cyclizations have been used for the preparation of lactones as

described below. Starting from the thionocarbonate 22, the cyclization gave

a mixture of three lactones: the derivative 25 (Scheme 1.1), which was

obtained as a minor component (20%), is enantiomer to the Corey lactone.

The major compound 23 is a versatile starting material for the synthesis of

the isoprostaglandins.16

Chapter-1

15

OO

O

O

O

OH OO

S

OH OH

CO2Me

O

OH

O

OHOH

O

OOH

O

OH

O

OH

5 Steps

31 %

Bu3SnH (1.3 eq)

AIBN (0.3 eq)Benzene, 80°C, 1h

47% over all

ratios: 57% 23 % 20 %

23 24 25

Scheme-1.1

21 22

+ +

A new cascade type reaction of radicals, which can be of interest for the

synthesis of various cyclopentane derivatives, has been developed recently.

It involve a 5-exo-digonal cyclization (radical 26), followed by a hydrogen

transfer in 27 to produce a silicon-centered radical and then a 5-endo-

trigonal cyclization process to give 29 which is finally reduced to 30

(Scheme 1.2)

Chapter-1

16

R

O

Si

t-But-Bu

H

.

CHRO

Si

Ht-Bu

t-Bu

O

Si

t-Bu

t-Bu

R

H

SiO

HH

R

t-But-Bu

SiO

H

R

t-But-Bu

.

26 27 28

.

2930

R'3 SnH

Scheme-1.2

.

.

.

Intramolecular C-H insertion reactions were developed to prepare Corey

lactone derivatives. Starting from optically active diazo compound 31,

the insertion is stereo selective (4:1) giving the cyclopentanone 32 in

50% yield. After a few functional group transformations, the required

lactone (-)-36 was obtained in optically pure form (Scheme 1.3).17

Chapter-1

17

ON

2

CO2Me

TBSO

Rh2(OAc)

