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Chapter III

Synthesis of Analogues of the Quararibea Metabolite Chiral Enolic-γ-Lactones from (2S,3S)- and (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylic acids

III. 1 Introduction

There are a large number of biologically active γ–butyrolactone based natural molecules which have matching structure and stereochemistry with that of Garcinia and Hibiscus acids (1 and 2). The ready availability and matching stereochemistry make these molecules ideal choice for the synthesis of several chiral γ-butyrolactone based molecules namely (+) isocitric acid, Quararibea metabolite lactone, (+) avenaciolide, (+) canadensolide, mescaline isocitrimide lactone, cinatrin C2 and C3, cis and trans whisky

lactones, (-) funebrine etc (Figure III.1).

Figure III.1

Chiral butenolides form an important class of compounds which appear as substructures in many natural products and they have been employed as key intermediates for the synthesis of a wide range of bioactive compounds.165 With representation in over 13,000 natural products, these class of synthon have become a valuable architectural platform for the development of new asymmetric methodologies.166 Synthesis of terpenoidal lactone, pheromones; (+) and (-) eldanolide, antileukaemic lignans, (+) trans-burseran, (-) Isostegane, (+) and (-) steganacin (-) verrucarinolactone, prostacycline analogues, chrysanthemic acid, polyoxin J, (-) ranunculin, lasalocid A are few examples. The use of butenolides as synthetic precursors, especially as Diels-Alder dienophiles or Michael acceptors are also frequently encountered.167-172In the interim considerable efforts have been extended on preparing butenolide chirons from chiral and nonchiral sources.173

III.2 Quararibea Metabolite Chiral Enolic-γ--Lactone

Chiral enolic-γ-lactone (126), chiral enamine (127), Funebrine (129) and γ-hydroxy alloisoleucine lactone (amino lactone) (128) are quararibea metabolites isolated from strongly odorous Mexican flowering plant; Quararibea funibris. The strongly odorous flowers of the tree have also been used since pre-Colombian times as a popular local folk medicine for cough, as antipyretic, to control menstrual disorders, psychopathic fears and as a hallucinogen. The chiral enol and enamines are responsible for the characteristic spicy odour which even persists for long in stored herbarium specimens and also used as additives to chocolate drinks from pre-Colombian times. The Zapotec people of Oaxaca, Mexico conducted funeral rites beneath the branches of the tree Quararibea funibris.174,154,157

Figure III.2

Literature shows virtually no synthetic work is ongoing on funebrine other than the synthetic strategy by Le Quesne et al. from β-angelica lactone which have already been discussed in chapter II.157

Very little is known about chiral enolic lactone (126) and related molecule (127). The absolute configuration of these molecules were established using the isolated samples and have not been further confirmed by the enantiopure total synthesis. Though the ethanopharmacological studies of the molecules are limited, certainly these promising molecules warrants further exploration to develop new leads.174

Few examples of butenolide based natural products are given below.

Annonaceous acetogenins are a class of compounds with potential biological properties like cytotoxic, antitumeral, pesticidal and immunosuppressive activities contain butenolide moiety is known to present in the Annonaceae plant species. Tonkinecin (130) is an Annonaceous acetogenin isolated from the roots of Uvaria tonkinesis with potential biological activities.175

Figure III.3

L-Ascorbic acid (131), widely distributed in plant and animal kingdom and the best sources include citrus fruits, hip berries and fresh tea leaves. The acid is known as an antioxidant, radical scavenger and serves as a reductant in some bio-transformations and known to

protect cellular components against oxidative damage.176

Figure III.4

(+) Dysidiolide (132), a novel sesquiterpenoid isolated from Caribbean sponge Dysidea ethria de Laubenfels, exhibits antitumor activity and most importantly it is the first natural product discovered thus far to inhibit protein phosphatase cdc25A.177

Figure III.5

Chiral butenolides can also be used as chirons for the synthesis of several natural products which do not bear any butenolide moiety. B.M. Trost and co-workers have synthesized Afllatoxin B1 (133), a member of a large family of mycotoxins that infect a variety of

agricultural products and animal products, using chiral butenolide (135) (Scheme III.1).178

Scheme III.1

III.2.1 (-) Kainic acid

(-) Kainic acid (136) isolated from the Japanese marine alga Digenea simplex is the parent member of the kainoids that display potent antihelmintic properties and neurotransmitting activities in the mammalian central nervous system. Thus, kainic acid has been widely used as a tool in neuropharmacology for the stimulation of the nerve cells and the mimicry of disease states such as epilepsy, Alzheimer’s disease and Huntington’s chorea. Y. Mortia and co-workers have reported a stereocontrolled total synthesis of 136 by the [3 + 2] cycloaddition of azomethine ylide with chiral butenolide (138) (Scheme III.2).179

Scheme III.2

Optically active unsaturated 4-alkyl γ-lactones (140) were obtained from propargylic carbinols (139) which are obtained by the asymmetric reduction of α-acetylenic carbinols. The butenolide 140 thus obtained is used for the preparation of (+) Tetrahydrocerulenin (141) (Scheme III.3).180

Scheme III.3

T. K. Chakraborthy and S. Chandrasekharan have effectively converted (Z)-2-Butene-1,4-diols (142) to corresponding simple α,β-butenolides (143) using silver carbonate/celite.

Also this methodology had been effectively applied for the synthesis of Eldanolide (144), the wing gland pheromone of the African sugarcane borer, Eldana saccharina (Scheme III.4).181

Scheme III.4

Often chiral butenolides have been obtained either from cabohydrates, γ-keto acids, glutamic acid or from acyclic systems like acetylenic compounds, pyruvic acid derivatives, cyanohydrins of conjugated aldehydes etc; mostly involving multi step synthetic strategies.

Alternatively chiral 5-alkoxy 2(5H)-furanones have obtained by Feringa and co-workers in moderate overall chemical and optical purity by the resolution method. Singlet oxygen photo oxidation of furfural (145) resulted in the formation of 5-hydroxyfuranone (146). 1-menthyloxyfuranones 147 and 148 were obtained via acetalization of 146 using menthol as chiral auxiliary (Scheme III.5).170,1 82,183

Scheme III.5

III.2.2 Syntheses of Chiral Butenolides

Ensuing discussion deals with the known synthesis of chiral butenolides.

Pd(0)/Ag+- co-catalyzed coupling cyclisation reaction of organic halides with allenoicacid resulted in poly substituted optically active butenolides (150) (Scheme III.6).184

Scheme III.6

J.M Concellon and co-workers have synthesized amino γ–butenolides (152) from 3-(1’-amino alkyl)-3,4-epoxy esters (151) (Scheme III.7).185

Scheme III.7

Stobbe condensation of diethyl succinate (153) with ethyl methyl ketone in presence of sodium alkoxide gives itaconic acid derivative (154). Further addition of bromine followed by dehydrobromination gives carboxy butenolide (155) (Scheme III.8). 186

Scheme III.8

α,β-butenolides were synthesized by the oxidation of O-trimethylsilyl cyanohydrin of α,β-unsaturated aldehyde using pyridinium dichromate (PDC) in dimethylformamide (DMF) by E. J. Corey and G. Schimdt. Geraniol (157) undergoes oxidative lactonisation to give 159 and 160 (Scheme III.9).187

Scheme III.9

Some instances of butenolides being used as Diels-Alder dienophiles or Michael acceptors are also available.

Thermal Diel’s–Alder reaction of γ-Menthyloxy butenolide (147) with 2,3-dimethyl butadiene (160) provided enantiomerically pure lactone annulated cyclohexene (161). Enantiomerically pure decalins are particularly attractive targets for asymmetric cycloadditions as numerous natural products and biologically active compounds contains 6,6-ring system. Among these are various classes of steroids, sesquiterpenes of drimane class and diterpenoids of labdane class (Scheme III.10).170,188

Scheme III.10

Intramolecular Diels-Alder reactions (IMDA reactions) are powerful tool in natural product synthesis to construct highly substituted polycyclic carbon skeltons. U. Reiser et al. have described the first IMDA reaction of substituted Feringa-butenolide (162) which contains a methacrylate type dienophile substructure. The butenolide activity is doubly enhanced by the oxidation of the hydroxyl to corresponding ketone (163) (Scheme III.11).167

Scheme III.11

Chiral butenolides have been used as dienophiles in Diels-Alder cycloadditions with

Figure III.16

A comparison of the VCD is made in the carbonyl region to assign the AC without any ambiguity.(Fig.III.17)

Figure III.17

On comparison of the experimental VCD with the calculated ones for the corresponding configurations, only in the case of (2S,3R) as shown in Figure III.17, the spectrum matches the position and phase correctly thereby confirming the AC of 2 as (2S,3R).

cyclopentadiene to generate polyfunctional norbornene derivatives which can be employed to prepare santalene, thromboxine antagonists etc among other interesting compounds (Scheme III.12).189

Scheme III.12

The 4-alkylamine substituted lactones are versatile precursors for the preparation of optically active β-amino acids and β-lactams. B.L. Feringa and co-workers have reported the synthesis of β-lactam using 5-menthyloxy butenolide.1,4-addition of alkyl amine with 5-menthyloxy butenolide (148) gave 4-amine substituted lactone (169). Ring opening with in situ acetylation without epimerization and further ring closure using Mukayama’s procedure resulted in β-lactam 170 (Scheme III.13).170

Scheme III.13

This chapter concerns with the conversion dialkyl esters of 1 and 2 to 2S-Dialkyl 4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, analogues of the Quararibea metabolite chiral enolic-γ-lactone (126a) and synthesis of aromatic dialkyl 5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates (209 and 210).

