Chapter 2 Tandem Wittig-Diels-Alder reaction -...
Transcript of Chapter 2 Tandem Wittig-Diels-Alder reaction -...
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