2

CH2Cl

2

reflux

TBSO

CO2Me

O

TBSO

OH

OH

TBSO

OH OTBDPS

TBSO

BPPO OTBDPS

OH

O

O

BPPO

15 min

50%

+ dia

LiAlH4, THF,

rt, 1 h

3132

33

TBDPS-ClEt3N, DMAP

CH2Cl2rt,

27 h, 76 % in 2 steps

34

PPB-Cl, DMAPPy, 100°C, 2.5 h 91 %

35

1. cat.RuCl3 NaIO4

CCl4-MeCN-H2O

rt, 5.5 h

2. 10 % HCl, MeOH, rt, 15 h 53 % in two steps

(-) 36

Scheme-1.3

Another strategy was to use Baeyer-Villiger reaction on bicycle [3.2.0] hept-

3-en-6-ones. The bicyclic cyclobutanone 39 (3:1 exo:endo mixture),

achieved in 5 steps from 37, gave the corresponding lactones 40 in

excellent yield. The latter derivatives were transformed in two steps into the

desired Corey lactone derivative (exo 41) and its endo diastereoisomer

Chapter-1

18

(Scheme 1.4) .18

OH

BnO

O

OH

OH

OBn

O

O

OBn

O

O

OBn

OH

Br

O

O

OBn

OH

Br

O

O

OBn

OH

O

O

OBn

OH

OBn

O

4 steps

65%

H2O2, CH3CO2H

10% aq.Na2S2O690%

NBS, DMF,/Water 1:1

70%

37 38 39

40exo-41endo-41

exo-42endo-42

1-ethylpiperidine hypophosphiteAIBN, dioxane,heate 85-90 %

CH3CO2K

AC2O, rt, 2h

3h 93%

Scheme-1.4

+

Cycloaddition strategies continue to be fruitful for the synthesis of

Corey lactone derivatives. The adduct 45 resulted from an inverse electron-

demand Diels-Alder reaction. After radical initiation, skeletal translocation

occurred giving the desired bicyclic lactone 47 in 78% overall yield. The

target molecule 50 was achieved in 56% overall yield from 47 in three steps

Chapter-1

19

(Scheme 1.5).19

O O

CO2Me PhSe

OMe

O

PhSe

MeO

CO2Me

O

O

O

OMe

CO2Me

O

O

OMe

O

O

OMe

AcO

Br

O

O

OMe

AcO

O

CO2Me

MeO

O

15 Kbar45°C

3 days

(Me3Si)3SiH

AIBN

silica gelCH2Cl2rt, 78% overall

110°C, 83%

LiCl ,DMSO, H2O

NBA, acetone/H2O, rt

AcCl, py, CH2Cl2o°C to rt91 %

Bu3SnH

AIBNbenzenereflux

70%

Benzenereflux

4344 45

464748

4950

Scheme-1.5

+

1.6.2 Cyclopentenones, Cyclopentenediols and Derivatives

The ring opening of 51 in non polar solvents like benzene mediated by

lithium (S)-2(pyrrolidin-1-ylmethyl) pyrrolidide 52, occurred to give 53 in

good ee (up to 92 %).20 By using piperidinyl analogue 53, the same

monoprotected diol 54 was achieved in 97 % e e in lower yield (Scheme

1.6.0).21

Chapter-1

20

NN

H

Li

O

OSBT

OH

OTBS

NNH

Ph51

52

53

90% ee

97 % ee

n-BuLi, benzene0°C,30 h, 66 %

Scheme-1.6.0

54

benzene, 4°C, 2 h 92 %

The use of transition metal catalysts offered another attractive opportunity

to perform enantioselective ring opening of meso epoxides. The reaction of

55 with the catalyst 56 (2 mol %) and TMSN3 afforded the

azidoketone, which after treatment with alumina gave the useful enone

57 in 94% ee (Scheme 1.6.1).22 Another approach was to use the

Gallium. Lithium.bis (naphthoxide) complexes at 10 mol %, in the presence

of a thiol. The ring opening of 51 occurred to give 58 in good yield and ee

(91 %). After oxidation and pyrolysis, the target enone ent- 60 was

obtained. 23

Chapter-1

21

t-Bu

O

N N

O

Cr

N3

t-Bu

t-Bu

t-Bu

HH

O

O O

TMSON

3

O

TMSO

O

OTBS

S

OH

TBSO

t-Bu

SO

O

TBSO

t-Bu

O

TMSO

TMSN3

Et2O, -10°C

Al2O3

CH2Cl2

94% ee77% over all yield

56

55

57

Scheme-1.6.1

(S)-GalB910 mol %)

t-BuSH/MS 4Atoluene, rt, 96 h, 90 %

1. SO3-Py DMSO

2. NaIO4

Toluene P(OCH3)3

ent-60

51 5859

+

A new approach to cyclopentenones was reported recently, starting from 4-

alkynals, involves either a rhodium catalyzed kinetic resolution (to give 63

for instance) or a desymmetrization process (affording 65) (Scheme 1.6.2).24

These reactions gave cyclopentenones bearing tertiary or quaternary stereo

centers which offer many opportunities, especially in the preparation of

new prostaglandin analogues.