III.3 Result and Discussion

It is clear from the above discussion that the chiral butenolides are important class of chiral synthons and thus enatioselective entry to them is methodologically important. Consequently, many methods dealing with the synthesis of this class of synthons have been published, most of them involve multi-step procedures with very low yield and enantiomeric purity. Structural features of (2S,3S)- and (2S,3R)-Tetrahydro–3-hydroxy-5-oxo-2,3-furandicarboxylic acids (1 and 2) are ideally suited for the synthesis of chiral

butenolides through simple dehydration. Pd/C reduction of the butenolide (171) thus obtained by the dehydration of 1 and 2 is expected to give a very potential natural product namely Isocitric acid (40), a member of Kreb’s tricarboxylic acid cycle. The detailed descriptions of the significance of Isocitric acid have been already discussed in chapter II (Scheme III.14).

Scheme III.14

III.3.1 Isolation of (2S,3S)- and (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids (1 and 2)

The plant materials for the isolation of 1 and 2, have been collected from different regions in South India. Fresh samples of dried rinds of the fruits of Garcinia cambogia and calyxes or leaves of Hibiscus sabdariffa or leaves of Hibiscus furcatus were used for the isolation of 1 and 2 following the procedure developed by Ibnusaud and co-workers. 19-21

III.3.1.1 Isolation of (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1)

1. The dried fresh rinds of the fruits of Garcinia cambogia were cut into small pieces and soaked in hot water. The water extract was collected after 10-20 hours. The extraction was repeated. The combined extract was evaporated to syrup (A).

2. To the syrup (A), sufficient quantity of methanol was added to remove pectin completely. The filtrate was concentrated to syrup (B).

3. After making syrup (B) alkaline by adding sufficient quantity of alkali at elevated temperatures, methanol was added to the solution. Separated thick syrup (lower layer) was washed several times with various proportions of aqueous methanol to get

a paste of alkali salt (C).

4. The alkali salt (C) on neutralization with mineral acid followed by evaporation gave the concentrate (D).

5. The concentrate (D) was triturated with sufficient quantity of acetone to precipitate the insoluble. The filtrate on concentration yielded crude 1.

6. The crude acid (1) was purified by recrystallisation and chemical and optical purity was assured by comparing the I.R, NMR, mass spectra and [α]D values with

that of the reported values (Figure III.6 a-d) .

Figure III.6a

Figure III.6b

Figure III.6c

Figure III.6d

III.3.1.2 Isolation of (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acid (2)

The fresh calyxes or leaves of Hibiscus sabdariffa or leaves of Hibiscus furcatus were extracted with water and was concentrated to syrup. To this methanol was added to precipitate inorganic materials. The organic layer was concentrated and aqueous alkali was added to yield the salt of 2. It was then washed several times with alcohol and mineral acid to regenerate the acid. After concentration the residue was triturated with acetone or methanol to get crude 2.The final purification of crude 2 was done by repeated extraction or crystallization from ether. The chemical as well as optical purity of 2 was confirmed by comparing the I.R, NMR and mass spectra with that of the reported values (Figure.III.7 a-d).

Figure III.7a

Figure III.7b

Figure III.7c

Figure III.7d

III.3.1.3 Determination of Absolute Configuration by Vibrational Circular Dichroism (VCD)

Two important challenges of chirality are the determination of absolute configuration and enantiomeric purity. To understand and fine-tune the mechanism of interaction of medicinal molecules with the corresponding therapeutic targets in the fat metabolism pathway, a determination of absolute configuration of the molecule and its predominant conformation in solution is necessary. Often the asymmetric centers are prone to racemization due to the presence of active hydrogen atoms. Also depending on the nature of the medium or conformation, the molecule attains different absolute configuration and thus functions differently. Hence establishing the absolute configuration of these molecules in solution is a matter of great interest. Vibrational Circular Dichroism (VCD) has emerged as an important tool for the determination of absolute configuration and enantiomeric purity of optically active molecules or entities in the solution state.190-193 A reinvestigation of the absolute configuration of these acids by VCD technique confirms 1 and 2 to be 2S,3S and 2S,3R respectively.

III.3.1.4 Analysis of absolute configuration of (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1) by Vibrational Circular Dichroism (VCD)

The absolute configuration of 1 and 2 is determined from Hudson lactone rule, Optical

rotatory dispersion curve and calculation of partial molar rotations. To the best of our knowledge no systematic conformational analyses of these molecules in the open form have been carried out. Hence 1 and 2 have been subjected to a systematic VCD analysis.

A three dimensional view of the molecule (1), along with the bond torsions (rotational bonds) and ring torsions (puckering) is shown in Figure III.8 and III.9. These torsions, in turn give rise to a large number of conformers in solution. The ring puckering shown in Figure III.9 gives rise to twist angle of 14.55 deg.

Figure III.8

Figure III.9

Only the first 8 conformers in the above list are used for the analysis as the others are lower in energy than 1k Cal/mole

The alignment of the conformers is shown in the experimental VCD spectrum of 1 in DMSO matrix is shown in Figure III.10. Most of the torsional motions occur in the side chains bearing the carboxylic acid groups.

Figure III.10 Aligned view of the conformers of 1 (2S,3S configuration). The atoms are color coded: Carbon skeleton (grey); Oxygen (red); hydrogen (white). The conformers are generated with MMFF using the default parameters as outlined in the SPARTAN manual.

The experimental VCD spectrum of 1 in DMSO matrix is shown in Figure III.11

Figure III.11 In DMSO, the carbonyl peaks are not well resolved, and only one positive phased signal could be discerned clearly. Hence spectra were measured in acetonitrile (100 % deuterated). As seen, in Figure III.12 all the three carbonyl peaks could be resolved in this solvent and their spectral phases match well with the calculated spectra. Thus the assignment is made as SS.

Figure III.12

In addition, it appears that the C-O stretching (band labeled 4) is blue shifted to 1320 cm-1 and agrees well with the experimental band.

As a control, the spectra for the SR configuration is also generated. However, the band patterns (position, phase and relative intensity distribution) seen in the SR do not match with the experiment (Figure III. 13).

Figure III.13

Thus SR configuration is ruled out for 1 and concluded as SS

III.3.1.5 Analysis of absolute configuration of (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acid (2) by Vibrational Circular Dichroism (VCD)

The yellow cylinders in Figure III.14 illustrate the torsional degrees of freedom for this molecule. Different conformers arise by rotations about these bonds (see below).

Figure III.14

Recollecting that torsions occur in the acid and hydroxy side chains the 60 conformers were aligned in Fig. III.14. One can see that maximum movements or “torsional noise” occurs in the side chains.

Figure III.15

The lactone ring itself is distorted (and not planar) and for the lowest energy conformer the twist angle (defined as the angle between any two planes in the ring) is 7 deg. The highest energy conformer has a distortion of about 16 deg. (shown below in two views, hydrogens are omitted for clarity). This is the well known ring strain energy that all the cyclic structure exhibit (Figure III.16)

III.3.2 Preparation of Dialkyl (2S,3S)- and (2S,3R)-tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylates from 1 and 2

During any functional group transformation of γ-butyrolactone containing target molecule, careful attention should be given to keep the lactone ring intact. The preparation of dimethyl esters of 1 and 2 following the usual procedures for the esterification of carboxylic group resulted in the formation of a mixture of cyclic dimethyl ester (9,13) and acyclic trimethyl ester(17,20) formed by the opening up of the lactone moiety (Scheme III.15).

Scheme III.15

Hence to overcome this difficulty, the diesters were prepared by first converting the lactone to its disodium salt (5 and 6) using aqueous sodium bicarbonate solution (Figure III.18a-b, Figure III. 22a-b). On treating 5 and 6 with thionyl chloride yielded the diacid chloride, which upon treatment with the alcohol gave the corresponding diester exclusively. 5 and 6 can be stored as white crystalline solid. It was suspended in dry methanol and two equivalents of thionyl chloride were added drop wise under ice-cold conditions with stirring. Stirring was continued for two hours and the reaction mixture was neutralized using aqueous sodium bicarbonate solution and the dimethyl esters (9 and 13) were isolated. The experiment was repeated using dry ethyl alcohol to yield the diethyl esters (10 and 172) and using dry isopropyl alcohol yielded the diisopropyl esters (11 and 173) as yellow oil. All the products were characterized using IR, 1H and 13C NMR and mass spectra10 (Scheme III.16) (Figure III.19a-d, FigureIII.20a-d, Figure III.21a-d, Figure III.23a-d, Figure III.24a-d. Figure III.25a-d).

