The first stereoselective total synthesis of (3R,6E)-1,7...

Total synthesis of (3R,6E)-1,7-bis(4-hydroxy phenyl)-hept-6-ene-3-ol Chapter ΙI

The first stereoselective total synthesis of (3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6- ene-3-ol:

2.0. INTRODUCTION:

Diarylheptanoids (constitute a distinct group of natural

plant metabolites) have been isolated from various genera such

as Acer (Aceraceae), Platycarya (Juglandaceae), Myrica (Myricaceae) and Centrolobium (Leguminosae) but with the

largest numbers occurring in Alpinia, Curcuma, Zingiber

(Zingiberaceae), Alnus and Betula (Betulaceae).1

The common structural feature of diarylheptanoids are two

aromatic rings linked by a linear seven-carbon aliphatic chain,

with varying functional groups on the aryl and C-moieties (Fig. 2.1, 1) and may be divided into three sub groups,

i.e. open chain (1), cyclic (2, 3) and macrocyclic (miscellaneous)

(Fig. 2.1, 4-8) diarylheptanoids. In cyclic diarylheptanoid, the

aromatic rings are connected through C-C or C-O bonds. Based on

this connectivity, the cyclic diarylheptanoids further divided

into two sub groups, i.e. cyclic biphenyls and cyclic diphenyl

ethers. Many diarylheptanoids possess biological activities such

as anti-inflammatory, anti-hepatotoxic, antibacterial and

antifungal activity.

7

2These units are also important for a wide variety of biological

activities, such as antibacterial, antioxidant,

anti-inflammatory, antitumor, anti-HIV and antiemetic

properties. Due to these biological activities, synthesis of

these molecules in optically pure form made them an attractive

target for many scientists. Isolation and biological activities

of some of these natural products are discussed below. Fig. 2.1:

38


39


2a Open chain diarylheptanoids:

The linear diarylheptanoids are a small group of bioactive

natural products occurring in various monocot and dicot plant

species, which are derived biosynthetically from phenylalanine

(C9 precursors).

3 More than 70 open chain diarylheptanoids have

been isolated from nature.

40

4They are known to have a variety of biological activities, such

as antifungal activity, inhibition of prostaglandin biosynthesis

and antihepatotoxic activity. The Zingiberaceae plant family is an

especially rich source of diarylheptanoids.

2a.1. Curcumins:

The most well known diarylheptanoid is a major spice and pigment principle of Curcuma longa (Zingiberaceae) and other Curcuma species (Fig. 2.2).

Curcuma longa known as turmeric, is a tropical plant native to India

and is cultivated in most tropical parts of the world including

Africa, Madagascar as well as South and South-East tropical Asia.

This plant has underground root-like stems and rhizomes which are

commonly used as a spice but are also utilized for medicinal

purposes in Indian ayurvedic medicine. Curcumin 10a was first

isolated in 1815 by Vogel and Pelletier.

5 In bioassays it exhibits strong antioxidant and chemopreventive

activities 6, 7and is responsible for the biological activity

(anti-inflammatory, anticancer, hepatoprotective, antiallergic,

cholesterol- lowering effect and anti-HIV) of this plant.

Diarylheptanoids of the Zingiberaceae structurally related to

curcumin are also referred to as curcuminoids. Later in 1953 two

minor components, demethoxycurcumin 10b and

bis-demethoxycurcumin 10c wereisolated. The first saturated curcumin derivative,

(S)-hexahydrocurcumin 10d and its enantiomer 10e was later found

in Alpinia Officinarum and (R) configuration was assigned based on its

CD spectrum.


Fig.

2.2:

2a.2. Betulaplatosides:

Yoshikawa et al isolated four new diarylheptanoids named

betulaplatosides (11) and (12) together with seventeen known

aromatic constituents from Betula platyphylla var. Japonica (Fig. 2.3).8

11, 12 Showed protective activity against-d-GalN-induced

cytotoxicity in primary cultured rat hepatocytes as well as Oscavenging and antioxidative activities.

Fig.

2.3:

41

2


2a.3. Yashabushiketols: Yashabushiketols 13a and 13b (Fig. 2.4) were

first extracted in 1970 from young shoots of the plant Alnus

sieboldiana and its structure and absolute configuration were

determined later.

Fig.

2.4:

9

2a.4. Yakuchinones:

Yakuchinone A (14a) and B (14b), diarylheptanoids (Fig. 2.5) from Alpiniaoxyphylla (Zingiberaceae) have been reported to show potent

anti-inflammatory and antitumor promotional activities through

the inhibition of COX-2 and iNOS expression.

42

10

Yakuchinone B (14b) and the structural analogues have been

extensively studied as inhibitors of acyl-CoA: cholesterol

O-acyltransferase that can be therapeutic agents for

hypercholesterolemia and atherosclerosis.Fig.

2.5:

2a.5. Letestuianins:

11

Cyrus Bacchi et al isolated four letestuianins 15a-d (Fig. 2.6) from Aframomumletestuianum in 2003.

12These diarylheptanoids were tested for growth inhibitory

activity in vitro versus bloodstream forms of African

trypanosomes. The ICvalues in the range of 1-3 µg/mL were found. 50


Fig.

2.6:

2a.6. Platyphyllosides: Terasawa et al isolated platyphylloside

(Fig. 2.7) from Betula platyphylla in 1984.

43

13Later, it was observed that extract of silver birch twigs (Betula

pendula Roth) caused a digestibility inhibition in goat, cow, moose

and sheep rumen fluid. The structure activity studies has shown

that platyphylloside (16) and (S)-5-hydroxy-3- platyphyllone

(17) had the same lowering effect on digestibility in vitro and

that racemic 17 possesses a lower effect and a lower turnover rate

than the (S)-enatiomer, thus leading to a lower concentration of

platyphyllone (18) in rumen liquor.Fig.

2.7: :


Recently, a novel diarylheptanoid 19 (Fig. 2.8) was isolated from Zingiber ottensii (Zingiberaceae) which is cultivated in Malaysia and used in

traditional medicine for its sedative effect.

Fig.

2.8:

14

Diarylheptanoid 20 (Fig. 2.9) isolated from a Chinese medicinal

herb, Alpinia officinarum (Zingiberaceae), inhibits nitric oxide

production in lipopolysaccharide- activated mouse peritoneal

macrophage.

15In addition, a novel diarylheptanoid 21 has been also isolated

from the same plant by Shin et al

44

16 and found to have antiemetic activity.

Fig.

2.9:

In the search for anti-cancer principles from ginger,

diarylheptanoid 22 (Fig.2.10) was isolated as a novel constituent

of Zingiber officinale (Zingiberaceae) and was found to possess

cytotoxic and apoptotic activity.

Fig. 2.10:

17


A potent inhibitor of collagen-induced, arachidonic

acid-induced and adenoside diphosphate-induced platelet

aggregation of human blood is diarylheptanoid 23 (Fig. 2.11) isolated from the seeds of Alpinia blepharocalyx (Zingiberaceae).

45

18

Fig. 2.11: Y.C. Lai et have been isolated new diarylheptanoids

24a-24d (Fig. 2.12) from A. formosana and were showing better in vitro

anti-inflammatory activities than oregonin, could serve as

potential leads for the development of anti-inflammatory drugs.

Fig. 2.12: The Epihirsutanonol (25) (Fig. 2.13) was

isolated from A. japonica

20in 2010 and was checked for their strong protective effects on

t-butylhydroperoxide-induced primary rat hepatocyte injury and

found to show significant hepatoprotective activity.

Fig.

2.13:


B. B. Zhang et al isolated Compounds 26, 27 and 28 (Fig. 2.14) from A. officinarumin 201021and were subjected to antimicrobial assessment and all proved

to be potent inhibitors against Helicobactor pylor.

Fig. 2.14:

Later I, N. Siddiqui et al identified nitidone A (Fig. 2.15) in A.

nitida and the compound was regarded to have Antibacterial activity.

Fig. 2.15:

46

22

J. Yin et al measured the antiosteoporotic activity of

diarylheptanoids and diospongin A (30), B (31) and C (32) (Fig.

2.16) were screened to exert potent inhibitory effects on bone

resorption induced by parathyroid hormone in a bone organ culture

system.

23


Fig. 2.16: 2a.7. Centrolobols: Craveiro et al isolated (+) and (-)

centrolobol (Fig. 2.17) from centrolobium robusstum in 1869.

24Araujo et al showed that compound 33 and 34 posses antileishmanial

activity.

Fig.

2.17:

Later Feng Quie et al isolated diarylheptanoids (Fig. 2.18) from

Curcuma kwangsiensis in 2010.25

These diarylheptanoids with one asymmetric carbon at 3-position

were found to exist as enantiomeric mixtures and showed the

inhibitory effect on NO production in LPS-activated macrophages.

Fig. 2.18:

47


48

Total synthesis of (3R,6E)-1,7-bis(4-hydroxy phenyl)-hept-6-ene-3-ol Chapter ΙI:

Section A

Stereoselective Total Synthesis of

(3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-ene-3-ol through cross metathesis.

2A.1 PRESENT WORK: Recently, a diarylheptanoid,

(3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35) has been

isolated in a very small quantity from the rhizomes of Curcuma

kwangrsiensis (Zingiberaceae).25 The compound was evaluated for its inhibitory effect on NO

production induced by lipopolysaccaride-activated macrophages.

The activity of the compound was found to be close to that of

Indomethacin and Hydrocortisone.

In continuation of the work26

49

25

in our laboratory on the construction of bioactive natural

products, herein we report the stereoselective first total

synthesis of (3R,6E)-1,7- bis(4-hydroxyphenyl)-hept-6-ene-3-ol

(35). Our planned approach to the target molecule involved Wittigs

olefination, hydrolytic kinetic resolution of a racemic epoxide

and olefin cross metathesis reaction as the key steps. Our

retrosynthetic approaches to this diarylheptanoid is outlined in

Scheme 11. Scheme 11:


Section A

Our synthesis was started from commercially available 4-hydroxy

benzaldehyde (47), which was converted to 4-vinylphenol (44) by

treating with C

Wittig salt in THF with n- BuLi at -78 oC (Eq. 2.1).

27

Eq. 2.1: The formation of compound 44

was established by IR,

50

1

1

H NMR, 13

C NMR and Mass spectra. In IR spectrum (Fig. 2A.1) the bands were

present at ν 3424, 2958, 2855, 1711 cm-1. The

1H NMR spectrum (Fig. 2A.2) showed three proton signals at ß 6.60

(1H, m), 5.55(1H, d, J = 17.3 Hz), 5.08 (1H, d, J = 11.3 Hz),

indicating compound 44. Additionally, the structure of 44 was

supported by

13C NMR spectrum (Fig. 2A.3) which showed signals at ß136.2, 127.6,

115.3 and 111.6. Finally, the structure was also confirmed by ESI

MS (Fig. 2A.4) which showed signal at m/z 121[M+H]+. Aldehyde 47 was protected with benzyl bromide by using NaH

in DCM to afford the corresponding benzyl protected aldehyde in

86 % yield (Eq. 2.2).

Eq. 2.2:

28

The formation of compound 4-(benzyloxy)benzaldehyde (48) was

explained by IR,

1H NMR,

13C NMR and Mass spectra. In IR spectrum of compound 48 (Fig. 2A.5),

the bands were observed at ν 1740, 1685, 1507, 1254 cm-1. The 1H NMR spectrum (Fig.

2A.6) showed proton signals at ß 5.12 (2H, s) and phenyl protons at ß 7.42-7.26 (5H, m).


Section A

Additionally, the structure of 48 was supported by

51

13C NMR spectrum (Fig. 2A.7) which showed signal at ß 70.0 indicating

presence of benzylic carbon and ß 135.6, 128.7, 128.2, 126.5

indicating the presence of phenyl ring in the compound. Finally

it was also confirmed by ESI MS signal (Fig. 2A.8) at m/z 213 [M+H]+. The aldehyde 48 was converted to (E)-ethyl

3-(4-(benzyloxy)phenyl)acrylate (49) by treating with C

Eq. 2.3:

228

Wittig salt in DCM at rt (Eq. 2.3).

