Chapter 2

Tandem Wittig-Diels-Alder reaction

C5fAq'TER 2

Tandem Wittig-Diels-Alder Reactions

Section

Tandem Wittig-Diels-Alder reactions: Synthetic studies in

furanosesquiterpenes

Sesquiterpenes are isoprenoids having 15 carbon atoms in the molecule.

Furanosesquiterpenes form an important and ever expanding class of bioactive

natural sesquiterpenes that have been derived from both terrestrial and marine

organisms. )-3

Marine sponges of the genus Dysidea are a rich source of structurally unique and

biologically active sesquiterpenes, including spiro-sesquiterpenes (spirodysin and

dehydroherbadysinolide), furanosesquiterpenes (furodysinin, furodysin, etc)

besides brominated diphenyl ethers, polychlorinated alkaloids, and other

compounds. 4

Most of the natural furanosesquiterpenes contain the tetrahydrobenzofuran linkage

(Fig I). Also functionalized furans and benzofurans represent the important

synthetic building blocks in a variety of biological relevant natural products. 5 '6

Fig I

25

Few of the naturally occurring furanosesquiterpenes are depicted below.

(1) R = H Furodysin (2) R = H Furodysinin

(3) R = OAc (4) R = OAc

Source: Dysidea herbaceal4a3

5

Source: Dysidea herbaceal4d

AcS AcS

(7) Thiofurodysin acetate (8) Thiofurodysinin acetate

Source: Dysidea herbaceal4a3

CH 3

(9) R = H Tubipofuran (11) Pallescensin A (12) Microcionin

(10) R = OAc 15-Acetoxytubipofuran

26

OR 1

(19) R 1 = H, R2= Me

(20) R 1 = Me, R2= CHO

OMe

(21) R= CHO

(22) R= CH 2OH

OMe

(23) R= H

(24) R= CHO

Source: 9, 10 Stolonifer tubipora musica Linnaeus, 8 11 Disidea

pallescens,9 12 Microciona toxystilla 9

CH3

(13)

(14)

(15)

Plant source: 13 Commiphora molmol, 10a 15 Buddleja crispa l°b

CH3

(16) R = H; (17) R = OH

(18) Secofuranoeremophilane

Plant source: 16, 17 Siphonochilus aethiopicus, 11 18 Euryops hebecarpus 12

Plant sources: 19, 24 Cacalia decomposita, 13 20-23 Senecio species13

27

OMe

(25)

0

(26) R i = CHO, R2= OH

(27) R 1 = CHO, R2= OAc

O

(28)

OH

H3C H 3C OH

SO

0 (29)

CH3 (30) R X

a) CHO =0

b) CH 2OH H, OH

c) Me =0

Plant source: 25-29 Trichillia cuneata, 14 30a-c Vitex negundo l5

OMe

CH3

Lindenenol (31)

CH3

Lindenene (32)

CH 3

Linderoxide (33)

CH3

Isolendenene (34)

CH3

Lindenenone (35) Euryoposl (36)

Plant source: 31-35 Lindera strychnifolia, 16-2° 36 Euryops spp . 21

28

CH3

0

O. CH 3

CH3 OH

(45) R (48) R1, R2= 0

(49)R 1 = OH, R2= H

CH 3 R CH3

(43)R= H (44)R= OH

s.s.‘ O R i

(38)

R 1 = Tigl Ang Sen Ang Sen Ang Sen R 1 = Tigl Ang

R2= Ac Ac Ac Ang. Sen Sen Ang R2= Ac Ac

= OSen OAng OAng OSen

R2= OTigl OH H H OSen

Tigl = tigelate Ang = angelate Sen = seneciolate

Plant source: 37-39 gynoxys species 22

Plant source: 40 Thespesia populnea, 23a 41, 42 Myrrh23b

(46)R= H (47)R= OH

Plant source: 43 Senecio othonal, 24 44-45 Senecio toluccanus, 25-26

46-49 Senecio family 27-29

29

CH3

OMe

CH3 CH3

(50) R a OMeBu b OAng c OSen

(51)R = OH

(52) R = 0

R (54) OMe

(55) OH

CH3

Plant source: 50(a-c)-57 Senecio flavus 3°

(58)

(59)

Plant source: 58, 59 Ligularia macrophylla31

CH3 OAc

Os R

CH 2 0

(60) H

(63)

(61) OH

(62) OAc

H C

30

OMe

(64) R= H

(65) R= OAc

R 1

(66) CH 3

(67) OH

(68) CH 3

(69) OOH

R2

OH

CH 3

OOH

CH 3

Plant source: 60-69 Psacalium beamanii32

Biological activities:

Several sesquiterpenes exhibit promising biological properties including

cytotoxicity, antifungal activity and immunostimulatory activity 33 , while different

furanosesquiterpenes exhibit anti-inflammatory, 34 ichtyotoxic and cytotoxic, 8 seed

germination inhibitory 35 and molluscicidal activities. 36 For example, tubipofuran

(9) shows ichtyotoxicity towards a killi-fish orizias latipes and its 1 5-acetoxy

derivative (10) shows cytotoxicity against B-16 melanoma cells in vitro. 8

Eremophilane derivative, cacalol (19) exhibits antihyperglycemic and

antimicrobial activity, while its derivative, compound 25 inhibits mitochondrial

lipid oxidation. 14 The sponge metabolites furodysin and furodysinin exhibit

ichythyotoxicity 37 and anti-inflammatory property, thioacetate of furodysinin is a

novel and specific high affinity agonist that can bind to LTB4 receptors and

activate the receptor mediated signal transduction process in human PMN and U-

937 cells. 38

I) Approach towards the synthesis of secofuranoeremophilane

Secofuranoeremophilane (18) 12 was isolated from the Arial part of the South

African composite, Euryops hebecarpus. It has a furan ring and y—lactone ring

attached to benzene in linear fashion.

31

OH

H3o* H3C BuLi / 100 °C

CO2

0

Tici3 H2N

EtOH

CH3

OH

DIBAL OH

CH3 CH3

18

1) NO

2) Cu(CNI

CH3

C H 3

Synthesis of secofuranoeremophilane (18): Bohlman and Fritz 12 have

synthesized this molecule in 7 steps starting from 4-bromo-3-nitrophenol (Scheme

I). 0-alkylation with haloaceteone gave corresponding phenylether, which was

subsequently reductively cyclised to give 3-methyl-5-bromo-6-amino benzofuran.

Modification of the amino group into cyano functionality (Sandmeyer reaction),

followed by its reduction with DIBAL gave corresponding aldehyde. Treatment of

the aldehyde with suitable lithio reagent yielded the corresponding benzyl alcohol,

which, upon treatment with BuLi followed by quenching with CO2 provided the

corresponding phthalide derivative. Acid hydrolysis of the above yielded the final

product, secofuranoeremophilane (18).

Scheme I

32

CHO Ph20, re flux

O

+ Ph 3P- a--..../CH2 Pd -C

Our retrosynthetic analysis of secofuranoeremophilane is depicted below (Scheme

II). The first cleavage identifies benzofuranophthalide as a synthon, which in turn

could be obtained by FGI (functional group interconverstion) from

tetrahydrobenzofurano lactone. The tricyclic system required could be constructed

by an intramolecular Diels-Alder reaction and the precursor for the Diels-Alder

reaction could be easily made via phosphorane (Wittig) chemistry.

H3

CHO

♦ Ph3P_

Scheme II

Our strategy for the synthesis secofuranoeremophilane based on above

retrosynthetic analysis is depicted in scheme III.

base

H2C:r—N(CH3

O 70

Scheme III

33

Wittig reaction of appropriate phosphorane on 3-formyl-4-methyl furan could give

the corresponding trans unsaturated ester. Under the reaction condition of

refluxing diphenyl ether (b.p. 250°C), the substrate formed would undergo

intramolecular Diels-Alder reaction followed by isomerisation of the incipient new

double bond to give stable tetrahydrobenzofurano lactone which, subsequently

under the reaction condition (Pd/C) could aromatize to give the benzofuran

phthalide (70). In this tandem sequence four reactions were visualized. Wittig

reaction, 4+2 cycloaddition, isomerisation and dehydrogenation. After obtaining

required benzofuran phthalide it was to be deprotonated with a suitable base

followed by Michael addition to give secofuranoeremophilane. Thus, the total

synthesis was planned as just two steps.

Initially, we thought of checking the viability of the visualized tandem Wittig-

Diels-Alder reaction on cheaply available 2-formyl furan (furfuraldehyde). The

allyl (triphenylphosphoranylidine)acetate 39 73 was prepared according to the

Scheme IV. Thus allyl alcohol was acylated by bromoacetyl bromide followed by

treatment of the allyl bromoacetate 40 with triphenylphosphine to obtain the

corresponding phosphonium salt 72.

O

H2C,7

OH bromoacetyl bromide O

PPh 3

pyridine, 0°C 71

Br O

CH2 0

72

73

NaOH O

Scheme IV

The strong IR (1(13r) peak at 1750 cm -1 indicated the presence of the ester group in

compound 71.

Its 'H NMR (400 MHz, CDC13) spectrum displayed signals at 8 3.83 (2H, CH2Br),

8 4.61 (2H, s, CH2O), 8 5.55-5.64 (2H, m, CH2=CH) and 5.82-5.90 (1H, m,

CH2=CH), further confirming the structure. Thus on the basis of mode of

formation & spectral properties structure 71 was assigned to it.

34

The allyl bromoacetate (71) was treated with triphenylphosphine to give

corresponding phosphonium salt 72. MP = 222-223 °C, IR (vmax): 1722 cm- '(C=0).

1 H NMR (CDC13, 300 MHz):

8 4.40 d (J = 5.7 Hz) 2H COH2

8 5.10 m 2H CH=CH2

8 5.55 d (J = 9.9 Hz) 2H CH2-P±Ph3Br-

8 5.78 m 1H CH=CH2

8 7.58-7.94 m 15H Ar-H

13 C NMR (CDC13): 8 33.00 (CH2-P +Ph3), 67.12 (CH20), 117.69 (3 X Cq), 119.73

(CH=CH2), 130.23 [CH=CH2 & 6 X CArH (ortho)], 133.86 [6 X CArH (meta)],

135.15 [3 X CArH (para)], 164.04 (C=0).

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

72 was assigned to this compound.

The phosphonium salt 72 was then treated with aq. sodium hydroxide to obtain the

required allyl (triphenylphosphoranylidine)acetate 73.

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

73 was assigned to the compound. MP = 72-73 °C, IR (vmax): 1734 cm- '(C=O).

NMR (CDC13, 300 MHz):

8 2.9 Broad hump 1H CH=PPh3

8 4.41 brs 2H CO

8 4.98 m 2H CH=CH2

8 5.80 m 1H CH=CH2

8 7.21-7.66 m 15H Ar-H

I3 C NMR (CDC13): 8 30.14 (CH=PPh3), 62.96 (CH2O) 115.75 (CH=CH2), 128.55

[CH=CH2 & 6 X CArH (ortho)], 130.93 (3 X Cq), 132.91 [6 X CArH (meta)], 132.88

[3 X CArH (para)], 170.69 (CO).=

35

Pd/C, PhOPh, N2

H 2C

0

0

0

0 CHO

74 75

77 76b

Scheme V

HRMS: m/z 361.1353 (observed), calculated for C23H2102P (M+H) ± : 361.1357.

The next step was to condense 73 with 2-formyl furan to get benzofuran using

Wittig and DieIs- Alder reactions in tandem fashion. Thus, allyl

(triphenylphosphoranylidine)acetate 73 was condensed with 2-formyl furan 74 in

presence of Pd/C in refluxing diphenyl ether for 6 h under nitrogen atmosphere

(monitored by tic). The mixture was purified by flash column chromatography

(Si02, hexanes - ethyl acetate (9:1) (Scheme V), to yield tetrahydrobenzofuran 76a

& 76b.

The compound that eluted first was solid in nature having MP at 182-184 °C. Its IR

spectrum had a strong peak at 1759 cm -1 indicating the presence of y-lactone

group, as expected.

Its 1 1-1 NMR spectrum (Fig la) had multiple signals in the region 8 2.33-2.69 (5H,

m), due to 4-H2, 8-H a, and two methine protons. The signal at 8 3.04 (1H, brd, 15

Hz) is attributed to 8-Hb, while the signals at 8 4.0 (1H, dd, 9.3 Hz) and 4.5 (1H,

dd, J = 9.3, 5.7 Hz) could be from the CH2O- group. The furan ring protons

appeared as two doublets (1H each, J = 1.8 Hz) at 8 6.18 (3-H) & 7.2 (2-H)

respectively.

36

The peaks at 8 24.92 (t), 25.51(t) in its 13 C NMR spectrum (Fig lb) is assigned to

the CH2 groups of six membered ring. Similarly, the peak at 73.09 (t) could be

assigned to the CH2O- group while those at 41.99 (d) and 44.0 (d) were assigned to

the ring junction carbons, C-4a and C-7a. Peaks at 143.54 (d), 111.65 (d), 118.13

(s) and 150.51(s) could be attributed to C-2, C-3, C-3a & C-8a of the furan ring

respectively. The y-lactone carbonyl carbon appeared at 177.53 (s). The

multiplicities of carbon signals mentioned were obtained from DEPT 135

experiment.

HRMS indicated the molecular formula to be CIOH1003 (Found: m/z 201.0538,

calculated: [M+Na] + = 201.0528

Thus on the basis of spectral properties structure 76 was assigned to it. However,

from the available NMR data, we could not confirm whether the corresponding

structure is 76a or 76b.

The second compound, eluted from the column also had strong IR absorption at

1760 cm-1 as expected for a five membered lactone.

The multiplet seen at 8 2.4-3.29 (6H) in its 1 H NMR spectrum could be easily

attributed to the protons of six membered ring. The signals 8 4.17 (1H, d, 8.7 Hz)

and 4.41 (1H, dd, 8.7 & 4.2 Hz) should be from the CH2O- group. The furan ring

protons were seen at 8 6.18 & 7.29 (1H each, s). The signals at 8 24.92 (t) and

25.51 (t) in its 13 C NMR and DEPT.135 spectra are assigned to the two methylene

carbons, C-4 and C-8 of six membered ring. The peak at 72.31 (t) should be due to

the CH2O- group. Similarly, the peaks at 44.0 (d) and 41.99 (d) were assigned to

C-4a and C-7a while the signals at 109.93 (d), 141.48 (d), 114.65 (s) and 147.14 (s)

could be attributed to C-3, C-2, C-3a & C-8a carbons of the furan ring. The

presence of the y-lactone moiety was confirmed by the peak at 177.84 (s).