Chapter-1

22

H

O

Me

Ph

OMe

H

O

MePh

OMe

O

Me

Ph

MeO

H

O

OMe

n-C5H

11

n-C5H

11

O

H11

C5n-

n-C5H

11

OMe

61

5 % [Rh((R)-Tol-BINAP)]BF4

CH2Cl2, 30°C

kinetic resolution

62

+

63

99 % ee

64

10 % [Rh((R)-Tol-BINAP)]BF4

CH2Cl2, 10°C, 95 %

desymmetrization

65

99 % ee

Scheme-1.6.2

1.6.3 Methylenecyclopentanones and Derivatives.

The methylenecyclopentenone 71, "Stork intermediate", is another highly

versatile key intermediate for the synthesis of prostaglandins and several

new syntheses of this intermediate have been reported. A first approach

started from the cyclopentenone ent-60 and involved, as key steps, a [2, 3]-

Wittig rearrangement followed by a 1, 3 Pd-catalyzed rearrangement of an

allylic acetate (Scheme 1.7).25

Chapter-1

23

TBSO

Br

OH

TBSO

O

O

TBSO

OSTB

TBSO

TBSOOH

TBSO

TBSO OAc

C5H

11

TBSO

TBSO

C5H

11

OAc

O

TBSO

C5H

11

TBSO

1. Br2, CCl4, 0°C

2. Et3N

3. NaBH4/CeCl3.7H2O

MeOH, -20°C96% overall

5 steps36% overall

1. Red-Al, 40°C2. Ac2O, Py

78%

[2,3]-Wittig rearrangement

t-BuLi, THF, -78°C, 1h, 59%

Pd(II)-Catalyzed rearrangmentPdCl2(MeCN)2

THF, reflux, 86%

3 steps60%

ent-6066

68 69

7071

67

Scheme-1.7

1.7 New total synthesis of cyclopentane derived Prostaglandins

(PGDs, PGEs, PGFs)

1.7.1 Two-Component Couplings

1.7.2 Cyclopentenones bearing the ά-chain

A short and efficient synthesis of PGE1 has been reported recently

using two component coupling strategy. The furanoic ketoester 72 was

obtained in three steps from furan and suberic acid. After reduction

Chapter-1

24

to 73, this hydroxyester was rearranged to the cyclopentenones 74 and

then to 75. Enzymatic resolution yielded the (S)-alcohol 76 and (R)-acetate

77 in good yield and optical purity achieved. The (S)-alcohol was again re

converted into the (R)-derivative by a Mitsunobu type inversion. After

protection as the silyl ether 78, the 1,4 addition of the cuprate derived

from the vinyl iodide 79, after deprotection, afforded the ester 80. A PPL

lipase saponification yielded the optically pure PG1 target, on a multigram

scale (Scheme 1.8)26

Chapter-1

25

O

O

CO2Me

OCO

2Me

OH

O

CO2Me

OH

O

OH

CO2Me

O

OH

CO2Me

O

AcO

CO2Me

O

TESO

CO2Me

I

OTMS

O

OH

CO2Me

OH

NaBH4, MeOH,

0°C,95%

ZnCl2dioxane:H2O (1.5:1),

reflux

Chloral, Et3N,

toulene, rt72%

Lipase (PPL)vinyl acetate,rt

(S)-alcohol

1. n-BuLi, CuCN Et2O, -78°C

2. PPTSacetone/H2O

72 73

7475

76

77

78

(R)-acetate

+

7980

Scheme-1.8

Chapter-1

26

1.7.3 Three-Component Coupling.

This elegant approach to prostaglandins was developed by Noyori's group. It

involves the use of a phosphine stabilized vinylic organ copper species but,

due to lack of reactivity it was important to convert the resulting enolate to

the triphenyltin derivative before attachment of the ά-side chain. The use of

mixed triorganozincates as nucleophiles yielded more reactive zinc enolates,

allowing a direct introduction of the desired side chain. More recently, a

new practical, one-pot six step, sequence has been developed by involving

zincates in the presence of catalytic amounts of a methyl cuprate. The

mechanistic proposal for the reaction detailed as: hydrozirconation of the

alkyne 81 with Swartz's reagent gave a vinylzirconocene 82 which was

transmetalated to a vinylcuprate ready for the 1,4-addition. Then, the

resulting copper enolate was transmetallated again to a more reactive zinc

enolate 83 which performed the trapping of the electrophilic species

affording type 84 adducts. This very efficient sequence was applied to

various types of enones as well as different electrophilic species. Two

representative examples of prostaglandin derived products 85 and 86

prepared using this approach are given in (Scheme 1.8.1).27

Chapter-1

27

R

R

O

R

ZrCp2Cl

R

O-ZnMe2Li

OOH

TBSO

CO2Me

OTMS

O

TBSO OPMB

CO2Me

Catalytic Cuprate-Induced 1,4-addition

Hydrozirconation-transmetallation

1,4-addition/transmetalation

Cp2Zr(H)Cl

THF, rt

1.cat Me2Cu(CN)Li2 MeLi, MeZnLi THF, -78°C

2. enone, ~1 h

Examples

ent-60

aq.NH4OH

NH4Cl

81

8283

84

85

86

Scheme-1.8.1

The next step in this area was to develop a catalytic asymmetric three

component coupling strategy. A first successful approach was reported

using chiral aluminium binaphthoxide complexes, as indicated in (Scheme

1.8.2).28 Using aluminum catalyst, the condensation of methylmalonate

anion with cyclopentenone and aldehyde 88 afforded the desired

Chapter-1

28

cyclopentenone 89 in excellent yield and as a mixture of stereoisomers.