The formation of compound 49 was explained by 1H NMR,

13C NMR and Mass spectra. The

1H NMR spectrum (Fig. 2A.9) showed two olefinic proton signals at

ß 7.59 (1H, d, J = 16.0 Hz) 6.26 (1H, d, J = 16.0 Hz). Additionally,

the structure of 49 was supported by 13

C NMR spectrum (Fig. 2A.10) which showed signals at ß 167.2, 144.5

and 116.0, indicating a,ß-unsaturated ester moiety present in the

compound. Finally the structure was also confirmed by ESI MS

signal (Fig. 2A.11) at m/z 283 [M+H]

+. Treatment of compound 49 with NaBH

4, NiCl2·6HO in MeOH afforded ethyl 3-(4- (benzyloxy)phenyl)propanoate (50)

in 86 % yield (Eq. 2.4).

2

Eq. 2.4: The formation of compound

50 was confirmed by IR,

1

29

H NMR, 13

C NMR and Mass spectra. In IR spectrum (Fig. 2A.12) the sample ester

group was observed at ν 1733 cm -1.


Section A

In 1

H NMR spectrum (Fig. 2A.13) the two olefinic signals were

disappeared at ß 7.59, 6.26. Additionally, the structure of 50

was supported by

52

13C NMR spectrum (Fig. 2A.14) which showed signals at ß 172.6, 157.5,

137.5, 133.2, 129.8, 129.0, 127.9, 127.2, 115.2, 70.2, 60.1, 35.8,

30.1 and 15.9, indicating the absence of signals at 144.5, 116.0

which can indicate the a,ß-unsaturated ester moiety was absent.

Finally, it was also confirmed by ESI MS signal (Fig. 2A.15) at

m/z 285 [M+H]

+. The treatment of compound 50 with LAH in dry THF afforded the

compound 51 in 83 % yield (Eq. 2.5).

30

Eq. 2.5: The formation of compound

3-(4-(benzyloxy)phenyl)propan-1-ol (51) was established by IR,

1H NMR,

13C NMR and Mass spectra. In IR spectrum (Fig. 2A.16) of compound

51 alcohol group observed at ν 3322 cm-1. In

1H NMR spectrum (Fig. 2A.17) the CH

protons adjacent to OH function appeared at ß 3.63 (2H, t, 7.0

Hz). Additionally, the structure of 51 was supported by

2

13C NMR spectrum (Fig. 2A.18) which showed signals at ß 157.4, 137.5,

134.8, 129.9, 129.0, 128.2, 127.6, 115.0, 70.0, 61.2, 34.8, and

30.8. Finally it was also confirmed by ESI MS (Fig. 2A.19) showed

signal at m/z 243 [M+H]+. The treatment of compound 51 with PCC in DCM afforded the

compound 3-(4- (benzyloxy)phenyl)propanal (46) in 81 % yield (Eq.

2.6).

Eq. 2.6:

31


Section A

The aldehyde 46 was converted to

1-(benzyloxy)-4-(but-3-enyl)benzene (52) by treating with C

Eq. 2.7:

1 Wittig salt in THF with n-BuLi at -78

53

oC (Eq. 2.7).

The formation of compound 52 was established by IR, 1

32

H NMR, 13

C NMR and Mass spectra. In IR spectrum (Fig. 2A.20) presence of

a band at ν 1460 cm -1and absence of band at ν 3322 cm-1indicated the unsaturation in the compound. The

1H NMR spectrum (Fig. 2A.21) showed three olefinic protons at ß 5.80

(1H, m), 5.02 (1H, m) and 4.86 (1H, m). Additionally, the structure

of 52 was supported by 13C NMR spectrum (Fig. 2A.22) which showed signals at ß 139.1 and

115.2, indicating terminal alkene group present in compound.

Finally, it was also confirmed by ESI MS (Fig. 2A.23) which showed

signal at m/z 239 [M+H]+. The treatment of compound 52 with m-CPBA in DCM afforded the

compound 2-(4- (benzyloxy)phenethyl)oxirane (53) in 86 % yield

(Eq. 2.8).

Eq. 2.8:

33

The formation of compound 53 was

established by IR, 1H NMR,

13C NMR and Mass spectra. In IR spectrum (Fig. 2A.24) the band at

ν 1460 cm -1was absent. The

1H NMR spectrum (Fig. 2A.25) showed that three olefinic protons at

ß 5.80(1H, m), 5.02 (1H, m) and 4.86 (1H, m) are absent.

Additionally, the structure of 53 was supported by 13C NMR spectrum (Fig. 2A.26) which showed signals at ß 51.3 and 46.0,

indicating absence of terminal alkene in compound. Finally, it

was also confirmed by ESI MS (Fig. 2A.27) which shows signal at

m/z 255 [M+H] +.


Section A

The racemic epoxide 53 was converted to diastereomerically pure

epoxide by means of Jacosen’s hydrolytic kinetic resolution

reaction conditions which would be given the compound

(S)-2-(4-(benzyloxy)phenethyl)oxirane (45) in 45 % yield (Eq.

2.10)

54

34 as a yellow liquid [a]D 25

= -4.6 (c = 1.0 M, CHCl3).

Eq. 2.10: According to Jacobsens,

initially, (S, S salen)Co

IItreated with AcOH in toluene at rt which could be given (S, S

salen)CoOAc (Fig. 2.19) as dark brown solid (Eq. 2.9).

Eq. 2.9:

Fig.

2.19:



13C NMR and Mass spectra. In IR spectrum (Fig. 2A.24) the band at

ν 1460 cm -1was absent. The

1H NMR spectrum (Fig. 2A.25) showed that two diastereomeric protons

present at ß 2.41 (1H, m), 2.29 (1H, m) and 1.79 (1H, m) indicating

the presence of epoxide. Additionally, the structure of 45 was

supported by 13C NMR spectrum (Fig. 2A.26) which showed signals

at ß 51.3 and 46.1indicating terminal epoxide present in compound.

Finally, it was also confirmed by ESI MS (Fig. 2A.27) which showed

signal at m/z 255 [M+H]

+and showed optical rotation [a]D 25

= -4.6 (c = 1.0 M, CHCl3).


Section A

Treatment of compound 45 with allyl magnesium bromide in dry THF

in the presence of CuI (I) afforded

(R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol (43) in 81 % yield

(Eq .2.11).

33

Eq. 2.11:


established by IR,

55

1H NMR, 13C NMR and Mass spectra. In IR spectrum (Fig. 2A.28) the bands were

present at ν 1637 and 1497 cm

1

-1. The

H NMR spectrum (Fig. 2A.20) showed that three olefinic protons at

ß 5.79 (1H, m), 5.02 (1H, m) and 4.92 (1H, m), indicating the

presence of terminal alkene. Additionally, the structure of 43

was supported by

13C NMR spectrum (Fig. 2A.30) which showed signals

at ß 138.7 and 114.8, indicating terminal alkene present in

compound. Finally, it was also confirmed by ESI MS (Fig. 2A.31)

which showed signal at m/z 297 [M+H]

+. The cross meta thesis of two alkenes (43 and 44) have been been

carried out successfully to obtain the diarylheptanoid by using

Grubbs 2

ndgeneration catalyst (Fig.

2.20) in dry DCM under reflux, which yields the

(R,E)-4-(7-(4-(benzyloxy)phenyl)-5- hydroxyhept-1-enyl)phenol

(54) in 68 % (Eq. 2.12).

35Eq. 2.12:


Section A

Fig. 2.20:


established by

56

1H NMR, 13C NMR and Mass spectra. The 1

H NMR spectrum (Fig. 2A.32) showed that protons at ß 7.39-7.21 (5H,

m), 7.20 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 8.0 Hz), 6.82 (2H,

d, J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 6.56 (1H, d, J = 16.0 Hz), 5.72 (1H, m) and 4.99 (2H,

s) were present, indicating the presence of compound 54.

Additionally, the structure of 54 was supported by 13

C NMR spectrum (Fig. 2A.33) which showed signals at ß 159.1, 154.7,

136.4, 134.8, 129.6, 128.7, 127.6, 126.5, 124.3, 114.9, 114.1,

71.2, 70.0, 39.8, 39.4, 31.8, and 30.8. Finally, the structure

was also confirmed by ESI MS (Fig. 2A.34) which showed signal at

m/z 389 [M+H]

+. Treatment of compound 54 with titanium tetrachloride in dry

DCM at at 0 °C afforded

(3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35) in 72 %

yield (Eq. 2.13).28

Eq. 2.13:


established by IR,

1H NMR,

13C NMR and Mass spectra. In IR spectrum (Fig. 2A.35) the bands were

present at ν 3423, 2926, 1608, 1510 and 1453 cm-1. The

1H NMR spectrum (Fig. 2A.36) showed that protons at ß 4.99 (2H, s)


Section A

were absent indicating presence of compound 35. Additionally, the

structure of 35 was supported by 13

C NMR spectrum (Fig. 2A.37) which showed signal at ß 70.0 was absent

indicating presence of compound 35. Finally, the structure was

also confirmed by ESI MS (Fig. 2A.38) which showed signal at m/z

389 [M+H]

57

+. The physical and spectral properties of 35 were found to be

identical to those reported earlier for the narural product,

(3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol.25

Our overall synthetic approaches were outlined in Scheme 12 and

Scheme 13 where the compounds were envisioned as arising from

starting material 47. The compound 44 could be generated from C

Wittig reaction of 4-hydroxy benzaldehyde and the compound 52

would be generated by C

1

Wittig reaction of 3-(4-benzyloxy)phenyl propanaldehyde.

Scheme 12:

Reagents, condition and yield: (l) PPh

3CH 2, CH2

2

Cl2, n BuLi, THF, -78 °C, 4 h, 76 %.


Section A

Scheme 13:

Reagents, conditions and yields: (a) NaH, BnBr, THF, 0 °C to

rt, 12 h, 86 %; (b) PPh

CHCOOEt, CH3 Cl2 2, rt, 8 h, 88 %; (c) NaBH

58

4, NiCl2. 6HO, MeOH, 0 °C to rt, 30 min, 86 %; (d) LiAlH

4

2

, THF, 0 °C to rt, 4 h, 83 %; (e) PCC, celite, CH2Cl, 0 °C to rt, 2 h, 81 %; (f) n-BuLi, THF, Ph

3PCH2

2

, 0 °C to rt, 4 h, 76 %; (g) m-CPBA, CH2Cl, NaHCO

3, 0 °C to rt, 3 h, 86 %; (h) (S, S salen)CoOAc (A) Dist H2

2

O, THF, 0 °C, 24 h, 45 %; (i) C

3H MgBr, CuI, THF, -78 °C, 4 h, 81 %; (j) Grubb’s 23nd

Generation catalyst (B) , CH

2Cl2, 50 °C, 4 h, 68 %; (k) TiCl4, CH2Cl2, 0 °C, 3 h, 72 %.


Section A

2A.2 EXPERIMENTAL:

General:

Spectra were recorded with the following instruments. IR:

Perkin-Elmer RX1 FT-IR spectrophotometer; 1H and

13C-NMR: Brucker 300 MHz; ESI MS: LC-MSD-Trap-SL. Optical rotation

was determined with a Jasco DIP 360 digital polarimeter. Column

chromatography was performed over silica gel (BDH 60-120 mesh)

and TLC with silica gel GF. The visualization of the spots in TLC plates was carried out

either in UV light or exposing the plates to iodine vapours or

spraying with 10 % sulfuric acid in MeOH and subsequently heating

on hot plate.

254

4-vinylphenol (44): To a stirred solution of tryphenyl phospine

alkylidine (50.05 g, 125.0 mmol ) in dry THF (30 mL) under

nitrogen at -78 °C n-BuLi (41.6 mL in 2.5 M hexane) was added

dropwise and the reaction mixture was stirred at that temperature

for few min until yellow color is generated. Now 4-hydroxy

benzaldehyde (10.0 g, 41.66 mmol) in THF (20 mL) was added dropwise

and the mixture was stirred at that temperature for 3 h. The

reaction mixture was quenched with saturated NH

Cl solution (20 mL) at 0 °C and extracted with EtOAc (2 x 50 mL).

The combined organic extracts were washed with brine, dried over

an. Na2SO4

59

4

and concentrated under reduced pressure. The residue was

purified by column chromatography (silica gel, 60-120 mesh, EtOAc

/hexane) to afforded 4-vinylphenol (7.53 g, 76 %) as light yellow

color solid.

Yield : 76 %.