Scheme III.16

The dimethyl esters (9 and 13) can also be prepared exclusively by the treatment of 1 or 2 with diazomethane in ether; hence it requires milder reaction conditions. However this method is limited only to the preparation of methyl esters (Scheme III.17).

Scheme III.17

Figure III.18a

Figure III.18b

Figure III.19a

Figure III.19b

Figure III.19c

Figure II.19d

Figure III.20a

Figure III.20b

Figure III.20c

Figure III.20d

Figure III.21a

Figure III.21b

Figure III.21c

Figure III.21d

Figure III.22a

Figure III.22b

Figure III. 23a

Figure II.23b

Figure II.23c

Figure II.23d

Figure III.24a

Figure III.24b

Figure III.24c

Figure III.24d

Figure III.25a

Figure III.25b

Figure III.25c

Figure III.25d

III.3.2.1 Preparation of Dibenzyl (2S,3S)- and (2S,3R)-tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylates from 1 and 2

Dibenzyl esters are not obtained by following the above mentioned procedure since high temperature is required for the formation of benzyl derivatives. However following a

reported procedure refluxing a suspension of 2 in dry benzyl alcohol, p-toluene sulphonicacid monohydrate and toluene for 13 hours at 130 0C and subsequent work-up and recrystallisation and with chloroform–hexane furnished white crystals of dibenzyl esters(12 and 14) (SchemeIII.18) (Figure III.26a-d).

Scheme III.18

Figure III.26a

Figure III.26b

Figure III.26c

Figure III.26d

III.3.3 Preparation of Dialkyl 2S-2(5H) furanone- 4,5-dicarboxylates using Dialkyl (2S,3S)- and (2S,3R)- tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates.

With the objective of preparing chiral butenolide (171) from 1 and 2, the halogenation of the tertiary hydroxyl group followed by dehydrohalogenation was planned. The following reagents were tried under different condition with out success (Scheme III.19).

1. Tetra butyl ammonium bromide/BF3 :Etherate

2. SOCl2/pyridine

Scheme III.19

3. Dehydration of 9 and 13 using BF3.Etherate was also failed to give the desired

butenolide 171a (Scheme III.20).

Scheme III.20

III.3.4 Dehydroacetylation of Dialkyl (2S,3S)- and (2S,3R)- Tetrahydro-3- actyloxy-5-oxo-2,3- furandicarboxylate.

The tertiary hydroxyl group of dialkylesters of 1 and 2 was protected as acetyl group by the treatment of the compounds with acetyl chloride at room temperature. Even though esters are undergoing complete conversion but could not isolate the acetylated product since they are found to be unstable which results in the sudden decomposition to the dialkyl esters. Acetylated dimethyl and diethyl esters were found to be highly unstable, where as acetylated diisopropyl esters were obtained as stable (SchemeII.21) (Figure III. 27a-d, Figure 28a-d).

.

Scheme III.21

The dehydroacetylation of 177 using DBU was expected to give chiral butenolide 171c. However this reaction failed (Scheme III.22).

Scheme III.22

Figure III.27a

Figure III.27b

Figure III.27c

Figure III.27d

Figure III.28a

Figure III.28b

Figure III.28c

Figure III.28d

105

III.3.5 Phosphorous oxychloride (POCl3) in Functional Group Transformations Phosphorous oxychloride is known to be a strong Lewis acid which is widely

used in various functional group transformations in the broad area of organic

synthesis including Vilsmeier-Haack and Bischler-Napieralski reactions.194

III.3.5.1 Vilsmeier-Haack and Bischler-Napieralski Reactions

The reaction of POCl3 with substituted amides, most often N,N-dimethyl

formamide (DMF) or dimethylacetamide (DMA) lead to the formation of

chloromethyleneammonium salts (182). These salts are highly versatile

intermediates and are involved in reactions like Vilsmeier-Haack and

Bischler-Napieralski reactions (Scheme III.23).194

N

OPOCl3

R1

R2

R3

N

Cl

+R3

R2

R1PO2Cl2

-

181 182

Scheme III.23

The Vilsmeier reagent attacks electron-rich aromatic systems to form aryl

methleneiminium ions which liberate a formylated aromatic compound upon

hydrolysis. Substitution occurs at electron-rich positions. Many heterocycles

are also readily formylated by POCl3/DMF (Scheme III.24).

106

POCl3, DMFOMe OMe

CHO

86%

183 184

POCl3, DMF

75%N

N

CHO

H H185 186

Scheme III.24

A widely used method for cyclization of N-β-phenylethyl amides to form

dihydroisoquinolines and isoquinolines is the Bischler-Napieralski reaction. A

nitrilium ion intermediate has been implicated in this reaction (Scheme III.25).

POCl3

85%NH

O

MeO

MeO

OMe

NO2

MeCN

MeO

MeO N

MeO

NO2

187 188

Scheme III.25

Treatment of tertiary amides with POCl3/DMF results in the formation of

β-dimethylamino α,β-unsaturated amides (Scheme III.26).

107

189190

191

POCl3

N O

Cl

Et

DMF N

Cl

Et

NMe2

Cl

+

N

Et

O

Cl

55%

Scheme III.26

III.3.5.2 Beckmann rearrangement Treatment of ketoximes with POCl3 induces Beckmann rearrangement to

form amides (Scheme III.27).194

192193

POCl3

OH

OH

NOH OH

O

N

DMF

Scheme III.27

Phosphorous oxychloride and zinc (II) chloride are used as catalyst in

Freidel-Crafts reactions (Scheme III. 28).

108

194 195 196

POCl3, ZnCl2OH

COOH

+

OHOH

OH

O

O

OH

OH

60-700C, 2h

47%

Scheme III.28

III.3.5.3 Dehydrating Agent POCl3 is one of the most effective dehydrating agents used in organic

synthesis. The combination of POCl3 and DMF can be used to halogenate

primary, secondary and tertiary aliphatic alcohols (Scheme III. 29).194

POCl3, DMF

90%OH Cl

CHCl3

OOH

CHO OCl

CHO

POCl3, DMF

90%

197 198

199 200

Scheme III.29

Unsubstituted amides undergo dehydration upon treatment with POCl3

(Scheme III.30).

t-Bu

O NH2

t-Bu

CN

+ t-Bu CNPOCl3

201 202 203

Scheme III.30

109

The combination of POCl3 and pyridine is an effective dehydrating agent for

alcohols and cyanohydrins with antielimination (Scheme III.31).194

204205

POCl3, py

OOH

H H

H O

H H

H75%

Scheme III.31

Though optically pure isocitric acid (40) plays a significant role in various

important biological processes like cell respiration, no methods are available

in literature for the enantiopure synthesis of 40 till date. As already

discussed, it is the objective of the present study to dehydrate dialkyl esters

of 1 and 2 using POCl3 in pyridine to get chiral butenolide 171, which upon

simple Pd/C reduction is expected to give optically active Isocitric acids (40a

and 40b).

III.3.6 Dehydration of Dialkyl (2S,3S)- and (2S,3R)- tetrahydro-3- hydroxy-5-oxo-2,3-furandicarboxylate with POCl3.

9 and 13 was dissolved in pyridine and POCl3 was added drop wise at –10 0C and the reaction mixture was stirred at that temperature for two hours.

The reaction was quenched using dil. HCl and the TLC shows the presence

of a highly polar species. The reaction mixture was treated with

diazomethane under the assumption that the ester groups may hydrolyze

under work-up conditions.195 The product formed (206) was isolated using

column chromatography and fully characterized by IR, 1H and 13C NMR and

mass spectra. Unexpectedly the product obtained was the 4-Methoxy

dimethyl 2S-2(5H) furanone-4,5-dicarboxylate (206) which is the analogue of

110

the Quararibea metabolite, methyl ether of chiral enolic-γ-lactone 126b

(Scheme III.32). Formation of these unusual compounds was convincingly

confirmed by further spectral analysis.

OO HCOOR

MeO COOR

1.POCl3pyridine

CH2N2

ether2.

9. R' =-OH, R''=-COOR,R=-CH3

OO H

R'COOR

R''

13. R' =-COOR, R''=-OH,R=-CH3

10. R' =-OH, R''=-COOR,R=-CH2CH3

12. R' =-OH, R''=-COOR,R=-CH2C6H5

172. R' =-COOR, R''=-OH,R=-CH2CH3

174. R' =-COOR, R''=-OH,R=-CH2CH5

R = -CH3

R = -C2H5

R = -CH2C6H5

206.

207.

208.

Scheme III.32

IR spectrum of 2S-Dimethyl-4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarbo-

xylate shows the absence of hydroxyl group and peak at 1750 cm-1 confirms

the presence of lactone moiety; 1H NMR shows the presence of three -OCH3

groups at δ 3.95, 3.89, 3.88 ppm. In 13C NMR signals at δ162.70, 163.30 and

158.37 ppm confirms the three carbonyl groups and signals at δ134 and 127

ppm shows the presence of olefinic carbons. In 13C NMR the signals at δ

84.80 indicates the presence of C2 carbon, signal at δ 58.80 shows the

presence of -OCH3 carbon and signals at δ 52.64 and 53.00 represent

methoxy carbons of the two ester groups(Fig III. 32a-d). In addition to these

DEPT clearly shows the absence of -CH2 and presence of three -CH3 and

one –CH( Figure III.29).