HRMS revealed the elemental composition of the molecule to be C1oH1003

(Observed: m/z 201.0528, calculated: [M+Na] + = 201.0528).

Thus on the basis of spectral properties this compound could have structure either

76a (trans fused) or 76b (cis fused). The combined yield of both these

diastereomers was found to be 59.60% (ratio = 1:1).

37

In the course of the reaction it was expected that first Wittig reaction would take

place to give trans ester, which then would undergo intramolecular Diels-Alder

reaction to give tetrahydrobenzofuran lactone. The tetrahydrobezofuran lactone

was then expected to undergo dehydrogenation reaction in the presence of Pd/C to

give expected bezofuran lactone. From the products obtained it was clear that the

last expected step of aromatization didn't take place. Indeed we got product of

intramolecular Diels-Alder reaction. As we got two diastereomers it was necessary

to analyze their formation. In a normal Diels-Alder reaction the geometry of the

product depends upon the geometry of the starting diene and dienophile. If Wittig

reaction gives trans unsaturated ester then the cis (4+2) adduct should arise from

endo T.S. and the trans (4+2) adduct from exo. T. S. as depicted below (Fig II).

endo

1,3

exo

1,3

Fig II

However, If the Wittig reaction gives cis unsaturated ester then trans (4+2) adduct

should arise from endo T. S. and the cis (4+2) adduct from exo T. S. as depicted

below (Fig III).

exo 1,3

Fig

38

_J IJL

Our expectation was Wittig product i.e, trans unsaturated ester would undergo

normally preferred endo cyclization to give cis (4+2) adduct. However, formation

of both diastereomers in equal proportion suggests that the energy levels for both

endo and exo T. S. are same.

f If I I

Fig la

Fig lb

39

76 a ♦ 76 b Ph 3P_

73

74 CHCI3

It was felt necessary to ascertain the geometry of the intermediate ester to know the

genesis of product formation. So we planned the reaction sequence in a stepwise

manner. Firstly phosphorane 73 was to be condensed with 2-formyl furan to get the

unsaturated Wittig product. If cis and trans esters are formed, separate them and

subject them separately for intramolecular Diels-Alder reaction. The strategy

visualized is given below (Scheme VI).

75b

Scheme VI

Thus, 2-formyl furan was condensed with phosphorane 73 in chloroform at room

temperature. The product (liquid) was separated from triphenylphosphine oxide by

column chromatography. Based on the mode of formation & spectral properties

mentioned below, structure 75a was assigned to the compound. Based on the

coupling constant in 1 1-1 NMR the trans geometry for the unsaturated ester was

assigned. Yield = 89.70%. IR (v max): 1715 cm-1 (C0).

'HNMR (CDC13, 300 MHz): (Fig 2a)

8 4.70 brd (J = 5.7 Hz) 2H CH2-CH=CH2

8 5.27 dd (J = 10.5 & 1.5 Hz) 1H H H

8 5.36 dd (J = 17.1 & 1.5 Hz) 1H > RH

8 6.00 m 1H CH2-CH=CH2

8 6.35 d (J = 15.6 Hz) 1H CH=CH-CO

8 6.47 d (J = 1.8 Hz) 1H 4-H

8 6.25 d (J = 3.3 Hz) 1H 3-H

8 7.49 brs 1H 5-H

8 7A3 d (J = 15.6 Hz) 1H CH=CH-CO

40

tl

•W 1, 4-0-1 , ka ,,,141.7

' 3 C NMR and DEPT 135: 8 65.06 (t, CH2-CH=CH2), 112.27 (d, C-4), 114.85 (d,

C-3), 115.48 (d, CH=CH-CO), 118.03 (t, CH2-CH=CH2), 131.30 (d, CH2-

CH=CH2), 132.33 (d, CH=CH-00), 144.79 (d, C-5), 150.85 (s), 166.57 (s, CO).

Fig 2a

The trans ester 75a was then heated in refluxing diphenyl ether for 6 h (monitored

by tic) under nitrogen. After flash chromatography we again got a mixture of

distereoisomers 76 in 62.60% yield in 1:1 ratio. During the reaction, tic indicated

the formation of the two diastereomers 76a & 76b but we did not notice any other

extra spot for the formation of 75b. The solid compound obtained was assumed to

have structure 76a (trans fused) and the liquid 76b (cis fused) based on single

crystal structure of corresponding trans fused amide adduct (vide infra).

After successfully utilising tandem Wittig-Diels-Alder reaction for the synthesis of

y-lactones 76a-b from 2-furyl aldehyde, we thought of synthesizing y-lactones

from 3-furyl aldehyde so that we can prepare the desmethyl analogues of naturally

occurring secofuranoeremophilane (18). Thus, 3-furyl aldehyde (from Aldrich)

was heated with allyl (triphenyl phosphoranylidine)acetate 73 in refluxing diphenyl

ether for 6 h under nitrogen atmosphere. The reaction mixture was subjected to

flash chromatography (eluent: hexanes-ethyl acetate, 9:1) leading to the isolation

of two diastereomeric products 80a & 80b (Scheme VII).

41

Ph 3P=-,..„..y° H2

0 73

Pd/C, PhOPh, N2 , 6h

4

80a

CHO

0

78

80b

4 .

Scheme VII

The compound that eluted first was found to be a solid, MP = 165-166 °C with a

strong IR absorption band at 1770 cm I , indicating the presence of a five

membered lactone.

Its 'H NMR (Fig 3a) peaks at 8 2.52-2.68 (4H, m) and 2.85-2.95 (2H, m) could be

attributed to protons of the six membered ring. The peaks at 8 4.0 (1H, dd, 10.2 &

8.7 Hz) and 4.50 (1H, dd, 8.7 & 6.0 Hz) should be from the CH2O- group. The

Furan protons, 3-H and 2-H appeared at 8 6.29 (1H, d, J = 1.8 Hz) & 7.32 (1H, d, J

= 1.8 Hz) respectively. The carbon signals at 8 21.41 (t), 26.27 (t) were assigned to

two methylene carbons of six membered ring. The peak at 71.29 (t) should be from

the CH2O- group. The peaks at 40.17 (d) and 42.70 (d) were assigned to two

methine carbons in the ring junction, while the peaks at 110.61 (d), 142.07 (d),

117.06 (s) and 148.76 (s) were attributed to C-3, C-2, C-3a and C-8a furan carbons.

Peak at 176.29 was assigned to the carbonyl carbon of lactone. The multiplicities

of carbon signals mentioned were obtained by DEPT 135 experiment.

HRMS data confirmed the elemental composition as C101-11003 (Observed: m/z

201.0542, calculated for [M+Nal- = 201.0528).

On the basis of mode of formation & spectral properties structure 80 was assigned

to the compound. But it was not possible to assign the stereochemistry at the ring

junction.

42

pf.4p- .P 5--

5

0 5 7 6.0 . .

4 I. 5 fj 0 3 . 0 2. . C1

The more polar liquid, which eluted after the above solid from the column also

displayed strong IR peak at 1770 cm -1 due to the presence of five membered

lactone moiety.

Its 1 H NMR spectrum (Fig 4a) also had peaks at 6 2.46-2.56 (1H, m) and 2.83-3.06

(5H, m) from the protons of six membered ring. The peaks at 6 4.1 (1H, d, 8.7 Hz)

and 4.42 (1H, dd, 8.7 & 3.9 Hz) should be from the CH2O- group. The furan

protons 3-H and 2-H appeared at 6 6.25 (1H, d, J = 1.8 Hz) & 7.28 (1H, brs)

respectively.

In its 13 C NMR spectrum, the three methylene carbons appeared at 19.51 (t), 23.37

(t) and 72.31 (t) as expected. Similarly, the peaks at 34.08 (d) and 38.49 (d) were

assigned to methine carbons at the ring junction, while the furan carbons and the

carbonyl peaks were found at 110.08 (d, C-3), 141.32 (d, C-2), 114.10 (s, C-3a),

147.26 (s, C-8a) and 178.13 (s, C=0) respectively. The multiplicities of carbon

signals mentioned were obtained from DEPT 135 experiment. HRMS confirmed

its elemental composition to be CI0H1003 (Found: m/z 201.0524, calculated for

[M+Na] + = 201.0528).

Fig 3a

43

pzip 5, • .6

Fig 4a

Thus, on the basis of spectral properties this compound should be an isomer of the

solid reported earlier and could be either 80a (trans form) or 80b (cis form). The

overall yield was found to be 60.70% with the products in the ratio 1:1. The solid

isomer was assumed to trans fused and the more polar liquid compound to be cis

based on the crystal structure of the solid compound of the corresponding amide

(104a) compound (vide infra).

We further studied the geometry of the intermediate product 79 by carrying out

Wittig reaction separately (Scheme VIII).

4

CHO Ph3P-

0

73

CH2 5

0 1

0 PhOPh

H2C

79a

80 a -I- 80 b

78

CHCI3

/*N_CH2 0 0 °

79b

Scheme VIII

44

Thus, 3-furylaldehyde was condensed with allyl (triphenylphosphoran-

ylidine)acetate 73 in chloroform at room temperature. The product (liquid) was

separated from triphenylphosphine oxide by column chromatography. Based on the

mode of formation & spectral properties mentioned below, structure 79a was

assigned to the compound. The high coupling constant (15.6 Hz) of the vinyl

protons indicated trans geometry of the product (yield = 91.00%).

IR (v.): 1712 cm -1 (CO).

1 H NMR (CDC13, 300 MHz): (Fig 5a)

8 4.70

85.28

8 5.40

brd (J = 5.4 Hz)

dd (J = 10.5 & 1.5 Hz)

dd (J = 18.3 & 1.5 Hz)

2H

1H

1H

CH2-CH=CH2

H < H

> RH

8 6.00 m 1H CH2-CH=CH2

8 6.20 d (J = 15.6 Hz) 1H CH=CH-00

8 6.61 d (J = 1.8 Hz) 1H 4-H

8 7.44 brs 1H 5-H

8 7.61 d (J = 15.6 Hz) 1H CH=CH-00

8 7.67 brs 1H 2-H

13 C NMR and DEPT 135:8 65.03 (t, CH2-CH=CH2), 107.41 (d, C-4), 117.5 (d,

CH=CH-CO), 118.12 (t, CH2-CH=CH2), 122.58 (s), 132.32 (d, CH 2-CH=CH2),

134.98 (d, CH=CH-CO), 144.40 (d, C-5), 144.56 (d, C-2), 166.52 (s, CO).

Trans ester 79a was then refluxed in diphenyl ether for 6 h under nitrogen

atmosphere, yielding the diastereomeric y-lactones 80a and 80b in the ratio 1:1

after column chromatography (yield = 62.00%).

It was observed that, in the case of the trans isomer, the CH 2O- protons appear

separately as doublet of doublet (dd) signals, whereas in the case of the cis isomer,

one of the protons appear as dd while the second proton is only a doublet (d). In

the latter case, perhaps, the vicinal dihedral angle may be 90 °, resulting in zero

vicinal coupling for one of the methylene protons.

45

agC 6, RP 0!i-33,

Ili

7.5 7,0 6.s 6,o

Fig 5a

5,9 PPM

j17,1,,k1 re'

te 4,4e; .5 n

\N:t I

Our repeated attempts to dehydrogenate the tetrahydronaphthofuran by refluxing

with Pd/C in different solvents: ethyl acetate, xylene, dichlorobenzene, cymene and

diphenyl ether failed to yield the aromatized product. However, refluxing in

toluene in presence of DDQ for 24 h, followed by usual work up yielded a solid

product having m.p. 180-182 °C. Its IR spectrum had a strong absorption at 1750

cm -1 , indicating the presence of a y-lactone moiety. The peak at S 5.4 (2H, s) in its

NMR spectrum (Fig 6a) could be due to benzylic CH2O- group. A doublet was

observed at 8 6.94 (J = 1.8 Hz), this could be due to the 3-H. Another doublet at

7.80 (J = 1.8 Hz) was observed which could be due to 2-H. The signals at 8 7.57

(1 H, s) & 8.19 (1 H, s) were assigned 8-H and 4-H of the benzene ring respectively.

The downfield shift of 4-H proton might be due to the desheilding effect of the

proximal carbonyl group. The structure was further supported by its 13C NMR and

DEPT. 135 (CDC1 3) spectra which had signals at 8 69.18 (t, OCH2), 104.95 (d, C-

3), 107.21 (d, C-8), 119.28 (d, C-4), 120.999 (s), 129.26 (s), 142.73 (s), 147.30 (d,

C-2), 158.49 (s), 171.0 (s, CO). Thus on the basis of formation and spectral data

structure 81 was assigned to this compound. The yield increased to 62% from 20%

by using dioxane in the place of toluene (Scheme IX).

46

i) LDA 0

)( • ii) Methyl vinyl ketone

81

DDQ

dioxane, 48h

76a -b

81

Scheme IX

Attempted alkylation (Scheme X) of 81 using methyl vinyl ketone as the

electrophile and LDA as a base gave a complex mixture which we could not be

separated by chromatography. Further alkylation experiments with other

electrophiles were not tried.

Scheme X

1, RP-08—C

8.6 8.0 7.5

7.0 6.5 6.0 5.5 5.0 4.5

4.0

Fig 6a

47

H3C CH3 H3C CH3

i) LDA

ii) ethyl bromoacetate

II) Approach towards the synthesis of furodysin and furodysinin

CH 3

Furodysin 1

CH 3

Furodysinin 2

In the previous section we saw that we could build a tricyclic system from furan

aldehyde using tandem Wittig-Diels-Alder reaction. One of the important aspects

of this sequence was formation of cis and trans system. We realized that if the 1 ,-

lactone could be converted to a six membered ring then it should be possible to

synthesize furanosesquiterpenes, furodysin 1 and furodysinin 2 and their

analogues.

Synthesis of furodysin and furodysinin - A literature survey:

a) Hirota et a1. 41 have synthesized racemic form of furodysin and furodysinin from

a cis-decalone derivative (Scheme XI & XII).