IR (neat). : 1H NMR (200 MHz, CDCl3

ν 3424, 2958, 2855, 1711cm-1(Fig. 2A.1).

) : ß 7.24 (2H, d, J = 8.3 Hz), 6.73 (2H, d,

J = 8.3 Hz), 6.60 (1H, m), 5.55 (1H, d, J = 17.3

Hz), 5.08 (1H, d, J = 11.3 Hz) (Fig. 2A.2).


Section A

13C NMR (50 MHz, CDCl3) : ß 136.2, 127.6, 115.3,

111.6 (Fig. 2A.3). ESI MS : m/z 121 [M+H]

Molecular formula : C 8H8O.

60

+(Fig. 2A.4).

Elemental analysis : Found; C, 79.88; H, 6.72 %.

Calcd; C, 80.00; H, 6.66 %.

4-(benzyloxy)benzaldehyde (48)

:

To a stirred suspension of NaH (3.77 g, 163.91 mmol) in THF (70 mL) a solution of 47 (10 g, 81.96 mmol) in THF (30 mL) was added dropwise at 0 °C

under a nitrogen atmosphere. After stirring for 15 min, BnBr (10.7

mL, 90.16 mmol) was added and the reaction mixture was stirred

over night. The reaction mixture was quenched with saturated aq

NHCl (50 mL) at 0 °C and extracted with EtOAc (3 x 50 mL). The combined

organic extracts were washed with brine, dried over an. Na

4

2SOand concentrated under reduced pressure. The residue was

purified by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) to afford pure 4- (benzyloxy)benzaldehyde (14.94

g, 86 %) as a white solid.

Yield : 86 %.

IR (neat) : ν 1740, 1685, 1507, 1254 cm1H NMR (200 MHz, CDCl

13C NMR (50 MHz, CDCl

3

3

-1

4

(Fig. 2A.5).

) : ß 9.84 (1H, s), 7.79 (2H, d, J = 8.0 Hz),

7.42- 7.26 (5H, m), 7.01 (2H, d, J = 8.0 Hz),

5.12 (2H, s) (Fig. 2A.6).

) : ß 189.8, 163.5, 135.9, 132.0, 130.3, 128.7,

128.2, 127.3, 115.0, 70.0 (Fig. 2A.7).

ESI MS : m/z 213 [M+H]

Molecular formula : C 14H12O 2.

+(Fig. 2A.8).


Section A


Calcd; C, 79.25; H, 5.66 %.

(E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate

(49):

To a stirred solution of 4-(benzyloxy)benzaldehyde (14.0 g,

66.03 mmol) in dry CH2Cl(50 mL) ethyl(triphenyl phosphorylidene)acetate (31.3 g, 99.05

mmol) was added and the mixture was stirred at ambient temperature

for 8 h. The reaction mixture was extracted with EtOAc (3 x 50

mL), the combined organic extracts were washed with brine, dried

over an. Na

2

2SOand concentrated under reduced pressure. The residue on

purification by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) to afforded pure (E)-ethyl

3-(4-(benzyloxy)phenyl)acrylate (20.79 g, 88 %) as a colorless

solid.

4

Yield : 88 %.

1H NMR (200 MHz, CDCl


3

3

) : ß 7.59 (1H, d, J = 16.0 Hz), 7.42 (2H, d,

J = 8.0 Hz), 7.40-7.32 (5H, m), 6.92 (2H, d,

J = 8.0 Hz), 6.26 (1H, d, J = 16.0 Hz), 5.07 (2H,

s), 4.21 (2H, q, J = 7.0 Hz, 6.0 Hz), 1.32 (3H,

t, J = 7.0 Hz) (Fig. 2A.9).

) : ß 167.5, 160.8, 144.5, 136.9, 129.6, 128.6,

128.0, 127.4, 115.8, 115.1, 70.0, 60.2, 14.5

(Fig. 2A.10).


Molecular formula : C 18H 18

61

O3.

+(Fig. 2A.11).

Elemental analysis : Found; C, 76.65; H, 6.43 %. Calcd;

C, 76.60; H, 6.38 %.


Section A

Ethyl 3-(4-(benzyloxy)phenyl)propanoate

(50):

To a stirred solution of (E)-ethyl

3-(4-(benzyloxy)phenyl)acrylate (20.0 g, 70.9 mmol) in dry MeOH

(30 mL) under nitrogen atmosphere at 0 °C, NiCl

62

2·6HO (3.37 g, 14.18 mmol) was added. After stirring for 5 min NaBH

4

2

(5.39 g, 141.4 mmol) was added slowly (intermittently) and the

reaction mixture was stirred for 30 min. The reaction mixture was

quenched with saturated aq NHCl (10 mL) and extracted with EtOAc (3 x 30 mL). The combined

organic extracts were dried over an. Na

4

2SOand concentrated in vacuo. The residue on purification by column

chromatography (silica gel, 60-120 mesh, EtOAc/hexane) afforded

pure ethyl 3-(4-(benzyloxy)phenyl)propanoate (18.42 g, 86 %) as

colorless liquid.

Yield : 86 %.

IR(neat) : ν 1733, 1512, 1250 cm1H NMR (200 MHz, CDCl


3

3

-1

4

(Fig. 2A.12).

) : ß 7.40-7.21 (5H, m), 7.06 (2H, d, J = 8.0

Hz), 6.83 (2H, d, J = 8.0 Hz), 5.00 (2H, s),

4.09 (2H, q, J = 7.0 Hz), 2.87 (2H, t, J = 7.0

Hz), 2.52 (2H, t, J = 7.0 Hz), 1.21 (3H, t, J

= 7.0 Hz) (Fig. 2A.13).

) : ß 172.6, 157.3, 137.1, 132.8, 129.3,

128.4, 127.7, 127.2, 114.6, 69.8, 60.1, 36.2,

30.1, 15.9 (Fig. 2A.14).


Molecular formula : C 18H 20O3.

+(Fig. 2A.15).


C, 76.06; H, 7.04 %.


Section A

3-(4-(benzyloxy)phenyl)propan-1-ol

(51):

To a stirred suspension of LiAlH(2.73 g, 76.05 mmol) in dry THF (30 mL) a solution of ethyl

3-(4-(benzyloxy)phenyl)propenoate (18.0 g, 63.3 mmol) in THF

(10 mL) was added dropwise at 0 °C under nitrogen atmosphere.

After stirring for 30 min, the reaction mixture was leaved to room

temperature for 4 h. The reaction mixture was quenched with

saturated aq. Na2SO4

4

solution (20 mL) at 0 °C and extracted with EtOAc (2 x 50 mL).


an. Na2SOand concentrated under reduced pressure. The residue was


EtOAc/hexane) to afford 3-(4- (benzyloxy)phenyl)-propan-1-ol

(13.03 g, 83 %) as a colorless liquid.

4

Yield : 83 %.

IR(neat) : ν 3322, 2926, 2858, 1512, 1251 cm



3

3

63

-1(Fig. 2A.16).

) : ß 7.49-7.30 (5H, m), 7.12 (2H, d, J = 8.0

Hz), 6.91 (2H, d, J = 8.0 Hz), 5.05 (2H, s),

3.63 (2H, t, J = 7.0 Hz), 2.90 (1H, brs), 2.68

(2H, t, J = 7.0 Hz), 1.95-1.80 (2H, m) (Fig.

2A.17).

) : ß 156.9, 137.1, 134.0, 129.2, 128.3,

127.7, 127.2, 114.6, 69.8, 61.7, 34.3, 31.1

(Fig. 2A.18).


Molecular formula : C 16H18O 2.

+(Fig. 2A.19).

Elemental analysis : Found; C, 79.41; H, 7.40 %. Calcd; C,

79.34; H, 7.44 %.


Section A

3-(4-(benzyloxy)phenyl)propanal

(46):

To a stirred suspension of celite (10.0 g) in dry CH

64

2Cl(30 mL) a solution of 3-(4- (benzyloxy)phenyl)propan-1-ol (12.5

g, 51.6 mmol) in dry CH

2

2Cl(10 mL) at rt was added and followed by careful addition of PCC

(22.1 g, 103.3 mmol). The reaction mixture was allowed slowly to

rt. After stirring for 1 h, the reaction mixture was filtered

through sintered funnel with CH2Cl2

2

(2 x 30 mL), the combined organic extracts were washed with brine,

dried over an. Na 2SOand concentrated under reduced pressure. The residue was

purified by column chromatography ((silica gel, 60-120 mesh,

EtOAc/hexane) to afford aldehyde (10.41 g, 81 %) as a colorless

liquid.

4

1-(benzyloxy)-4-(but-3-enyl)benzene (52):

To a stirred solution of tryphenyl phospine alkylidine (50.05

g, 125.0 mmol ) in dry THF (30 mL) under nitrogen at -78 °C n-BuLi

(41.6 mL in 2.5 M hexane) was added dropwise and the reaction

mixture was stirred at that temperature for few min until yellow

color is generated. Now 3-(4-(benzyloxy)phenyl)propanal (10.0 g,

41.66 mmol) in THF (20 mL) was added dropwise and the reaction

mixture was stirred at that temperature for 3 h. The reaction

mixture was quenched with saturated NH



an. Na2SO4

4



EtOAc/hexane) afforded 1-(benzyloxy)-4-(but-3-enyl)benzene

(7.53 g, 76 %) as pale yellow color liquid.


Section A

Yield 76 %.

IR(neat) : ν 2925, 2855, 1460, 1376, 1250 cm



3

3

65

-1(Fig. 2A.20).

) : ß 7.41-7.19 (5H,m), 7.02 (2H, d, J = 8.0

Hz), 6.87 (2H, d, J = 8.0 Hz), 5.80 (1H, m),

5.02 (1H, m), 4.99 (2H, s), 4.86 (1H, m), 2.62

(2H, t, J = 7.0 Hz), 2.39-2.22 (2H, m) (Fig.

2A.21).

) : ß 157.8, 137.9, 137.5, 133.9, 129.3,

128.5, 127.7, 127.2, 115.0, 114.7, 69.8, 37.5,

32.4 (Fig. 2A.22).


Molecular formula : C 17H 18O.

+(Fig. 2A.23).


C, 85.71; H, 7.53 %.

2-(4-(benzyloxy)phenethyl)oxirane

(53):

To a stirred solution of compound 52 (7.0 g, 29.4 mmol) in dry CH2Cl(10 mL) under nitrogen at 0 °C was added m-CPBA (6.07 g, 35.2

mmol) dissolved in dry CH

2

2Cl(10 mL). The reaction mixture was stirred for 2 h. After

completion of reaction, the mixture was quenched with saturated

aq. NaHCO3

2

(6 mL) and stirred for 1 h and then extracted with CH

2Cl(2 x 30 mL). The combined organic layers were dried over an. Na

2SO4

2

and concentrated in vacuo. The residue on purification by column


pure 2-(4- (benzyloxy)phenethyl)oxirane (6.91 g, 86 %) as pale

yellow liquid.


Section A

(S)-2-(4-(benzyloxy)phenethyl)oxirane

(45):

A solution of epoxide 53 (6.0 g, 23.1 mmol) and (S, S salen)CoOAc

(A) (0.076 g, 0.12 mmol) in THF (30 mL) was stirred at 0 °C for

5 min and then distilled water (229 mL, 12.7 mmol) was added. After

stirring for 24 h, this mixture was concentrated and purified by

column chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to

afford 45 (2.3 g, 45 %) as a yellow liquid.

Yield : 45 %.

[a]D 25

: -4.6 (c = 1.0 M, CHCl

66

3).

IR(neat) : ν 2926, 2854, 1730, 1253 cm



3

3

-1(Fig. 2A.24).

) : ß 7.45-7.24 (5H, m), 7.08 (2H, d, J = 8.0

Hz), 6.84 (2H, d, J = 8.0 Hz), 5.02 (2H, s),

2.88 (1H, m), 2.80-2.60 (2H, m), 2.41 (1H, m),

2.28 (1H, m), 1.80 (1H, m), 1.59 (1H, m) (Fig.

2A.25).

) : ß 155.4, 137.5, 134.1, 129.8, 128.5,

127.8, 127.3, 114.9, 70.2, 51.3, 47.1, 34.8,

31.5(Fig. 2A.26).


Molecular formula : C 17H 18O 2.

+(Fig. 2A.27).


80.32; H, 7.09 %.

