aljlaxItER 2

Tandem Wittig-Diels-Alder reaction

Section IV

Tandem Wittig-Diels-Alder reaction: Synthesis of lignan and

heterolignans

Introduction:

Haworth introduced the term `lignan' in 1936 to describe a group of optically

active extracts isolated from plant materials.' These extract contained dimeric

compounds consisting of two phenypropanoid units linked 13-13' (8-8') through the

central carbons of their propane side chains as represented in Fig I. 1 Several

hundred lignans have been discovered in different parts of various plants, including

wooden parts, roots, leaves, flowers, fruits and seeds.

2 X

Fig I

The presence of C-C bonds and oxygen bridges in the bisphenylpropane structure

has been used to structurally classify lignans in different groups (Fig II). Broadly

they may be classified as: 1) Acyclic lignans and others containing no additional

C-C bonds (1), such as substituted furans, furofurans, dibenzylbutyrolactones; 2)

Arylnaphthalene derivatives (2), having a C6-C7' bond, which includes the

174

podophyllotoxins; and 3) Derivatives of dibenzocyclooctene skeleton (3), with a

C6-C2' bond, which include the steganacins. 2

The variations in the lignan structures have been mainly brought about by the

modification of the substituents in the basic skeleton. Several modifications

affecting the substitution pattern of the aromatic rings, 3 '4 the substituent at C7, 5-9

the change of 9, 9' lactone into a 9, 9' lactam, 10 and many other modification have

been carried out."

1 2 3

Fig II

Gottlieb extended the lignan family to include `neolignans' , 12-14 a class of

compounds created by the coupling of different phenylpropanoid units via carbon-

oxygen bonds.

The term heterolignan was first introduced by Ramos et al. 15 Heterolignans are

those synthetic analogues of lignans designed as a result of replacing one or more

carbon atoms of the propane moieties (C7-C9 and/ or replacing one or both

benzene rings (C1-C6 and/or C1'-C6') by heteroaromatic system.

Biogenesis:

Biosynthetically, lignans are synthesized in plants via the shikimate pathway. This

is a major metabolite pathway for the construction of many aromatic compounds.

The biosynthesis of lignans in plants is hypothesized to occur via radical

dimerization of phenylpropanoids catalysed by peroxidase enzymes. I6 A

representative example of the oxidative couplings of two cinnamic residue is given

below (Scheme I). 1

1 75

(0)

HO

-H+

OH

dimerization

X= CH2OH, COOH, CH3, H

R= OCH3, H

Scheme I

Biological activity of lignans:

Lignans have attracted attention due to its interesting pharmacological

activities. 17 ' 18 A heterolignan substructure can also be found in pharmacologically

promising new molecules such as potent dopamine 131 agonists used for the

treatment of Parkinsons disease. 19'2° The spectrum of biological activity includes

anti-cancer activity, 21 anti-inflammatory activity, 22 analgesic activity, 23 antifungal

activity, 24 anti-asthmatic activity, 25 antirheumatic activity, 26 antineoplastic

properties.27'28 '29 The furanone moiety is the structural feature of a number of

biologically active lignans. 3°

Several research groups have studied the Podophyllum lignans for their anticancer

properties. 31 '32 Podophyllotoxin was first isolated from Podophyllum peltatum.' 7

Several derivatives of podophyllotoxin were synthesized (Fig III) and structure-

activity relationships studied on their binding to tubulin. 31 It was found that some

analogues possessed comparable activity whereas some others were inactive. A

semisynthetic derivative of etoposide, teniposide, (4), shows anticancer activity.33

176

OH HN

NO 2

OH OH

Teniposide

Etoposide

4

CH3

podophyllotoxin R= "3,

R=

OH

Beta-peltain

8

OH

Epipodophyllotoxin

9

MeO

OH

Azatoxin

10

OMe

OH OH

MeO OMe

OMe

Picropodophyllotoxin 6

OH

Alpha-peltain

7

4'-Demethylpodophyllotoxin

5

Fig III

All the podophyllotoxin derivatives depicted in Fig III exhibited promising

antitumour activity. Azatoxin (10), 34 a hybrid molecule of ellipticine and etoposide

is a DNA Topoisomerase II inhibitor.

177

Some of the naturally occurring lignans are shown below,

Me0

Me0

OMe

11 R = H 13 R=OMe

12 R OH 14 R. OH

Plant source:

4-Deoxy-isodiphyllin (11) and isodiphyllin (12), Umbellifera bupleurum frutiscens

L 35

5-Methoxyjusticidin A (13)

Protium unifoliolatum 36

5-Hydroxyjusticidin A (14)

Mananthes patentiflora37

178

HO OH

18

OH

17

HO OH ox 0

MeO

MeO

0

Retrojusticidin B

20 21

Plant source:

MeO

MeO

Justicidin B

Plant source: 15, 16, 17, 18 Mananthes patentiflora37

Plant source: Justicidin E Hypoestes purpurea (19)3438b

Justicidin B (20) Justicia procumbens39' 39"

Rretrojusticidin (21) Phyllanthus myrtifolius 39b ' 39e ' d

1 79

Taiwanin C - .1, 2, 3, 4-Dehydrodeoxypodophyllotoxin

22 23

Plant source

Taiwanin C (22)

Taiwania cryptomerioide4oa

1,2,3,4-Dehydrodeoxypodophyllotoxin (23) Hernandia ovigera, L. 40b

Synthesis of lignans:

Lignans and heterolignans have been prepared by different methods. Some of the

methods making pericyclic reaction are depicted below.

a) Charlton and Alauddin have synthesized (+)-isolariciresinol dimethyl ether

using a cycloaddition reaction. 4 " The key synthetic step was the pericyclic

extrusion of sulfur dioxide to yield the ortho-quinone-methide. This compound

underwent a DieIs-Alder cycloaddition with methyl fumarate to afford a 70% yield

of the major adduct (Scheme II). Later from same laboratory 41b has reported

synthesis of (-)-a-dimethylretrodendrin.

180

MeO

MeO Me0

Ph

0)4PC H 3

MeO

MeO

MeO

MeO

Ph

MeO

MeO Ar

CO 2 Me

MeO 2 C

Ph

( +)-isolariciresinol dimethyl ether

Scheme II

Madalengoitia & Mcdonald have reported 42 synthesis of 10-Ary1-3a,4,10,10a-

tetrahydrofuro[3,4]carbazol- 1 -ones by an intramolecular Diels-Alder reaction.

Exo/endo product ratios were found to be sensitive to both solvent and

temperature. The synthesis of isoelliptitoxin, a hybdrid molecule of ellipticine and

4'-demethylpodophyllotoxin is presented (Scheme III).