COOEt i) KOH in Me0H

ii) NaOAc,

acetic anhydride

i) DIBAL in THE

ii) 1-14-

H3C CH3 (+) furodysin

Scheme XI

48

i) LDA

ii) MoOPH

i) MOMCI

OMOM

CO0Bul

i) p-TS SO

S

H3C CH3 H3C CH3

i) sodium acetate, H3

acetic anhydride C001-1

ii) DIBAL

iii) H

H H3C CH3

(+) furodysinin

H3C Li/N H3 Na Napthalenide,

).-- (Et0)2POCI

(-)-furodysinin

Zn/ HOAc i) LDA

ii) 2-furfuraldehyde

Ac 20, DMAP/Et 3N CH3 OAc

3

i) Hg(NO3)2

ii) NaBH 4 , NaOH

Scheme XII

b) The synthesis of (-) furodysinin has been accomplished in five steps from (+)-ir-

bromocamphor by Albizati et al. 42 (Scheme XIII).

Scheme XIII

49

H3C i) Hg(NO3)2

ii) NaBH 4, NaOH

H3C 200 °C

ii) 1-1 3O CH 3 OH H

H3C CH3

(-)-furodysinin

H C H3C H3C 3

CH2

./ • CH3

ii) o -nitrobenzyloxy acetaldehyde

CH2

H C NO2

i) photolysed

Scheme XIV

i) MeMgl/Cul

NM OH

HN(Me) 2 CH2 H C

CH3 150 °C

CH3 pyrolysis

i) 30% H202 H3C cH 2

cat. DMAP H3C

phenyl isocynate

OCONHPh lithium di -(furylmethyl) H 3C

CH2 cuprate

CH3

c) Ho et a/. 43 have described the synthesis of (-)-furodysinin from (1S, 2R, 4R)-1,2-

epoxymenth-8-ene. The key step of this synthesis is the use of Claisen

rearrangement and an intramolecular ene reaction in one pot (Scheme XIV). Later,

same authors 44 have synthesized furodysin from trans limonene oxide which

involves transformation into the phenylcarbamate of 2,8-methadien-l-ol, allylic

displacement with lithium di-(0-furylmethypcuprate and cyclisation (Scheme XV).

Scheme XV

50

CH3

CH3

CH3

HO CH3 ii) H3PO4 , H2O, Toluene

i) Li/NH3 , THE

)0-

i) Li/NH 3 , THE

ii) H 3 PO4 , H 20, Toluene CH3

CH3

r"CF13

H2C^CH3

CH3

CH 3

d) Moiseenkov et a1. 45 have synthesized racemic form of furodysinin and furodysin

using cationic cyclisation of the a or 13 furyl derivative of linalool, geraniol and

nerol (Scheme XVI).

Scheme XVI

Present work:

Our retro synthetic approach for the synthesis of compounds 1 & 2 is depicted in

schemes XVIIa and XVIIb. Accordingly, ring C of the tricyclic sesquiterpene

could be constructed by a metathesis approach. The required diolefinic system for

metathesis reaction could be made from the lactone 84, made by an intramolecular

Diels Alder reaction of a diene, prepared using an appropriate phosphorane with 2-

furyl aldehyde or 3-furyl aldehyde.

432 51

H3C CH3

0

Furodysinin

CH3

CH3

CHO H3C oD

H3C CH3

0 H3C CH3

Furodysin

84

Scheme XVIIa

Scheme XVIIb

Proposed synthetic scheme for furodysinin (Scheme XVIII).

2-Furyl aldehyde 74 on tandem Wittig-Diels-Alder reaction could provide the

lactone 84 as observed during synthetic studies of secofuranoeremophilane. The

lactone 84 could then be reduced with DIBAL to lactol which on subsequent

Wittig olefination could give the hydroxyolefin. The hydroxy group could be

manipulated to corresponding halide 85. Reaction of the 85 with appropriate

lithium cuprate reagent should provide the required diolefine 86. Metathesis of 86

in presence of Grubbs catalyst can then provide the desired product furodysinin.

A similar approach for the production of furodysin, starting from 3-furyl aldehyde

is given in scheme XIX.

52

1) DIBAL

2) Wittig

3) PPh3/CBr4 85

CH3

Grubbs catalyst

86 2

CH 3

Ph3 P

0 CHO

74

0 82

CH3

0 CH3

—CH2 Grubbs catalyst

,--CH2

H3C CH 3

Scheme XVIII

CHO CH3

1) DIBAL

2) Wittig

3) PPh 3/CBr4

H3C

2CuLi

CH3

Scheme XIX

53

To check the feasibility of our idea, initially we thought of introducing one methyl

group in the B ring system of furanosesqueterpenes. Towards this end, we prepared

the phosphonium salt 88 from crotyl bromoacetate 4° 87 and triphenyl phosphine,

which was then converted into the ylide, crotyl (triphenylphosphoran-

ylidine)acetate (89) by alkali treatment (Scheme XX).

0 OH bromoacetyl bromide

CH3 PPh3

87

0 Br-

CH3

88

0 NaOH

Ph3P 0

89

Scheme XX

The compound 87 in its IR spectrum (KBr) showed a band at 1751 cm -1 indicating

the presence of carbonyl group of ester. The signal at 8 1.74 (3H, d, 3.99 Hz) in its

1 H NMR spectrum indicated the presence of a CH3-CH= group, whereas the singlet

at 8 3.84 (2H) could be attributed to CH2Br group. The signal at 8 4.95 (2H, d)

could be attributed to the CH 2O group while the peaks at 8 5.60 (1H, m) and 5.85

(1H, m) could be from the olefinic protons of CH=CH group. Thus on the basis of

mode of formation & spectral properties structure 87 was assigned to it.

The crotyl bromoacetate 87 was treated with triphenylphoshine to give

corresponding phosphonium salt 88.

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

88 was assigned to the compound. MP = 87-88°C.

IR (v.): 1730

54

'H NMR (CDC13 , 300 MHz):

8 1.60 d (J = 6.0 Hz) 3H =CH-CH3

8 4.37 d (J = 6.6 Hz) 2H CH2O

8 5.26 m 1H CH=CH-CH3

8 5.48 d (J = 13.8 Hz) 2H CH2-P+Ph3 Br"

8 5.63 m 1H CH=CH-CH3

8 7.63-7.91 m 15H Ar-H

13C NMR and DEPT 135:8 17.64 (q), 32.59 (t, CH2-P +Ph3), 67.22 (t, CH2O),

117.05 (s), 118.23 (s), 123.30 (d, CH=CH-CH 3), 130.21 (d, CH=CH-CH 3 & 6 X

CArH (ortho)), 133.83 (d, 6 X CArH (meta)), 135.15 (d, 3 X CArH (para)), 163.96 (s,

C=0).

The phosphonium salt 88 was then treated with aq. sodium hydroxide to obtain the

required crotyl (triphenylphosphoranylidine)acetate 89.

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

89 was assayed to the compound.

IR (vmax): 1651 cm"'

'H NMR (CDC13 , 300 MHz):

8 1.58 d (J = 6.0 Hz) 3H =CH-CH

8 3.25 d (J = 13.5 Hz) 1H CH=PPh3

84.32 d (J = 5.7 Hz) 2H CH20

8 5.50 m 2H CH=CH-CH3

8 7.18- 7.62 m 15H Ar-H

13 C NMR and DEPT 135:8 17.68 (q, =CH-CH 3), 30.12 (d, CH=PPh3), 62.80 (t,

CH2O), 127.18 (d, CH=CH-CH3), 127.39 (d, CH=CH-CH3), 128.52 (s & d, CArH),

131.95 (d, CA,H), 132.91 (d, CA rH), 170.88 (s, C=0).

55

The HRMS of the compound indicated the pseudomolecular ion peak at m/z

375.1507 [M+H] + , (Calculated for C24H2302P = 375.1514).

Thus, once we had crotyl (triphenylphosphoranylidine)acetate 89 in our hand, our

next step was to get lactone via Wittig reaction and Diels-Alder reaction in one pot.

Towards this end, 2-furyl aldehyde was refluxed with the phosphorane 89 in

diphenyl ether for 6 h. The reaction mixture purified by flash chromatography

(silica gel, ethyl acetate-hexanes 1:9) to yield compound 91 (Scheme XXI).

Ph3P_ H

0 CHO I 0

74 89 0

- 90 0

91

Scheme XXI

The strong band at 1770 cm -i in the IR spectrum of 91 confirmed the presence of

y-lactone moiety in the molecule. Its I FI NMR spectrum had four doublets (3H

each) at 6 1.19 (J = 6.6 Hz), 1.24 (J = 6.6 Hz), 1.41 (J = 6.3 Hz), 1.45 (J = 6.0 Hz)

indicating the presence of methyl of =CH-CH 3 groups. The multiplet signal at 6

2.06-3.10 could be attributed to the protons of the six membered ring system, while

the multiplet at 6 4.0-4.63 could be attributed to the CH2O- group. In the aromatic

region, signal at 6 6.2-6.3 (m) and 7.27-7.3 (m) could be assigned to 3-H and 2-H

protons respectively of the furan ring. The HRMS of the compound had a strong

peak at m/z 215.0685 [M+Na] +, indicating its molecular formula to be C11141 203 .

(Calculated = 215.0684 for [M+Na] +).

The I FI NMR spectrum indicated it to be a mixture of four isomeric compounds in

the ratio 3:2.3:1.8:1(combined yield = 59.70%). The structures of all the possible

diastereomers are given below (Fig IV)

PhOPh

56

91c

H CH 3 CH3

91d

0

Fig IV

Further, we also carried out this reaction in a stepwise manner to confirm the

geometry of the postulated intermediate. Towards this end, we first condensed the

crotyl (triphenylphosphoranylidine)acetate (89) with 2-furyl aldehyde, the ester

compound was separated from triphenylphosphine oxide by column

chromatography using ethyl acetate and hexanes (5:95) as solvent to give the

Wittig product (Scheme XXII).

O CHO Ph

CH C I 3

91

74

89

Scheme XXII

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

90 was assigned to the compound (Yield = 87.90%). Based on the high coupling

constant (15.6 Hz) in 1 1-1 NMR, trans geometry was assigned to this compound.

IR (vmax): 1708 cm*

57

7Z 8.0

It M

6.0 5.0 5.0 4.5 4,0

fl

,5 3,0 2.5 2.0 t • • • ; 7.0 (5.5

RP-05-11, 1-1C3=1:Z.8

'H NMR (CDC13, 300 MHz): (Fig 7a)

8 1.75 d (J = 7.5 Hz) 3H CH3

8 4.63 t (J = 7.2 Hz) 2H CH2-CH=CH

8 5.70 m 1H CH2-CH=CH

8 5.83 m 1H CH2-CH=CH

8 6.33 d (J =15.6 Hz) 1H CH=CH-CO

8 6.68 dd (J = 1.8, 3.3 Hz) 1H 4-H

86.61 d (J = 3.3 Hz) 1H 3-H

8 7.44 d (J =15.6 Hz) 1H CH=CH-CO

8 7.49 brs 1H 5-H

13C NMR and DEPT 135 (Fig 7b): 8 17.75 (q, CH 3), 65.17 (t, CH2-CH=), 112.23

(d, C-4), 114.68 (d, C-3), 115.75 (d, CH=CH-CO), 125.23(d, CH=CH-CH3),

131.12 (d, CH=CH-CH3), 131.25 (d, CH=CH-CO), 144.71 (d, C-5), 150.92 (s),

166.77 (s, CO).

Fig 7a

58

$01. 14, PP-05-11, <1„13 .7.,

!:It 13 RP-C-11, I3C

Fig 7b

The trans ester 90 was then refluxed in diphenyl ether for 6 h under nitrogen

atmosphere to yield the mixture of products in 60.90%.

We have also synthesized the regioisomer of diastereomer 91 by refluxing 3-

furfuraldehyde with crotyl (triphenylphosphoranylidine)acetate (89) in diphenyl

ether for 6 h under nitrogen atmosphere. The products were purified by flash

chromatography (SiO2, ethyl acetate - hexanes 1:9) (Scheme XXIII).

59

78

H CH 3 CH3

93b 93c

CH 3

93a

CHO

+ Ph

0

89

PhOPh

/ I 0

O H3C

92

Scheme XXIII

The strong band at 1770 cm -I in the IR spectrum of purified 93 confirmed the

presence of y-lactone moiety in the molecule. Its 1 11 NMR spectrum had four

doublets (all 3H each) at 6 1.74 (J = 6.6 Hz), 1.32 (J = 6.0 Hz), 1.43 (J = 6.3 Hz),

1.56 (J = 6.3 Hz) indicating presence of methyl of =CH-CH3 groups. Multiplet at 6

2.1-3.0 could be attributed to the protons of six membered ring. Signals at 6 4.0-

4.61 (m) could be from the CH 2O- group. In the aromatic region two multiplets

were seen at 6 6.23-6.17 and 6 7.21-6.31, which could be assigned for 3-H and 2-H

protons of furan ring.

HRMS confirmed its elemental composition to be C1 ,H 1 203 (Observed [M+Na] + :

m/z 215.0688, Calculated: 215.0684).

Thus on the basis of mode of formation & spectral properties the product formed

was a mixture of four diastereomers in the ratio 3.2:3:2.4:1 (yield = 60.30%).

The four possible structures of the diastereomers are given below (Fig V).

Fig V

60

Further, Wittig reaction of 74 and 89 in CHC13 solution led to the isolation of the

intermediate 92 (Scheme XXIV), which was purified from triphenylphosphine

oxide by Si02 column chromatography (Yield = 87.80%) .

CHO Ph3P_

PhOPh 93

74

92

Scheme XXIV

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

92a was assigned to the compound. Trans geometry of the double bond was

inferred from the high coupling constant (15.6 Hz) in 'H NMR spectrum.

IR (vmax): 1712 cm 1

'H NMR (CDC13, 300 MHz):

8 1.74 d (J = 7.8 Hz) 3H CH3

8 4.62 t (J = 7.5 Hz) 2H C.112-CH=CH-CH3

8 5.65 m 1H CH2-CH=CH-CH3

8 5.80 m 1H CH2-CH=CH-CH3

8 6.17 d (J = 15.6 Hz) 1H CH=CH-CO

8 6.58 brs 1H 4-H

8 7.42 brs 1H 5-H

8 7.58 d (J = 15.6 Hz) 1H CH=CH-CO

8 7.64 s 1H 2-H

' 3 C NMR and DEPT 135:8 17.71 (q, CH 3), 65.17 (t, CH2-CH=CH), 107.39 (d, C-

4), 117.82 (d, CH=CH-00), 122.60 (s), 125.22 (d, CH=CH-CH3), 131.27 (d, CH2-

CH=CH), 134.71 (d, CH=CH-CO), 144.35 (d, C-2), 144.46 (d, C-5), 166.65 (s,

CO).