(R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol

(43):


Section A

A round-bottomed flask was charged with copper(I) iodide (0.28

g, 1.46 mmol), gently heated under vacuum, and then slowly cooled

under a flow of N. THF (10 mL) was then added and the resulting suspension was

cooled to -78 °C and stirred for few minutes and allyl magnesium

bromide (9.4 mL in 1M THF) was added. A solution of epoxide 45

(2.0 g, 7.8 mmol) in THF (10 mL) was added to the above reagent

and the mixture was stirred at -78 °C for 4 h. After consumption

of starting material, the reaction mixture was quenched with

saturated aq. NH

67

4

2

Cl. The water layer was extracted with EtOAc (50 mL) and the

combined organic layers were washed with brine, dried over an.

Na2SOand concentrated in vacuo. The residue on purification by column


(R)-1-(4- (benzyloxy)phenyl)hept-6-en-3-ol (1.88 g, 81 %) as

yellow color liquid.

4

Yield 81 %. D 25

[a] : + 10.3 (c = 1.0 M, CHCl ). 3

IR(neat) : ν 3451, 2925, 2855, 1637, 1459 cm



3

3

-1(Fig. 2A.28).

) : ß 7.41-7.23 (5H, m), 7.04 (2H, d, J = 8.0

Hz), 6.82 (2H, d, J = 8.0 Hz), 5.78 (1H, m),

5.02 (1H, m), 5.00 (2H, s), 4.92 (1H, m),

3.59 (1H, m), 2.75-2.52 (2H, m), 2.20-2.05

(2H, m), 1.75-1.63 (2H, m), 1.58-1.40 (2H, m)

(Fig. 2A.29).

) : ß 157.1, 138.7, 137.5, 134.8, 129.6,

128.5, 127.0, 127.3, 115.0, 114.8, 70.4, 69.8,

39.8, 36.7, 31.2, 30.1(Fig. 2A.30).

ESI MS : m/z 297 [M+H]+

(Fig. 2A.31). Molecular formula : C

20H 24O2.


81.08; H, 8.12 %.


Section A

(R,E)-4-(7-(4-(benzyloxy)phenyl)-5-hydroxyhept-1-enyl)phenol

(54):

A solution of compound 43 (0.5 g, 1.68 mmol) and compound 44

(0.506 g, 4.22 mmol) in dry CH2Cl2 (50 mL) was first bubbled with Nflow, after which Grubbs second generation catalyst (0.045 g,

0.054 mmol) was added at once and the resulting mixture was heated

under N2

68

2

at 50 °C for 4 h. After cooling, the reaction mixture was

extracted with EtOAc (2 x 50 mL). The combined organic extracts

were washed with brine, dried over anhydrous Na2SOand concentrated under reduced pressure. The residue on

purification by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) afforded

(R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol (54) (0.348 g, 68 %)

as yellow color liquid.

4

Yield : 68 %. D 25

[a]1

: + 2.9 (c = 1.0 M, CHCl

H NMR (200 MHz, CDCl


3

3

3).

) : ß 7.4-7.25 (5H, m), 7.20 (2H, d, J = 8.0

Hz), 7.01 (2H, d, J = 8.0 Hz), 6.78 (2H, d,

J = 8.0 Hz), 6.68 (2H, d, J = 8.0

Hz), 6.56 (1H, d, J = 16.0 Hz),

5.72 (1H, m), 4.99 (2H, s), 3.58

(1H, m), 2.58 (2H, t, J = 7.0 Hz),

2.30-2.02 (4H, m), 1.78-1.58 (2H,

m), 1.48-1.30 (2H, m) (Fig.

2A.32). ) : ß 159.1, 154.7, 136.4, 134.8, 129.6, 128.7,

127.6, 126.5, 124.3, 114.9, 114.1, 71.2, 70.0,

39.8, 39.4, 31.8, 30.8 (Fig. 2A.33).



+(Fig. 2A.34).


Section A


80.41; H, 7.22 %.

(3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol

(35):

To a solution of 54 (0.30 g, 0.77 mmol) in dry CH

69

2Cl(5 mL) was added a solution of TiCl

4 (0.16 mL, 2.64 mmol) in dry CH2Cl2

2

(5 mL) under Nat 0 °C. The reaction was monitored by TLC until the starting

material was consumed. Water was added and the compound was

extracted into CH2Cl2

2

. The combined organic extract was washed with brine, dried over

an. Na 2SO. The solvent was removed under reduced pressure and the crude

mass purified by silica gel chromatography (EtOAc/hexane)

afforded pure compound 35 (0.22 g, 72 %) as yellow color liquid.

4

Yield : 72 %. D 25

[a] : + 15.5 (c = 3.0 M, CHCl ). 3

IR (neat) : ν 3423, 2926, 1608, 1510, 1453 cm



3

3

-1(Fig. 2A.35).

) : ß 7.22 (2H, d, J = 8.0 Hz), 7.02 (2H, d,

J = 8.0 Hz), 6.83 (2H, d, J = 8.0 Hz), 6.72 (2H,

d, J = 8.0 Hz), 6.58 (1H, d, J = 16.0 Hz), 5.82

(1H, m), 3.59 (1H, m), 2.78 (1H, m), 2.28 (1H,

m), 2.22-2.01 (2H, m), 1.79-1.61 (2H, m),

1.59-1.48 (2H, m) (Fig. 2A.36).

) : ß 159.2, 156.7, 135.8, 134.6, 129.5,

128.8, 127.5, 126.4, 114.9, 70.0, 39.6, 39.3,

30.8, 30.2 (Fig. 2A.37).

ESI MS : m/z 299 [M+H]+(Fig. 2A.38).


Section A

Molecular formula : C

70

19H 22O3.


76.51; H, 7.38 %.

Total synthesis of (3R)-1,7-bis(4-hydroxyphenyl)-(6E)-6-heptene-3-ol Chapter ΙI: Section B

Section B: Stereoselective total synthesis of

(3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6- ene-3-ol through Wittig olefination.

2B.1 PRESENT WORK: Our second approach to the target molecule

involved Wittigs olefination, hydrolytic kinetic resolution of

a racemic epoxide and hydroxylation reactions as the key steps.

Our retrosynthetic approaches to this diarylheptanoid is outlined

in scheme 14. Scheme 14:

The treatment of compound 43 (previously prepared, see pages

50-55) with OsO

, NMO in aq. acetone afforded the compound 57 in 83 % yield (Eq.

2.14).

Eq. 2.14: The formation of compound 57 was

established by IR,

71

1H NMR,

13

36

4

C NMR and Mass spectra. In IR spectrum (Fig. 2B.1), the bands

observed at ν 3390, 2928, 1744 cm -1. The


1H NMR spectrum (Fig. 2B.2) showed that three olefinic protons at

ß 5.80 (1H, m), 5.02 (1H, m) and 4.86 (1H, m) are absent.

Additionally, the structure of 57 was supported by 13C NMR spectrum (Fig. 2B.3) which showed signals at ß 51.3 and 46.0.

Finally, it was also confirmed by ESI MS (Fig. 2B.4) which showed

signal at m/z 331 [M+H]

72

+. The treatment of compound 57 with NaIO

55 in 79 % yield (Eq.2.15).37

4, NaHCO3 in DCM afforded the compound

Eq.2.15: The treatment of compound 55 with commercially

available 4-hydroxy phosphonium ylide afforded the compound 54

in 73 % yield (Eq. 2.16).

Eq. 2.16:

28


established by 1H NMR,

13C NMR and Mass spectra. The

1H NMR spectrum (Fig. 2B.5) showed that protons at ß 7.39-7.21 (5H,

m), 7.20 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 8.0 Hz), 6.82 (2H,

d, J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 6.56 (1H, d, J = 16.0 Hz), 5.72 (1H, m) and 4.99 (2H,

s) were present, indicating the presence of compound 54.


C NMR spectrum (Fig. 2B.6) which showed signals at ß 159.1, 154.7,

136.4, 134.8, 129.6, 128.7, 127.6, 126.5, 124.3, 114.9, 114.1,

71.2, 70.0, 39.8, 39.4, 31.8, 30.8 indicating presence of

compound 54. Finally, it was also confirmed by ESI MS (Fig. 2B.7) which shows signal at m/z 389 [M+H]+.


The compound 54 was deprotected as reported earlier to obtain 35. [a]

73

D 25 = + 15.5 (c = 3.0 M, CHCl

). The optical and spectral properties of the compounds were

identical to those of the naturally occurring bioactive

diarylheptanoid, (3R,6E)-1,7-bis(4-

hydroxyphenyl)-hept-6-ene-3-ol.

3

25 Our second synthetic approaches were overally outlined in

scheme 15 where the compounds were envisioned as arising from two

starting materials 55 and 56. The compound 55 would be generated

by hydroxylation and oxidative cleavage of chiral alcohol (43)

and the compound 56 was commercially available.

Scheme 15: Reagents,

conditions and yields: (a) OsO

4, NMO, aq. acetone, rt, 4 h (b) NaIO, NaHCO

3, CH2Cl, rt, 2 h. 2

4

Conclusion: In conclusion, we have developed the first

stereoselective total synthesis of the natural bioactive

heptanoid, (3R)-1,7-bis(4-hydroxyphenyl)-(6E)-6-heptin-3-ol

starting from commercially available, 4-hydroxy benzaldehyde

through two different approaches employing hydrolytic kinetic

resolution of a racemic epoxide, Wittig olefination and olefin cross

metathesis reaction as the key steps. Both the synthetic methods

are simple and can be utilized for the generation of various

analogues of 1.


2B.2 EXPERIMENTAL:

General:

Spectra were recorded with the following instruments. IR:

Perkin-Elmer RX1 FT-IR spectrophotometer; 1H and

13C-NMR: Varian Gemini 200 MHz, Brucker 300 MHz, Varian 400 MHz;

ESI MS: LC-MSD-Trap-SL. Optical rotation was determined with a

Jasco DIP 360 digital polarimeter. Column chromatography was

performed over silica gel (BDH 60-120 mesh) and TLC with silica

gel GF. The visualization of the spots in TLC plates was carried out

either in UV light or exposing the plates to iodine vapours or

spraying with 10 % sulfuric acid in MeOH and subsequently heating

on hot plate.

74

254

(5S)-7-(4-(benzyloxy)phenyl)heptane-1,2,5-triol (57): To stirred

solution of 43 (1.0 g, 3.37 mmol) in aq acetone (10 mL) was added

NMO (1.2 g, 10.13 mmol) followed by OsO

(2.5 wt % in isobutanol). The reaction mixture was stirred for

3 h. After completion of reaction, the mixture was quenched with

saturated NaHSO3

4

(5 mL) and stirred for 30 min and then extracted with EtOAc (3

x 20 mL). The combined organic layers were washed with brine, dried

over an. Na2SOand concentrated in vacuo. The crude mass purified by column


pure compound 57 (0.92 g, 83 %) as yellow color liquid.

Yield 83 %.

IR (neat) : ν 3390, 2928, 1744 cm1H NMR (200 MHz, CDCl3

-1(Fig. 2B.1).

4

) : ß 7.48-7.29 (5H, m), 7.10 (2H, t, J = 8.0

Hz), 6.90 (2H, d, J = 8.0 Hz), 5.02 (1H, s),

4.29 (1H, d, J = 12.0, 4.0 Hz), 4.13 (1H,

dd, J = 12.0, 7.0 Hz), 3.49 (1H, m), 3.37

(1H, m), 2.68-2.52 (2H, m), 1.64-1.45 (6H,

m) (Fig. 2B.2).



ESI MS

3) : 167.2, 138.1, 136.9, 134.7, 133.9,

133.1, 132.9, 127.5, 114.8, 73.9,

72.7, 72.1, 71.1, 39.1, 34.6, 33.9,

29.2 (Fig. 2B.3). : m/z 331 [M+H]

Molecular formula : C 20H26O

75

4.

+(Fig. 2B.4).

Elemental analysis : Found: C, 72.64; H 7.93 %. Cald:

C, 72.73; H, 7.88 %.

(S)-6-(4-(benzyloxy)phenyl)-4-hydroxyhexanal

(55).