After dehydration the cyclopentenone 90 was obtained in 92% ee. At this

point the lower chain of PGs was introduced in a multistep sequence leading

to 91. After Luche reduction, followed by esterification, the 1,3-

transposition of these allylic acetates was performed with Pd catalyst

affording an equilibrium mixture from which 93 could be obtained

after saponification.

Chapter-1

29

O

OAl

O

OLi

OH (CH

2)5CO

2Me

O

C(Me)(CO2Bn)

2

OH

OH

CO2Me

C(Me)(CO2Bn)

2

O

CO2Me

C(Me)(CO2Bn)

2

O

CO2Me

CO2Me

TBSO

O

CO2Me

TBSO

OAc

CO2Me

TBSO

OH

OH

OH

COOH

(S)-ALB 87

75 (5 mol%)t-BuONa (4.5 mol%)MS 4A, THF, rt, 84%

(-)C(CH3)(CO2Bn)2

1. MsCl, DMAP, Toluene2. Al2O3, 87%

1. (Ph3P)3RhCl, Et3SiH

2. aq HF, CH3CN, 88%

6 steps53% overall yield 1. NaBH4, CeCl 3 ,

CH3OH

2. Ac2O, DMAP,

Pyridine, 96%

1. PdCl2(CH3CN)2, THF

2. K2CO3, CH3OH, 65%

1. HF-Pyridine, THF2. Aq NaOH, THF, 61%

11-deoxy-PGF1alfa

88

89

91

92

93

94

Scheme-1.8.2

90

Chapter-1

30

1.7.4 Synthesis of Analogues of Cyclopentane Derived Prostaglandins.

The wide range of biological activity of PGs has prompted much

synthetic effort directed towards various types of analogues to be used, for

instance, as potential drugs in the treatment of osteoporosis and

glaucoma. The first series of analogues have maintained the cyclopentane

scaffold and explored the modifications on the side chains (either on the ά-

side chain or on the ώ-chain, and eventually on both chains). Other

analogues have exchanged the cyclopentane ring by a cyclohexane or five

member heterocycles.

1.7.5 Analogues Modified on the ά-Side Chain

The introduction of an extra C4-C5 double bond in the ά-side chain of

PGs has been demonstrated to be a useful modification. A

representative example is Enprostil, a synthetic PGE2 analogue used for

the treatment of gastric and duodenal ulcers. The molecule is available

as the mixture of two racemates, which differ from PGE2 not only by

the presence of the allene in the ά-chain but also by the replacement

of the 15-amyl group by a 15-phenoxy-methyl group in the ώ-chain.

These modifications induced a slower metabolic decomposition, decreased

the unwanted side effects and increased the chemical stability. Even

though this drug was synthesized as double racemate, the clinical trial

showed that one of the individual enantiomers was distinctly active.

Therefore, a convergent three-component strategy was used for the

preparation of each isomer of Enprostil. (Scheme 1.8.3).29 The reaction

employed organocopper reagents 95 obtained from the optically active

Chapter-1

31

vinyltin reagent to selectively introduce the ώ-side chain to enantiopure

enone ent-60 followed by the trapping of the so formed enolates as

silyl enol ethers 96a and 96b. The key step was the alkylation under

carefully controlled reaction conditions of the regiochemically defined

lithium enolates, generated from these silyl enol ethers, with the

optically pure ά-side chain triflate 97. The deprotection of silyl group of

98 yielded the most active component of enprostil in 37% overall yield

from ent-60. The other stereoisomers were prepared similarly starting from

the appropriate optically active components. This approach was found to be

general for the propargylic and allenic ά-side chains but was

unsuccessful for the cis-allylic and saturated ά-side chains found in

PGE2 and PGE1 respectively.