61

The trans ester 92 upon refluxing in diphenyl ether for 6 h under nitrogen

atmosphere, followed by flash chromatography yielded the mixture of

diastereomers in 61.70% yield.

Thus our attempt to synthesize tricyclic lactone with methyl substituent in the B

ring system was fairly fruitful. But the marine metabolites furodysin and

furodysinin has gem dimethyl group in the B ring. Towards this end, we had to

prepare prenylbromo acetate 94, 40 starting from the prenyl alcohol, which could

then be converted into the Wittig salt 95 (Scheme XXV).

OH bromoacetyl bromide

CH3

PPh 3 O CH3

CH 3 94

+ 0 CH3 NaOH Ph 3P Br

O CH3

95 82

Scheme XXV

IR spectrum (KBr) of the compound 94 had a strong band at 1725 cm -I , indicating

the presence of ester group. The signal at .3 1.74 (6H) in its 'H NMR spectrum

indicated the presence of two methyls, possibly as (CH3)2C=CH group. In addition,

the spectrum had signals at .3 3.84 (2H, s) and 4.95 (2H, d, 5.5 Hz) assigned to the

CH2Br and CH2O groups. The olefinic proton appeared .3 5.60 (1H, m).

Thus on the basis of mode of formation & spectral properties structure 94 was assigned to it.

Treatment of prenyl bromoacetate 94 with triphenylphosphine yielded the

corresponding phosphonium salt 95, MP = 188-190°C. The compound 95, upon

treatment with NaOH yielded the required phosphorane 82.

O CH 3

O

'CH3

62

CHO

CH 3

O CH 3

82 84

OH

97 0

IR (vmax): 1730 cm-1 .

1 11 NMR (CDC13, 300 MHz) spectrum:

8 1.26 d (J = 5.7 Hz) 3H CH3

8 1.64 d (J = 5.7 Hz) 3H CH3

8 3.26 d (J = 13.5 Hz) 1H CH=PPh3

84.5 d (J = 7.2 Hz) 2H CH20

8 5.1 m 1H CH=CH3

8 7.6 m 15H Ar-H

HRMS of the compound confirmed its elemental composition to be C25H2502P

(Observed: m/z 389.1670, Calculated for [M+H] + = 389.1673)

After having prenyl (triphenylphosphoranylidine)acetate 82, it was condensed with

2-furyl aldehyde in refluxing diphenyl ether. The products obtained were purified

by flash chromatography over silica gel (eluant: ethyl acetate - hexanes = 1:9,

Scheme XXVI).

96

Scheme XXVI

However, spectral data indicated the reaction products to be 96 and 97 and not the

expected compound 84.

63

83

IR spectrum of compound 96 had a band at 1759 cm -1 due to lactone moiety. Its 1 14

NMR spectrum had signals at 6 1.30 (3H, s) and 1.51 (3H, s) for the gem dimethyl

groups. The signals at 6 2.32-2.89 (6H, m) could be attributed to the protons of the

B ring. The peaks at 6 6.24 (1H, d, 1.8 Hz) and 7.28 (1H, d, 1.8 Hz) are from 3-H

and 2-H respectively of the furan ring. The structure was further confirmed by its

13C NMR and DEPT.135 spectra. The peaks at 6 21.27 (q) and 27.48 (q) could be

as§igned to the methyl groups. Similarly, the peaks at 21.88 (t) and 23.98 (t) are

from the methylene groups of the B ring, while the signals at 41.7 (d) and 48.87 (d)

could be assigned to two methine carbons of the B-C ring junction. The signals at

110.48 (d) and 141.97 (d) could be attributed to C-3 and C-2 carbons of furan ring.

The quaternary carbons at 84.45 (s), 116.78 (s) and 148.96 (s) could be attributed

to saturated alkane carbon (C-5) and furan carbons (C-3a & C-8a). The lactone

carbonyl carbon appeared at 175.45 (s) as expected.

Thus, on the basis of mode of formation & spectral properties structure 96 was

assigned to it.

The formation of 96 could be explained by the following mechanism (Scheme

XXVII).

Scheme XXVII

Yield of 96 was negligible in comparison to the large excess of furyl acrylic acid

97 isolated. Based on the mode of formation & spectral properties mentioned

below structure 97 was assigned to the compound (Yield = 95.50 %). Based on the

coupling constant in 1 14 "NMR the trans geometry for the unsaturated acid was

assigned.

64

7/ 0

O 83

82

CHO CHC1 3 PhOPh

CH3 H3ta

4

IR (vmax): 1712 cm -1 .

NMR (CDC13, 400 MHz) spectrum:

S 6.33 d (J = 15.6 Hz) 1H CH=CH-COOH

8 6.49 m 1H 4-H

8 6.66 d (J = 1.2 Hz) 1H 3-H

8 7.50 d (J= 1.2 Hz) .1H 5-H

8 7.53 d (J = 15.6 Hz) 1H CH=CH-COOH

The structure was further confirmed by comparison of its melting point. Found:

139°C, lit46 m.p 139-140 °C.

We also attempted the above synthesis of 84 in a stepwise manner, to see whether

the triphenyl phosphine oxide formed during the reaction has any role in the

hydrolysis of the ester (Scheme XXVIII). For this purpose, prenyl

(triphenylphosphoran- ylidine)acetate 82 was subjected with 2-furyl aldehyde to

form Wittig product in CHC13 solution.

Scheme XXVIII

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

83 was assigned to the compound (yield: 89.70%). Based on the coupling constant

in t H NMR the trans geometry to the unsaturated ester was assigned.

OH

0

65

IR (vmax): 1712 cm -I

NMR (CDC13, 300 MHz) spectrum: (Fig 8a)

S 1.76 s 3H CH3

S 1.79 s 3H CH3

S 4.70 d (J = 7.2 Hz) 2H O-CH2

S 5.42 t (J = 7.2 & 14.4 Hz) 1H =CH-CH2O

8 6.34 d (J =15.9 Hz) 1H CH=CH-CO

56.47 dd (J = 1.8 & 3.3 Hz) 1H 4-H

8 6.61 d (J = 3.3 Hz) 1H 3-H

8 7.44 d (J = 15.9 Hz) 1H CH=CH-CO

8 7.49 brs 1H 5-H

13 C NMR and DEPT 135: S 18.01 (q, CH3), 25.75 (q, CH3), 61.31 (t, 0-CH2-CH=),

107.42 (d, C-4), 117.96 (d, C-3), 118.66 (d, CH=CH-00), 122.63 (s), 134.59 (d,

=CH), 139.13 (s), 144.35 (d, C-5), 144.42 (d, CH=CH-00), 166.97 (s, CO).

,logt 9, RP- C;5- ■ , f 161. 3

r 7.5 7.0 6 (.6 6.0 5.5 5.0 4.5 4.0 3.6 3.0 .5 2.0 1.6

?

Fig 8a

66

CH3

'CH3

98 0.O 0 CHO

PhOPh

H 3C

H 3C CH3 NH2

OH -I.-

The trans ester 83 was then refluxed in diphenyl ether for 6 h under nitrogen

atmosphere. Upon cooling the reaction mixture, furyl acrylic acid crystallized out.

TLC indicated this was the sole product of the reaction.

Thus, instead of the expected intramolecular Diels-Alder reaction, we only got the

hydrolysed ester as the product. Perhaps, under the reaction conditions, cleavage of

the ester to furyl acrylic acid and isoprene is a favorable process rather than the

intramolecular Diels-Alder reaction (Scheme XXIX).

( 1, 7) sigmatropic shift OH

H2C

O

Scheme XXIX

We didn't attempt the similar reaction on 3-furyl aldehyde, expecting that only

similar cleavage might occur here too.

In order to avoid the cleavage process and to force the intramolecular Diels-Alder

reaction, we thought of using amide functionality 98 instead of ester functionality

82 as depicted in Scheme XXX below.

99

Scheme XXX

67

Ri + PPh3 Br-

'R2 Bn Bn

0 R i

NaOH Ph3P-■-,„. /\R2 Bn

To check the feasibility of using amide approach we needed to prepare the

phosphorane 98 (R=benzyl). We choose the bulky benzyl (Bn) group at the

nitrogen atom for providing the right stereochemistry for Diels-Alder reaction.

Further, introduction and removal of the Bn group are comparatively easy

processes. In addition, we also envisaged use of chiral amines like ethyl

benzylamine for enantioselective synthesis in the same manner later on. The

product obtained by the domino sequence could be converted to the required

lactone via basic hydrolysis (acid hydrolysis may lead to decomposition of furan

ring) followed by debenzylation and diazotization as depicted above.

Towards this end, initially we prepared the phosphorane containing amide

functionality by treating allyl bromide with bezyl amine. 47 The product obtained

was acylated with bromoacetyl bromide to give N-benzyl-N-ally1-2-

bromoacetamide 48 100 (Scheme XXXI).

H 2N—Bn R2 NH—Bn

R2

bromoacetyl bromide

100 Ri, R2 = H 101 R i , R2 = H 102 Ri, R2 = H

107 R i = H, R2 = CH3 108 R i = H, R2 = CH3 109 Ri = H. R2 = CH 3

114 Ri, R2 = CH3 115 R i . Ft2 = CH 3 98 Ri. R2 = CH3

Scheme XXXI

IR (KBr) spectrum of the compound 100 had a strong band at 1651 cm -1 indicating

the presence amide moiety. Its 1 H NMR spectrum had signals at 8 4.0 (2H, d, 5.7

Hz) 5.22 (2H, m) and 5.78 (1H, m) due to allyl (—CH2-CH=CH2) group. The peak

at 8 3.91 (2H, brs) could be due to the BrCH2CO- group, while the signals at 8 4.61

(2H, s), 7.3 (5H, m) could be assigned to benzylic methylene and phenyl protons.

The structure was further confirmed by 13C NMR and DEPT 135 spectra. Thus the

peaks at 8 26.09 (t) and 49.78 (t) could be assigned to BrCH2CO- and benzylic

methylene groups. Peaks at 8 48.26 (t), 126.27 (d) and 117.27 (t) are typical of a

CH2-CH=CH2 system. Peaks at 127.40-135.93 (d) could be attributed to benzene

68

carbons. The quaternary carbon of the benzene ring and the amide carbonyl appear

at 8 136.62 and 167.20 respectively.

Thus on the basis of mode of formation & spectral properties structure 100 was

assigned to it.

The N-benzyl-N-allyl-2-bromoacetamide 100 was treated with triphenyl phosphine

to give the corresponding phosphonium salt 101.

The compound 101 in its IR (KBr) spectrum showed a band at 1639 cm'

indicating the presence of carbonyl group of amide.

The 1 H NMR spectrum had one doublet (J= 5.7 Hz) at 8 .3.4 [3.95] which could be

assigned to two methylene protons of ally! group. The signal 8 4.35 (2H, brs) could

be assigned to benzylic methylene group, while the signals at 8 5.09 (2H, m) could

be attributed to methylene of allyl group and 5.64 (3H, m) could be attributed to

olefinic methine proton of ally! group and methylene group attached to the

phosphorous atom. The multiplet at 8 6.98-7.75 could be attributed to aromatic

protons.

Its 13 C NMR and DEPT 135 spectra also supported the above structure. Thus the

peaks at 33.69 (t) [34.58] could be attributed to methylene carbon next to

positively charged phosphorous. Peaks at 51.09 (t) [51.87], 116.49 (t) [118.28]

could be assigned to the allylic methylene carbons while the peak at 49.52 (t) could

be from the benzylic methylene group. The quaternary carbons appearing at 118.77

(s), 119.97 (s), 135.99 (s) as well as the signals at 126.37-134.37 could be

attributed to the aromatic carbons and unsaturated alkene carbons. The amide

carbonyl signal was seen at 164.52 as expected.

Thus on the basis of mode of formation & spectral properties structure 101 was

assigned to it.

The phosphonium salt 101 was treated with 2N NaOH to obtain phosphorane 102,

as evidenced by the IR (KBr) peak at 1655 cm -1 (amide carbonyl). Its 'H NMR

spectrum had a broad hump at 2.38 (1H), which could be assigned to ylidic

(CH=P) proton. Proton signals at 8 3.7 [3.9] (2H, J = 4.8 Hz), 8 5.12 (2H, m) and

5.67 (1H, m) are from the —CH 2CH=CH2 moiety. The benzylic protons appeared at

69

H2C-\ N Bn

104a

S 4.4 [4.5] (2H, s) while the aromatic protons were seen at 8 7.12-7.57 (15H, m).

Its 13C NMR and DEPT 135 spectra were compatible with the proposed structure.

Thus, the signals at 21.25 (d) [21.48] could be due to ylide carbon (CH=P). The

peaks at 47.70 (t) [48.01] and 116.68 (t) [117.36] could be assigned to methylene

carbons of CH2-CH=CH2 system. The benzylic methylene carbon signal appeared

at 49.79 (d) [50.83]. The quaternary carbons appearing at 132.90 (s), 133.173 (s),

136.58 (s), 137.46 (s) could be attributed to aromatic carbons. Peaks at 126.21(d)-

132.36(d) could be assigned to aromatic methine carbons. The amide carbonyl

signal was seen at 170.65 ppm as expected. HRMS of the compound confirmed its

elemental composition to be C30H280NP (Obsvd, m/z 450.1946 for [M+Na] +

calcd: 450.1987).

Thus on the basis of mode of formation & spectral properties structure 102 was

assigned to it.

With the phosphorane 102 in hand, our next task was to prepare the y-lactam via

tandem Wittig reaction and Diels-Alder reaction in one pot. Refluxing 2-furyl

aldehyde and the phosphorane (102) in diphenyl ether for 8 h under nitrogen

atmosphere, followed by purification of the products on a Si02 column (ethyl

acetate — hexanes = 2:8) yielded a diastereomeric mixture 104a & b (Scheme

XXXII).

0

Bn

I 102 0 CHO

PhOPh

103

Scheme XXXII

70

The solid compound that eluted first, MP = 122-123 °C, displayed strong IR band at

1693 cm-1 , as expected for the lactam group. In its 1 1-INMR spectrum (Fig 9a), the

multiplets between 8 2.22 - 2.71 (5H) were assigned to the aliphatic protons of ring

B. The signal at 8 3.07 (2H) could be due to one of the methylene protons 8-H2 and

5-H2 each. The remaining proton of 5-H2 was seen at 8 3.34 (1H, m). The signal at

8 4.50 (2H, s) was assigned to the benzylic methylene group, while the broad

signal at 8 6.19 (1H, brs) appeared to be from the 3-H of the furan ring. The 2-H

signal of furan ring and five benzene protons appeared at 8 7.23-7.34 (6H, m).