To a stirred solution of 57 (0.9 g, 2.72 mmol) in dry CH2Cl(10 mL) at 0 °C aq. NaHCO

3

2

(5 mL) was added and followed by careful addition of NaIO(1.1 g, 5.45 mmol). The reaction mixture was allowed slowly to

rt. After stirring for 2 h, Na

4

2SO(1.0 g) was added and stirred vigorously for 30 min. The reaction

mixture was filtered through sintered funnel with CH

2Cl2

4

(2 x 30 mL). The combined organic extracts were washed with brine,

dried over an. Na 2SOand concentrated under reduced pressure. The residue was


EtOAc/hexane) to afford aldehyde (55) as yellow color liquid.

4

(R,E)-4-(7-(4-(benzyloxy)phenyl)-5-hydroxyhept-1-enyl)phenol (54):

To a stirred

solution of C

25HOP (2.9 g, 6.03 mmol) in dry THF (10 mL) under nitrogen at -78

°C n-BuLi (2.0 mL in 2.5 M hexane) was added dropwise and the

reaction mixture was stirred at that temperature for few minutes

until yellow color is generated.

21


Later, aldehyde was added dropwise and the reaction mixture was

stirred at that temperature for 4 h. The reaction mixture was

quenched with saturated aq NH



an. Na2SO

76

4

4



EtOAc/hexane) to afforded (54) as pale yellow color liquid (0.52

g, 73 %).

Yield : 73 %. D 25

[a]1

: + 2.9 (c = 1.0 M, CHCl

H NMR (200 MHz, CDCl


3

3

3).

) : ß 7.4-7.25 (5H, m), 7.20 (2H, d, J = 8.0

Hz), 7.01 (2H, d, J = 8.0 Hz), 6.78 (2H, d,

J = 8.0 Hz), 6.68 (2H, d, J = 8.0

Hz), 6.56 (1H, d, J = 16.0 Hz),

5.72 (1H, m), 4.99 (2H, s), 3.58

(1H, m), 2.58 (2H, t, J = 7.0 Hz),

2.30-2.02 (4H, m), 1.78-1.58 (2H,

m), 1.48-1.30 (2H, m) (Fig. 2B.5). ) : ß 159.1, 154.7, 136.4, 134.8, 129.6, 128.7,

127.6, 126.5, 124.3, 114.9,

114.1, 71.2, 70.0, 39.8, 39.4,

31.8, 30.8 (Fig. 2B.6). ESI MS : m/z 389 [M+H]


+(Fig. 2B.7).


80.41; H, 7.22 %. The compound 54 was deprotected as

reported earlier to obtain 35 [a]D 25

= + 15.5 (c = 3.0 M, CHCl

). The optical and spectral properties of the compounds were

identical to those of the naturally occurring bioactive

diarylheptanoid, (3R,6E)-1,7-bis(4-


3

Total synthesis of (3R)-1, 7-bis (4-hydroxyphenyl)-(6E)-6-heptene-3-ol Chapter ΙI: References

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Whiting. J. Chem. Soc. Perkin Trans. 1973, I, 2379. 4 K. K. Lee, B.

D. Bahler, G. A. Hofmann, M. R. Mattern, R. K. Johnson and D. G.

I. Kingston. J. Nat. Prod. 1998, 61, 1407. 5 E. Vogel and S.

Pelletier. J. Pharm. 1815, 2, 50. 6 A. Gescher, U. Pastorino, S.

M. Plummer and M. M. B. Manson. J. Clin. Pharm.

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79

Total synthesis of (3R,6E)-1,7-bis(4-hydroxy phenyl)-hept-6-ene-3-ol Chapter ΙI: Section A

49

HO

OH

OH

35

Stereoselective Total Synthesis of (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-ene-3-ol

through cross metathesis.

2A.1 PRESENT WORK:

Recently, a diarylheptanoid, (3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35)

has been isolated in a very small quantity from the rhizomes of Curcuma kwangrsiensis

(Zingiberaceae).25

The compound was evaluated for its inhibitory effect on NO

production induced by lipopolysaccaride-activated macrophages. The activity of the

compound was found to be close to that of Indomethacin and Hydrocortisone.25

In continuation of the work 26

in our laboratory on the construction of bioactive

natural products, herein we report the stereoselective first total synthesis of (3R,6E)-1,7-

bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35). Our planned approach to the target molecule

involved Wittigs olefination, hydrolytic kinetic resolution of a racemic epoxide and olefin

cross metathesis reaction as the key steps. Our retrosynthetic approaches to this

diarylheptanoid is outlined in Scheme 11.

Scheme 11:

HO

OH

OH BnO

OH

43

+

OH

BnO

45

44

BnO

CHO

46

H

O

HO

47

35

O


50

Our synthesis was started from commercially available 4-hydroxy benzaldehyde (47),

which was converted to 4-vinylphenol (44) by treating with C1 Wittig salt in THF with n-

BuLi at -78 oC (Eq. 2.1).

27

Eq. 2.1:

The formation of compound 44 was established by IR, 1H NMR,

13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.1) the bands were present at ν 3424, 2958, 2855, 1711

cm-1

. The 1H NMR spectrum (Fig. 2A.2) showed three proton signals at δ 6.60 (1H, m),

5.55(1H, d, J = 17.3 Hz), 5.08 (1H, d, J = 11.3 Hz), indicating compound 44.


C NMR spectrum (Fig. 2A.3) which

showed signals at δ136.2, 127.6, 115.3 and 111.6. Finally, the structure was also

confirmed by ESI MS (Fig. 2A.4) which showed signal at m/z 121[M+H]+.

Aldehyde 47 was protected with benzyl bromide by using NaH in DCM to afford the

corresponding benzyl protected aldehyde in 86 % yield (Eq. 2.2).28

Eq. 2.2:

The formation of compound 4-(benzyloxy)benzaldehyde (48) was explained by IR,

1H NMR,

13C NMR and Mass spectra. In IR spectrum of compound 48 (Fig. 2A.5), the

bands were observed at ν 1740, 1685, 1507, 1254 cm-1

. The 1H NMR spectrum (Fig.

2A.6) showed proton signals at δ 5.12 (2H, s) and phenyl protons at δ 7.42-7.26 (5H, m).

H

O

HO

47

OH

44

P+Ph3CH

2-, THF

n-BuLi, -78 °C,

4 h

76 %

H

O

HO

H

BnO47

O

48

NaH, BnBr,

THF, 0 °C to rt,12 h

86 %


51


C NMR spectrum (Fig. 2A.7) which

showed signal at δ 70.0 indicating presence of benzylic carbon and δ 135.6, 128.7, 128.2,

126.5 indicating the presence of phenyl ring in the compound. Finally it was also

confirmed by ESI MS signal (Fig. 2A.8) at m/z 213 [M+H]+.

The aldehyde 48 was converted to (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (49) by

treating with C2 Wittig salt in DCM at rt (Eq. 2.3).28

Eq. 2.3:

The formation of compound 49 was explained by 1H NMR,

13C NMR and Mass

spectra. The 1H NMR spectrum (Fig. 2A.9) showed two olefinic proton signals at δ 7.59

(1H, d, J = 16.0 Hz) 6.26 (1H, d, J = 16.0 Hz). Additionally, the structure of 49 was

supported by 13

C NMR spectrum (Fig. 2A.10) which showed signals at δ 167.2, 144.5

and 116.0, indicating α,β-unsaturated ester moiety present in the compound. Finally the

structure was also confirmed by ESI MS signal (Fig. 2A.11) at m/z 283 [M+H]+.

Treatment of compound 49 with NaBH4, NiCl2·6H2O in MeOH afforded ethyl 3-(4-

(benzyloxy)phenyl)propanoate (50) in 86 % yield (Eq. 2.4).29

Eq. 2.4:

The formation of compound 50 was confirmed by IR, 1H NMR,

13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.12) the sample ester group was observed at ν 1733 cm-1

.

BnO

49

O

OEt

BnO

50

O

OEtNaBH4, NiCl2. 6H2O,

MeOH, 0 °C to rt,

30 min

86 %

H

BnO

O

48

BnO

49

O

OEtP+Ph3CH-COOEt,

CH2Cl

2, rt,

8 h

88 %


52

In 1H NMR spectrum (Fig. 2A.13) the two olefinic signals were disappeared at δ 7.59,

6.26. Additionally, the structure of 50 was supported by 13

C NMR spectrum (Fig. 2A.14)

which showed signals at δ 172.6, 157.5, 137.5, 133.2, 129.8, 129.0, 127.9, 127.2, 115.2,

70.2, 60.1, 35.8, 30.1 and 15.9, indicating the absence of signals at 144.5, 116.0 which

can indicate the α,β-unsaturated ester moiety was absent. Finally, it was also confirmed

by ESI MS signal (Fig. 2A.15) at m/z 285 [M+H]+.

The treatment of compound 50 with LAH in dry THF afforded the compound 51 in

83 % yield (Eq. 2.5).30

Eq. 2.5:

The formation of compound 3-(4-(benzyloxy)phenyl)propan-1-ol (51) was


13C NMR and Mass spectra. In IR spectrum (Fig. 2A.16) of

compound 51 alcohol group observed at ν 3322 cm-1

. In 1H NMR spectrum (Fig. 2A.17)

the CH2 protons adjacent to OH function appeared at δ 3.63 (2H, t, 7.0 Hz). Additionally,

the structure of 51 was supported by 13

C NMR spectrum (Fig. 2A.18) which showed

signals at δ 157.4, 137.5, 134.8, 129.9, 129.0, 128.2, 127.6, 115.0, 70.0, 61.2, 34.8, and

30.8. Finally it was also confirmed by ESI MS (Fig. 2A.19) showed signal at m/z 243

[M+H]+.

The treatment of compound 51 with PCC in DCM afforded the compound 3-(4-

(benzyloxy)phenyl)propanal (46) in 81 % yield (Eq. 2.6).31

Eq. 2.6:

BnO

50

O

OEt

BnO

51

OHLiAlH4, THF,

0 °C to rt,

4 h

83 %

BnO

51

OH

BnO

46

CHOPCC, celite,

CH2Cl2,

0 °C to rt,

2 h81 %


53

The aldehyde 46 was converted to 1-(benzyloxy)-4-(but-3-enyl)benzene (52) by

treating with C1 Wittig salt in THF with n-BuLi at -78 oC (Eq. 2.7).

32

Eq. 2.7:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.20) presence of a band at ν 1460 cm-1

and absence of

band at ν 3322 cm-1

indicated the unsaturation in the compound. The 1H NMR spectrum

(Fig. 2A.21) showed three olefinic protons at δ 5.80 (1H, m), 5.02 (1H, m) and 4.86 (1H,

m). Additionally, the structure of 52 was supported by 13

C NMR spectrum (Fig. 2A.22)

which showed signals at δ 139.1 and 115.2, indicating terminal alkene group present in

compound. Finally, it was also confirmed by ESI MS (Fig. 2A.23) which showed signal

at m/z 239 [M+H]+.

The treatment of compound 52 with m-CPBA in DCM afforded the compound 2-(4-

(benzyloxy)phenethyl)oxirane (53) in 86 % yield (Eq. 2.8).33

Eq. 2.8:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.24) the band at ν 1460 cm-1

was absent. The 1H NMR

spectrum (Fig. 2A.25) showed that three olefinic protons at δ 5.80(1H, m), 5.02 (1H, m)

and 4.86 (1H, m) are absent. Additionally, the structure of 53 was supported by 13

C NMR

spectrum (Fig. 2A.26) which showed signals at δ 51.3 and 46.0, indicating absence of

terminal alkene in compound. Finally, it was also confirmed by ESI MS (Fig. 2A.27)

which shows signal at m/z 255 [M+H]+.

BnO

52

BnO

53

Om-CPBA, CH2Cl2,

NaHCO3, 0 °C to rt,

3 h

86 %

BnO

46

CHO

BnO

52

n-BuLi, THF,

Ph3PCH2,

-78 °C to rt,

4 h76 %


54

The racemic epoxide 53 was converted to diastereomerically pure epoxide by means

of Jacosen’s hydrolytic kinetic resolution reaction conditions which would be given the

compound (S)-2-(4-(benzyloxy)phenethyl)oxirane (45) in 45 % yield (Eq. 2.10) 34

as a

yellow liquid [α]D25

= -4.6 (c = 1.0 M, CHCl3).