MeO

MeO

COOH i) BF 3 OEt2 , Me0H

ii) Br 2 , CHC1 3 (71%)

ill) KOH, EtOH, H2O (28%)

MeO

MeO OOH

OMe iv) Lindlar cat. (75%)

CHO

i) Ph3P=CHCOOMe (67%)

ii) DIBAL (92%) OMs

iii) MsCI, TEA (98%)

B

181

PhO 2S1

A -I- B DMF

NaHCO3

PhO 2S PhO 2S

N u N

MeO

OMe MeO

47% 24%

Scheme III

Ayres et a1. 43 synthesized I -Arylnaphthalenes lignan related to podophyllotoxin

(Scheme N).

OMe

Scheme IV

182

Se02

30%

OMe

OMe

Gonzalez et al." have synthesized 4-deoxy-isodiphyllin by sequential

condensation of sodium salt of 3,4-dimethoxyphenylpropionic acid and

methylenedioxycinnamyl chloride, intermolecular Diels-Alder reaction followed

by oxidation (Scheme V).

OMe

Scheme V

Oppolzer et al. 45 have shown the stereoselective synthesis of BenzMisoindoline

derivative by intramolecular cycloaddition of styrenes to olefins (Scheme VI).

183

OH CI

DBU •

CO2 Me

CO2Me

CI Na104 .RuC13 ,xH 20 op-

94%

O sP

Ac20, p-TsOH

dimethyl maleate

toluene, reflux

CI CI SPh

CI

SPh

..„CO2Me

'CO2Me

48%

180 °C/ 6 d

18% Ph

hv

NBn

Scheme VI

Sarkar et a1. 46 have described the Pummerer reaction of o-benzoyl substituted

pyridylmethyl sulfoxides which generates a-thiocarbocations, the interception of

which by the neighbouring keto functionality produces thio-substituted furo[3,4-c]

pyridine as transient intermediates. This undergoes [4+2] cycloaddition with an

added dienophile. Base-induced ring opening of the cycloadducts followed by

aromatization gives substituted isoquinolines related to heterocyclic analogues of

1-arylnaphthalene lignans (Scheme VII).

OMe i) CH 2N2 CI r. ii) DIBAL-H

90%

Scheme VI I

184

O-menth

heat

79%

O-menth

O-menth 1) HCI 2) CH 2 N 2 3) LiEt 3 13H

4) HCI

5)ZnCI 2

OAc OH

Jones and co-workers' achieved a very efficient synthesis of (-)-podophyllotoxin

(Scheme VIII) based on an asymmetric Diels-Alder addition to 1-ary1-2-

benzopyran-3-one. 48

AcOH 1)Pd/C, H 2

2) AcOH, Pb(OAc) 4

87% 56%

39%

Scheme VIII

Jana and Ghorai describes 49 the synthesis of nitrogen containing heterocylic

analogues of 1-arylnaphthalene lignans using tandem furo[3,4-b]pyridines/

furo [3,4-b]quinolines-Diels-Alder reaction. Furo [3 ,4-b]pyridines/furo [3 ,4-b]

quinolines are synthesized from the coupling of alkynyl derivative with Fischer

carbene complexes. This intermediate was trapped through Diels Alder reaction

with dienophiles leading to the synthesis of lignan in a single step (Scheme IX).

185

Cr(CO)5

H3COMe

A

SiMe3

C H3

OH

cyclisation

Ar OMe

Me02C CO2 Me cat. CICH2CO2H

0

OMe

OMe

cat. TsOH

Scheme IX

Zheng et a1. 5° have showed the rearrangement of 1H-2,3-benzoxazine derivatives

to the corresponding cyclic hemiaminal derivatives, which was trapped by various

dienophiles to afford skeletal congeners of 1-arylnapthalene lignans (Scheme X).

Scheme X

186

CHO

CHO

piperidine, AcOH NH

Pd(OAc)2

The discovery of a new Pd-catalysed benzannulation reaction of

bisbenzylidenesuccinimide to arylnaphthalene lignan aza-analogues (Scheme XI)

is described by Mizufune et al. 51

Scheme XI

Sugahara et al. 52 reported the acid catalysed transformation of pyridine substituted

hydroxyl acetal to 1-pyridylisobenzofuran intermediate which undergoes rapid

Diels-Alder reaction with dimethyl maleate to give mixture of exo and endo

diastereomers. This on treatment with BF3.Et 20 gave 1-pyridylnaphthalene lignan

(Scheme XII).

Me0

Me0

Me0 DMAD

89% MeO

,„CO 2Me

'''CO2Me

CO 2Me

CO2Me

BF 3.EtO

90%

MeO

MeO

Scheme XII

187

Sato et aL 53 have developed a novel method for the construction of arylnaphthalene

skeleton through a Pd catalysed [2+2+2] co-cyclisaion of aryens and diynes. This

co-cyclisation was the key step in the total synthesis of taiwanins C and E (Scheme

XIII).

5 mol% Pd2(dba)3 40mni t 6 P(-tnl)3

CsF

0 CH3CN, RT

Taiwan E Taiwan C

Scheme XIII

188

Present work:

Lignans and heterolignans being attractive targets due to their biological activities

related to anticancer, we also could not resist evaluating our protocol of tandem

Wittig-Diels-Alder reaction for their synthesis. Our strategy for their synthesis is

depicted below (Scheme XIV).

♦ RCHO

1,3-hydrogen shift

Scheme XIV

Phosphorane "X" having a cinnamyl ester/amide linkage would undergo a Wittig

reaction with aromatic/heteroaromatic aldehyde to give a unsaturated trans-

ester/amide intermediate. This intermediate in situ would undergo a [4+2] addition

reaction (Diels-Alder reaction). The cinnamyl part of the ester/amide would act as

a diene and a newly formed unsaturated trans ester/amide as a dienophile. The

Diels-Alder adduct would then undergo a 1,3-sigmatropic shift leading to lignan

structure "Y". The later part of the reaction being similar to Oppolzer et al. 's work

(Scheme VI), a stereoselective product with all cis geometry was expected. It was

also interesting to study the effect of triphenylphosphine oxide on this tandem

process as it is observed 54 to assist in [2+2] cycloadditon reaction. The required

phosphorane was prepared according to scheme XV.

189

NaB H4

DCM, Me0H

Mol. Selves

NH Ph

_ bromoacetyl bromide Ph PPh3

benzene

K2C 03, C HC 13

25

Ph NaOH

27

Scheme XV

Cinnamyl aldehyde was converted to N-benzyl-3-phenprop-2-en-amine 24 by

reductive amination. 55 This was then acylated by bromoacetyl bromide followed

by treatment of the resultant N-benzy1-2-bromo-N-[(2E)-3-phenylprop-2-in-1-yl]

acetamide 25 with triphenylphosphine to obtain the corresponding phosphonium

salt 26.