111

Figure III.29

The structure of the unusual product (206) obtained was further confirmed by

recording HMBC (Heteronuclear Multiple Bond Connectivity) spectrum which

further confirms the position of the olefinic bond at the C3-C4 position. The 1H-13C long range correlations observed are shown in figure (FigureIII.30a-c.)

112

Figure III.30a-c

113

The correlation diagram for 5a on the basis of HMBC spectrum can be drawn

as follows (Figure. III.31)

OO H

C OO C

H

H

H

C O

OC

H

H

H

OC

H

H H

3.88

3.953.89

162.3

158.37

163.3

5358.8

52.64

134 127

84.8

Figure III.31

To clearly understand the reaction pathway attempts were made to isolate

the intermediate of the reaction, however not successful as it is a highly polar

species. The reaction of 10 and 172 and 12 and 174 with POCl3 in pyridine at

00C resulted in corresponding 4-Methoxy dialkyl-2S-2(5H)-furanone-4,5-

dicarboxylates (207 and 208). IR, 1H and 13C NMR and mass spectra clearly

confirms the structures of 207 and 208 (Figure III.33a-d, Figure III.34a-d).

114

206

OO H

MeO

CO2CH3

CO2CH3

Figure III.32a

Figure III.32b

115

Figure III.32c

Figure III.32d

116

207CO2C2H5

OO H

MeO

CO2C2H5

Figure III.33a

Figure III.33b

117

Figure III.33c

Figure III.33d

118

208

CO2CH2C6H5

OO H

MeO

CO2CH2C6H5

Figure III.34a

Figure III.34b

119

Figure III.34c

Figure III.34d

120

III.3.7 Dehydration of Diisopropyl (2S, 3R)- tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylate with POCl3.

It is interesting to note that when the diisopropyl (2S,3S)- and (2S,3R)-

tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates were treated with

POCl3 under the same conditions mentioned for the preparation of 206-208 no significant reaction was observed. But when the reaction was

carried out at room temperature following the usual work-up with dil.

Hydrochloric acid resulted in the isolation of normal dehydration product

(171c) (Scheme III.33).

OO H

R'COOCH(CH3)2

R''

OO HCOOCH(CH3)2

H COOCH(CH3)2

POCl3pyridine

171c11.R'= -OH, R''= -COOCH(CH3)2

173.R'= -COOCH(CH3)2 , R''= -OH

Scheme III.33

IR, 1H and 13C and mass spectra of 209 confirms the structure of the

product. A signal at δ 6.90 indicates the presence of –C=C-H, multiplet at

δ 4.9 0- 5.00 and at 5.10-5.20 are due to the presence of –CH protons of

the isopropyl ester group and multiplet at δ1.20-1.40 stands for methyl

protons of isopropyl ester groups. Signal at δ 4.0 is due to hydrogen on

C2 carbon atom. In the 13C spectrum signals at δ169.3, 165.5 and 164.9

121

are due to the three carbonyl carbons. Signals at δ140.0and 129.1

indicate the presence of two unsaturated carbons (Figure III.35a-d).

It has been seen that the behavior of POCl3 with dialkyl esters were unusual

and interesting. Depending upon the substitution at the alkyl group of the

carboxylic esters different products were formed.

122

OO HCO2CH(CH3)2

H CO2CH(CH3)2171c

Figure III.35a

Figure III.35b

123

Figure III.35c

Figure III.3d

124

III.3.8 Preparation of aromatic Dialkyl-5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates

To have a clear understanding of the observation described for the formation of

206-208, the dehydration of 9 and 13 was effected using another known

dehydrating agent methanesufonyl chloride in triethylamine.196 9 and 13 was

dissolved in dry dichloromethane and 2 mL triethylamine and methanesulfonyl

chloride was added drop wise at 0 0C and the reaction mixture was stirred at

that temperature for two hours. The reaction was quenched using dil.HCl and

extracted in dichloromethane after brine wash. Interestingly, instead of

anticipated dehydration product (171), aromatic dimethyl-5-[(methylsulfonyl)

oxy]-2,3-furandicarboxylate (210) was obtained in quantitative yield. The

reaction was repeated with 11 and 173 resulted in the formation of diisopropyl-

5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate (211) (Scheme III.34).

O COOR

COOR

OCH3SO2

MeSCl,TEA

209. R=-CH3

210. R=-CH(CH3)2

0oC,2hrs

9. R' =-OH, R''=-COOR,R=-CH3

OO H

R'COOR

R''

13. R' =-COOR, R''=-OH,R=-CH311. R' =-OH, R''=-COOR,R=-CH(CH3)2

173. R' =-COOR, R''=-OH,R=-CH(CH3)2

Scheme III.34

The formation of 209 and 210 was confirmed by IR, 1H and 13C NMR, and

mass spectra, for example: 209, the aromatic proton appears at δ 6.4ppm,

ester -CH3 at 5.20 and 5.30 ppm and the -CH3 of methylsulfonyl- at

3.37ppm. Signals at δ 161.0 and157.0ppm in the 13C NMR clearly shows the

presence of only two carbonyls (Figure III.36a-d, Figure III.37a-d).

125

OCH3SO2O COOCH3

COOCH3209

Figure III.36a

Figure III.36b

126

Figure III.36c

Figure III.36d

127

OCH3SO2O COOCH(CH3)2

COOCH(CH3)2210

Figure III.37a

Figure III.37b

128

Figure III.37c

Figure III.37d

129

In view of the formation of 209 and 210 under the condition for normal

dehydration using methanesulfonyl chloride in triethylamine, plausible

mechanism for the formation of 206-208 using POCl3 in pyridine can be

explained.

III.3.9 Plausible mechanism for the formation of Dimethyl 2S-3-methoxy- 2(5H) furanone-4,5-dicarboxylate (206):

Dehydration of 9 and 13 with Methane sulfonyl chloride in triethyl amine

resulted in the formation of aromatic 210 and 211. The structure of 210 and

211 indicates that enolisation of lactone carbonyl is taking place to 9 and 13 in presence of a base. In this view, initially enolisation of lactone carbonyl is

taking place in presence of pyridine (a base) leading to the formation an O-

substituted intermediate 206a. This undergoes a (2,3)-sigmatropic

rearrangement 197(via 5 membered transition state involving six electron

system) gives an α-substituted intermediate 206b. The nucleophilic attack of

C3-hydroxyl group at the phosphorous atom leads to the elimination of

chloride ion which resulted in the formation of a cyclic intermediate 206c.

During work-up using dil. HCl, water molecule attacks the cyclic intermediate

206c leading to the formation of 206d. Finally α-hydroxylated lactone 206e is

formed by the elimination of H3PO3 from 206d. Treatment of diazomethane in

ether with 206e resulted in the final product 206 (Scheme III.35). The (2,3)-

sigmatropic rearrangement is the key step involved in the α-hydroxylation of

9 and 13. This may be the first case where POCl3 is used for the α-

hydroxylation of γ-lactones(dialkyl tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylates).

130

PyridineOO H

OHCOOCH3

COOCH3

OO H

O O HPCl

COOCH3COOCH3

Cl

OO H

O OP

Cl

COOCH3COOCH3H O

H

OO H

OHO

P

H

OHOH

COOCH3

COOCH3

OO H

OH

COOCH3

COOCH3

CH2N2,OO H

MeO

COOCH3

COOCH3

OP

Cl

Cl O H

OH

O COOCH3

COOCH3

-HCl

-H3PO3

H3O+

POCl3

9

206

206a

206b

206c

206d

206e

ether

Scheme III.35: Plausible mechanism for the formation of Dimethyl-2S- 3- methoxy-2(5H)-furanone-4,5-dicarboxylate.

III.3.10 Plausible mechanism for the formation of Dimethy-5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate(209)

On treatment of 9 and 13 with methanesulfonyl chloride in triethyl amine,

enolisation of lactone carbonyl is taking place and hence an O-substituted

intermediate 209a is formed. Since sulfur is reluctant to accommodate 2

electrons no intramolecular sigmatropic rearrangement is involved in the

formation of 209 as in the mechanism of formation of 206. Mesitylation of C3

hydroxyl group followed by elimination of one molecule of MSOH resulted in

the final aromatic product 209 (Scheme III.36).