Eq. 2.10:

According to Jacobsens, initially, (S, S salen)CoII treated with AcOH in toluene at rt

which could be given (S, S salen)CoOAc (Fig. 2.19) as dark brown solid (Eq. 2.9).

Eq. 2.9:

Fig. 2.19:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.24) the band at ν 1460 cm-1

was absent. The 1H NMR

spectrum (Fig. 2A.25) showed that two diastereomeric protons present at δ 2.41 (1H, m),

2.29 (1H, m) and 1.79 (1H, m) indicating the presence of epoxide. Additionally, the


C NMR spectrum (Fig. 2A.26) which showed signals

at δ 51.3 and 46.1indicating terminal epoxide present in compound. Finally, it was also

confirmed by ESI MS (Fig. 2A.27) which showed signal at m/z 255 [M+H]+ and showed

optical rotation [α]D25

= -4.6 (c = 1.0 M, CHCl3).

N N

O

tBu

O

tBu

tButBu

Co

OAc

H H

Catalyst A

BnO

53

BnO

45

OO

S ,S-Salen-Co-(OAc) (A),

Dist H2O, THF, 0 °C,

24 h

45 %

(S,S- Salen)Co + AcOH + 1/4O2 (S,S- Salen)CoOAc (A) + 1/2H2O


55

Treatment of compound 45 with allyl magnesium bromide in dry THF in the presence

of CuI (I) afforded (R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol (43) in 81 % yield (Eq

.2.11). 33

Eq. 2.11:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.28) the bands were present at ν 1637 and 1497 cm-1

. The

1H NMR spectrum (Fig. 2A.20) showed that three olefinic protons at δ 5.79 (1H, m), 5.02

(1H, m) and 4.92 (1H, m), indicating the presence of terminal alkene. Additionally, the


C NMR spectrum (Fig. 2A.30) which showed signals

at δ 138.7 and 114.8, indicating terminal alkene present in compound. Finally, it was also

confirmed by ESI MS (Fig. 2A.31) which showed signal at m/z 297 [M+H]+.

The cross meta thesis of two alkenes (43 and 44) have been been carried out

successfully to obtain the diarylheptanoid by using Grubbs 2nd

generation catalyst (Fig.

2.20) in dry DCM under reflux, which yields the (R,E)-4-(7-(4-(benzyloxy)phenyl)-5-

hydroxyhept-1-enyl)phenol (54) in 68 % (Eq. 2.12).35

Eq. 2.12:

BnO 54

OH

BnO

43

OH

OH

+

OH

Grubb's

2nd Generation

catalyst (B),

CH2Cl2, 50 °C,

4 h4468 %

BnO

45

BnO43

OOH

C3H

3MgBr,

CuI, THF, -78 °C,

4 h

81 %


56

Fig. 2.20:

The formation of compound 54 was established by 1H NMR,

13C NMR and Mass

spectra. The 1H NMR spectrum (Fig. 2A.32) showed that protons at δ 7.39-7.21 (5H, m),

7.20 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 8.0 Hz), 6.82 (2H, d, J = 8.0 Hz), 6.68 (2H, d, J

= 8.0 Hz), 6.56 (1H, d, J = 16.0 Hz), 5.72 (1H, m) and 4.99 (2H, s) were present,

indicating the presence of compound 54. Additionally, the structure of 54 was supported

by 13

C NMR spectrum (Fig. 2A.33) which showed signals at δ 159.1, 154.7, 136.4,

134.8, 129.6, 128.7, 127.6, 126.5, 124.3, 114.9, 114.1, 71.2, 70.0, 39.8, 39.4, 31.8, and

30.8. Finally, the structure was also confirmed by ESI MS (Fig. 2A.34) which showed

signal at m/z 389 [M+H]+.

Treatment of compound 54 with titanium tetrachloride in dry DCM at at 0 °C

afforded (3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35) in 72 % yield (Eq.

2.13).28

Eq. 2.13:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2A.35) the bands were present at ν 3423, 2926, 1608, 1510

and 1453 cm-1

. The 1H NMR spectrum (Fig. 2A.36) showed that protons at δ 4.99 (2H, s)

Ru

Ph

P(Cy)3

Cl

Cl

N N

Catalyst B

(Grubbs' 2nd generation)

HO 35

OH

OHBnO 54

OH

OH

TiCl4, CH2Cl2,

0 °C, 3 h

72 %


57

were absent indicating presence of compound 35. Additionally, the structure of 35 was

supported by 13

C NMR spectrum (Fig. 2A.37) which showed signal at δ 70.0 was absent

indicating presence of compound 35. Finally, the structure was also confirmed by ESI

MS (Fig. 2A.38) which showed signal at m/z 389 [M+H]+.

The physical and spectral properties of 35 were found to be identical to those reported

earlier for the narural product, (3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol.25

Our overall synthetic approaches were outlined in Scheme 12 and Scheme 13 where

the compounds were envisioned as arising from starting material 47. The compound 44

could be generated from C1 Wittig reaction of 4-hydroxy benzaldehyde and the

compound 52 would be generated by C2 Wittig reaction of 3-(4-benzyloxy)phenyl

propanaldehyde.

Scheme 12:

Reagents, condition and yield: (l) PPh3CH2, CH2Cl2, n BuLi, THF, -78 °C, 4 h, 76 %.

H

O

HO

l

47

OH

44


58

Scheme 13:

Reagents, conditions and yields: (a) NaH, BnBr, THF, 0 °C to rt, 12 h, 86 %; (b)

PPh3CHCOOEt, CH2Cl2, rt, 8 h, 88 %; (c) NaBH4, NiCl2. 6H2O, MeOH, 0 °C to rt, 30

min, 86 %; (d) LiAlH4, THF, 0 °C to rt, 4 h, 83 %; (e) PCC, celite, CH2Cl2, 0 °C to rt, 2

h, 81 %; (f) n-BuLi, THF, Ph3PCH2, 0 °C to rt, 4 h, 76 %; (g) m-CPBA, CH2Cl2,

NaHCO3, 0 °C to rt, 3 h, 86 %; (h) (S, S salen)CoOAc (A) Dist H2O, THF, 0 °C, 24 h, 45

%; (i) C3H3MgBr, CuI, THF, -78 °C, 4 h, 81 %; (j) Grubb’s 2nd

Generation catalyst (B) ,

CH2Cl2, 50 °C, 4 h, 68 %; (k) TiCl4, CH2Cl2, 0 °C, 3 h, 72 %.

H

O

HO

BnO

BnO

OH

BnO

CHO

BnO

OH

BnO BnO

OH

k

47

51

4652

53 4543

54: R= Bn

35: R= H

BnO

OH44

OO

BnO

49

O

OEtH

BnO

O

48

BnO

50

O

OEta b c

d

ef

g

h i

j

OH


59

2A.2 EXPERIMENTAL:

General:

Spectra were recorded with the following instruments. IR: Perkin-Elmer RX1 FT-IR

spectrophotometer; 1H and

13C-NMR: Brucker 300 MHz; ESI MS: LC-MSD-Trap-SL.

Optical rotation was determined with a Jasco DIP 360 digital polarimeter. Column

chromatography was performed over silica gel (BDH 60-120 mesh) and TLC with silica

gel GF254. The visualization of the spots in TLC plates was carried out either in UV light

or exposing the plates to iodine vapours or spraying with 10 % sulfuric acid in MeOH

and subsequently heating on hot plate.

4-vinylphenol (44):

To a stirred solution of tryphenyl phospine alkylidine (50.05 g, 125.0 mmol ) in dry

THF (30 mL) under nitrogen at -78 °C n-BuLi (41.6 mL in 2.5 M hexane) was added

dropwise and the reaction mixture was stirred at that temperature for few min until

yellow color is generated. Now 4-hydroxy benzaldehyde (10.0 g, 41.66 mmol) in THF

(20 mL) was added dropwise and the mixture was stirred at that temperature for 3 h. The

reaction mixture was quenched with saturated NH4Cl solution (20 mL) at 0 °C and

extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with

brine, dried over an. Na2SO4 and concentrated under reduced pressure. The residue was

purified by column chromatography (silica gel, 60-120 mesh, EtOAc /hexane) to afforded

4-vinylphenol (7.53 g, 76 %) as light yellow color solid.

Yield : 76 %.

IR (neat). : ν 3424, 2958, 2855, 1711cm

-1(Fig. 2A.1).

1H NMR (200 MHz, CDCl3) : δ 7.24 (2H, d, J = 8.3 Hz), 6.73 (2H, d, J = 8.3

Hz), 6.60 (1H, m), 5.55 (1H, d, J = 17.3 Hz),

5.08 (1H, d, J = 11.3 Hz) (Fig. 2A.2).

OH


60

13C NMR (50 MHz, CDCl3) : δ 136.2, 127.6, 115.3, 111.6 (Fig. 2A.3).

ESI MS : m/z 121 [M+H]+ (Fig. 2A.4).

Molecular formula : C8H8O.


Calcd; C, 80.00; H, 6.66 %.

4-(benzyloxy)benzaldehyde (48) :

To a stirred suspension of NaH (3.77 g, 163.91 mmol) in THF (70 mL) a solution of

47 (10 g, 81.96 mmol) in THF (30 mL) was added dropwise at 0 °C under a nitrogen

atmosphere. After stirring for 15 min, BnBr (10.7 mL, 90.16 mmol) was added and the

reaction mixture was stirred over night. The reaction mixture was quenched with

saturated aq NH4Cl (50 mL) at 0 °C and extracted with EtOAc (3 x 50 mL). The

combined organic extracts were washed with brine, dried over an. Na2SO4 and

concentrated under reduced pressure. The residue was purified by column

chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to afford pure 4-

(benzyloxy)benzaldehyde (14.94 g, 86 %) as a white solid.

Yield : 86 %.

IR (neat) : ν 1740, 1685, 1507, 1254 cm-1

(Fig. 2A.5).

1H NMR (200 MHz, CDCl3) : δ 9.84 (1H, s), 7.79 (2H, d, J = 8.0 Hz), 7.42-

7.26 (5H, m), 7.01 (2H, d, J = 8.0 Hz), 5.12 (2H,

s) (Fig. 2A.6).

13C NMR (50 MHz, CDCl3) : δ 189.8, 163.5, 135.9, 132.0, 130.3, 128.7, 128.2,

127.3, 115.0, 70.0 (Fig. 2A.7).

ESI MS : m/z 213 [M+H]+ (Fig. 2A.8).

Molecular formula : C14H12O2.

H

BnO

O


61


Calcd; C, 79.25; H, 5.66 %.

(E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (49):

To a stirred solution of 4-(benzyloxy)benzaldehyde (14.0 g, 66.03 mmol) in dry

CH2Cl2 (50 mL) ethyl(triphenyl phosphorylidene)acetate (31.3 g, 99.05 mmol) was added

and the mixture was stirred at ambient temperature for 8 h. The reaction mixture was

extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with

brine, dried over an. Na2SO4 and concentrated under reduced pressure. The residue on

purification by column chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to

afforded pure (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (20.79 g, 88 %) as a colorless

solid.

Yield : 88 %.

1H NMR (200 MHz, CDCl3) : δ 7.59 (1H, d, J = 16.0 Hz), 7.42 (2H, d, J = 8.0

Hz), 7.40-7.32 (5H, m), 6.92 (2H, d, J = 8.0

Hz), 6.26 (1H, d, J = 16.0 Hz), 5.07 (2H, s),

4.21 (2H, q, J = 7.0 Hz, 6.0 Hz), 1.32 (3H, t, J =

7.0 Hz) (Fig. 2A.9).

13C NMR (50 MHz, CDCl3) : δ 167.5, 160.8, 144.5, 136.9, 129.6, 128.6,

128.0, 127.4, 115.8, 115.1, 70.0, 60.2, 14.5

(Fig. 2A.10).

ESI MS : m/z 283 [M+H]+ (Fig. 2A.11).



Calcd; C, 76.60; H, 6.38 %.

BnO

O

OEt


62

Ethyl 3-(4-(benzyloxy)phenyl)propanoate (50):

To a stirred solution of (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (20.0 g, 70.9

mmol) in dry MeOH (30 mL) under nitrogen atmosphere at 0 °C, NiCl2∙6H2O (3.37 g,

14.18 mmol) was added. After stirring for 5 min NaBH4 (5.39 g, 141.4 mmol) was added

slowly (intermittently) and the reaction mixture was stirred for 30 min. The reaction

mixture was quenched with saturated aq NH4Cl (10 mL) and extracted with EtOAc (3 x

30 mL). The combined organic extracts were dried over an. Na2SO4 and concentrated in

vacuo. The residue on purification by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) afforded pure ethyl 3-(4-(benzyloxy)phenyl)propanoate (18.42 g, 86 %)

as colorless liquid.