The compound 25 in its IR spectrum showed a band at 1643 cm -1 indicating the

presence of carbonyl group of amide.

In its 'H NMR (300 MHz, CDCI3) spectrum one singlet (2H) was seen at ö 3.84

[3.92] which could be assigned to methylene attached to the bromine. The singlet

(2H) at ö 4.63 [4.69] could be attributed to benzylic methylene protons. Doublet

(2H, J = 6.3 Hz) at ö 4.0 [4.1] could be attributed to allylic methylene group. One

multiplet (1H) and one doublet of doublet (1H, J = 15.9 Hz) was seen at ö 6.10 and

6.44 could be attributed to two olefinic protons of CH=CH-Ph group. One

multiplet (10H) at ö 7.3 could be attributed to aromatic protons.

190

The peak at ö 26.23 (t) in its NMR spectrum is assigned to the CH2 groups of

CH2Br group. Similarly, the peak at 48.53 (t) could be attributed to carbon of

allylic methylene group. Peak at 49.50 (t) could be attributed to benzylic

methylene carbon. Peaks at 123.24 (d) and 123.46 (d) could be attributed to two

olefinic carbons. Peaks at 126.39 (d), 127.55 (d), 128.04 (d), 128.66 (d), 129.02

(d), and 132.47 (d), could be attributed to aromatic methine carbons. The

quaternary carbons at 135.75 (s) and - 136:62 (s) could be attributed to aromatic

carbons. Peak at 167.17 (s) could be due to carbonyl carbon of amide. The

multiplicities of carbon signals mentioned were obtained from DEPT 135

experiment.

Thus on the basis of mode of formation & spectral properties N-benzy1-2-bromo-

N-[(2E)-3-phenylprop-2-en-l-yl]acetamide (25) was assigned to it.

The salt 26 in its IR spectrum showed a band at 1640 cm -1 indicating the presence

of carbonyl group of amide.

In its 'H NMR (300 MHz, CDC13) spectrum doublet (2H, J = 6 Hz) at 8 4.10 [4.67]

could be attributed to allylic methylene group. Singlet (2H) at 8 5.15 [5.24] could

be due to benzylic methylene protons. The doublets (2H, J = 15.6 Hz) at 5.72

[5.83] could be attributed to methylene attached to the phosphorous. One multiplet

(1 H) and two doublets (J = 15.9 Hz) at 8 6.10 and 6.50 could be attributed to two

olefinic protons. Two multiplets (25 H) at 8 7.34 and 7.88 could be attributed to

aromatic protons. The structure was further supported with 13 C NMR and DEPT

135 spectra. Thus, peak at 34.1 (t) could be assigned to carbon of methylene group

attached to phosphorous. Peaks at 49.84 (t) and 51.05 (t) could be attributed to

methylene carbon of allylic and benzylic methylene carbons. Peaks at 124.55 (d)-

129.85 (d), 130.0 (d), 133.89 (d), 134.45 (d), 135.80 (d) could be attributed to

olefinic and aromatic methine carbons. The quaternary carbons appearing at

118.86 (s), 120.06 (s), 135.93 (s), 136.23 (s) could be attributed to aromatic

carbons. The amide carbonyl carbon appeared at 164.66 (s).

Thus on the basis of mode of formation & spectral properties structure 26 was assigned to it.

191

The phosphorane 27 in its IR spectrum showed a band at 1663 cm' indicating the

presence of carbonyl group of amide.

Its 1 1-1NMR (300 MHz, CDC1 3) spectrum showed a doublet at 8 2.20 (1H, J = 13.8

Hz) which could be attributed to ylidic proton of CH=P group. Doublet (2H, J =

6.3 Hz) at 8 4.0 [4.18] could be attributed to allylic methylene group. Two singlet

at 8 4.44 [4.64] and 4.55 [4.67] could be due to benzylic methylene protons. One

multiplet (1 H) and two overlapping doublets (1 H, J = 15.6 Hz) seen at 8 6.10 and

6.40 could be attributed to the two olefinic protons. Multiplet at 8 7.40-7.70 could

be attributed to aromatic protons.

The peak at 8 25.4 (d) in its 13C NMR spectrum is assigned to ylide carbon

(CH=P). Peaks at 47.98 (t) and 50.73 (t) could be attributed to allylic carbon of

methylene group and benzylic methylene carbon. Peaks at 126.38 (d)-128.95 (d),

131.93 (d) - 136.3 (d) could be attributed to olefinic carbons and aromatic methine

carbons. The quaternary carbons appearing at 123.81 (s), 124.47 (s), 136.62 (s),

137.53 (s) could be attributed to aromatic carbons. Peak at 170.89 (s) attributed for

carbonyl carbon of amide, as expected. HRMS data confirmed the elemental

composition as C36H32NOP (Observed: m/z 526.2291, calculated for [M+H] + =

526.2300).

Thus on the basis of mode of formation & spectral properties structure 27 was

assigned to it.

Initially, we tried 3,4,5-trimethoxybenzaldehyde as a substrate as this unit is

present in podophyllotoxin (naturally occurring lignan). Thus 3,4,5-trimethoxy

benzaldehyde 28 was treated with phosphorane 27 in refluxing diphenyl ether for

10 h (monitored by TLC). The usual chromatographic separation provided a solid

compound (Scheme XVI).

192

OMe

30

29

NBn

MeO

MeO

28

CHO Ph3P- MeO

MeO

en 27

diphenyl ether

MeO OMe

OMe

31

Scheme XVI

Its IR spectrum had a strong peak at 1681 cm' indicating the presence of y-lactam

group (MP = 80-81 °C, Yield = 62.10%).

'H NMR (CDC13, 300 MHz): (Fig la).

8 2.70

8 2.99

8 3.10

m

m

m

3H

1H

1H

Saturated carbon protons

83.57 ls and lm 3H arid 1H OCH3

8 3.87 is and lm 3H and 1H OCH3

8 3.92 s 3H OCH3

8 4.48 s 1H CH2Ph

8 4.82 d (Jgen, = 15 Hz) 1H CH2Ph

8 6.63 m 3H Ar-H

8 7.13 m 8H Ar-H

193

From the above PMR data the product obtained appeared like a mixture. So HPLC

analysis of it was done. It was found that the product obtained is actually a mixture

of two compounds in approximate ratio of 6:1. Repeated column chromatography

or preparative TLC failed to separate the mixture.

The possible modes of cycloaddition are depicted below (Fig IV),

rPh

100

H

endo

Structure I

exo

N—\ Ph

Structure II

Fig IV

If the cyclization takes place by endo route it will give a product with cis-ring

junction (cis- adduct) and if the cyclization takes place by exo route it will give

product with trans-ring junction (trans- adduct).