O

TBSO

Li2Me(NC)Cu

R

OTBS

TBSO

R

OTBS

TMSO

TfO

O

OMe

O

TBSO

R

OTBS

*

O

OMe

THF, -78°C

TMSCl, Et3N

96a R=C5H11

96b R= CH2OPh

CH3Li

98

97

95

ent-60

Scheme-1.8.3

.

.

Chapter-1

32

1.7.6 Analogues Modified on the ώ-Side Chain.

Various types of modifications have been performed on ώ-Side chain in

order to modulate the biological properties of PGs. A first possibility was to

use the OH group in position 15. From PGE2, various ester linked

bisphosphonate and thioester conjugates have been prepared and

studied as potential agents for treatment of osteoporosis.

The introduction of aromatic groups in the ώ-chain was extremely

successful, especially in the search for antiglaucoma agents. This was based

on the fact that PGF2ά esters have been found to be intraocular pressure

(IOP) reducing agents and phenyl substituted PGs have been found to be

very potent in this area, 30 as exemplified by Latanoprost for instance.

Therefore, many analogues have been prepared in this series and a

representative example is given in (Scheme 1.8.4).31 The synthesis started

from Corey lactone aldehyde 99 and using the appropriate phosphonate

100, yielded the brominated PG analogue 104.

Chapter-1

33

O

O

OBzO

H

P

O

MeO

O

Br

MeO

O

O

O

Br

BzO

O

O

THPO

Br

OTHP

OH

THPO

BrCO

2iPr

OTHP

OH

BrCO

2iPr

OHOH

NaHMDS, DME

3 Steps

1. DIBAL-H, -78°C2. Ph3P(CH2)4COiPrBr

NaDHMDS

Small Library

104

103

102

101

100

99

THF:H2O:AcOH

(1:1:1)

Scheme-1.8.4

1.7.7 Analogues Modified on Both Side Chains.

Modifications have been performed also on both side chains, usually with

the aim of getting more information on the SAR for the corresponding

families of PGs analogues. The 6-keto-PGs have attracted interest and

Ornoprostil, 111 is a representative example. One synthetic route to this

molecule is given in (Scheme 1.8.5).32 The coupling of the enone 105 with

the vinyl borane 106 gave silyl ether of 107. After epoxidation, followed by

rearrangement, the 6-keto intermediate 109 was obtained. A final 1, 4-

addition process with the cuprate 110, followed by deprotection and

saponification gave dornoprostil.

Chapter-1

34

Br

O

TBSO

(c-C6H

11)2B CO

2Me

O

TBSO

CO2Me

OO

TBSO

CO2Me

O

Cu

OSBT

O

OHO

OH

CO2H

O

TBSO

CO2Me

Cat.Pd(PPh3)4-NaOH

m-CPBACH2Cl2

BF3OEt2MeOH, 73%

2. HF-Py, 95%3. PLE, 84%

1.

105

106

107

108109

110

Scheme-1.8.5111

81 %

TMS

TMS

TMS

A series of 9-chloro-3-oxa-15-cyclohexyl PG analogues were prepared

and among them, AL-6598, was found to be a potent full agonist of

the DP receptor. The intermediate 112, easily accessible from Corey

lactone, was transformed in three steps (reduction, protection and

selective oxidation) to the aldehyde 113. A Wittig olefination followed

by desilylation gave allylic alcohol 115 ready for phase transfer

alkylation to 116. Final chlorination and deprotection steps yielded the

target molecule 117 (Scheme 1.8.6).33

Chapter-1

35

O

O

O

THPO OTHP THPO OTHP

TESO CHO

THPO

TESOCO

2Me

OTHP

THPO

OH

OTHP

CH2OH

THPO

OH

OTHP

O

CO2iPr

OH

Cl

OH

O

CO2iPr

3 steps

63%

(CF3CH2O)2P(O)CH2CO2Me

KHMDS, TDA-1THF-toluene, -60°C to -20°C

69%

1.DIBAL-H,THF, -20°C to 5°C, 97%2. TBAF,THF, 0°C, 86%

1.MsCl,pyridine,0°C2.Bu4NCl, toluene, 55°C

3. AcOH, H2O, 65%, 54%

1.BrCH2CO2tBu,

KOH,Bu4NHSO4,

toluene-H2O, 86%

2. Ti(OiPr)4,iPrOH,

heat, 96%

117116

115

114

113112

Scheme-1.8.6

Chapter-1

36

1.8 Synthetic approaches towards opthalmic prostagladins

(Prostaglandin F2 derivatives)