Yield : 86 %.

IR(neat) : ν 1733, 1512, 1250 cm-1

(Fig. 2A.12).

1H NMR (200 MHz, CDCl3) : δ 7.40-7.21 (5H, m), 7.06 (2H, d, J = 8.0 Hz),

6.83 (2H, d, J = 8.0 Hz), 5.00 (2H, s), 4.09

(2H, q, J = 7.0 Hz), 2.87 (2H, t, J = 7.0 Hz),

2.52 (2H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.0

Hz) (Fig. 2A.13).

13C NMR (50 MHz, CDCl3) : δ 172.6, 157.3, 137.1, 132.8, 129.3, 128.4,

127.7, 127.2, 114.6, 69.8, 60.1, 36.2, 30.1,

15.9 (Fig. 2A.14).

ESI MS : m/z 285 [M+H]+ (Fig. 2A.15).



Calcd; C, 76.06; H, 7.04 %.

BnO

O

OEt


63

3-(4-(benzyloxy)phenyl)propan-1-ol (51):

To a stirred suspension of LiAlH4 (2.73 g, 76.05 mmol) in dry THF (30 mL) a

solution of ethyl 3-(4-(benzyloxy)phenyl)propenoate (18.0 g, 63.3 mmol) in THF (10

mL) was added dropwise at 0 °C under nitrogen atmosphere. After stirring for 30 min,

the reaction mixture was leaved to room temperature for 4 h. The reaction mixture was

quenched with saturated aq. Na2SO4 solution (20 mL) at 0 °C and extracted with EtOAc

(2 x 50 mL). The combined organic extracts were washed with brine, dried over an.

Na2SO4 and concentrated under reduced pressure. The residue was purified by column

chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to afford 3-(4-

(benzyloxy)phenyl)-propan-1-ol (13.03 g, 83 %) as a colorless liquid.

Yield : 83 %.

IR(neat) : ν 3322, 2926, 2858, 1512, 1251 cm-1

(Fig.

2A.16).

1H NMR (200 MHz, CDCl3) : δ 7.49-7.30 (5H, m), 7.12 (2H, d, J = 8.0

Hz), 6.91 (2H, d, J = 8.0 Hz), 5.05 (2H, s),

3.63 (2H, t, J = 7.0 Hz), 2.90 (1H, brs),

2.68 (2H, t, J = 7.0 Hz), 1.95-1.80 (2H, m)

(Fig. 2A.17).

13C NMR (50 MHz, CDCl3) : δ 156.9, 137.1, 134.0, 129.2, 128.3, 127.7,

127.2, 114.6, 69.8, 61.7, 34.3, 31.1 (Fig.

2A.18).

ESI MS : m/z 243 [M+H]+ (Fig. 2A.19).



Calcd; C, 79.34; H, 7.44 %.

BnO

OH


64

3-(4-(benzyloxy)phenyl)propanal (46):

To a stirred suspension of celite (10.0 g) in dry CH2Cl2 (30 mL) a solution of 3-(4-

(benzyloxy)phenyl)propan-1-ol (12.5 g, 51.6 mmol) in dry CH2Cl2 (10 mL) at rt was

added and followed by careful addition of PCC (22.1 g, 103.3 mmol). The reaction

mixture was allowed slowly to rt. After stirring for 1 h, the reaction mixture was filtered

through sintered funnel with CH2Cl2 (2 x 30 mL), the combined organic extracts were

washed with brine, dried over an. Na2SO4 and concentrated under reduced pressure. The

residue was purified by column chromatography ((silica gel, 60-120 mesh,

EtOAc/hexane) to afford aldehyde (10.41 g, 81 %) as a colorless liquid.

1-(benzyloxy)-4-(but-3-enyl)benzene (52):

To a stirred solution of tryphenyl phospine alkylidine (50.05 g, 125.0 mmol ) in dry

THF (30 mL) under nitrogen at -78 °C n-BuLi (41.6 mL in 2.5 M hexane) was added

dropwise and the reaction mixture was stirred at that temperature for few min until

yellow color is generated. Now 3-(4-(benzyloxy)phenyl)propanal (10.0 g, 41.66 mmol) in

THF (20 mL) was added dropwise and the reaction mixture was stirred at that

temperature for 3 h. The reaction mixture was quenched with saturated NH4Cl solution

(20 mL) at 0 °C and extracted with EtOAc (2 x 50 mL). The combined organic extracts

were washed with brine, dried over an. Na2SO4 and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) afforded 1-(benzyloxy)-4-(but-3-enyl)benzene (7.53 g, 76 %) as pale

yellow color liquid.

BnO

CHO

BnO


65

Yield 76 %.

IR(neat) : ν 2925, 2855, 1460, 1376, 1250 cm-1

(Fig.

2A.20).

1H NMR (200 MHz, CDCl3) : δ 7.41-7.19 (5H,m), 7.02 (2H, d, J = 8.0

Hz), 6.87 (2H, d, J = 8.0 Hz), 5.80 (1H, m),

5.02 (1H, m), 4.99 (2H, s), 4.86 (1H, m),

2.62 (2H, t, J = 7.0 Hz), 2.39-2.22 (2H, m)

(Fig. 2A.21).

13C NMR (50 MHz, CDCl3) : δ 157.8, 137.9, 137.5, 133.9, 129.3, 128.5,

127.7, 127.2, 115.0, 114.7, 69.8, 37.5, 32.4

(Fig. 2A.22).

ESI MS : m/z 239 [M+H]+ (Fig. 2A.23).

Molecular formula : C17H18O.


Calcd; C, 85.71; H, 7.53 %.

2-(4-(benzyloxy)phenethyl)oxirane (53):

To a stirred solution of compound 52 (7.0 g, 29.4 mmol) in dry CH2Cl2 (10 mL)

under nitrogen at 0 °C was added m-CPBA (6.07 g, 35.2 mmol) dissolved in dry CH2Cl2

(10 mL). The reaction mixture was stirred for 2 h. After completion of reaction, the

mixture was quenched with saturated aq. NaHCO3 (6 mL) and stirred for 1 h and then

extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were dried over an.

Na2SO4 and concentrated in vacuo. The residue on purification by column

chromatography (silica gel, 60-120 mesh, EtOAc/hexane) afforded pure 2-(4-

(benzyloxy)phenethyl)oxirane (6.91 g, 86 %) as pale yellow liquid.

BnO

O


66

(S)-2-(4-(benzyloxy)phenethyl)oxirane (45):

A solution of epoxide 53 (6.0 g, 23.1 mmol) and (S, S salen)CoOAc (A) (0.076 g,

0.12 mmol) in THF (30 mL) was stirred at 0 °C for 5 min and then distilled water (229

mL, 12.7 mmol) was added. After stirring for 24 h, this mixture was concentrated and

purified by column chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to afford

45 (2.3 g, 45 %) as a yellow liquid.

Yield : 45 %.

[α]D25

: -4.6 (c = 1.0 M, CHCl3).

IR(neat) : ν 2926, 2854, 1730, 1253 cm-1

(Fig.

2A.24).


Hz), 6.84 (2H, d, J = 8.0 Hz), 5.02 (2H, s),

2.88 (1H, m), 2.80-2.60 (2H, m), 2.41

(1H, m), 2.28 (1H, m), 1.80 (1H, m), 1.59

(1H, m) (Fig. 2A.25).

13C NMR (50 MHz, CDCl3) : δ 155.4, 137.5, 134.1, 129.8, 128.5, 127.8,

127.3, 114.9, 70.2, 51.3, 47.1, 34.8,

31.5(Fig. 2A.26).

ESI MS : m/z 255 [M+H]+ (Fig. 2A.27).



Calcd; C, 80.32; H, 7.09 %.

(R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol (43):

BnO

O

BnO

OH


67

A round-bottomed flask was charged with copper(I) iodide (0.28 g, 1.46 mmol),

gently heated under vacuum, and then slowly cooled under a flow of N2. THF (10 mL)

was then added and the resulting suspension was cooled to -78 °C and stirred for few

minutes and allyl magnesium bromide (9.4 mL in 1M THF) was added. A solution of

epoxide 45 (2.0 g, 7.8 mmol) in THF (10 mL) was added to the above reagent and the

mixture was stirred at -78 °C for 4 h. After consumption of starting material, the reaction

mixture was quenched with saturated aq. NH4Cl. The water layer was extracted with

EtOAc (50 mL) and the combined organic layers were washed with brine, dried over an.

Na2SO4 and concentrated in vacuo. The residue on purification by column

chromatography (silica gel, 60-120 mesh, EtOAc/hexane) afforded (R)-1-(4-

(benzyloxy)phenyl)hept-6-en-3-ol (1.88 g, 81 %) as yellow color liquid.

Yield 81 %.

[α]D25

: + 10.3 (c = 1.0 M, CHCl3).

IR(neat) : ν 3451, 2925, 2855, 1637, 1459 cm-1

(Fig.

2A.28).


Hz), 6.82 (2H, d, J = 8.0 Hz), 5.78 (1H, m),

5.02 (1H, m), 5.00 (2H, s), 4.92 (1H, m),

3.59 (1H, m), 2.75-2.52 (2H, m), 2.20-2.05

(2H, m), 1.75-1.63 (2H, m), 1.58-1.40 (2H,

m) (Fig. 2A.29).

13C NMR (50 MHz, CDCl3) : δ 157.1, 138.7, 137.5, 134.8, 129.6, 128.5,

127.0, 127.3, 115.0, 114.8, 70.4, 69.8, 39.8,

36.7, 31.2, 30.1(Fig. 2A.30).

ESI MS : m/z 297 [M+H]+ (Fig. 2A.31).



Calcd; C, 81.08; H, 8.12 %.


68


A solution of compound 43 (0.5 g, 1.68 mmol) and compound 44 (0.506 g, 4.22

mmol) in dry CH2Cl2 (50 mL) was first bubbled with N2 flow, after which Grubbs second

generation catalyst (0.045 g, 0.054 mmol) was added at once and the resulting mixture

was heated under N2 at 50 °C for 4 h. After cooling, the reaction mixture was extracted

with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried

over anhydrous Na2SO4 and concentrated under reduced pressure. The residue on

purification by column chromatography (silica gel, 60-120 mesh, EtOAc/hexane)

afforded (R)-1-(4-(benzyloxy)phenyl)hept-6-en-3-ol (54) (0.348 g, 68 %) as yellow color

liquid.

Yield : 68 %.

[α]D25

: + 2.9 (c = 1.0 M, CHCl3).


Hz), 7.01 (2H, d, J = 8.0 Hz), 6.78 (2H, d,

J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 6.56

(1H, d, J = 16.0 Hz), 5.72 (1H, m), 4.99

(2H, s), 3.58 (1H, m), 2.58 (2H, t, J = 7.0

Hz), 2.30-2.02 (4H, m), 1.78-1.58 (2H, m),

1.48-1.30 (2H, m) (Fig. 2A.32).

13C NMR (50 MHz, CDCl3) : δ 159.1, 154.7, 136.4, 134.8, 129.6, 128.7,

127.6, 126.5, 124.3, 114.9, 114.1, 71.2,

70.0, 39.8, 39.4, 31.8, 30.8 (Fig. 2A.33).

ESI MS : m/z 389 [M+H]+ (Fig. 2A.34).


BnO

OH

OH


69


Calcd; C, 80.41; H, 7.22 %.

(3R,6E)-1,7-bis(4-hydroxyphenyl)-hept-6-ene-3-ol (35):

To a solution of 54 (0.30 g, 0.77 mmol) in dry CH2Cl2 (5 mL) was added a solution of

TiCl4 (0.16 mL, 2.64 mmol) in dry CH2Cl2 (5 mL) under N2 at 0 °C. The reaction was

monitored by TLC until the starting material was consumed. Water was added and the

compound was extracted into CH2Cl2. The combined organic extract was washed with

brine, dried over an. Na2SO4. The solvent was removed under reduced pressure and the

crude mass purified by silica gel chromatography (EtOAc/hexane) afforded pure

compound 35 (0.22 g, 72 %) as yellow color liquid.