The stereochemical structure for these possible products is depicted below (Fig V).

194

N—\ Ph

66.63

OCH3

OCH 3

cis I

H3CO

H H

N"...\ ph

OCH3 OCH3

trans II 66.63

Fig V

The other possible isomers which may arise if the unsaturated amide is having cis

geometry (Fig VI).

Ph

Ph

III

IV

Fig VI

The I HNMR data suggested that the major product to be cis fused formed via endo

transition state as in the shielded aromatic region at 8 6.63, three protons were

seen. This could be due to the two protons from the benzene ring containing

trimethoxy groups and the other proton could be from the fused benzene ring. This

proton gets shielded due to the presence of it-cloud of benzene ring having

trimethoxy group in the equatorial position (structure I). The fusion of the ring

could not be decided by coupling constants as some other aliphatic proton signals

were also overlapping in its place. The second minor product could be the trans

adduct (structure II) formed by exo addition. The other possible products (III) and

(IV) were also considered. Their formation required the cis geometry in the

intermediate unsaturated amide. As normally stable Wittig reagent gives the trans

product as the major product it was assumed that the geometry for the intermediate

amide as trans amide (confirmed subsequently by carrying out Wittig reaction

separately). Again if products (III) and (IV) were formed the equatorial protons

shown in the figure should have appeared as a doublet (J = 3 - 4 Hz) at 8 4 - 4.5,

195

which was not ooservea. ne only signals wmcn were amicuit to explain were

from the benzylic methylene group appearing as a singlet at 8 4.48 and as a doublet

at 8 4.82. The plausible explanation for this could be either the five membered ring

is continuously flipping at room temperature to show the distinct nature of the two

conformations or it is because the compound is tautomerizes to lactam & lactim

form. Lastly the structure formed by the other possible Diels-Alder reactions

(Scheme XVII) was not considered due to nature of the dienophile and diene

though it cannotbe entirely ruled out. -

Scheme XVII

13C NMR spectrum (Fig la) of the mixture had a peak at 30.0 (t), which could be

assigned to the CH2 group of six membered ring. Peak at 46.16 (t) could be

attributed to methylene carbon of lactam ring. Peak at 52.30 (t) could be assigned

to benzylic methylene carbon. Peaks at 33.91 (d), 41.51 (d), 41.57 (d) could be

attributed to three methine carbons of six membered ring. Peaks at 56.03 (q), 60.83

(q), and 60.97 (q) could be attributed to three methyl carbons attached to the

oxygen of OCH3 group. Peaks at 108.14 (d), 126.18 (d)-128.70 (d) could be

attributed to the aromatic methine carbons. The quaternary carbons appearing at

123.07 (s), 132.49 (s), 135.64 (s), 140.84 (s), 142.05 (s), 151.88 (s), and 152.52 (s)

could be due to the aromatic carbons. Peak at 176.38 (s) could be due to carbonyl

carbon of lactam. HRMS data confirmed the elemental composition as C28H2904N

(Observed: m/z 444.2177, calculated for [M+H] + = 444.2175).

In order to confirm the geometry of the intermediate unsaturated amide. 3,4,5-

Trimethoxy benzaldehyde was condensed with N-benzyl-N-[(2E)-3-phenylprop-2-

en-ly1]-2-(triphenylphosphoranylidene)acetamide in refluxing chloroform

(Scheme XVIII).

196

PhOPh

CHO

OMe

NBn

3

H 3C0 5 4 OCH3

OCH 3

30 ♦ 31

CHCI 3

29

Scheme XVIII

Based on the triode of formatimi and spectral properties mentioned below, structure

29 was assigned to the compound. The high coupling constant (J = 15.3 Hz) of

vinyl protons indicated trans geometry of the product (yield = 84.96%).

IR (vmax): 1649 cm-1 (CO).

1 1-1 NMR (300 MHz, CDC13):

S 3.86 [3.88]

8 4.20 [4.31]

s

d (J = 4.5 Hz)

9H

1H

3 X OCH3

-CH-CH=CH

8 4.56 [4.64] s 2H CH2-Ph '

8 6.1-6.29 m 1H CH2-CH=CH

8 6.49 [6.55] d (J = 9.0 Hz) 1H CH2-CH=CH

8 6.67 s 1H Ar-H

8 6.75 s 1H Ar-H

8 6.76 [6.84] d (J = 15.3 Hz) 1H CH=CH-CO

8 7.31 m 5H Ar-H

8 7.74 [7.77] d (J = 15.3 Hz) 1H CH=CH-CO

13 C NMR and DEPT 135: 8 48.27 (t, CHrCH=CH), 49.13 (t, CH2Ph), 56.18 (q, 2

X OCH3), 60.94 (q, OCH3), 105.16 (d, C-2 and C-6), 116.80 (d, -CO-CH=CH-),

124.55 (d, Ph-CH=CH-), 126.42-129.00 (d, CA,H), 130.90 (s), 132.17 (d, -CH=CH-

Ph), 137.55 (s), 139.73 (s), 143.57 (d, -CH=CH-CO), 153.40 (s), 166.97 (s, CO).

197

• -

5;11• -4* 44 S:4;

r6PAI 7, uP-07 ,21.... !;0.11,3

3,0 :Zs

The trans unsaturated amide 29 was then heated in refluxing diphenyl ether tor 10

h under nitrogen atmosphere, followed by chromatography gave diastereomers in

65.00%.

felr,:ifzstso, . 44; 777p \U V

J

Fig la

OM

Fig lb

198

34

CHO

H

32

Ph 8n

xylene

H

35

Having successful synthesised, one terahydronaphthalene lignan we thought of

extending this methodology for the synthesis of heterolignans.

Indole-3-carboxyaldehyde was heated with phosphorane 29 in xylene for 12 h.

Purification of the crude mixture by flash column chromatography gave compound

34 (Scheme XIX). Compound 34 on HPLC analysis indicated to be a single pure

compound.

Scheme XIX

The solid compound 34, MP = 244-246 °C (Yield = 62.30%), in its IR spectrum

showed bands at 1678 and 3300 cm -I indicating the presence of carbonyl group of

lactam ring and nitrogen of indole group respectively.

In its IHNMR (300 MHz, CDC13) (Fig 2a) spectrum a multiplet (1H) seen at 8 2.5

could be attributed to proton of 9a-H. One multiplet at 8 2.75 (1H) could be

attributed to proton of 6a-H group. One multiplet (1 H) at 8 2.90 could be attributed

to proton of 6-H. Multiplet (3H) seen at 8 3.10-3.60 could be attributed to protons

of 9-H2 and 6-H group. One doublet was seen at 8 4.07 (1H, J = 10.5 Hz) which

could be attributed to methine proton of 10-H. One doublet seen at 8 4.35 [4.64]

(2H, J = 15 Hz) could be attributed to benzylic methylene protons. In the aromatic

region two multiplets were seen at 8 7.14-7.37 (13H) and 7.60 (1H) could be

199

PsP kP-6,6-91‘

6 .