Its 13 C NMR and DEPT spectra further confirmed the structure. Thus, the peaks at

24.26 (t) and 25.0 (t) could be assigned to the methylene carbons of ring B, while

the two ring junction methines appeared at 38.75 (d) and 45.43 (d). Signals due to

the -CH2NCH2Ph methylenes were seen at 46.61 (t) and 50.16 (t). Two furan

methine signals were located at 110.26 (d) and 141.55 (d) while the aromatic

methine carbons appeared at 127.55 (d), 128.17 (d) and 128.63 (d). Two

quarternary carbons of the furan and one of benzene appeared at 117.06 (s), 136.53

(s) and 149.89 (s) and the lactam carbonyl appeared at 174.31 (s). HRMS

confirmed the elemental composition of the compound to be C17H 1702N

(Observed: m/z 268.1308, calculated for [M+H] + : m/z 268.1337).

Thus on the basis of mode of formation & spectral properties structure 104 was

assigned to it. However whether the compound is trans fused (104a) or cis fused

(104b) could not be decided from the above spectral data.

IR and NMR spectral properties of the more polar compound (may be 104b)

eluting from the column were also very similar to the previous compound, IR:

1683 cm', 'H NMR (300 MHz, CDC13): 8 2.10-3.43 (8H, m, 4-H2, 4a-H, 5-H2,

7a-H & 8-H2; 8 4.35 & 4.61 (1H each, dd, 14.7 Hz, CH2-Ph); 8 6.12 (1H, s, 3-H);

7.20-7.35 (6H, m, 2-H & Ar-H). Its 13 C NMR and DEPT 135 spectral were: 8

20.06 (t, C-4), 24.0 (t, C-8), 30.84 (d, C-4a), 41.16 (d, C-7a), 46.96 (t, C-5), 51.30

(t, CH2-Ph), 109.80 (d, C-3), 140.89 (d, C-2). The aromatic and other vinyl carbon

signals were seen at 8 127.56 (d), 128.17 (d), 128.63 (d), 114.56 (s), 136.37 (s, C-

3a) and 148.25 (s, C-8a). The lactam carbonyl signal was seen at 8 175.02, as

expected. HRMS of the compound confirmed its elemental composition to be

CI7H2702N (Observed for [M+H] m/z 268.1337; Calculated: 268.1337).

71

/

pxp 25, itr 0 1 (II nal 0.15

On the basis of mode of formation and spectral properties, structure 104 was

assigned to it.

X-ray crystallographic structure of the less polar, solid product (Fig VI) confirmed

its structure as in 104a (trans ring fusion). Hence the more polar compound must

have cis fusion, 104b. The combined yield of two diastereomers was 80%.

Figure VI: ORTEP figure of the solid compound 104a.

Crystal data for Fig VI: Ci7Ci7NO2, M= 267.32, monoclinic, space group P21Ic, a = 11.479(3) A °, b = 6.4481(17) A ° , c = 18.655(5), fl = 92.839(5) ° , V= 1379.1(6) A03 , Z= 4, n cacd 1.287 g cm-3, F(000) = 568, µ = 0.084 mm-1, R = 0.0497, wR = 0.1094, GOF = 1.027 for 1540 reflections with I> 24/), CCDC-629551.

I s' 1

.5- 7.0 6,.5 6.0 5.5 5.,0 4 *4 .11 1. 0 2.! 2.0 I II

Fig 9a

72

Ph3P__ CHO

Bn NrzzcH2 CHCI3

3

NBn PhOPh O

O 104

102 103

Further, we also carried out the synthesis of above lactam 104 in a stepwise

manner. Thus, treatment of N-allyl-N-benzyl-2-(triphenylphosphoranylidene)

acetamide 102 with 2-formyl furan in low boiling solvent CHC1 3 yielded

compound 103 as the sole product (Yield = 90.20%, scheme XXXIII).

Scheme XXXIII

IR (vmax): 1693 cm' (amide).

For 'H NMR (CDC13, 300 MHz): (Fig 10a)

S 3.98 [4.89] d (J = 5.4 Hz) 2H CH2-CH=CH2

8 4.65 [4.70] s 2H CH2-Ph

8 5.20 m 2H CH2-CH=C1j2

8 5.82 m 1H CH2-CH=CH2

8 6.45 brs 1H 4-H

8 6.55 brs 1H 3-H

8 6.75 m 1H CH=CH-CO

8 7.21-7.43 m 6H 5-H & ArH

8 7.56 d (J = 15 Hz) 1H CH=CH-CO

' 3 C NMR and DEPT 135: 8 48.33 [48.92] (t, CH2-CH=CH2), 49.09 [50.02] (t,

CH2Ph), 112.06 (d, C-4), 113.85 (d, C-3), 114.91 (d, CH=CH-CO), 116.96

[117.49] (t, CH2-CH=CH2), 126.55-128.78 (d, CA,H), 129.92 (d, CH2-CH=CH2),

132.82 (d, CH=CH-00), 137.53 (s), 143.87 (d, C-5), 151.62 (s), 166.75 (CO).

73

Trans ester 103, upon refluxing in diphenyl ether for 8 h under nitrogen

atmosphere, followed by purification by flash chromatography, yielded the

diastereomeric i-lactones 104a & b (yield: 88 %, product ratio = 1:1).

Fig 10a

In a similar fashion, treatment of the phosphorane 102 with 3-formyl furan

provided the tricyclic lactams 106a & b. The reaction proceeded in tandem fashion

to yield the final products in diphenyl ether or stopped with the formation of Wittig

product 105 with CHC13 as solvent.

106a

106b

105

74

Spectral data of 106a, 106b and 105 are given below.

Lactam 106a: MP = 108-110°C, IR: 1693 cm -1 (amide C=0);

NMR (300 MHz, CDC13): 8 2.20-2.88 (m, 6H, 4-H2, 4a-H, 7a-H & 8-H2), 3.0

(m, 1H, 7-H), 3.3 (m, 1H, 7-H), 4.45 (s, 2H, CI:1_2Ph), 6.22 (d, 1H, J = 1.8 Hz, 3-H),

7.18-7.32 (m, 6H, 2-H & Ar-H).

13 C NMR and DEPT 135: 8 22.11 (t, C-8), 27.07 (t, C-4), 38.19 (d, C-7a), 45.53 (d,

C-4a), 46.59 (t, C-7), 49.99 (t, CH2Ph), 110.70 (d, C-3), 117.13 (s), 127.53 (d,

CAJH), 128.02 (d, CAJH), 128.65 (d, CA,14), 136.53 (s), 141.43 (d, C-2), 149.41 (s),

174.41 (s, C=0).

HRMS; m/z calcd for C 1711 1702N [M+H]+ = 268.1337; found = 268.1337.

Lactam 106b: IR: 169 cm-1 (amide C=0).

NMR (300 MHz, CDC13): 8 2.22-3.44 (m, 8H, 4-H2, 4a-H, 7-H2, 7a-H, 8-H2),

4.35 [4.59] (s, 2H, CH2Ph), 6.24 (d, 1H, J = 1.5 Hz, 3-H), 7.20-7.36 (m, 6H, 2-H &

ArH).

I3C NMR (CDC1 3): 8 19.61 (t, C-8), 24.19 (t, C-4), 31.39 (d, C-7a), 40.66 (d, C-

4a), 46.89 (t, C-7), 51.43 (t, CH 2Ph), 110.20 (d, C-3), 114.56 (s), 127.55 (d, C ArH),

128.14 (d, CArH), 128.64 (d, CArH), 136.38 (s), 140.80 (d, C-2), 147.69 (s), 175.28

(s, C=0).

HRMS; m/z calcd for C 17 111 702N [M+H] + = 268.1337; found = 268.1337.

Trans ester 105: Yield- 89.92 %; IR (vmax ): 1652 cm-I (C=0).

I H NMR (CDC13, 300 MHz): S 3.98 [4.13] (d, 2H, J = 5.4 Hz, CII__2-CH=), 4.65

[4.71] (s, 2H, CH2-Ph), 5.20 (m, 2H, CH=0:1), 5.81 (m, 1H, CH=CH2), 6.58 (m,

1H, CH-CH=CO), 7.26-7.43 (m, 8 H, 2-H, 4-H, 5-H & ArH), 7.69 (d, 1H, J = 15

Hz, CH=CH-CO).

13 C NMR (CDC13): 8 48.59 [49.05] (t, CH2-CH=), 49.23 [50.19] (t, CH 2Ph),107.46

(t, C-4), 116.98 (d, CH=CH-00), 116.99 [117.67] (t, CH=CH2), 123.06 (s),

126.52-128.95 (d, CArH), 132.93 (d, CH2-CH=), 133.64 (d, CH=CH-CO), 137.52

(s), 144.17 (d, C-2 & C-5), 167.13 (s, CO).

75

Subsequently we synthesized the 7-lactams (111 & 113) containing methyl

substituent in the B ring by using phosphorane 109. In case of 111 we could not

separate the diastereomers by column chromatography. Based on the GCMS

analysis, the compound was found to be a mixture of four diastereomers in a ratio

of 9.4:7.8:1.1:1. In case of 113 we could separate two pure diastereomers of the

four diastereomers by column chromatography and other two were obtained as a

mixture. We were not able to assign the geometry to the pure compounds. We

found the ratio of the diastereomers in the mixture as 18.9:15.6:2.3:1 by GCMS

analysis. Detailed spectral data of 107, 108, 109, 110, 111, 112 and 113 are given

below.

N-benzyl-N-crotyl-2-bromoacetamide 107: IR (v.): 1656 cm -1 (C=0).

1 H NMR (CDC13, 300 MHz): 8 1.61 (d, 3H, J = 6.6 Hz, CH 3), 3.82-4.12 (m, 4H,

CH2Br & CH2-CH=), 4.58 (s, 2H, CH2Ph), 5.42 (m, 1H, CH=CH-CH3), 5.60 (m,

1H, CH=CH-CH3), 7.18-7.38 (m, 5H, Ar-H).

13 C NMR and DEPT 135: 8 17.54 (q, CH3), 26.29 (t, CH 2Br), 41.25 (t, CH 2N-),

48.81 (t, CH2Ph), 124.69 -129.10 (d, CH=CH-CH3 & ArH), 136.77 (s), 166.85 (s,

CO).

Phosphonium salt 108: IR (v.): 1743 cm -I (C=0).

1 H NMR (CDC13, 300 MHz): 8 1.54 (m, 3H, CH 3 ), 3.81 [4.31] (d, 2H, J = 6.3 Hz,

CH2-CH=), 4.37 [5.05] (s, 2H, CH2Ph), 5.43 (m, 1H, CH=CH-CH3), 5.49 (m, 1H,

CH=CH-CH3), 5.52 [6.82] (d, 2H, J= 12.9 Hz, CH2-P), 7.63-7.91 (m, 20H, Ar-H).

13 C NMR and DEPT 135: 8 17.54 (q, CH 3), 33.67 [34.55] (t, CH 2-P+Ph3), 48.79

[49.17] (t, CH2-CH=CH), 50.55 [51.01] (t, CH 2Ph), 118.80 (s), 119.99 (s), 124.15-

134.34 (d, CArH & CH=CH), 136.14 (s), 136.65 (s), 164.24 (s, CO).

76

N-crotyl-N-benzy1-2-(triphenylphosphoranylidene)acetamide 109:

IR (vmax): 1637 cm-1 .

1 H NMR (CDC13): 8 1.63 (m, 3H, CH3), 2.08 (d, 1H, J = 11.1 Hz, CH=PPh3), 3.81

[4.31] (d, 2H, J = 5.4 Hz, CH 2-CH=), 4.42 [4.51] (s, 2H, CH2Ph), 5.30 (m, 1H,

CH=CH-CH3), 5.50 (m, 1H, CH=CH-CH3), 7.10-7.62 (m, 20H, Ar-H).

13 C NMR and DEPT 135:8 17.58 (q, CH3), 21.43 (d, CH=PPh3), 46.96 [47.69] (t,

CH2-CH=), 49.24 [50.65] (t, CH 2Ph), 125.18-133.08 (s and d, CAJH & CH=CH),

137.64 (s), 170.61 (CO).

Lactam 111: IR (v.): 1681 cm'.

'H NMR (CDC13, 300 MHz): 8 1.15 (m, 3H, CH3), 1.86-3.37 (m, 7H, 4-H, 4a-H,

7a-H, 8-H2), 4.52 (s, 2H, CH2Ph), 6.15 & 6.26 (2 X brs, 1H, C3-H), 7.24-

7.37 (m, 6H, 2-H & ArH).

HRMS; m/z calcd for C18I-11902N [M+H] + = 282.1494; found = 282.1480.

Trans ester 110 (Fig 11a): IR (vmax): 1654 cm -1 (C=0).

'H NMR (CDC13, 300 MHz): 8 1.68 (m, 3H, CH3), 3.89 [4.01] (d, 2H, J = 5.4 Hz,

CH2-CH=), 4.63 [4.68] (s, 2H, CH2Ph), 5.41-5.65 (m, 2H, CH=CH-CH3), 6.43 (m,

1H, 4-H), 6.54 (m, 1H, 3-H), 6.77 (m, 1H, CH=CH-CO), 7.21-7.44 (m, 6H, 5-H &

Ar-H), 7.55 (d, 1H, J = 15 Hz, CH=CH-CO).

13 C NMR and DEPT 135:8 17.70 (q, CH3), 47.73 (t, CI32-CH=CH), 48.66 (t,

CH2Ph), 112.17 (d, C-4), 113.95 (d, C-3), 115.00 (d, CH=CH-CO), 125.71-129.25

(d, CH2-CH=CH & CAJH), 129.95 (d, CH=CH-CO), 137.67 (s), 143.96 (d, C-5),

151.72 (s), 166.69 (CO).

Lactam 113a & b (mixture of two compounds): IR (vmax): 1681 cm -1 .

1 H NMR (CDC13): 8 1.08 (3H, d, 6.6 Hz), 1.18 (3H, d, 6.6 Hz), 1.87-3.34 (m, 7H,

4-H2, 4a-H, 7-H2, 7a-11, 8-H), 4.44 (dd, 2H, J = 14.7 Hz, CH2Ph), 6.18 (d, 1H, J =

1.8 Hz, 3-H), 6.20 (d, 1H, J = 1.8 Hz, 3-H), 7.18-7.32 (m, 6H, 2-H & ArH).

13 C NMR and DEPT 135:8 15.85 (q, CH3), 22.42 (t, C-4), 34.35 (d, C-7a), 45.38

(d, C-4a), 45.59 (d, C-8), 46.66 (t, C-7), 48.98 (t, CH2Ph), 110.63 (d, C-3), 127.53

77

(d, 2 X CAJH (ortho)), 128.02 (d, 2 X CAJH (meta)), 128.66 (d, CAJH (para)), 116.55

(s), 136.53 (s), 141.46 (d, C-2) 153.48 (s), 174.72 (s, CO).