131

OO H

OHCOOCH3

COOCH3

OH

O

OH

COOCH3

COOCH3

CH3SO2Cl,TEA

OH

OS

CH3O

O

O

COOCH3

COOCH3

SCH3

OO

OCH3SO2O COOCH3

COOCH3

SCH3

O

O

0OC

9 209a

209b

209

-CH3SO3H

Scheme III.36: Plausible mechanism for the formation of Dimethyl-5-[(methylsulfonyl)oxy] -2,3-furandicarboxylate

Though the enolisation of the lactone carbonyl of 9 or 13 is taking place with

both POCl3 and methanesulfonyl chloride; these acid chlorides reacted

differently with 9 and 13. The cyclic intermediate of the type 206c is not

formed in the case of 9 and 13 on reaction with methanesulfonyl chloride. A

(2,3)-sigmatropic rearrangement involved is the key step for the α-

hydroxylation of γ-butyrolactones (dialkyl tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylates). No α-hydroxylation is observed when POCl3 react with

diisopropyl (2S,3S)- and (2S,3R)- tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylates. The bulkiness of the isopropyl group may be the

132

contributing factor for this observation. Reaction of Dialkyl (2S,3S)- and

(2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates with methane-

sulfonyl chloride in triethyl amine resulted in the formation of aromatic

compounds irrespective of the bulkiness of the alkyl substituent of C2 and C3

carboxylic group.

III.3.11 Applications of 2S- Dimethyl 4-methoxy- 5- oxo - 2, 5- dihydro- 2,3- furan-dicarboxylate (206)

206 is a potential precursor for the synthesis of 126b, 98 and 212 (Scheme

III.37).

OO H

MeO

COOCH3

COOCH3

OO H( )n

OO H

MeO

CH3

CH3

OO H

MeO

COOCH3HCOOCH3

126b

98

211

206

Scheme III.37

III.3.12 Attempted reactions of 2S-Dialkyl-4-methoxy-5-oxo-2,5-dihydro-2,3- furan dicarboxylate

As discussed earlier butenolides are susceptible to Michael type reactions.

Michael addition of benzyl amine with 207 was carried out expecting the

formation of 3-alkylamine substituted lactone 212. 207 was dissolved in

toluene and benzyl amine was added and refluxed the reaction mixture for 4

133

hours with Dean and Stark apparatus, resulted in the formation of substituted

benzyl amide 213 instead of the expected 212 (Scheme III.38).

OO H

COOCH2CH3MeO

COOCH2CH3

OO H

COOCH2CH3MeO

COOCH2CH3

PhCH2NH

OO H

COOCH2CH3MeO

COCONHCH2Ph

212

213

207

Scheme III.38

Butenolides can be used as good dienophiles in Diels-Alder reactions with

cyclopentadiene to generate polyfunctional norbornene derivatives. In this

view Diels-Alder reaction of 206 was carried out with cyclopentadiene

expecting the formation of 215. 206 was dissolved in dry CH2Cl2 and freshly

distilled cyclopentadiene is added drop wise and stirred for 2 hours at room

temperature. TLC showed complete conversion of starting material but the

product formed was not stable and it decomposed back to the starting

material (Scheme III.39).

134

OO H

MeO

COOCH3

COOCH3

+ O

O

HH3COOCH3COOC

MeO

215

206

214

Scheme III.39

III.3.13 Chemoselective Reduction of C2 and C3 Carboxylic Group of 1

Appropriate borane reagents were effectively used for the selective reduction

of carboxylates especially in the case of molecules containing other

functionally identical groups. The preferences for borane reagents like BH3

THF, BH3.SMe2 towards reducing -COOH groups in presence of lactone

carbonyl are well known.

Attempts were made to synthesize 216 from 1. With this objective, reduction

of C2 and C3-COOH of 1 has been attempted using BH3 THF, BH3SMe2, BH3.

THF/Trimethyl Borate and NaBH4/ I2 (Scheme III.40).

OO HCOOH

OHCOOH

OO H OH

OHOH1

216 Scheme III.40

135

217 could be a potential chiral precursor for the syntheses of various natural

products and catalysts (Scheme III.41).

OO H OH

OHOH

216

OO H

OO H OH

O

OO H OH

OH

OO H

O

O

Ti

Cl

Cl

OH

CH3

H

()3

98

217

218

219

220

Scheme III.41

However repeated attempts for the reduction of 1 with the borane reagents

listed above failed to give any desired products. This can be attributed on the

basis of an earlier observation that insoluble polymeric intermediates are

formed during the reaction, which may hinder the completion of the reduction

reactions. The laxity of the reaction could also be due to the formation of

stable acyloxy borane complex (221) (Scheme III.42).

1

OO HCOOH

O

O BO H

OO HCOOH

OHCOOH

BH3

221

Scheme III.42

136

Trimethyl borane is known to facilitate the dissolution of polymers formed

during the reaction using BH3. The alternative procedure developed by

Periasamy et al. by using NaBH4 /I2 was also tried without success.

III.3.14 Efficient Site Selective Reduction Employing BH3SMe2 and Catalytic NaBH4

Saito, S. et al., succeeded in reducing selectively the ester group located

α-to the hydroxyl group in hydroxy esters in presence of another ester group,

using borane-dimethyl sulphide complex and catalytic amount of sodium

borohydride198,199(Scheme III.43).

CO2EtOH

OHEtO2C

OH OH+BH3SMe2 /THF

NaBH4(5 mol %)CO2Et

EtO2C

OH

222 223 224

Scheme III.43

The advantage of this chemoselective reduction had been effectively tried to

reduce C3 COOR group in the case of 9 (Scheme III.44).

OO H

OHCOOCH3

COOCH3

OO H

OHOH

COOCH3BH3SMe2 /THFNaBH4(5 mol %)

9 225

Scheme III.44

With this background attempts were made to reduce triisopropyl ester 19

using borane-dimethyl sulphide complex and catalytic amount of sodium

borohydride expecting the formation of 226 where the selective reduction of

ester groups occurs at C1 and C2 positions of 19. Upon treatment with

PTSA, 226 can undergo cyclization. There are two possible ways of

137

cyclization due to the presence of two –OH group in the γ-position to the

ester group leading to the formation of 216 and 227. The molecule 227 is

also a potential chiral synthon, which can also be effectively used for the

synthesis of several naturally occurring molecules (Scheme III.45).

HOH

OH

COOCH(CH3)2

COOCH(CH3)2

COOCH(CH3)2

19

HOH

OH

CH2OH

CH2OH

COOCH(CH3)2

BH3SMe2. Dry THF

NaBH4

OO

OH

OH

H

OH

OO

OH

OH OHH

PTSA

+

226

216227

Scheme III.45

The selective reduction of 19 was carried out using borane-dimethyl sulphide

complex and catalytic amount of sodium borohydride, expecting the

formation of 226. This has been done by dissolving 19 in dry THF and one

equivalent of borane dimethyl sulphide was added drop wise to the stirred

solution at 25 0C to form the oxyborane intermediate. After one hour 5 mol%

of sodium borohydride was thrown into the reaction mixture and stirring was

continued for two hours. The reaction was quenched using dry methanol and

evaporated to get a colourless oil in quantitative yield. The reaction mixture

has been acetylated to avoid the problem during the isolation of hydroxyl

138

compounds. Acetyl chloride was added drop wise to the reaction mixture

under stirring for overnight. It is clear from the physical data that only two

hydroxyl groups were protected and the product obtained is 230 instead of

expected 228, where cyclization occurs prior to the selective reduction

(Scheme III. 46).

HOH

OH

COOCH(CH3)2

COOCH(CH3)2

COOCH(CH3)2

HOH

OH

CH2OH

CH2OH

COOCH(CH3)2)

BH3SMe2. Dry THF

NaBH4

226

HCOCH3O

COCH3O

CH2OCOCH3

CH2OCOCH3

COOCH(CH3)2

CH3COCl

22819

OO H

OH

COOCH(CH3)2

OH

OO H

OCOCH3

COOCH(CH3)2

OCOCH3229

230

CH3COCl

BH3SMe2. Dry THFNaBH4

Scheme III.46

1H NMR clearly shows the presence of two –COCH3 groups at δ 2.05 and

2.08, one –OCH group at δ 5.11, one –CH2 at 2.90-3.00 and two –CH3 at

1.26 ppm. 13C shows the presence of four carbonyls at δ172.3,169.8,169.6

and166.0 (Figure III. 38a-d).

139

OO H

OCOCH3

COOCH(CH3)2

OCOCH3230

Figure III.38a

Figure III.38b

140

Figure III.38c

Figure III.38d

141

III.4 GENERAL EXPERIMENTAL DETAILS

All commercial solvents were distilled prior to use. Dry solvents and reagents

were prepared by following the procedures described in “Purification of

Laboratory Chemicals” by D. D. Perrin and W. L. F. Armarego (3rd edition,

Pergamon Press, 1988). Dry THF was distilled from sodium benzophenone

ketyl just before use. Dried fruit rind of Garcinia cambogia was procured

from a local plantation. Leaves or calyxes of Hibiscus sabdariffa and the

leaves of Hibiscus furcatus were collected from local area. All reactions

which require anhydrous condition, were carried out under a positive flow of

dry nitrogen. Anhydrous sodium sulphate was used to dry organic extracts.

Melting points were determined on ‘’Sunbim’’ make electrically heated

melting point apparatus and are uncorrected. IR spectra were recorded using

a Shimadzu IR 470 spectrophotometer as KBr pellets (solids) or thin films

(liquids). 1H-NMR spectra were recorded on a Brucker W M 300 MHz or

Brucker Avance 300 or Jeol GSX 400MHz or Brucker AMX 400MHz NMR

system and chemical shift values are reported in parts per million (ppm)

relative to tetramethylsilane as internal standard (0.00 ppm). 13C NMR were

recorded on a Brucker WM 300 (75.5 MHz) or jeol GSX 400 (100.6 MHz) or

Brucker AMX 400 (100.6MHz) NMR system and chemical shift values are

reported in parts per million (ppm) relative to tetramethylsilane (0.00 ppm).