In recent years, attention has been focused on prostaglandins (PGs),

primarily prostaglandin F2α esters as IOP-lowering substances for the

treatment of glaucoma.34 There are currently four prostaglandin analogues

Latanoprost, Bimatoprost, Travoprost and uniprostone 35 (Fig. 8) approved

for Glaucoma treatment by the USFDA. Several studies have established

that PGs of the F2α type reduce IOP by increasing uveoscleral outflow of

aqueous humor.36

The prostaglandin ocular hypotensives are PGF2 derivatives in which the α-

side chain has been converted to either ester or amide functionality. These

esters are more lipophilic than the corresponding acid and penetrate ocular

tissues more readily and in these the ω-side chain is modified with aromatic

units. We discussed below literature methods available for synthesis of

following ophthalmic prostaglandins

Chapter-1

37

OCH(CH3)2

O

OHOH

OH

OCH(CH3)2

O

O

OHOH

OH

CF3

OCH(CH3)2

O

CH3

O

OH

OH

NHCH2CH

3

O

OHOH

OH

Latanoprost (7)

Travoprost (9)

Unoprostoneisopropyl (16) Bimatoprost

(3)

Fig.8 Ophthalmic prostaglandins

1.8.1 Latanoprost (7): Synthesis of 7 undergoes following key

transforma- tions based on literature methods

The primary alcohol Corey lactone (118) is oxidized to a Corey aldehyde

(119). The Corey’s aldehyde (119) is then condensed with dimethyl-(2-

oxo-4phenylbutyl) phosponate to give the enone (120), reduction with

sodium borohydride to give alcohol function (121) is reported. Catalytic

hydrogenation using palladium on carbon to give lactone intermediate

(122), and then transformation of the lactone intermediate function

(122) into lactol (123) by using diisobutylaluminum hydride (DIBAL-H).

Wittig reaction with ylide (Ph3P=CH(CH2)3COO-) in presence of

triphenylphosphine oxide and (4-carboxyybutyl) diphenylphosphine

followed by esterification with isopropyl iodide in the presence of DBU

gave Latanoprost (7) is reported (Scheme-1.9).37

Chapter-1

38

O

O

OH

PGO

O

O

PGOCHO

O

O

PGO

O

O

O

PGO

OH

O

O

PGO

OH

O

O

OH

OH

O

OH

OH

OH

OH

OH

OH

COOH

OH

OH

OH

COOPr-i

P

O

PhO

O

O

Latanoprost

121 122

123 124

125

7

THF, H2O, NaBH4, 85 %

EtOH,Pd/C

H2, 90 %

Dibal-H PH3P=CH(CH2)3COO-

PMHS Cp2TiF2

(CH3)2CHI

118119 120

Scheme-1.9

Dess martin

DCM,NaHCO3

-70°C, 4h, 65 % t-BuOK/THF, 60 %

DBU, 80 %

85 %

NaH, THF, 65 %

40 %

1.8.2 Bimatoprost (3): Synthesis of (3) undergoes following key

tranformations based on literature methods.

P-phenyl-benzoyl (PPB) protected Corey lactone (126) is converted into the

corresponding aldehyde (127) by oxidation using DCC/DMSO. Compound

(127) is not isolated but reacted in solution with an appropriate

phosphonium salt to give intermediate (128). Reduction of the ketone group

to form the corresponding alcohol (129) as a mixture of diastereomers. After

deprotection of PPB group to form diol (130), the lactone is selectively

Chapter-1

39

reduced to the lactol (131). A subsequent Wittig reaction forms acid (132),

esterification using methyl iodide followed by an amide formation using ethyl

amine to give (±) Bimatoprost (3) is reported (Scheme-1.9.1).38

O

O

OHPPBO

O

O

OPPBO

O

PO

O

O

O

O

PPBOO

O

O

PPBOOH

O

O

OHOH

O

OH

OHOH OH

OH

OH

O

OH

OHOH

O

OH

OMe

OHOH

O

OH

NH

126 127

NaH

128

NaBH4/CeCl3

129

K2CO3 / MeOH

130

131 132

133

3

Methyliodide

Bimatoprost

Ethylamine

Scheme-1.9.1

DCC/DMSO

Chapter-1

40

1.8.3 Travoprost (9): Synthesis of 7 undergoes following key tranfomations

based on literature methods.