HRMS: m/z calcd for C18141902N [M+H] + = 282.1416, found = 282.1418.

Lactam 113c (pure compound) (Fig 12a): IR (v max): 1681 cm-1 .

1 14 NMR (CDC13, 300 MHz): 8 1.18 (d, 3H, J = 6.6 Hz, CH 3), 2.21-3.37 (m, 7H, 4-

H2, 4a-H, 7-H2, 7a-H, 8-H), 4.41 (dd, 2H, J = 14.7 Hz, CH 2Ph), 6.17 (d, 1H, J = 1.8

Hz, 3-H) 7.15-7.30 (m, 6H, 2-H & Ar-H).

13 C NMR and DEPT 135:8 17.69 (q, CH3), 19.51 (t, C-4), 29.86 (d, C-7a), 40.30

(d, C-8), 40.86 (d, C-4a), 46.98 (t, C-7), 50.26 (t, CH2-Ph), 110.21 (d, C-3), 114.09

(s), 127.54-128.64 (d, 5 X C AJH), 136.41 (s), 140.98 (d, C-2), 151.56 (s), 175.38 (s,

C=0).

HRMS; m/z calcd for C18141902 N [M+Na] + = 304.1313, found = 304.1311.

Lactam 113d (pure compound) (Fig 12b): IR (y r.): 1685 cm 1.

1 H NMR (CDC13, 300 MHz): 8 1.11 (d, 3H, J = 6.6 Hz, CH 3), 2.49-3.14 (m, 7H, 4-

H2, 4a-H, 7-H2, 7a-H, 8-H), 4.44 (dd, 2H, J = 14.7 Hz, CH 2Ph), 6.16 (d, 1H, J = 1.8

Hz, 3-H) 7.13-7.30 (m, 6H, 2-H & Ar-H).

13 C NMR and DEPT 135:8 13.80 (CH3), 21.63 (t, C-4), 27.75 (d, C-7a), 38.50 (d,

C-8), 40.42 (d, C-4a), 46.40 (t, C-7), 47.16 (t, CH 2-Ph), 110.08 (d, C-3), 114.40 (s),

127.50-128.64 (d, CAJH), 136.4 (s), 140.96 (d, C-2), 151.5 (s), 177.37 (s, C=0).

HRMS; m/z calcd for C181-11902N (M+Na) = 304.1313, found = 304.1318.

Trans ester 112: IR (vmax): 1654 cm4 (C=0).

1 14 NMR (CDC13, 300 MHz): 8 1.63 (m, 3H, CH3), 3.83 [3.97] (d, 2H, J = 5.7 Hz,

CI-12-CH=), 4.47 [4.62] (s, 2H, CI-1_ 2Ph), 5.35-5.660 (m, 2H, CH=CH-CH3), 6.46

(m, 1H, CH=CH-CO), 7.16-7.36 (m, 8H, 2-H, 4-H, 541 & Ar-H), 7.58 (m, 1H,

CH=CH-CO).

13C NMR and DEPT 135:8 17.59 (q, CH3), 47.70 [48.55] (t, CH 2-CH=CH), 48.56

[49.84] (t, CH2Ph), 107.40 (d, C-4), 117.16 (d, CH=CH-CO), 123.05 (s), 125.74-

78

1:, • •

. • - - . •-• ,

w.f ere-

v 11, 1.0.= —05 AI:

• T ' • • • • ! ""

-3

" • •

• . „..,...

•.:.;;•,

F.SF • 4:16

129.19 (d, CH=CH & CA,H), 132.15 (d, CH=CH-CO), 137.40 (s), 143.90 (d, C-2 &

C-5), 166.68 (s, CO).

Fig lla

iv. 5 6 ..4.* ; 6. 5 3 . , 2.11

Fig 12a

79

• '1 -

t^:+

Fig 12b

Thus, in both the case of allyl and crotyl phosphoranes we got the desired tricyclic

product in >80% yield in a tandem manner. Using N-crotyl-N-benzy1-2-

(triphenylphosphoranylidene)acetamide 109, we could introduce one methyl

substituent in the B ring. Since the target molecules, furodysin and furodysinin

have gem dimethyl groups in B ring, we next prepared N-prenyl-N-benzy1-2-

(triphenylphosphoranylidene)acetamide 98. Acylation of N-benzylprenyl ' amine

with bromoacetyl bromide gave N-benzyl-N-prenyl-2-bromoacetamide 114, which

on treatment with triphenylphosphine yielded the salt 115 (Scheme XXXI).

N-benzyl-N-prenyl-2-bromoacetamide 114: IR (vmax): 1654 cm -1 (C=0).

'H NMR (CDC13, 300 MHz): 8 1.53-1.73 (4 X s, 6H, CH3), 3.84-4.00 (m, 4H,

CI32Br & CH2-CH=), 4.55 [4.56] (s, 2H, CH2Ph), 5.11-5.14 (m, 1H, CH2-CH=),

7.18-7.39 (m, 5H, Ar-H).

13 C NMR and DEPT 135:8 17.80 (q, CH3), 25.60 (q, CH3), 26.54 (t, CH2Br),

43.46 [45.68] (t, CH2-CI-I=), 48.34 [50.78] (t, CH2Ph), 119.29 [118.48] (d, CH2-

CH=), 126.31 -128.88 (d, CA,,H), 136.83 (s), 166.84 (s, CO).

80

Phosphonium salt 115:

IR (v..): 1748 cm' (CO);=

1 H NMR (CDC13, 300 MHz): 8 1.48 [1.64] (s, 3H, CH3), 1.66 [1.78] (s, 3H, CH3),

3.94 [4.36] (d, 2H, J = 5.4 Hz, CH2-CH=), 4.44 [5.10] (s, 21-I, CH2Ph), 5.05 (m,

1H, CH2-CH=), 5.57 [5.81 .] (d, 2H, J= 9.6 Hz, CH2-P+Ph3), 7.01-7.93 (m, 20H, Ar-

il).

13C NMR and DEPT 135: 8 17.70 (q, CH3), 25.52 (q, CH3), 34.00 (t, CH2-P), 44.00

[47.00] (t, CI-12-CH), 49.13 [51.00] (t, CH2Ph), 119.91 (d, CI-12-CH=), 126.91-

135.04 (s & d, CArH & CH=C), 164.25 (s, CO).

N-prenyl-N-benzv1-2-Itriphenylphosphoranylidenelacetamide 98:

IR (v..): 1640 cm'.

'H NMR (CDCI3 , 300 MHz): 8 1.20 [1.23] (s, 3H, CH3), 1.48 [1.52] (s, 3H, CH 3), 2.09 (d, 11-I, CH=PPh3), 3.70 [3.90] (d, 21-I, J = 5.4 Hz, CL1_2-CH=), 4.41 [4.50] (s,

21-1, CH2Ph), 5.05 (m, 11-I, C112-CH=), 7.10-7.51 (m, 20H, Ar-H).

13C NMR and DEPT 135: 8 17.78 (q, CH3), 21.53 (q, CH3), 22.57 (s), 25.59 (d,

CH=P), 42.61 [45.58] (t, CH2-CH), 47.77 [50.80] (t, CH2Ph), 119.59 (d, CH2-

CH=), 126.24-132.14 (s & d, CArH & CH=C), 170.12 (s, CO).

Preparation of 116:

Refluxing 2-furyl aldehyde and the phoshorane 98 in diphenyl ether for 8 h.

yielded the diastereomeric mixture of tricyclic compounds 116 in tandem manner.

The products 116a & b were purified by column chromatography (ethyl acetate-

hexanes = 2:8) (Scheme XXX1V).

81

C CH 3

0 CHO

0 • CH,

CH 3

an 98

PhOPh 99

116a 116b

Scheme XXXIV

The solid compound that eluted first had a strong IR band at 1686 cm 1, due to the

amide group. Its 1 H NMR (300 MHz, CDC13) spectra (Fig 13a) had signals at 8

1.09 (3H, s, CH 3) and 1.20 (3H, s, CH 3), 8 2.11-3.18 could be attributed to

cyclohexane protons and lactam protons (6H, m, 4a-H, 5-H2, 7a-H, and 8-H 2). One -

doublet of doublet was seen at 8 4.52 (2H, J = 14.7 Hz) which could be attributed

to benzylic methylene group. One doublet 8 6.26 (1H, J = 1.8 Hz) could be

attributed to 3-H proton of furan ring. One multiplet was seen in aromatic region at

8 7.25-7.39 which could be attributed to 2-H proton of furan and benzene protons.

Its 13 C NMR (CDC13) and DEPT 135 spectra further confirmed the structure. Thus,

peaks at 24.25 (q) and 27.77 (q) could be assigned to two methyl carbons. Peak at

24.66 (t) could be assigned to methylene carbon attached to furan ring. Two peaks

at 40.73 (d) and 48.70 (d) could be assigned to methine carbon of CH-CH grouping

respectively. Peaks at 45.55 (t) and 46.69 (t) could be assigned to methylene

carbon of lactam ring and benzylic methylene carbon. Peaks at 107.63 (d) and

141.65 (d) could be attributed to C-3 and C-2 carbons of furan ring. Peaks at

127.51 (d), 127.99 (d), and 128.67 (d) could be attributed to benzene carbons. The

quaternary carbons appearing at 31.99 (s), 136.53 (s) and 148.18 (s) could be

attributed to saturated carbon and aromatic carbons. Peak at 174.47 (s) was

assigned to carbonyl carbon of lactam.

HRMS of the compound confirmed its elemental composition to be Ci9H2 1 02N

(Observed for [M+H] m/z 296.1648; calculated: 296.1650).

82

Thus on the basis of mode of formation & spectral properties structure 116 was

assigned. However, it was not possible to assign the stereochemistry at the ring

junction of the compound based on the above structural data.

Single crystal X-ray (Fig VII) of this solid confirmed its structure as 116a.

Figure VII: ORTEP figure of the solid compound 116a.

Fig VII Crystal data for Fig VII: C19C21NO2, M= 295.37, monoclinic, space group P21/c, a

= 7.879(2) A °, b = 20.578(5) A°, c = 9.851(3), 16 = 96.6064)° , V= 1586.6(7) A°3 , Z

= 4, And = 1.237 g cm-3 , F(000) = 632, II = 0.084 mm -1 , R = 0.0439, wR = 0.1147,

GOF = 1.045 for 2511 reflections with / > 2 6(/), CCDC-629552.

The second eluted compound was found to be a liquid. Its spectral data is given

below.

IR (vmax): 1693 cm -1 .

NMR (CDC1 3 , 300 MHz): (Fig 14a)

6 1.09

6 1.19

s

s

3H

31-1

CH3

CH3

6 2.44-3.35 m 6H 4a-1-I, 5-H2 , 7a-1-I, 8-1-1 2

6 4.44 dd (J = 14.7 Hz) 2H CH2-Ph

6 6.24 brs 1H 3-H

6 7.21-7.34 m 6H 2-H & Ar-H

83

13 C NMR and DEPT 135:8 21.48 (t, C-8), 24.72 (q, CH3), 31.48 (q, CH3), 31.80

(s, C-4), 38.98 (d, C-4a), 38.99 (d, C-7a), 46.43 (t, C-5), 47.90 (t, CH 2-Ph), 107.70

(d, C-3), 123.71 (s), 127.52-128.65 (d, C AJH), 136.40 (s), 141.01 (d, C-2), 146.49

(s), 176.95 (s, C=0).

HRMS of the compound confirmed its elemental composition to be CI9H2102N

(Observed for [M+Na] m/z 318.1467; Calculated: 318.1470).

Fig 13a

84

+ Ph

CHO

Bn CH 3 CHCI 3

CH 3

NBn PhOPh 116 0

H3C H3C

99

Fig 14a

As the first eluted solid compound 116a was trans fused, the later eluted liquid

compound assumed to be cis. The yield of the two diastereomeres found was

79.10% and they are formed in 1:1 ratio.

We have also carried out the synthesis of lactam 99 in a stepwise manner. We have

first condensed the phosphorane 98 with 2-furyl aldehyde to get the Wittig product

(Scheme XXXV).

Scheme XXXV

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

99 was assigned to the compound. Based on the coupling constant in NMR the

trans geometry for the unsaturated amide was assigned (Yield = 89.20 %).

85

IR (v.): 1654 cm -I .

1 H NMR (CDC13, 300 MHz):

S 1.59 & 1.64 [1.73] s 6H 2 XCH3

8 3.93 [4.07] d (J = 6.9 Hz) 2H N-CH-C1-1—

8 4.61 [4.67] s 2H CH2-Ph

8 5.18 m 1H CH2-CH=

8 6.44 m 1H 4-H

8 6.55 m 1H 3-H

8 6.79 m 1H CH=CH-CO

8 7.21-7.44 m 6H 5-H & Ar-H

8 7.54 d (J =15 Hz) 1H CH=CH-CO

13C NMR and DEPT 135: 8 17.81 (q, CH 3), 25.60 (q, CH3), 43.30 [45.00] (t, CH2-

CH=), 48.75 [50.04] (t, CH2Ph), 112.03 (d, C-4), 113.65 (d, C-3), 115.26 (d,

CH=CH-CO), 119.87 [120.16] (d, CH2-CH=), 126.56-128.69 (d, C AJH), 129.84 (d,

CH—CH-CO) 135.77 [136.37] (s), 137.14 [137.71] (s), 143.76 (d, C-5), 151.64

(s),166.44 (CO).

Thus, trans unsaturated amide 99 was then heated in refluxing diphenyl ether for 8

h under nitrogen atmosphere, followed by purification of the products on a SiO2

column (ethyl acetate — hexanes = 2:8) yielded a diastereomeric mixture 116a & b

(Yield = 89.80% product ratio = 1:1).

Preparation of 118:

Refluxing 3-furyl aldehyde and the phoshorane 98 in diphenyl ether for 8 h,

yielded the diastereomeric mixture of tricyclic compounds 118 in tandem manner.

The products 118a & b were purified by column chromatography (ethyl acetate-

hexanes = 2:8) (Scheme XXXVI). The yield of the diastereomers was found to be

79.87%.