HMBC spectrum was recorded on Brucker DRX 600 NMR system. Electron

impact mass spectra were recorded on a Finnigan MAT MS 8230 or jeol D-

300. Specific rotations were recorded using Jasco D I P 370 or Jasco DIP

1000 digital polarimeter. Elemental analyses were carried out on a Carlo-

Erba CHNS-O-EA 1108 elemental analyzer.

142

III.5 EXPERIMENTAL III.5.1 (2S,3S)-Tetrahydro-3hydroxy-5-oxo-2, 3-furandicarboxylic acid (1)

Dried rinds of the fruits of Garcinia cambogia (1 Kg) were cut into

small pieces and soaked in hot water (IL). The extract was collected after 20

hours and the process was repeated 4-5 times. The combined extract was

concentrated and methanol (2.5L) was added to precipitate pectin. Upon

filtration the filtrate was concentrated to a syrup. It was made alkaline with

sufficient quantity of 10% aqueous sodium hydroxide, followed by the

addition of methanol (IL) till two layers separated. Sodium salt separated as a

paste (lower level) and was washed with 60% aqueous methanol (5x100ml).

The pure sodium salt was dissolved in sufficient quantity of 2N hydrochloric

acid to regenerate the free acid. It is concentrated and added acetone to

precipitate the impurities. The filtrate on concentration yielded crude crystals

of Garcinia acid. Pure crystals of 1 were obtained upon recrystallisation from

acetone-ether mixture.

Yield : 67.5g (6.75% to the dry wt of fruit rinds)

Melting point : 178° C. Reported: 178° C

25D][α : +102.15° (c 1.0,H2O) Reported: +100°

IR (KBr) : ν max 3400 (OH, broad), 1790 (γ-lactone) and 1741cm-1 (carbonyl)

1H NMR (DMSO-d6) : δ 4.80 (s, IH), 3.07 (d,.J = 17.4Hz,IH),

2.60 (d,J =17.4 Hz, IH) ppm

13C NMR(DMSO-d6) : δ 174.9, 171.9, 169.2, 84.8, 79.0, 39.7 ppm.

Mass spectrum (E.I) : m/z 191 (M+1) (2), 173 (1), 162 (6), 145 (35), 127 (10), 116 (48), 99 (70), 88(100), 60 (40) and 55 (20)

143

Molecular formula : C6H6O7

Elemental analysis

Found : C 37.23, H 2.73

Calculated : C 37.91, H 2.18

III.5.2 (2S, 3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (2)

Fresh calyxes or leaves (1 Kg) of Hibiscus sabdariffa or leaves of Hibiscus

furcatus were soaked in water (1 Lt). After washing with hexane, the

concentrated extract was made alkaline with 8N sodium hydroxide solution

(80ml). Methanol was added to precipitate the sodium salt followed by the

addition of 2N hydrochloric acid to regenerate the acid. Upon concentration

followed by the addition of acetone precipitated the impurities. The residue

obtained after concentration was further extracted with ether which on

concentration yielded 10 g of 2 when leaves of Hibiscus furcatus or 16 g of 2

when fresh calyxes (1Kg) of Hibiscus sabdariffa were used.

Melting point : 180°C Reported : 182-183°C (decomp)

25D][α : +111° (c 1.0, H2O) Reported : +110°

IR (KBr) : νmax 3400 (OH, broad), 1790 (γ-lactone) and 1735 cm-1 (carbonyl)

1H NMR (acetone-d6) : δ 5.3 6 (s, 1H), 3.3 (d, J =17.09 IH), 2.8(d, .J

=17.09Hz, 1H), ppm

13C NMR (DMSO-d6) : δ 173.2, 172.3, 167.1, 82.9, 78.4, 42.2 ppm

Mass spectrum (E.I) : m/z191 (M+1) (2), 172 (1), 162 (5), 145 (60), 127 (12), 116 (38), 99 (84), 88(100), 60 (48) and 55 (28)


144

Elemental analysis

Found : C 37.23, H 2.73

Calculated : C 37.91, H 3.18

III.5.3 Disodium (2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (5)

To an aqueous solution of 1 (2.0 g, 10.5 mmol, in 10 ml of water), saturated

aqueous sodium bicarbonate was added till the pH of the reaction mixture

became neutral (ca 15 ml). The residue obtained after evaporation of the

reaction mixture under reduced pressure, was triturated and washed with dry

methanol followed by acetone (5 X 20 ml). The product 5 was finally dried

under vacuum to give a colourless solid.

Yield : 2.0 g (82%)

25D][α : +81.8° (c 1.63, H2O)

IR (KBr) : ν max 3400, 1800, 1600 cm-1

1H NMR (D2O) : 4.84(s, 1H); 3.19(d, 1H), 2.83(d, 1H), 2.27 (s,

1H)

13C NMR (D2O) : 179.4, 177.4, 174.69, 89.1, 81.5, 42.7 ppm;

Mass spectrum (E.I) : 257(M+ 23, 100), 240(58), 195(35.5), 155(20.9)

Molecular formula : C6H4O7Na2

Elemental analysis

Found : C, 30.68, H, 1.70

Calculated : C, 30.76, H, 1.71

145

III.5.4 Dimethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (9)

A solution of 1 (1.0gm, 5mmol) in ether (25ml) was treated with excess

diazomethane in ether. The reaction mixture upon concentration gave diester

9 as yellow oil.

Yield : 1.1 gm (100%)

25D][α : +65.32.° (c 0.32,CHCl3)

IR (film) : νmax 3450, 1795, 1740 cm-1

1H NMR (CDCl3) : δ 4.96(s,1H), 3.82(s,3H), 3.78 (s,3H),

3.20 (d,J =19.0Hz, 1H), 2.82(d, J =

19.0Hz,1H)ppm

13CNMR (CDCl3) : δ 172.5,170.2,166.9,84.2, 79.2, 53.7, 52.9,

39.7ppm

Mass spectrum (E.I) : m/z 219(M+1) (1), 191 (3), 159(26), 141(6),

131(25), 99(100), 59(93)

III.5.5 Diethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (10)

To a precooled (-5-00C) suspension of 5 (1.0 g, 4.4 mmol) in dry ethanol (10

ml), thionyl chloride (0.7 ml, 10 mmol) was added. The mixture was then

stirred for 48 h at room temperature. After filtration of the reaction mixture, pH

of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium

bicarbonate and was extracted with chloroform (3X10ml). The combined

extract upon drying and evaporation gave the compound (no) as a pale

yellow liquid.

146

Yield : 0.9 g (77%)

25D][α : -81.0° (c 1.0, CHCl3)

IR (liquid film) : ν max 3500, 2990,1800,1740 cm-1

1H NMR (CDCl3) : 4.90(s, 1H), 4.30(m, 4H), 3.10(d, 1H), 2.8(d, 1H),

1.18-1.32 (m, 6H)

13C NMR (CDCl3) : 172.0, 170.5, 170.0, 84.0, 75.0, 62.5, 62.0, 40.0,

15.2, 15.0 ppm;

Mass spectrum (E.I) : 246(M+ 1, 5.5), 218(29.8), 200(5.96), 188(41.7),

172(99.8), 156(17.9), 144(87.9), 127(5.9),

114(67.05), 104(90.9), 99(95.4), 88(20.8), 76(70),

59(5.9), 42(65.6%)


Elemental analysis

Found : C, 48.74, H, 5.69


III.5.6 Diisopropyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (11)

The procedure adopted for 10 was followed with 5 (1.0 g, 4.4 mmol),

isopropyl alcohol (10 ml) and thionyl chloride (0.7 ml, 10 mmol). After work-

up, gave 11 as yellow oil.

Yield : 0.5 g (41%)

25D][α : +32.0° (c 1.0, CHCl3)

IR (liquid film) : ν max 3500, 2980 ,1800,1740 cm-1

147

1H NMR (CDCl3) : 5.10-5.18(m, 1H), 3.96(s, 1H), 2.98(d, 1H),

2.93(d, 1H), 1.18-1.32 (m, 6H)

13C NMR (CDCl3) : 171.5, 170.1, 169.2, 83.9, 74.6, 71.7, 69.8, 40.0,

21.6, 21.5 ppm

Mass spectrum (E.I) : 274(M+, 7.4), 246(60.3), 232(34.2), 216(21.8),

204(37.1), 190(15.8), 174(23), 162(52.3),

144(58.7), 1 32(43.6), 117(12), 98(15), 76(52),

42(100%)


Elemental analysis

Found : C, 52.32, H, 6.59


III.5.7 Dibenzyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (12) To a suspension of 1 (4.0 g, 20.8 mmol) in dry benzyl alcohol (6.4 ml), p-

toluene sulphonic acid monohydrate (50.0 g, 0.26 mmol) and toluene (42.4

ml) were added. The mixture was then refluxed for 13 h at about 1300C. The

mixture was allowed to cool, diluted with chloroform and poured into

saturated aqueous sodium bicarbonate. The organic layer was separated

and the aqueous layer was extracted with chloroform. The combined organic

phase upon drying, evaporation and recrystallisation from chloroform-hexane

gave 12 as colourless crystals.