11

S■1146.1rox

6:4 4)1 S 3.0 25

MUM

1,11 l;

attributed to aromatic protons. The coupling constants were attributed based on the

decoupling experiment.

Fig 2a

1 r 3 1.70 1O 100. )40 1;0 1.2 219 :00 59 99 /9 99 SO 40 39 ppm

Fig 2b

200

H 8 4.64 (J = 15 Hz)

8 7.5 H

H

54.07 (J= 10.5 Hz)

52.4 (J= 12, 10.5, 9.6, 6.9 Hz)

H H

) 8 3.1 (J = 9.9, 9.6 Hz)

ArH = 8 7.14 — 7.37 (13H)

j3.2 (J = 9.9, 6.9 Hz)

8 2.9 (J = 15, 12 Hz) 8 3.4 (J = 15, 4.5 Hz)

... 52.75 (J = 12, 12, 4.5, Hz)

--4- f I.---H H Hip, 54.35 (J = 15 Hz)

87.6 5

H--}

The possible cyclisation mode of the intermediate Wittig products is given below (Fig VIIa)

—Bn

endo exo

34

III

III

201

0

NH

Hydrogen should be shielded due to the presence of equatorial indole D

A

.Fig VIIa

OR

exo

III

Fig VIIb

202

Based on which diene system acts as a dienophile, mixture of products was

possible (Fig VIIa,b). In one case, if unsaturated amide acts as a diene then it could

give 34 (regioisomeric mixture) or it may act as a dienophile as observed in the

earlier example of trimethoxy benzaldehyde leading to 30 (regioisomeric mixture).

Both the possibilities with the endo and exo transition states are depicted in Fig

VIIa,b.

Decoupling experiment indicated anti-anti relationship of the hydrogen of the

cyclohexene ring (J = 12 & 10 Hz). This excluded the two possible compounds A

and C, to be formed via endo transition state. The other two possible products

could be B and D to be formed by exo transition state. If compound D was formed

it was expected that one of the aromatic proton (Fig VIIb) of the

tetrahydronaphthalene should have appeared at upfield around 8 6.7 as a doublet

which was not seen in the spectrum. Also proton on nitrogen of indole was

observed at comparative upfield region at 8 7.5 suggesting structure B (34) over

structure D for the product obtained. The chemical shift of the axial benzylic

methine proton (8 4.07) could be due to its diallylic nature. However the possibility

that the proton is not equatorial (Fig VIIc, structure E) was ruled out based on

coupling constant and the geometrical requirements for the transition state. For the

formation of E the double bond of the dienophile should be cis and stable Wittig

reagents give mostly exclusively trans-product.

Fig VIIc

The structure of compound 34 was further supported by its 13 C NMR and DEPT

135 spectra (Fig 2b). Thus, the peak at 21.90 (t) could be assigned to the methylene

carbon of six membered ring. Peak at 46.78 (t) could be assigned to methylene

carbon of lactam ring. Peak at 49.40 (t) could be attributed to benzylic methylene

203

38a 38b

Ph 3P ----,, Ph

Bn

0 CHO diphenyl ether, reflux

36

8 H

37

carbon. Peaks at 45.55 (d), 45.59 (d) and 4(101 (a) coula ne assigned to tnree

methine carbons of six membered ring. Peaks at 110.87 (d), 118.41 (d), 119.67 (d),

121.97 (d), 127.26 (d) - 129.14 (d) could be attributed to aromatic methine

carbons. The quaternary carbons appearing at 111.35 (s), 127.27 (s), 135.51 (s),

136.40 (s), 136.64 (s), and 140.21 (s) could be attributed to aromatic carbons. Peak

at 174.86 (s) could be assigned to carbonyl carbon of lactam. HRMS data

confirmed the elemental composition as C27H2,40N2 (Observed: m/z 416.1819,

calculated for [M+Na] + = 416.1865).

Thus on the basis of mode of formation & spectral properties, structure 34 was

assigned to it.

The successful synthesis of the indole heterolignan by tandem Wittig reaction and

Diels Alder reaction methodology opened new possibilities for the preparation of

many analogues of heterolignan. We have extended this methodology for the

synthesis of furano lignans. Thus, 2-furyl aldehyde was condensed with

phosphorane 27 in refluxing diphenyl ether for 8 h. The crude reaction mixture

when subjected to column chromatography gave a liquid compound (Scheme XX).

Scheme XX

204

—Bn exo

endo

38a

The liquid compound 38 in its IR spectrum showed a band at 1670cm - ' indicating

the presence of carbonyl carbon of lactam ring. Its 'H NMR spectrum had signals

at 8 2.2-3.2 (m, 6H) could be assigned to 4a-H, 5-H2, 7a-H, 8-H2 group. One broad

doublet at 8 3.7 (1H, J = 10.5 Hz) could be attributed for the methine proton

attached to the furan ring. One doublet of doublet (2H, J = 14.7 Hz) at 8 4.4-4.5

could be attributed for benzylic methylene group. One doublet at 8 5.93 (1H, J =

1.8 Hz) could-be attributed to 3-H of furan ring. In aromatic region one multiplet at

8 7.3 (11H) could be attributed to benzene protons and 2-H of furan ring. In

addition to these major peaks, some minor peaks were observed close by the major

ones. This suggested that this is in fact a mixture of two regioisomers. The ratio of

the two compounds based on the NMR spectrum is calculated to be 1:2.5 (yield =

70.10).

The possible mode of cycloaddition is depicted below (fig VIIIa,b)

Bn

38b

Fig Villa

OR

205

5

39a

endo

exo

39b

Fig VIIIb

Depending upon the mode of cyclisation (endo and exo) and the nature of diene

and dienophile four isomeric products were visualized (Fig VIIIa,b). Products 39a

and 39b were expected to show two doublets (J = 3.6 Hz) for the C-3 & C-4

protons for furan ring at around 8 6.0, where as 38a and 38b were expected to

show one doublet (J = 1.8 Hz) for one C-3 proton. As the spectrum showed a

doublet (J = 1.8 Hz) at 8 5.93 for one proton the product is a mixture of 38a and

38b. This was further supported by 13C NMR spectrum where it shows only two

methine furan carbons. From NMR values we could not decide the major and the

minor product. We were also not able to separate the isomers by chromatographic

methods. We assumed the endo product 38a as a major product and exo 38b as the

minor product based on literature precedence for the endo cyclisation of similar

Diels-Alder reaction products.