86

H

0 8a

H3C CH 3

118a

6

NBn

O CH3

H3C CH 3

117

Bn 98

PhOPh, A, 8h fi,CHO

0

118b

Scheme XXXVI

Based on mode of formation & spectral properties structure 118a was assigned to

the first eluted solid. On the basis of crystal structure of the corresponding

regioisomer it was assumed to have trans junction.

IR (v.): 1686 cm -1

1 HNMR (CDC13, 300 MHz): (Fig 15a)

S 1.09

8 1.22

s

s

3H

3H

CH3

CH3

8 2.12-3.14 m 6H 4412, 4a-H, 7-H2, 7a-H

8 4.43 dd (J = 14.7 Hz) 2H CH2-Ph

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

8 7.19-7.30 m 6H 2-H & Ar-H

13 C NMR and DEPT 135 (Fig 15b): 8 22.43 (q, CH 3), 22.81 (t, C-4), 25.62 (q,

CH3), 34.4 (s, C-8), 41.27 (d, C-7a), 45.06 (t, C-7), 46.70 (t, CH2-Ph), 48.64 (d, C-

4a), 110.39 (d, C-3), 115.20 (s), 127.52-128.68 (d, C ArH), 136.50 (s), 141.26 (d, C-

2), 156.97 (s), 174.83 (C=0).

87

Bn ry CH3 CHCI3

CH3

CHO Ph

118

HRMS of the compound confirmed its elemental composition to be C19H2102N

(Observed for [M+H] m/z 296.1650; calculated: 296.1650).

The second eluted compound 118b was assumed to have cis junction.

IR (vmax): 1689 cm -I

I HNMR (CDC1 3 , 300MHz): (Fig 16a)

S 1.10

8 1.19

s

s

3H

3H

CH3

CH3

8 2.43-3.46 m 6H 4-H2 , 4a-H, 7-H2, 7a-H

8 4.38 dd (J = 14.7 Hz) 2H CH2-Ph

8 6.12 d (J = 1.8 Hz) 1H 3-H

8 7.14-7.29 m 6H 2-H & Ar-H

I3C NMR and DEPT 135 (Fig 16b): 8 21.62 (t, C-4), 22.28 (q, CH3), 29.64 (q,

CH3), 32.30 (s, C-8), 38.92 (d, C-4a), 45.96 (d, C-7a), 46.40 (t, C-7), 47.89 (t,

CH2-Ph), 109.93 (d, C-3), 112.97 (s), 127.52-128.64 (d, CA,-H), 136.41 (s), 140.83

(d, C-2), 154.55 (s), 177.44 (s, C=0).

HRMS of the compound confirmed its elemental composition to be C19H2102N

(Observed for [M+Na] m/z 318.1467; calculated: 318.1470).

We have also carried out the synthesis of lactam 118 in stepwise manner (Scheme

XXXVII).

Scheme XXXVII

88

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

117 was assigned to the compound (Yield = 87.70%).

IR (vmax): 1654 cm -1

'H NMR (CDC13, 300 MHz):

S 1.51 s CH3

8 1.59 s 6H CH3

8 1.68 brs CH3

8 3.86 [4.02] d (J = 6.9 Hz) 2H N-CH-CH=

8 4.54 [4.61] s 2H CH2-Ph

8 5.14 m 1H CH2-CH=

8 6.52 m 2H 4-H & CH=CH-CO

8 7.16-7.37 m 6H 5-H & Ar-H

8 7.58 m 2H 2-H & CH=CH-CO

13 C NMR and DEPT 135: 8 17.77 (q, CH3), 25.59 (q, CH3), 43.40 [45.00] (t, CH 2

-CH=), 48.76 [48.10] (t, CH2Ph), 107.37 (d, C-4), 117.26 (d, CH=CH-00), 120.19

(d, CH2-CH=), 123.06 (s), 126.46-128.75 (d, CA,H), 132.80 (d, CH=CH-00),

135.59 [136.40] (s), 137.0 [137.71] (s), 143.88 (d, C-2 & C-5), 166.58 (s, CO).

Thus, trans unsaturated amide 117 was refluxed diphenyl ether for 8 h under

nitrogen atmosphere, followed by purification of the products on a SiO2 column

(ethyl acetate — hexanes = 2:8) yielded a diastereomeric mixture 1118a & b (Yield

= 89.60%, product ratio = 1:1 ratio).

89

V it; 012 11 4 tt

I

LJ A

Fig 15b

90

0

Fig 15a

Fig 16a

Fig 16b

91

After completing successfully the syntheses of AB ring system of marine natural

sesquiterpenes. Our next task was to build the C ring to complete the total

synthesis as depicted Scheme XXV, we needed to convert the lactam into lactone.

First we tried to hydrolyse tertiary amide. In all the experimental condition we

failed to get the desired product (Scheme XXXVIII).

X

Scheme XXXVIII

a) Reagent used;

i) KOH in Me0H, reflux

ii) NaOH in Me0H, reflux

iii) KOH in EtOH, reflux

iv) KOH in ethylene glycol, reflux

v) KOH in Me0H/H20, reflux

vi) NaOH in EtOH, reflux

The hydrolysis was not taking place may be due to nitrogen being tertiary, so we

thought of removing benzyl group first and then try the hydrolysis ( Scheme

XXXIX).

H 3C CH 3

Scheme XXXIX

b) ><

92

We tried the following reagent for hydrogenolysis of lactam, in all cases we got

starting material unchanged or we got the decomposed product.

b) Reagent used:

i) H2, Pd/C, Me0H

ii) H2, Pd/C, EtOH

iii) H2, Pd/C, ethylacetate

iv) H2, Pd/C, Me0H, acetic acid (decomposed)

v) H2, Pd(OH)2/C, Me0H

vi) Pd/C, ammonium formate, Me0H

vii) TMSCl/NaI, acetonitrile (decomposed)

viii) CAN, acetonitrile/ H2O (decomposed)

ix) TsOH, toluene

x) Na-Naphthalene

Conclusion:

1) A model study on desmethylsecufuranoeremophilane till naphthofuran

lactone was successful and further alkylation failed in our hands.

2) Extending the tandem Wittig-Diels-alder reaction using ester functionality

was tried , for furanosesquiterpenes like furodysin and furodysinin. Using

this strategy we could get parent and mono methyl substituent in B ring.

However extending to get the gem dimethyl group in ring B failed.

3) A new strategy was developed for the introduction of gem dimethyl group

in the B ring using amide phosphorane 98. However, the lactam hydrolysis

was found problematic. Debenzylation to get the secondary amide failed in

our hands.

93

Experimental Section:

Expt. 2.1.1: General procedure for preparation of bromo ester.

A solution of alcohol (1 mmol) & pyridine (1 mmol) in dry chloroform (10 mL)

was cooled to 0 °C. Bromoacetyl bromide (Immo') 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 (15 mL) was added and

extracted in chloroform (2 X 20 mL). The organic layer was washed with 2N HC1

(2 X 15 mL), sat. sodium bicarbonate (2 X 15 mL) and finally with water (15 mL).

The chloroform layer was dried over sodium sulphate and was evaporated under

vaccuo to give yellow liquid.

Expt. No

Substrate Product Nature Yield

(%)

2.1.1.1

OH H f-./ 7 ..2...

° Eir, ,.....7■ v----....,./...CH2

Light yellow viscous oil 85.00%

2.1.1.2 -0H

o Br...,.,.0.,-N

Light yellow viscous oil 82.00%

2.1.1.3 OH

o

Br..,..„. ., 0

Light yellow viscous oil 81.00%

Expt. 2.1.2: General procedure for preparation of substituted allyl

(triphenylphosphoranylidine)acetate.

The solution of substituted allyl bromoacetate (1 mmol) & triphenyl phosphine (1

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

94

X 20 mL). The combined benzene layer was dried over anhy. sodium sulphate and

the solvent was evaporated under vaccuo pump to give substituted allyl

(triphenylphosphoranylidine)acetate.

Expt. No

Substrate Product Nature Yield

(%)

2.1.2.1

o Br„,... (:) C H2

° Ph3P.-. 0./CH2

Solid

(m.p.72- 73 °C )

66.00%

2.1.2.2

o

Br ./\ 0/%\

o

Ph3P \c,\,\

Gummy mass

65.00%

2.1.2.3

o Br.., --......

o Ph3P--......0

Gummy mass

60.00%

Expt. 2.1.3: General procedure for the preparation of substituted allyl

furylacrylate.

A solution of furan aldehyde (1 mmol) & substituted allyl (triphenyl-

phosphoranylidine)acetate (1.2 mmol) in chloroform (10 mL) was stirred for 1 h at

room temperature. The solvent was evaporated under reduced pressure to leave

crude product which was purified by column chromatography over silica gel using

hexanes and ethylacetate (9:1) as solvent to provide sweet smelling colourless

liquid.

95

Expt. No

Substrate Product Nature Yield

(%)

2.1.3.1

H2cN Sweet smelling liquid

89.70% 1 0

o ------=y 0

L II

O CHO

2.1.3.2

Sweet smelling liquid

87.90% o''.---------%Thri ' ° 0

L o CHO

2.1.3.3

Sweet smelling liquid

89.70% e.--------%.Y1 o

0

L 1

o CHO

2.1.3.4 ,CHO (

ofl

o

--0

Sweet smelling liquid

91.00% t I /

, 0 H2cz

2.1.3.5 CHO

°

\ 0 Sweet smelling liquid

87.80% to j z ( of

Expt. 2.1.4: Tandem Wittig-Diels Alder reaction: Preparation of tricyclic y-

lactone.

A solution of furan aldehyde (1 mmol) & substituted allyl (triphenyl-

phosphoranylidine)acetate (1,.2 mmol) in diphenyl ether (10 mL) was refluxed

under nitrogen atmosphere for 6 h. The crude mixture was purified by flash

column chromatography over silica gel using hexanes to remove diphenyl ether

first and further elution with 10% ethylacetate and hexanes to afford

diastereomeric y-lactone.

96

Expt. No

Substrate Product Nature Yield

(%)

2.1.4.1

Trans: m.p.182-183 °C

Cis: liquid 59.60% le II 1

0 CHO

2.1.4.2

H

liquid 59.70% O

1 0 CHO

2.1.4.3

Tandem product: --- -Liquid (96)

-furyl acrylic acid:

m.P. 139 °C

20mg

95 .50% LOCHO

+ furyl acrylic acid

2.1.4.4 ,CHO

Trans: m.p.165-166 °C

Cis: liquid 60.70%

of

2.1.4.5 O

liquid 60.30% ECHO

O

Expt. 2.1.5: Preparation of tricyclic y-Iactone from substituted furyl

allylacrylate.

Substituted furyl allyl acrylate (1 mmol) was refluxed in diphenyl ether(10 mL) for

6 h under nitrogen atmosphere. The crude mixture was purified by flash column

chromatography over silica gel using hexanes to remove diphenyl ether first and

further elution with 10% ethylacetate and hexanes to afford diastereomeric 7-

lactone.

97

Expt. No

Substrate Product Nature Yield

(%)

2.1.5.1 1-12c-.

Trans: m.p.182- 183 °C

Cis: liquid 62.60% 0

L 4 0

2.1.5.2

H

liquid 60.90%

O

I 0 o : 10 L) .

2.1.5.3

._):c Trans: m.p.165- 166 °C

Cis: liquid 62.00% t I --- 1 O 0'H2o-

2.1.5.4

_DL0

liquid 61.70% t j I O o t- o

Expt. 2.1.6: General procedure for the preparation of substituted allyl benzyl

amine:

Substituted allylbromide (1 mmol) was added dropwise to a stirred solution of

benzylamine (3 mmol), potassium carbonate (1 mmol) in dry chloroform (30 mL)

and the reaction mixture was stirred overnight. To the mixture water (20 mL) was

added and extracted in chloroform (2 X 20 mL). The chloroform layer was dried

over sodium sulphate and was removed under vaccuo. The crude product obtained

was purified by column chromatography using ethyl acetate and hexanes (2:8) as

an eluent to give yellow oil.

98

Expt. No

Substrate Product Nature Yield (%)

2.1.6.1 PhNH2 H2CNH ph Light yellow oil 61.80%

2.1.6.2 PhNH2 \/\.-- NH ph Light yellow oil 55.40%

2.1.6.3 Pi.iNH 2 NH Ph Light yellow oil 53.00%

Expt. 2.1.7: General procedure for the preparation of N-allyl-N-benzy1-2-

bromoacetamide:

A solution of allyl benzylamine (1 mmole) and potassium carbonate (1.1 mmole)

in dry chloroform (20 mL) was cooled to 0 °C. Bromoacetyl bromide (1.1 mmole)

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 sulphate and was evaporated under vaccuo

to give yellow liquid.

99

Expt. No

Substrate Product Nature

Yield (%)

2.1.7.1 H2C..,

,,,NH ph ° Br___,........... .CH2

1-- Ph

yellow Oil

83.70%

2.1.7.2 NI-IN„,,ph ° Br/\ N/\"

`Ph

yellow Oil

82.00%

2.1.7.3 ,,,, NIAN___ph ° Br.......■, N

l'Ph

yellow oil

78.00%

Expt. 2.1.8: General procedure for preparation of N- substituted allyl-N-

benzyl-2-(triphenylphosphoranylidene)acetamide.

The solution of N-substitutedallyl-N-benzyl-2-bromoacetamide (1 mmole) &

triphenyl phosphine (1 mmole) 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 evaporated under vaccuo to give

substituted N-allyl-N-benzyl-2-(triphosphoranylidene)acetamide.

100

Expt. No

Substrate Product Nature Yield

(%)

2.1.8.1

Br o

„,.....-cH 2 N

I Bn

0

Ph3R.,-- CH2

I Bn

Gummy mass

79.00%

2.1.8.2

Br

o N„.......„...,..-CH2

I Bn

ph3P-N,

0

N I Bn

- .,.,,,CF12

Gummy mass

68.40%

2.1.8.3

Br

o

N„.„..—..-cH2

In

o

ph3 13 :----,..fr..,..... ...,.....„..CH2

I Bn

Gummy mass

70.50%

Expt. 2.1.9: General procedure for the preparation of substituted allyl furylbenzyl acrylamide.

A solution of furan aldehyde (1 mmol) & substituted N-allyl-N-benzy1-2-

(triphenylphosphoranylidene)acetamide (1.2 mmol) in chloroform (10 mL) was

stirred for 1 h at room temperature. The solvent was evaporated under reduced

pressure to leave crude product which was purified by column chromatography

over silica gel using hexanes and ethylacetate (9:1) as solvent to provide sweet

smelling colourless liquid.