Yield : 7.0 g (90%)

Mp : 81-830C

25D][α : +34.7° (c 1.0, CHCl3)

148

IR (KBr) : ν max 3500, 3100 ,1820,1700 cm-1

1H NMR (CDCl3) : 7.25-7.34(m, 10H), 5.09-4.92(m, 4H), 4.87(s, 1H),

3.07(d, 1H, J=13.5 Hz), 2.80(d, 1H, 13.5 Hz)

13C NMR (CDCl3) : 171.8, 170.0, 166.2, 134.3, 133.8, 129.1, 128.8,

128.7, 128.6, 84.1, 78.9, 69.0, 67.9, 39.7 ppm;

Mass spectrum (E.I) : m/z 370(M+ 7.0), 280(6.6), 251(3.9), 180(9.4),

107(86.4), 91(100), 65(20.8), 43(4.4%)


Elemental analysis

Found : C, 64.55, H, 4.87

Calculated : C, 64.86, H, 4.89.

III.5.8 Disodium (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (6) To an aqueous solution of 2 (2.0 g, 10.5 mmol, in 10 ml of water), saturated

aqueous sodium bicarbonate was added till the pH of the reaction mixture

became neutral (ca 15 ml). The residue obtained after evaporation of the

reaction mixture under reduced pressure, was triturated and washed with dry

methanol followed by acetone (5 X 20 ml). The product 6 was finally dried

under vacuum to give a colourless solid.

Yield : 2g (82%) 25D][α : +56.5o (c 1.02, H2O)

IR (KBr) : ν max 3400, 1800, 1600 cm-1

1H NMR (D2O) : 5.17(s, 1H), 3.21(d, 1H, J=17.8 Hz), 2.24(d, 1H,

J=17.8

Hz), 2.27 (s, 1H) 13C NMR (D2O) : 179.9, 178.1, 173.9, 88.5, 80.5, 43.7 ppm;

149

Mass spectrum (E.I) : m/z 257(M+ 23, 100), 238(41.23), 195(43.59),

168(39.9),142.1(15.96%)

Molecular formula : C6H4O7Na2

Elemental analysis

Found : C, 30.68, H, 1.70

Calculated : C, 30.76, H, 1.

III.5.9 Dimethyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (13) A solution of 2 (1.0 gm, 5.25 mmol) in 25 ml ether was treated with excess

diazomethane in ether. The reaction mixture on concentration gave 13

colourless crystals of diester.

Yield : 1.13gm (98%)

Melting point : 128°C

25D][α : +116o (c 0.4952,CHCl3)

IR (KBr) : νmax 3500, 1795, 1745cm-1

1H NMR (CDCl3) : δ 5.31(s,1H), 3.95(s,3H), 3.84 (s,3H),

3.1 (d, J=20.3Hz, 1H), 2.87 (d, J=20.3Hz, 1H)

ppm

13C NMR (DMSOd6) : δ 172.74, 170.80, 166.14, 81.96, 77.90, 53.12,

53.03, 40.14ppm

Mass spectrum (E.I) : m/z 219(M+1) (66), 191 (2), 159(100), 141(10),

130(38), 99(100), 74(25%).

III.5.10 Diethyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (172) To a precooled (-5-00C) suspension of 6 (1.0 g, 4.4 mmol) in dry ethanol (10

ml), thionyl chloride (0.7 ml, 10 mmol) was added. The mixture was then

150

stirred for 48 h at room temperature. After filtration of the reaction mixture, pH

of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium

bicarbonate and was extracted with chloroform (3X10ml). The combined

extract upon drying and evaporation gave the compound 172 as a pale

yellow liquid.

Yield : 0.8g (68%)

25D][α : +51.4o (c 1.0, CHCl3)

IR (liquid film) : ν max 3500, 2990,1800,1740 cm-1

1H NMR (CDCl3) : 5.10(s, 1H), 4.20(m, 4H), 3.90(d, 1H, J=19.6 Hz),

2.10(d, 1H, J=19.6 Hz), 1.18-1.32 (m, 6H)

13C NMR (CHCl3) : 173.0, 170.5, 170.0, 82.0, 74.0, 62.5, 62.0, 44.0,

15.0 ppm;

Mass spectrum (E.I) : 246(M+ 1, 5.5), 218(30.80),188(27.9), 144(100),

114(27.9), 103(28), 98(57.3), 82(52.9), 75(55.8),

57(5.88), 46(26.4), 42(44.1%)


Elemental analysis

Found : C, 48.74, H, 5.69


III.5.11 Diisopropyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (173) The procedure adopted for 172 was followed with 6 (1.0 g, 4.4 mmol),

isopropyl alcohol (10 ml) and thionyl chloride (0.7 ml, 10 mmol). After work-

up, gave 173 as yellow oil.

151

Yield : 0.5g (41%)

25D][α : +41.2(c 1.0, CHCl3)

IR (liquid film) : ν max 3500, 1800,1740 cm-1

1H NMR (CDCl3) : 5.10(m, 1H),4.90(m, 1H), 4.27(s, 1H), 3.10(d,

1H, J=17.3 Hz), 2.80(d, 1H, J=17.3 Hz),

1.10-1.30 (m, 12H)

13C NMR (CDCl3) : 171.7, 170.21, 169.5, 82, 74.6, 70, 68.4, 40.6,

21.5, 20.6 ppm

Mass spectrum (E.I) : 274(M+,2.9), 246(5.9), 232(4.9), 216(5.9),

204(13.4),

190(11.9), 174(20.8), 162(35.8), 144(52.2),

132(47.7),

117(10.4), 98(14.9), 86(4.4), 76(41.7), 42(100%)


Elemental analysis

Found : C, 52.32, H, 6.59


III.5.12 Dibenzyl (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylate (14) To a suspension of 1 (4.0 g, 20.8 mmol) in dry benzyl alcohol (6.4 ml),

p-toluene sulphonic acid monohydrate (50.0 g, 0.26 mmol) and toluene (42.4

ml) were added. The mixture was then refluxed for 13 h at about 1300C. The

mixture was allowed to cool, diluted with chloroform and poured into

saturated aqueous sodium bicarbonate. The organic layer was separated

and the aqueous layer was extracted with chloroform. The combined organic

152

phase upon drying, evaporation and recrystallisation from chloroform-hexane

gave 174 as colourless crystals.

Yield : 7.5g (90.9%)

Mp : 900C

25D][α : +26.9 o(c 1.0, CHCl3)

IR (KBr) : ν max 3495, 3100 ,1820,1790, 1750 cm-1

1H NMR (CDCl3) : 7.26-7.38(m, 10H), 5.17-5.35(m, 4H),5.10(s, 1H),

3.03(d, 1H, J=7.47 Hz), 2.83(d, 1H, J=7.47 Hz)

13C NMR (CHCl3) : 171.3, 170.8, 165.2, 134.6, 133.9, 129.2, 128.9,

128.8, 128.7, 85.6, 81.9, 69.5, 67.9, 40.3 ppm;

Mass spectrum (E.I): m/z 370(M+ .4), 268(0.7), 278(10.3), 179(9.7),

145(2.5), 107(78.52), 91(100), 77(11.1),

65(34.07), 51(5.93), 40(7.41%)


Elemental analysis

Found : C, 64.55, H, 4.87

Calculated : C, 64.86, H, 4.89.

III.5.13 Diisopropyl (2S,3S)-tetrahydro-3-acetyloxy-3-acetyloxy-5-oxo-2,3-furandicarboxylate (178)

,

Acetyl chloride (4 equ.) was added drop wise to the diester 11

(3.5 mmol) under stirring and the stirring was continued for 12 hours. The

reaction mixture was concentrated under vacuum. 178 obtained as a white solid

153

Yield : 1.036g (85%)

MP : 78 0C

25D][α : +99.85° (c 0.12, CHCl3)

IR (liquid film) : ν max 2989,2939,1800,1755, 1469, 1010, 979, 864

cm-1

1H NMR (CDCl3) : 4.9(m,2H), 3.42-3.55(d, 1H, J=18.44 Hz), 2.82-

2.92(d,1H,J=18.43Hz),2.07(s,3H),1.12-1.259

(m,12H)

13C NMR (CDCl3) : 172, 169.4, 165, 164.7, 83.7, 81, 71.1, 36, 30.7,

21.3, 20.5 ppm

Mass spectrum : 317(M+1)


Elemental analysis

Found : C, 53.60, H, 6.11


III.5.14 Diisopropyl (2S,3R)-tetrahydro-3-acetyloxy-5-oxo-2,3-furandicarboxylate (180)

Acetyl chloride (4 equ.) was added dropwise to the diester 173

(3.5 mmol) under stirring and the stirring was continued for 12 hours. The

reaction mixture was concentrated under vacuum. 180 obtained as colourless

liquid.