Yield : 72 %.

[α]D25

: + 15.5 (c = 3.0 M, CHCl3).

IR (neat) : ν 3423, 2926, 1608, 1510, 1453 cm-1

(Fig.

2A.35).

1H NMR (200 MHz, CDCl3) : δ 7.22 (2H, d, J = 8.0 Hz), 7.02 (2H, d, J =

8.0 Hz), 6.83 (2H, d, J = 8.0 Hz), 6.72 (2H,

d, J = 8.0 Hz), 6.58 (1H, d, J = 16.0 Hz),

5.82 (1H, m), 3.59 (1H, m), 2.78 (1H, m),

2.28 (1H, m), 2.22-2.01 (2H, m), 1.79-1.61

(2H, m), 1.59-1.48 (2H, m) (Fig. 2A.36).

13C NMR (50 MHz, CDCl3) : δ 159.2, 156.7, 135.8, 134.6, 129.5, 128.8,

127.5, 126.4, 114.9, 70.0, 39.6, 39.3, 30.8,

30.2 (Fig. 2A.37).

ESI MS : m/z 299 [M+H]+ (Fig. 2A.38).

HO

OH

OH


70



Calcd; C, 76.51; H, 7.38 %.


71

Section B: Stereoselective total synthesis of (3R,6E)-1,7-bis(4-hydroxyphenyl)hept-6-

ene-3-ol through Wittig olefination.

2B.1 PRESENT WORK:

Our second approach to the target molecule involved Wittigs olefination, hydrolytic

kinetic resolution of a racemic epoxide and hydroxylation reactions as the key steps. Our

retrosynthetic approaches to this diarylheptanoid is outlined in scheme 14.

Scheme 14:

The treatment of compound 43 (previously prepared, see pages 50-55) with OsO4,

NMO in aq. acetone afforded the compound 57 in 83 % yield (Eq. 2.14).36

Eq. 2.14:


13C NMR and Mass

spectra. In IR spectrum (Fig. 2B.1), the bands observed at ν 3390, 2928, 1744 cm-1

. The

H

O

HO

47BnO

OH

43

HO

OH

OH

BnO

OH

O

55

+ Ph3P

OH

56

35

BnO

OH

43

BnO

OH

57

OH

OH

OsO4, NMO,

aq. acetone,

rt, 4 h

83 %


72

1H NMR spectrum (Fig. 2B.2) showed that three olefinic protons at δ 5.80 (1H, m), 5.02

(1H, m) and 4.86 (1H, m) are absent. Additionally, the structure of 57 was supported by

13C NMR spectrum (Fig. 2B.3) which showed signals at δ 51.3 and 46.0. Finally, it was

also confirmed by ESI MS (Fig. 2B.4) which showed signal at m/z 331 [M+H]+.

The treatment of compound 57 with NaIO4, NaHCO3 in DCM afforded the compound

55 in 79 % yield (Eq.2.15).37

Eq.2.15:

The treatment of compound 55 with commercially available 4-hydroxy phosphonium

ylide afforded the compound 54 in 73 % yield (Eq. 2.16).28

Eq. 2.16:

The formation of compound 54 was established by 1H NMR,

13C NMR and Mass

spectra. The 1H NMR spectrum (Fig. 2B.5) showed that protons at δ 7.39-7.21 (5H, m),

7.20 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 8.0 Hz), 6.82 (2H, d, J = 8.0 Hz), 6.68 (2H, d, J

= 8.0 Hz), 6.56 (1H, d, J = 16.0 Hz), 5.72 (1H, m) and 4.99 (2H, s) were present,

indicating the presence of compound 54. Additionally, the structure of 54 was supported

by 13

C NMR spectrum (Fig. 2B.6) which showed signals at δ 159.1, 154.7, 136.4, 134.8,

129.6, 128.7, 127.6, 126.5, 124.3, 114.9, 114.1, 71.2, 70.0, 39.8, 39.4, 31.8, 30.8

indicating presence of compound 54. Finally, it was also confirmed by ESI MS (Fig.

2B.7) which shows signal at m/z 389 [M+H]+.

BnO

OH

57

OH

BnO

OH

O

55

OH

NaIO4, NaHCO3,

CH2Cl2,rt, 2 h.

79 %

BnO

OH

O

55

BnO

OH

OH

Ph3P

OH

56

+n-BuLi, THF,

-78 °C to rt,4 h

54

73 %


73

The compound 54 was deprotected as reported earlier to obtain 35. [α]D25

= + 15.5 (c

= 3.0 M, CHCl3). The optical and spectral properties of the compounds were identical to

those of the naturally occurring bioactive diarylheptanoid, (3R,6E)-1,7-bis(4-

hydroxyphenyl)-hept-6-ene-3-ol.25

Our second synthetic approaches were overally outlined in scheme 15 where the

compounds were envisioned as arising from two starting materials 55 and 56. The

compound 55 would be generated by hydroxylation and oxidative cleavage of chiral

alcohol (43) and the compound 56 was commercially available.

Scheme 15:

Reagents, conditions and yields: (a) OsO4, NMO, aq. acetone, rt, 4 h (b) NaIO4,

NaHCO3, CH2Cl2, rt, 2 h.

Conclusion: In conclusion, we have developed the first stereoselective total synthesis of

the natural bioactive heptanoid, (3R)-1,7-bis(4-hydroxyphenyl)-(6E)-6-heptin-3-ol

starting from commercially available, 4-hydroxy benzaldehyde through two different

approaches employing hydrolytic kinetic resolution of a racemic epoxide, Wittig

olefination and olefin cross metathesis reaction as the key steps. Both the synthetic

methods are simple and can be utilized for the generation of various analogues of 1.

BnO

OH

43

BnO

OH

57

OH

BnO

OH

O

55

a

OH

b


74

2B.2 EXPERIMENTAL:

General:

Spectra were recorded with the following instruments. IR: Perkin-Elmer RX1 FT-IR

spectrophotometer; 1H and

13C-NMR: Varian Gemini 200 MHz, Brucker 300 MHz,

Varian 400 MHz; ESI MS: LC-MSD-Trap-SL. Optical rotation was determined with a

Jasco DIP 360 digital polarimeter. Column chromatography was performed over silica

gel (BDH 60-120 mesh) and TLC with silica gel GF254. The visualization of the spots in

TLC plates was carried out either in UV light or exposing the plates to iodine vapours or

spraying with 10 % sulfuric acid in MeOH and subsequently heating on hot plate.

(5S)-7-(4-(benzyloxy)phenyl)heptane-1,2,5-triol (57):

To stirred solution of 43 (1.0 g, 3.37 mmol) in aq acetone (10 mL) was added NMO

(1.2 g, 10.13 mmol) followed by OsO4 (2.5 wt % in isobutanol). The reaction mixture

was stirred for 3 h. After completion of reaction, the mixture was quenched with

saturated NaHSO3 (5 mL) and stirred for 30 min and then extracted with EtOAc (3 x 20

mL). The combined organic layers were washed with brine, dried over an. Na2SO4 and

concentrated in vacuo. The crude mass purified by column chromatography (silica gel,

60-120 mesh, EtOAc/hexane) afforded pure compound 57 (0.92 g, 83 %) as yellow color

liquid.

Yield 83 %.

IR (neat) : ν 3390, 2928, 1744 cm-1

(Fig. 2B.1).

1H NMR (200 MHz, CDCl3) : δ 7.48-7.29 (5H, m), 7.10 (2H, t, J = 8.0 Hz),

6.90 (2H, d, J = 8.0 Hz), 5.02 (1H, s), 4.29 (1H,

d, J = 12.0, 4.0 Hz), 4.13 (1H, dd, J = 12.0, 7.0

Hz), 3.49 (1H, m), 3.37 (1H, m), 2.68-2.52 (2H,

m), 1.64-1.45 (6H, m) (Fig. 2B.2).

BnO

OH

OH

OH


75

13C NMR (50 MHz, CDCl3)

: 167.2, 138.1, 136.9, 134.7, 133.9, 133.1, 132.9,

127.5, 114.8, 73.9, 72.7, 72.1, 71.1, 39.1, 34.6,

33.9, 29.2 (Fig. 2B.3).


+ (Fig. 2B.4).


Elemental analysis : Found: C, 72.64; H 7.93 %.

Cald: C, 72.73; H, 7.88 %.

(S)-6-(4-(benzyloxy)phenyl)-4-hydroxyhexanal (55).

To a stirred solution of 57 (0.9 g, 2.72 mmol) in dry CH2Cl2 (10 mL) at 0 °C aq.

NaHCO3 (5 mL) was added and followed by careful addition of NaIO4 (1.1 g, 5.45

mmol). The reaction mixture was allowed slowly to rt. After stirring for 2 h, Na2SO4 (1.0

g) was added and stirred vigorously for 30 min. The reaction mixture was filtered through

sintered funnel with CH2Cl2 (2 x 30 mL). The combined organic extracts were washed

with brine, dried over an. Na2SO4 and concentrated under reduced pressure. The residue

was purified by column chromatography (silica gel, 60-120 mesh, EtOAc/hexane) to

afford aldehyde (55) as yellow color liquid.


To a stirred solution of C25H21OP (2.9 g, 6.03 mmol) in dry THF (10 mL) under

nitrogen at -78 °C n-BuLi (2.0 mL in 2.5 M hexane) was added dropwise and the reaction

mixture was stirred at that temperature for few minutes until yellow color is generated.

BnO

OH

O

BnO

OH

OH


76

Later, aldehyde was added dropwise and the reaction mixture was stirred at that

temperature for 4 h. The reaction mixture was quenched with saturated aq NH4Cl solution

(10 mL) at 0 °C and extracted with EtOAc (2 x 50 mL). The combined organic extracts

were washed with brine, dried over an. Na2SO4 and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, 60-120 mesh,

EtOAc/hexane) to afforded (54) as pale yellow color liquid (0.52 g, 73 %).

Yield : 73 %.

[α]D25

: + 2.9 (c = 1.0 M, CHCl3).


Hz), 7.01 (2H, d, J = 8.0 Hz), 6.78 (2H, d,

J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 6.56

(1H, d, J = 16.0 Hz), 5.72 (1H, m), 4.99

(2H, s), 3.58 (1H, m), 2.58 (2H, t, J = 7.0

Hz), 2.30-2.02 (4H, m), 1.78-1.58 (2H, m),

1.48-1.30 (2H, m) (Fig. 2B.5).

13C NMR (50 MHz, CDCl3) : δ 159.1, 154.7, 136.4, 134.8, 129.6, 128.7,

127.6, 126.5, 124.3, 114.9, 114.1, 71.2,

70.0, 39.8, 39.4, 31.8, 30.8 (Fig. 2B.6).

ESI MS : m/z 389 [M+H]+ (Fig. 2B.7).



Calcd; C, 80.41; H, 7.22 %.

The compound 54 was deprotected as reported earlier to obtain 35 [α]D25

= + 15.5 (c

= 3.0 M, CHCl3). The optical and spectral properties of the compounds were identical to

those of the naturally occurring bioactive diarylheptanoid, (3R,6E)-1,7-bis(4-


Fig. 2A.1. IR Spectrum of compound 44

Fig. 2A.2. 1H NMR Spectrum of compound 44

Fig. 2A.3. 13

C NMR Spectrum of compound 44

Fig. 2A.4. ESIMS Spectrum of compound 44

Fig. 2A.7. 13




Fig. 2A.10. 13


Fig. 2A.14. 13



Fig. 2A.18.

13C NMR Spectrum of compound 51



Fig. 2A.21.

1H NMR Spectrum of compound 52

Fig. 2A.22.



Fig. 2A.26.



Fig. 2A.30.




Fig. 2A.33. 13


Fig. 2A.37.



Fig. 2B.1. IR Spectrum of compound 57

Fig. 2B.2. 1H NMR Spectrum of compound 57

Fig. 2B.3. 13


Fig. 2B.4. ESIMS Spectrum of compound 57

Fig. 2B.5. 1H NMR Spectrum of compound 54

Fig. 2B.6. 13


Fig. 2B.7. ESIMS Spectrum of compound 54


77

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The first stereoselective total synthesis of (3R,6E)-1,7...

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