The 13 C NMR and DEPT of the product obtained are mentioned below.

8 24.14 (t, C-8), 41.38 (d, C-4a), 45.12 (d, C-7a), 46.70 (d, C-4), 48.43 (t, C-5),

49.28 (t, CH2-Ph), 109.85 (d, C-3), 121.50 (s), 126.8-128.63 (d, CArH), 136.41 (s),

140,95 (s), 141.7 (d, C-2), 150.39 (s), 174.07 (s, CO).

HRMS data confirmed the elemental composition as C23H2INO2 (Observed: in/z

366.1474, calculated for [M+Naf = 366.1470).

206

We have also carried out the synthesis of 3Sa-b in stepwise manner (Scheme XX1).

Thus 2-furylaldehyde was condensed with phosphorane 27 in refluxing

chloroform. The usual work up and purification produced a thick liquid.

0

0.,, Ph3P.z...Nr.,,.." ph

4 NBndiphenyl ether

38a -b

O CHO CHCI3 , A 3

36 5 (:,' 0 37

Scheme XXI

Based on the mode of formation & spectral properties mentioned below, structure

37 was assigned to the liquid obtained. The coupling constant of the vinyl protons

(J = 15.3 Hz) indicated trans geometry to the product (yield = 86.80%).

IR (vmax): 1655 cm-1 (CO).

1 H NMR (CDC13, 300 MHz):

S 4.17 [4.26]

8 4.71 [4.78]

d (J = 5.1 Hz)

s

2H

2H

CH2-CH=

CH2-Ph

8 6.20 m 1H CH2-CH=

8 6.46-6.58 m 3H 3-H, 4-H, & =CH-CO

8 6.81-6.86 2 X d (J = 15.3 Hz) 1H CH=CH-Ph

8 7.34-7.44 m 11H 5-H & Ar-H

8 7.58-7.63 d (J = 15.3 Hz) 1H CH=CHCO

13C NMR and DEPT 135 (CDC13): 8 48.37 (t, CH2-CH=CH), 49.56 (t, CH2Ph),

112.22 (d, CO-CH=), 114.18 (d, C-4), 114.80 (d, CH=CH-Ph),124.27 (d, C-3),

126.48-130.30 (d, C A,H), 132.14 (d, CH=CH-CO), 133.20 (d, =CH-Ph), 136.24 -

137.57 (s), 144.07 (d, C-5), 151.66 (s), 166.92 (s, CO).

Thus, trans unsaturated amide 37 was then heated in refluxing diphenyl ether for 8

h under nitrogen atmosphere, followed by chromatography separation gave 7-

lactams 38a-b in 80.00%.

Ph

207

40

Bn

diphenyl ether

We also prepared the regioisomer of 38a -b. Thus, 3 -turyl aldehyde was heated

with phosphorane 27, in refluxing diphenyl ether. The product was separated from

triphenylphosphine oxide by flash chromatography (Scheme XXII).

42a 42b

Scheme XXII

IR (vmax): 1673 cm -1 (CO).

'H NMR (300 MHz, CDC13):

8 2.20-3.40 m 611 4-H2 , 4a-H,

7-H2, 7a-H

8 3.93 brd (J = 9.6 Hz) 1H 8-H

8 4.30 [4.60] d (J = 14.7 Hz) 2H CH2Ph

86.30 d (J = 1.8 Hz) 1H 3-H

8 6.84-7.20 m 11H Ar-H & 2-H

208

—CNMR and DEPT 135 (CDC1 3): 8 22.58 (t, C-4), 41.76 (d, C-7a), 45.44 (d, C-

4a), 46.41 (d, C-8), 46.72 (t, C-7), 49.70 (t, CH2Ph), 110.59 (d, C-3), 118.95 (s),

127.36-128.65 (d, CA,H), 136.40 (s), 139.57 (s), 142.13 (d, C-2), 151.06 (s), 174.28

(s, CO).

HRMS data confirmed the elemental composition as C23H2INO2 (Observed: • m/z

366.1464, calculated for [M+Na] + = 366.1470). The yield of the compound was

found to be 67.90%.

Again from the PMR spectrum, we could not assign the stereochemistry at the ring

junction due to overlapping signals. The product is a mixture in the ratio 1:2.5. We

assumed the major product obtained cis fused (42a) formed via endo transition

state. The other minor product could be product obtained from exo transition state

(trans fused, 42b).

The other posible structures 43a & 43b (Fig IX) were discarded as the PMR

spectrum had only one proton at 8 6.33. If compounds 43a and 43b were formed,

additional signals in the region 6.0-6.5 would have been present. Besides, its 13 C

NMR spectrum were also devoid of additional furan methine carbon signals. The

formation of product 42a & 42b was assumed to be formed from trans unsaturated

amide intermediate.

43a 43b

Fig IX

To confirm the structure of the intermediate we separately isolated the Wittig

product .(trans unsaturated amide) and carried out (4+2) intramolecular Diels-Alder

reaction (Scheme XXIII).

209

CHO

0

40

0

ph

Bi n 5 0 2

1 PhOPh

42 CHCI 3

41

.Scheme XXIII

Based on mode of formation and spectral properties mentioned below, structure 41

was assigned to the compound. The high coupling constant (J = 15.6 Hz) of the

vinyl protons indicated trans geometry to the product (yield = 88.20%).

IR (vmax): 1658 cm -1 (CO).

1 H NMR (CDC13, 300 MHz):

S 4.15 [4.28]

8 4.69 [4.77]

brd (J = 6.0 Hz)

s

2H

2H

CL-1_2-CH=

CL-1_2-Ph

8 6.19 m 1H CH2-CH=

8 6.48- 6.58 m 3H CH=CH-Ph, 4-H & =CH-C=0

8 7.28-7.36 m 11H Ar-H& 5-H

8 7.65 brs 1H 2-H

8 7.98 d (J = 15.6 Hz) 1H CH=CHCO

13C NMR and DEPT 135 (CDC13): 8 48.70 (t, CH2-CH=), 48.90 (t, CH2Ph), 107.49

(d, -CHCO), 116.91 (d, C-4), 123.06 (s), 126.44 (d, CH=CHPh), 127.70-128.97 (d,

CIE), 132.125 (d, CH=CH-CO-), 133.66 (d, CH=CH-Ph), 144.19 (d, C-2 & C-5),

167.02 (s, CO).

210

44 diphenyl ether

0 CHO

Thus, trans unsaturated amide 41 upon, refluxing in diphenyl ether for 8 h,

followed by purification of crude product by flash chromatography gave

compound 42 in 79.10% yield, and they were formed in 1:2.5 ratio.

For the synthesis of furanoindole lignans, indole-3-carboxyaldehyde was

condensed with the phosphorane 56 44 in refluxing diphenyl ether for 8 h.