Yield : 0.99g (82%)

25D][α : +51.5° (c 0.1, CHCl3)

154

IR (liquid film) : ν max 2989,2939,1800,1755, 1469, 1010, 979, 864

cm-1

1H NMR (CDCl3) : 5.2(m,2H), 5(s, 1H), 3.35-3.6(d, 1H, J=18.13 Hz), 3-

3.2(d, 1H, J=18.13 Hz), 2.58(s,3H), 1.1-1.5(m,12H)

13C NMR (CDCl3) : 171.1, 169, 166.4, 164.7, 80.5, 79.2, 71.3, 40.4, 37,

21.4, 21.2 ppm

Mass spectrum : 317(M+1)


Elemental analysis

Found : C, 53.22, 6.09.


III.5.15 Dimethyl 3-methoxy 2(5H) furanone 4, 5 dicarboxylate (206)

To a solution of 13 or 9 (1g, 4 mmol) in pyridine, POCl3 (4 mmol) was

added at 0oC and stirred for two hours. The reaction mixture was quenched

with 2N hydrochloric acid, extracted with CHCl3 and concentrated. The oil

residue obtained was dissolved in methanol, followed by the addition of

diazomethane in ether. After completion of the reaction (monitored by TLC),

excess diazomethane was removed and concentrated. The residue obtained

was purified by column chromatography (silica gel, hexane – chloroform 8:2).

Yield : 0.4gm (40 %),

Melting point : 71oC

25D][α : -31° (c 1.0, CHCl3)

IR (KBr) : ν max 2970, 1750, 1730, 1420 cm-1

155

UV(CHCl3) λmax : 295nm

1H NMR (CDCl3) : δ 5.60 (s, 1H); 3.95 (s, 3H), 3.89 (s,3H), 3.88

(s,3H) ppm

13C NMR (CDCl3) : δ 162.7, 161.9, 157.7, 133.4, 126.7, 84.4,

58.9, 52.4, 52 ppm

Mass spectrum (E.I) : m/z 230(M+1, 7.1), 217(2.5), 216(13.6),

215(100), 185(3.4), 184(26), 172(21.7),

156(15.1), 141(4.1), 127(8.7%).


Elemental analysis

Found : C, 47.01, H, 4.37


III.5.16 Diethyl 3-methoxy 2(5H) furanone 4, 5 dicarboxylate (207)

The procedure adopted for 206 was followed using 10 or 172. After work-up

the product was isolated as pale yellow oil.

Yield : 0.5g (59%)

25D][α : -14° (c 1.0,CHCl3)

IR (liquid film) : ν max 2990, 1750, 1420 cm-1

1H NMR (CDCl3) : 5.60(s, 1H);4.30(m, 4H), 3.90(s, 3H), 1.50(m,6H)

13C NMR (CDCl3) : 170, 162, 158, 135, 126, 84, 62, 61. 2, 59, 42,

25,15 ppm;

156


200(23.4), 198(43.5), 186(25), 172(27),

171(100), 169(73.9), 158(34), 144(49.9),

127(32.3), 126(52%).


Elemental analysis

Found : C, 51.05, H, 5.32


III.5.17 Dibenzyl 3-methoxy 2-(5H) furanone 4, 5-dicarboxylate (208)

The procedure adopted for 206 was followed with 12 or 174. After work-up

the product was isolated as pale yellow oil.

Yield : 0.4g(38.5%) 25D][α : -11(0.1o/o, CHCl3);

IR (liquid film ) : ν max 2970,1740,1718,1558,1123, 752, 697 cm-1

1H NMR (CDCl3) : δ 7.30(m, 5H), 5.60(s, 1H), 5.30(q, 2H), 3.90(s,

3H) ppm

13C NMR (CDCl3) : δ 162.2, 162, 157, 135, 128,126, 84.5, 67.2,

66.6, 58.2ppm

Mass spectrum (E.I) : m/z 382 (M+, 3), 366(72.8), 260(12.8), 232(31.5),

214(12.5), 169(49.5), 91(100), 65(20.5%).


Elemental analysis

Found : C, 65.13, H, 4.17


157

III.5.18 Diisopropyl 3-methoxy- 2-(5H) furanone 4, 5- dicarboxylate (171C)

To a solution of 11 or 173 (4 mmol), in pyridine, POCl3 (4 mmol) was added

at 25o C and stirred for two hours. The reaction mixture was quenched with

2N hydrochloric acid, extracted with CHCl3 and concentrated. The residue

obtained was purified by column chromatography (silica gel, hexane –

chloroform 8:2).

Yield : 0.45g (53%)

25D][α : -14° (c 1.0,CHCl3)

IR (liquid film) : ν max 2990, 1750, 1420 cm-1

1H NMR (CDCl3) : 6.90(s, 1H), 5.10(m, 1H), 5.00 (m, 1H), 3.90(s,

1H), 1.50(m, 12H)

13C NMR (CDCl3) : 169.3, 165.5, 164.9, 140, 129.7, 69.4, 68.3, 33,

21.6 ppm;


200(23.4), 198(43.5), 186(25), 172(27),

171(100), 169(73.9), 158(34), 144(49.9),

127(32.3), 126(52%).


Elemental analysis

Found : C, 56.15, H, 6.18


158

III.5.19 Dimethyl 5-[(methylsulfonyl) oxy] -2,3-furandicarboxylate(209):

To a solution of 9 or 13 (4 mmol), triethyl amine (2ml) in 20 ml

dichloromethane, methanesulfonyl chloride (4 mmol) was added at 0oC and

stirred for two hours. The reaction mixture was quenched with 2N

hydrochloric acid followed by brine wash and extracted with CHCl3. The

residue obtained after concentration was purified by column chromatography

(silica gel, hexane –chloroform 8.5:1.5).

Yield : 0.779g (70%)

IR (liquid film) : ν max 2956, 1733, 1548, 1442, 1386, 1278,

1185, 1065cm-1


1H NMR (CDCl3) : 6.40(s,1H), 3.93(s, 3H), 3.90(s,3H), 3.40(s,3H)

13C NMR (CDCl3) : 161.4, 157.1, 149, 137.9,125.2,81.6, 52.59,

52.56, 39.07 ppm

Mass spectrum (HRMS),

Calculated : 278.1570(M+),

Observed : 278.0037(M+),

III.5.20 Diisopropyl 5-[(methylsulfonyl) oxy] -2,3-furandicarboxylate (210) : To a solution of 11 or 173 (3.64 mmol,), triethyl amine (2ml) in 20 ml

dichloromethane, methanesulfonyl chloride (4 mmol) was added at 0oC and

stirred for two hours. The reaction mixture was quenched with 2N

hydrochloric acid followed by brine wash and extracted with CHCl3. The

residue obtained after concentration was purified by column chromatography

(silica gel, hexane –chloroform 8.5:1.5).

159

Yield : 1.015 g (76%)

IR (liquid film) : ν max 2981, 1735, 1373, 1180, 1103, 1080,

800cm-1;


1H NMR (CDCl3) : 6.87(s,1H), 5.10-4.90(m,2H), 3.90(s,3H), 1.22-

132(m,6H);

13C NMR (CDCl3) : 169.4,165.5,164.9,140.2,129,17,128.7,69.4,

68.5, 33.4,21.7 ppm

Mass spectrum (FAB) : m/z 334 (M+).

III.5.21 Isopropyl (2S,3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate (230)

To a solution of 19 (4 mmol) in dry tetrahydrofuran, borane dimethyl sulphide

(1.03 equ.) was added drop wise at 20oC under stirring during 10 minutes.

The solution was stirred at that temperature until evolution of hydrogen

ceased. Then the flask was cooled with a water-ice bath (10oC) and stirring

was continued for 10minutes. To the solution was added NaBH4 powder

(5 mol%) in one portion under vigorous stirring at that temperature. After

10minutes, the water bath was removed and the reaction was continued at

room temperature until the disappearance (TLC monitoring) of the starting

molecule. The reaction was quenched using MeOH (3ml) and was stirred for

30min. at room temperature and concentrated to give a clear colourless gum.

This was dissolved in MeOH and again evaporated and this operation was

repeated to eliminate B(OMe)3 as thoroughly as possible. Acetyl chloride

(4 equ.) was added dropwise to the concentrate under stirring and the stirring

was continued for 12 hours. The reaction mixture was concentrated under

vacuum.

160

Yield : 0.589g (65%)

25D][α : +26 (c 1.0, CHCl3)

IR (liquid film) : ν max3494, 3009, 2969, 1780, 1748, 1452,

1128, 1081, 1013 cm-1

1H NMR (CDCl3) : 5.21(s,1H), 5.09(m, 1H), 4.50(s,2H), 2.902-

3.02(dd,2H), 2.12(s,3H), 2.08(s,3H),

1.31(s,6H)

13C NMR (CDCl3) : 172.3, 169.8,169.6, 166.0, 84, 80, 71.1, 69, 37,

21.5, 21.4, 20.3 ppm

Mass spectrum(LCMS) : 303(M+)

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