101

Expt. No

Substrate Product Nature Yield

(%)

2.1.9.1

H2 cN____--\N Sweet smelling liquid

90.20% k I \NBn

o"---------'y 0

( 1

o CHO

2.1.9.2

Sweet smelling liquid

90.40% NBn o'"----1(

0

1 Co CHO

2.1.9.3 N

Sweet smelling liquid

89.20% ( 1

o CHO I I NBn - 0 ---..---'1r

0

2.1.9.4 ,CHO

° Sweet smelling liquid

89.90% NBn I I /

II fi o

-.0v H2C

2.1.9.5 ,CHO

° Sweet smelling liquid

88.00% NBn I I

ofl

2.1.9.6

,CHO 0

----/ - NBn Sweet smelling liquid

87.70% ° fi

I 1 'o Z

Expt. 2.1.10: Tandem Wittig-Diels-Alder reaction: Preparation of tricyclic y-lactam.

A solution of furan aldehyde (1 mmole) & substituted N-allyl-N-benzy1-2-

(triphenylphosphoranylidene)acetamide (1.2 mmole) in diphenyl ether (10 mL)

was refluxed under nitrogen atmosphere for 8 h. The crude mixture was purified by

flash column chromatography over silica gel using hexanes to remove diphenyl

ether and further elution with 20% ethylacetate and hexanes to afford

diastereomeric y-lactam.

102

Expt. No

Substrate Product Nature Yield (%)

2.1.10.1

H Trans: m.p.122-123 °C

Cis: liquid 80.00 %

I 0 NBn

II 0 CHO

2.1.10.2

H

liquid 79.90% 0 NBn

I I O CHO

o o

2.1.10.3

Trans: m.p.165-166°C

Cis: liquid

rn LOCHO

2.1.10.4 /CHO

Trans: m.p.108-109°C

Cis: liquid 80.30%

NBn

o II II

oj

2.1.10.5

zCHO 1 liquid

79.90% II

° I e NBn

H

2.1.10.6

zCHO Trans: m.p.165-166°C

Cis: liquid 79.80% °

• NBn Expt. 2.1.11: Preparation of tricyclic y-lactam from N-substituted allyl-N-

benzyl furylacrylamide.

N-substituted allyl-N-benzyl furylacrylamide (1 mmol) was refluxed in diphenyl

ether (10 mL) for 8 h under nitrogen atmosphere. The crude mixture was purified

by flash column chromatography over silica gel using hexanes to remove diphenyl

ether and further elution with 20% ethylacetate and hexanes to afford

diastereomeric y-lactam.

103

Expt. No Substrate Product Nature Yield

(%)

2.1.11.1

H2C . .., n Trans: m.p.122-123 °C

Cis: liquid 88.00

1014B0 op NBn

2.1.11.2

n .

liquid 87.70%

h . 1 4c)

NBn

0 H

2.1.11.3

---\___N

NBn

71 Trans:

m.p.165-166 °C

Cis: liquid 89.80%

NBn

0-% 0 I S

2.1.11.4 0 LNBn ----1

H 0 Trans: m.p.108-109 °C

Cis: liquid 90.00%

I 1 ,___I c)- H 2c/

NBn 10 H

2.1.11.5 ----'r jB

liquid 88.20% I I n

0 NBn

t

2.1.11.6 NBn .---.)°L, NBn

•

Trans: m p 165

• • -

166 °C

Cis: liquid 89.60% & 0 /

104

Expt.2.1.12: Preparation of furo[2,34][2]benzofuran-5(7H)-one (81).

DDQ

dioxane

76

81

A mixture of compound 76 (0.2 gm, 1.12 mmole) and DDQ (0.76 g, 3.37 mmole)

in dioxane (15 mL) was refluxed for 48 h. The reaction mixture was allowed to

cool to ambient temperature and then was concentrate under reduced pressure. The

resulting residue was dissolved in ethyl acetate (50 mL) and then saturated aqueous

sodium bicarbonate (20 mL) was added and transferred into separating funnel. The

organic phase was washed with water (20 mL). The organic phase was dried over

sodium sulphate and concentrated under reduced pressure. The resulting residue on

purification over silica gel column chromatography with (8:1) hexanes/ethylacetate

gave benzofuran 81 in 62.00% (0.12 g).

105

References:

1) a) Menut, C.; Cabalion, P.; Hnawia, E.; Agnaniet, H.; Waikedre, J.; Frucheir,

A. Flavour Frag. J. 2005, 20, 621.

b) El-Hamouly, M. M.; Ammar, H. A.; Awaad, A. K. J. Pharm. Sci. 2001, 28,

60.

c) Jenet-Siem, K.; Witte, L.; Eich, E. J.; J. Nat. Prod. 2001, 64, 1471.

2) a) Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 245.

b) Faulkner, D. J. Nat. Prod. Rep. 1986, 1, 3.

c) Faulkner, D. J. Nat. Prod. Rep. 1987, 4, 539.

d) Faulkner, D. J. Nat. Prod. Rep. 1988, 5, 613.

e) Faulkner, D. J. Nat. Prod. Rep. 1997, 7, 267.

f) Faulkner, D. J. Nat. Prod. Rep. 1991, 8, 97.

g) Faulkner, D. J. Nat. Prod. Rep. 1992, 9, 323.

h) Faulkner, D. J. Nat. Prod. Rep. 1997, 10, 497.

3) a) Fontana, A.; Tramice, A.; Cutignano, A.; D'ippolite, G.; Gavagnin, M.;

Cimino, G. J. Org. Chem. 2003, 68, 2405.

b) Fontana, A.; Giminez, F.; Mafin, A.; Mollo, E.; Cimino, G. Experientia

1994, 50, 510.

c) Faulkner, D. J.; Molinsky, T. F.; Andersen , R. J.; Dilip , De. S. E.

Pharmacol Toxicol Endocrinol 1990, 97,233.

d) Fontana, A.; Avila, C.; Martinez, E.; Ortea, J.; Trivellone , E.; Cimino, G. J

Chem. Ecol. 1993, 19, 339.

4) a) Kazlauskas, R.; Murphy, P. T.; Wells, R. J. Tetrahedron Lett. 1978, 49,

4949.

b) Schram, T. J.; Cardellina, J. H. J. Org. Chem. 1985, 50, 4155.

106

c) Cameron, G. M.; Stapleton, B. L.; Simonsen, S. M.; Brecknell, D. J.; Garson,

M. J. Tetrahedron 2000, 56, 5247.

d) Xu, Y-M.; Johnson, R. K.; Hecht, S. M. Bioorg. Med. Chem. 2005, 13, 657.

5) a) Rompp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.; Lang-Fugmann, S.;

Eds.; Thieme: Stuttgart, 1997:

b) Bach, T.; Kruger, L. Eur. J. Org. Chem. 1999, 2045.

6) a) Friedrichsen, W. In Comprehensive Heterocyclic Chemistry; Katritzky, A.

R.; Rees, C. W.; Scriven, E. F. V. Eds.; Elsevier: Oxford, 1996, 2, 359.

b) Konig, B. In Science of Synthesis; Thieme: Stuttgart, 2001, 9, 183.

7) Searle, P. A.; Jamal, N. M.; Lee, G. M; Molinski. Tetrahedron 1994, 50, 3879.

8) Iguchi, K.; Mori, K.; Suzuki, M.; Takahashi, H.; Yamada, Y.; Chem. Lett. 1986,

1789.

9) a) Cimino , G.; De Stefano, S.; Guerrieo , A.; Minale , L. Tetrahedron Lett.

1975, 16, 1417.

b) Cimino , G.; De Stefano, S.; Guerrieo , A.; Minale , L. Tetrahedron Lett.

1975, 16, 3723.

c) Cimino , G.; De Stefano, S.; Minale , L.; Trivellone, E. Tetrahedron Lett.

1975, 16, 3727.

10) a) Maradufu, A.; Warthen, J. D. Jr. Plant Sci. 1988, 57, 181.

b) Ahmad, I.; Afza, N.; Anis, I.; Malik, A.; Fatima, I.; Azhar-ul-Haq.; Tareen,

R. B. Heterocycles, 2004, 63, 1875.

11) Holzapfel, C. W.; Marais, W.; Wessels, P. L.; Van Wyk, B-E. Phytochemistry,

2002, 59, 405.

12) Bohlmann, F.; Zdero, R.; Grenz, M. Chem. Ber. 1974, 107, 2730.

107

13) Hirai, Y.; Doe, M.; Kinoshita, T.; Morimoto, Y. Chemistry Lett. 2004, 33,

136.

14) Doe, M.; Hira, Y.; Kinoshita, T. Shibata, K.; Haraguchi, H.; Morimoto, Y.

Chem. Lett. 2004, 33, 714.

15) Vishnoi, S. P.; Shoeb, A.; Kapil, R. S.; Popil, S. P. Phytochemistry 1983, 22,

597.

16) Takeda, K.; Ikata, M.; Miyawaki, M. Tetrahedron 1964, 20, 2991,

17) Takeda, K.; Ishii, H.; Tozyo, T.; Minato, H. J. Chem. Soc (C), 1969, 1920.

18) Ishii, H.; Tozyo, T.; Nakamura, M.; Takeda, K. Tetrahedron 1968, 24, 625.

19) Takeda, K.; Minato, H.; Horibe, I.; Miyawaki, H. J Chem. Soc (C) 1967,

631.

20) Takeda, K.; Horibe, I.; Minato, H. J. Chem. Soc (C) 1968, 2786.

21) Eagel, G. A.; Rivette, D. E. A., William, D. H.; Wilson, R. G. Tetrahedron

1969, 25, 5227.

22) Jakipovic, J.; Zdero, C.; King, R. M. Phytochemistry, 1995, 40, 1677.

23) a) Puckhaber, L. S.; Stipanovic, R. D. J. Nat. Prod. 2004, 67, 1571.

b) Brieskorn, C. H.; Noble, Pia. Phytochemistry 1983, 22, 187.

24) Bohlmann, F.; Knoll, K. H.; Zdero, C.; Mahanta, P. K.; Grenz, M.; Suwita,

A.; Eblers, D.; Van, N. L.; Abraham, W. R.; Natu, A. R.; Phytochemistry

1977, 16, 965.

25) Arciniegas, A.; Perez-Castorena, L.; Parada, G.; Villasenor, J. L.; Romo de

Vivar, A. Rev. Latinoam. Quim. 2000, 28, 131.

26) Burgueno-Tapia, E.; Hernanadez, L. R.; Reserdiz-Villalobos, A. Y.; Joseph-

Nathan, P. Magn. Reson. Chem. 2004, 42, 887.

27) a) Perez, A. L.; Vidales, P.; Cardenas, J.; Romo de Vivar, A. Phytochemistry

1991, 30, 905.

•

108

b) Dupre, S.; Grenz, M.; Jakupovic, J.; Bohlmann, F.; Niemeyer, H. M.

Phytochemistry 1991, 30, 1211.

28) a) Bohlmann, F.; Forster, H.-J.; Fischer, C. H. Justus Liebigs Ann. Chem.

1976, 1487.

b) Yamakawa, K.; Satoh, T. Chem. Pharm. Bull. 1977, 25, 2535.

29) a) Jacobi, P. A.; Walker, D. G. J Am. Chem. Soc. 1981, 103, 4611.

b) Jacobi, P. A.; Craig, T. A.; Walker, D. G. Amick, B. A.; Frechette, R. F. J.

Am. Chem. Soc. 1984, /06, 5586.

30) Torres, P.; Ayala, J.; Grande, C.; Anaya, J.; Grande, M. Phytochemistry 1999,

52, 1507.

31) Shen, T.; Xie, W-D.; Jia, Z-J. Chin. Chem. Lett. 2005, 16, 1220.

32) Perez-Castorena, A.1.; Arciniegas, A.; Villasenor, J. L.; Romo de Vivar, A.

Rev. Soc. Quim. Mex. 2004, 48, 21.

33) Sakemi, S.; Higa, T. Experientia 1987, 43, 624.

34) Endo, K.; Taguchi, T.; Taguchi, F.; Hikino, H.; Yamahara, J.; Fujimura, H.;

Chem. Pharm. Bull. 1979, 27, 2954.

35) Kubo, J.; Ying, B. F.; Castillo, M.; Brinen, L. S.; Clardy, J. Phytochemistry

1992, 31, 1545

36) Deigado, G.; Garcia, P. E.; Bye, R. A.; Linares, E. Phytochemistry 1991, 30,

1716.

37) Mong, S.; Votta, B.; Sarau, H.; Foley, J. J.; Schmidt, D.; Carte, B. K.;

Poehland, B.; Westly, J. Prostaglandins 1990, 39, 89.

38) Hellou, J.; Andersen, R. J.; Thompson, J. E. Tetrahedron 1982, 38, 1875.

39) a) Toke, H.; Jaszay, Z. M.; Petnehazy, I.; Clementis, G.; Vereczkey, G. D.;

Koresdi, I.; Rockenbauer, A.; Koratis, K. Tetrahedron 1995, 51, 9167.

109

b) Liu, Fa.; Stephen, A. G.; Andamson, C. S.; Gousset, K.; Aman, M. J.;

Freed, E. O.; Fisher, R. J.; Burke, T. R. Org. Lett. 2006, 8, 5165.

40) a) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941.

b) Toke, L.; Jaszay, Z. M.; Petnehazy, I.; Clemenitis, G.; Vereczkey, G. D.;

Pockenbauer, A.; Kovats, K. Tetrahedron Lett. 1995, 51, 9167.

41) •Hirota, H.; Kitano, M.; Komatsubara, K-I.; Takahashi, T. Chemistry Lett.

1987, 2079.

42) Richou, O.; Vaillancourt, V.; Faulkner, D. J.; Albiazati, K. F. J. Org. Chem.

1989, 54, 4729.

43) Ho, T-S.; Lee, K-Y. Tetrahedron Lett. 1995, 36, 947.

44) Ho, T-S.; Chein, R-J. Chem. Commun. 1996, 1147.

45) Moiseenkov, A. M.; Lozanova, A. V.; Surkova, A. A.; Buevich, A. V.;

Veselovsky, V. V. Izv. Akad. Nauk. SSSR. Ser. Khim. 1996, 7, 1842

46) Vogels, textbook of practical Organic Chemistry, 5 th ed. 1994.

47) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059.

48) Yang, S-C.; Shea, F-12. J. Chin. Chem. Soc. 1995, 42, 969

110