Reaction of alkenylcuprate 134 with tricyclic ketone 135 formed the single

isomer bicyclic ketone 136. Baeyer–Villiger oxidation of 136 gave the lactone

137 as a crystalline solid. DIBAL-H reduction, Wittig reaction and

esterification followed by silyl group deprotection completes the synthesis of

Travoprost (9) is reported (Scheme-1.9.2).39

HH

O

OTBDMS

O

OTBDMS

CF3

Cu(CN)Li2

S

O

CF3

OTBDMS

O

OTBDMS

OAr

OTBDMS

OO

OTBDMS

OAr

OTBDMS

OOH

OTBDMS

OAr

CO2iPr

OH

OH

OH

OAr

CO2iPr

OTBDMS

RO

RO

CH3CO3H

AcOH,NaOAc

20°C

DIBAL-H

PhMe

-70°C

i) Br-Ph3P+(CH2)4CO2H KOtBu, THF, <2°C

ii) DBU, iPri, 20°C

20a: R=TBDMS, R'=H20b: R=H, R'=TBDMS

HCl (Aq)iPrOH

Ar = m-F3CC6H4

PhMe, -78°C

Travoprost

134 135 136

137 138

1399

Scheme-1.9.2

Chapter-1

41

1.8.4 Special precautions for handling PG’s

PG’s are very sensitive molecules, and would degrade very rapidly when

exposed to higher temperature, and harsh conditions such as high & low pH

medium. Special precautions needs to be taken for undertaking purification

of these materials and often purification of these compounds would involve

preparative HPLC methods. Persons handling prostaglandins should

exercise extreme caution and should wear personal protective coat and

gloves. Pregnant women and people with respiratory problems need to be

extremely careful when handling prostaglandins. These compounds have an

extremely rapid skin absorption rate and are highly irritant. If there is any

accidental spillage on the skin or mucous membrane should be washed off

immediately. Should accidental inhalation or injection occur, medical advice

should be sought immediately.

1.8.5 Conclusion

During the last two decades significant developments have been made

in the chemistry of prostaglandins. New routes of synthesis to the

naturally occurring prostaglandins, as well as various analogues, have been

described. In parallel to these synthetic achievements, progress has also

been made in biology, in particular with the discovery of new receptor,

subtypes and/or isoforms. At the interface of both domains, new

molecules have been prepared which proved to be valuable as

pharmacological tools. On the other hand, SAR studies on prostaglandin

analogues paved the way towards new and more selective drugs in various

Chapter-1

42

areas of medicinal chemistry. Therefore, taking into account the

importance of prostanoids in human biology, it is clearly expected that

strong developments will be continuing in the future both in chemistry

and in biology.

In view of significant potential displayed by PG’s in various therapeutic

actions, the author has developed a general synthesis of ophthalmic

prostaglandins (Anti-glaucoma agents) and their analogues and the details

are described in five chapters of the thesis.

Chapter-2: Deals with synthesis of Key intermediate, (±)(Z)-4-formyl-5-(7-

isopropoxy-7-oxohept-2-enyl) cyclopentane-1,3-diyl dibenzoate from (±)Corey

lactone which can be elaborated into several clinical ophthalmic

prostaglandins viz., Latanoprost, Bimatoprost ,Travoptost and Uniprostone

Chapter-3: Describes the details on the synthesis the of (±) Bimatoprost and

its analogues from key intermediate (148)

Chapter-4: Consists of details of the syntheses of (±) Travoprost and its

analogues from key intermediate (148)

Chaper-5: Comprises the details on synthesis of structural analogs for

Latanoprost from key intermediate (148)