Separation of reaction mixture by flash chromatography gave a solid compound

(Scheme XXIV).

46a 46b

Scheme XXIV

HPLC analysis of the compound indicated that it's a mixture of two compounds in

a ratio of 1:3.

The solid compound 46, MP =212-214°C, (Yield = 60.30%) IR showed bands at

1750 and 3230 cm -I indicating the presence of carbonyl group of lactone and

nitrogen proton of indole group respectively.

In its 'HNMR (300 MHz, CDC1 3) spectrum showed three multiplets at 8 2.7 (3H),

3.4 (1H), 4.3 (3H) which could be attributed to the protons of six membered ring

and lactam ring. Multiplet (9H) seen at 8 7.14 - 7.64 could be attributed to aromatic

protons. One singlet at 8 8.40 could be attributed to indole nitrogen proton.

211

The structure was tUrther supported by its —C NMR and DEPT spectra. Thus, a

peak at 21.12 (t) could be assigned to the methylene carbon of six membered ring.

Peaks at 42.72 (d), 46.00 (d), 48.39 (d) could be assigned to methine carbons of six

membered ring. Peak at 68.99 (t) could be assigned to methylene carbon of lactam

ring. Peaks at 111.10 (d), 117.43 (d), 118.44 (d), 119.58 (d), 120.99 (d), and

125.32 (d) -129.85 (d) could be attributed to aromatic methine carbons. The

quaternary carbons appearing at 134.75 (s), 136.51 (s), 139.33 (s), 141.80 (s) could

be attributed to aromatic carbons. The peak at 176.62 (s) could be assigned to

carbonyl carbon of y-lactam.

HRMS data confirmed the elemental composition as C20111702N (Observed: m/z

326.1157, calculated for [M+Na] + = 326.1142).

The possible cyclisation mode of the intermediate Wittig products is given below (Fig Xa)

endo exo

III

III

212

46a 46b

Fig Xa

OR

endo

H

47a

exo

47b

Fig Xb

Based on our previous assumption for indolepyrallo lignan which have anti-anti

relationship of the hydrogen of cyclohexene ring. We assumed similar

stereochemistry for this compound. Our attempts to carry out decoupling failed to

conclusively establish the stereochemistry.

213

We assumed trans adduct (46b) is formed via exo transition state and the minor

product 46a (cis adduct) formed from endo transition state. The other two

possibilities 47a & 47b were eliminated due to the absence of expected additional

signal in the region in PMR at around 8 6.3 (d, J = 8 Hz) due to the benzene

protons being shielded by equatorial indole ring.

To confirm the geometry of the intermediate, we separately prepared the Wittig

product and then carried out the cyclisation reaction (Scheme XXV).

CHO Ph

O

PhOPh

45a -b

xylene

45

Scheme Scheme XXV

Based on the mode of formation & spectral properties mentioned below, structure

45 was assigned as Wittig product. Based on the coupling constant of the vinyl

protons (J = 15.9 Hz) indicated the trans geometry to the product (yield = 70.20%).

IR (v.): 1658 cm -1 (CO).

'H NMR (CDC13 , 300 MHz): (Fig 3a)

8 4.9 d (J = 5.7 Hz) 2H CH2-CH=CH

8 6.38 m 1H CH2-CH=CH

8 6.53 d (J = 15.9 Hz) 1H CH-00-

8 6.75 d (J = 16.2 Hz) 1H CH2-CH=CH

8 7.25-7.53 m 9H Ar-H

8 7.95 brs 1H 2-H

8 8.01 'd (J = 15.9 Hz) 1H CH=CH-00-

8 8.50 brs 1H NH

214

13C NMR and DEPT 135 (Fig 3b): 8 64.79 (CH2-CH=), 111.7 (d, C-7), 113.10 (d,

CH-CO), 113.67 (s), 120.50 (d, C-4), 121.57 (d, C-6), 123.38 (d, C-5), 123.77 (d,

C-2), 125.30 (s), 126.62 (d, CH=CH-Ph), 127.95-128.88 (d, C AJH), 133.88 (d,

CH=CH-Ph), 136.38 (s), 137.07 (s), 138.68 (d, CH=CH-00-), 167.98 (s, CO).

The trans .unsaturated ester 45 was heated in refluxing diphenyl ether for 8 h,

followed by purification by chromatography gave tetracyclic 7-lactams in 62.5%.

`\, (//7 1 1r

0

14 HY

pr.ip 2,

Fig 3a

215

mbc OD n_ils

es* rODC PM.'0...41, 11(.

, 7r- 170 460 . 160

Tr, •

iao 12t 1•0 100 90 80 140 70 GO. PM

Fig 3b

Conclusion:

1) We have successfully synthesized the podophyllotoxin analogous by using

tandem Wittig Diels-Alder reaction.

2) By using tandem sequence we have synthesized four different

heterolignans.

216

Experimental section:

Expt. 2.4.1: Preparation of N-benzyl-3-phenylprop-2-en-1-amine (24).

H2N

NaBH4

DCM, Me0H

Mol. Seives

Benzyl amine (1.95 mL, 18.18 mmol) was added to a stirred solution of

cinnamaldehyde (2 g, 15.15 mmol), sodium borohydride (0.84 g, 22.7 mmol) in

dichloromethane (50 mL) containing 4 A ° molecular sieves (0.4 g). The mixture

was stirred for 2 h. The reaction mixture was cooled to 0 °C. Methanol (5 mL) was

added and stirring continued at 0 °C for 10 min. The reaction mixture was allowed

to come to room temperature and further stirred for 30 min. It was then filtered and

the residue washed with ethyl acetate (25 mL). The combined filtrate was

concentrated and ether (50 mL) and water (25 mL) were added. The ether layer

was separated, dried over sodium sulphate and concentrated. Purification by silica

gel column chromatography (ethyl acetate and hexanes, 8:2) gave a desired liquid

product (2.3 g, 68.70%).

Expt. 2.4.2: Preparation of N-benzy1-2-bromo-N-[(2E)-3-phenylprop-2-en-1-

yl]acetamide (25).

NH Ph bromoacetyl bromide

K2CO3, CHCI3

Ph

25

A solution of N-benzy1-3-phenylprop-2-en-l-amine (1.8 g, 8.14 mmol) and

potassium carbonate (1.1 g, 8.14 mmol) in dry chloroform (20 mL) was cooled to

0°C. Bromoacetyl bromide (1.6 g, 8.14 mmol) was added dropwise with stirring

over a period of 10 min. The mixture was stirred for 1 h at 0 °C and further at room

temperature for 1 h. To the reaction mixture water (15 mL) was added and

extracted in chloroform (2 X 20 mL). The chloroform layer was dried over sodium

217

sulphate and was removed under vaccum pump to give yellow liquid (2.4 g,

86.33%).

Expt. 2.4.3: Preparation of N-benzyl-N-R2E)-3-phenylprop-2-en-1-341-2-

(triphenylphosphoranylidene) acetamide (27).

Ph i) PPh3

ii) NaOH

Ph

25 27

The solution of N-benzy1-2-bromo-N-[(2E)-3-phenylprop-2-en-l-yl]acetamide (

1.5 g, 4.4 mmol) & triphenyl phosphine (1.2 g, 4.4 mmol) in dry benzene (10 mL)

was stirred overnight at RT. The salt formed was dissolved in water (50 mL),

benzene (40 mL) was added and 2N sodium hydroxide solution was added to the

solution with stirring to phenolphthalein end point. The benzene layer was

separated and the aqueous layer was extracted with benzene (2 X 20 mL). The

combined benzene layer was dried over anhy. sodium sulphate and the solvent

removed under vaccum pump to give N-benzyl-N-[(2E)-3-phenylprop-2-en- 1 -y1]-

2-(triphenylphosphoranylidene) acetamide (27) (1.7 g, 73.90%).

Expt. 2.4.4: Preparation of (2E)-3-phenylprop-2-en-l-y1 bromoacetate.

OH Bromoacetyl bromide

pyridine, CHC13

A solution of cinnamyl alcohol (2.0 g, 14.39 mmol) & pyridine (1.1 mL, 14.39

mmol) in dry chloroform (20 mL) was cooled to 0 °C. Bromoacetyl bromide (2.9 g,

14.39 mmol) was added dropwise with stirring over a period of 15 min. The

mixture was stirred for 1 h at 0 °C and further at room temperature for 1 h. To the

reaction mixture water (20 mL) was added and extracted in chloroform (2 X 25

mL). The organic layer was washed with 2N HCl (2 X 15 mL), sat. sodium

218

bicarbonate (2 X 20 mL) and finally with water (20 mL). The chloroform layer was

dried over sodium sulphate and was evaporated under vaccuo to give yellow liquid

(3.7 g, 92.5%).

Expt. 2.4.5: Preparation of (2E)-3-phenylprop-2-en-1-y1 (triphenylphosphoran- ylidene)acetate (44).

i)PPh3

ii) NaOH

The solution of (2E)-3-phenylprop-2-en- 1 -yl bromoacetate (2.1 g, 7.6 mmol) &

triphenylphosphine (2 g, 7.6 mmol) in dry benzene (20 mL) was stirred overnight

at RT. The salt formed was filtered and dissolved in methanol (5 mL). To this

water (20 mL), benzene (40 mL) was added and then 2N sodium hydroxide

solution was added with stirring to phenolphthalein end point. The benzene layer

was separated and the aqueous layer was extracted with benzene (2 X 20 mL). The

combined benzene layer was dried over anhy. sodium sulphate and the solvent

removed under vaccum pump to give (2E)-3-phenylprop-2-en-l-y1

(triphenylphosphoranylidene) acetate (2.5 g, 71.42%).

Expt. 2.4.6: General procedure for the synthesis of unsaturated amides and ester.

A solution of aromatic/heteroaomatic aldehyde (1 mmol) & N-benzyl-N-[(2E)-3-

phenylprop-2-en-l-yl] -2-(triphenylphosphoranylidene)acetamide(27)/phosphorane

44 (1.5 mmol) in chloroform/xylene (10 mL) was refluxed for 1 to 5 h. The

solvent was evaporated under reduced pressure to leave crude product which was

subjected to column chromatography over silica gel using hexanes and ethyl

acetate (9:2) as solvent.

219

Expt. No

Substrate Product Solvent Nature Yield

(%)

2.4.6.1 H3c0 0 CHO

H 3C 0

OCH3

+ 27

el NBn " 0

H 3c0 0 OCH 3 OCH3

CHC13 liquid 84.96%

2 .4 . 6 .2

Ph

NBn CHC13 Liquid 86.80%

lc, I I I 0 CHO

+ 27

O

2.4.6.3 /C HO O

---) NBn CHC13 Liquid 88.20%

ol + 27

I t j o r Ph

2.4.6.4 CHO Xylene Solid

(m.p.170 -171 °C)

70.20%

+ 44

o

a -=---\z .

S ,

Expt. 2.4.7: Tandem Wittig-Diels Alder reaction: Preparation of tricyclic y-lactam/lactone.

A solution of aromatic/heteroaromatic (1 mmol) & N-benzyl-N-[(2E)-3-

phenylprop-2-en-1-y1]-2-(triphenylphosphoranylidene)acetamide (1.5 mmol) in

diphenyl ether/xylene (10 mL) was refluxed under nitrogen atmosphere for 8 to 12

h. The crude mixture was subjected to flash column chromatography over silica gel

using hexanes to remove diphenyl ether first and further elution with 30-50%

ethylacetate and hexanes to afford diastreomeric y-lactams/lactone.

220

Expt. No

Substrate Product Nature Yield (%)

2.4.7.1 H 3CO la CHO

H3C0 I" ocH3

+ 27

H

IS 7n

0

101 H3C0 OCH 3 OCH 3

Solid

(m.p. 80-81 °C)

62.10 %

2.4.7.2 CHO H 0

NBn

Solid

(m.p. 244-246 °C)

62.30% ®I I N H

+27

0 I* Ph

2.4.7.3

Ph H

NB n Liquid

70.10% ( I

0 CHO

+ 27

\ o

2.4.7.4 ECHO NBn

L iqu id 67.90%

t. j 0 + 27

H Ph

2.4.7.5 CHO H 0 Solid (m.p. 212- 214 °C

60.30% I I

0 N H

+ 44

0 O H H

Ph

221

Expt. 2.4.8: Preparation of tricyclic y-lactam/lactone from amides/ester.

Unsaturated amide/esters was refluxed in diphenyl ether (10 mL) for 8 to 10 h

under nitrogen atmosphere. The crude mixture was subjected to column

chromatography using hexanes to remove diphenyl ether first and further elution

with 30-40% ethylacetate and hexanes to afford diastreomeric y-lactams/lactone.

Expt. No

Substrate Product Yield (%)

2.4.8.1 0 NBn

elO H 3 C 0 0

OCH 3

NBn

65 % \

H 3 CO 0 OCH 3 0 C H 3

\c> H

OCH 3

2.4.8.3

Ph ... NBn

Ph H

NBn 80% I , 401

o'--- \H

2.4.8.4 o -- --), NBn

F1 O

NBn 79% I I I

010

Ph

'V Ph

H

2.4.8.5

0 H 0

62% 0 0 INI ..-------/ H

Ph

S i O H H

222

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