Synopsis
SYNOPSIS
The thesis entitled “Towards the synthesis of camptothecin analogues and
development of new methodologies” has been divided in to three chapters.
Chapter-I: This chapter deals with an introduction to cancer, including some of potent
anticancer biogenetically novel alkaloid, marine macrolides and the approaches cited in
the literature total synthesis of camptothecin analogues, including the total syntheses.
Chapter-II: This chapter deals with towards the synthesis of camptothecin analogues.
Chapter-III: This chapter describes the development of new methodologies pertaining
to the application of microwave radiation in organic synthesis. Including one-pot
synthesis of -aminophosphonates, aynthesis of aryl hydrazides and stereoselective
synthesis of aryl- substituted (E)-and (Z)-allyl iodides and bromides.
Section-A: This section describes montmorillonite clay-catalyzed one-pot synthesis of
-aminophosphonates.
Section-B: This section describes the InCl3-SiO2 catalyzed electrophilic amination of
Arenes: as a facile and rapid route aryl hydrazides.
Section-C: This section describes the montmorillonite clay-catalyzed stereoselective
synthesis of aryl- substituted (E)-and (Z)-allyl iodides and bromides.
CHAPTER-I: An introduction to cancer including some potent anticancer
biogenetically novel alkaloid, marine macrolides and the approaches cited, including the
total synthesis camptothecin.
I
Synopsis
CHAPTER-II:
Synthesis of camptothecin analogues
In continuation of our programme on the synthesis of biologically active
antitumor agents, we under took a demanding programme on the total synthesis of
camptothecin analogues.
Camptothecin has a unique bifunctional (4-1-hydroxy) 6 membered lactone ring
that is labile to alkali and alkaline reagents. Structure Activity Relationship (SAR)
studies revealed that the 6-memberedlactone ring is essential for bio-activity. In view of
these observations, we reasoned that isosteric replacement of 6-memberd ketone 2
might be an useful molecule with higher activity and also provide additional
information pertaining to SAR.
O
O
N
N
N
N
HO
OH
O
2
1
Figure 1
By a retrosynthetically analysis compound 2 can be cleaved into two major
fragments tricyclic amine 3 and a chlorolactone 4 (Scheme 1).
The primary object was to prepare N-carboethoxy-3-keto pyrrolidine 16 in large
quantities from inexpensive and readily available starting materials. (Scheme 2).
II
Synopsis
O
N
N
2
OH
O
O
+
NH
O
OBn
N
Cl
3
4
COOMe
CHO
OH +
+
NH2
5
O
COOMe
Br
8
7
6
H
N
NCO2 Et
O
10
9
+
CO2 Et
CO2Me
Et2 OC
11
scheme 1
Glycine 12 on treatment with 2 eq of aq 4N. NaOH and ethylchloroformate 13
gave N-carboethoxy glycine 14 in 90% yield. The compound 14 on treatment at room
temperature with methanol in presence of BF3. OEt2 furnished N-carboethoxy
methylglycinate 10. Compound 10 and ethylacrylate 11 underwent tandem N-alkylation
and Dieckmann cyclization to afford 15 Refluxing with 6N aq HCl yielded the key
intermediate N-carboethoxy-3-keto pyrrolide 16 in 20% yield. The compound 5.was
obtained pure from 2-nitrobenzaldehyde 18 by a reduction process with FeSO4 in
presence of ferrous sulphate and ammonium hydroxide in 70 % yield. The compound
III
Synopsis
16 failed to an reaction with 5 under a variety of reaction. The compound 16 with 5 and
PTSA were mixed and then heated at 190oc for 5 min under nitrogen atmosphere.
4N NaOH
COOH
H2 N
ClCO2Et
12
O
H
N
BF3. OEt2
CO2 Et
13
H
MeOH
COOH
N
NaH, C6H6
CO2 Et
14
11 CO2Et
COOMe
10
O
CO2Me
6N HCl, H2O
reflux
N
X
+ 5
NCO2 Et
N
N
CO2 Et
CO2 Et
15
16
17
Scheme 2
Therefore an alternative method ABC ring system from commercially available
dimethyl acetylene dicarboxylate 6 was developed as outlined in (Scheme 3).
CO2Me
6
CHO
FeSO4
NH4OH
CHO
NO2
or
Pd / C, H2
NH2
CO2Me
CO2Me
MeOH - H+
N
reflux
5
18
CO2Me
19
1. Et3N
LiAIH4
OH
2. MSCl
THF, N2
0oC - reflux
OH
DCM, N2
N
20
N
21
liq. NH3
NH
MeOH
OMS
N
3
Scheme 3
IV
OMS
Synopsis
Further treatment of 6 with 5 in the presence of 3-4 drops of H2SO4 in MeOH at
65oC for 6 h. gave 19. in 60% yield as a solid. Reduction of compound 19 with LAH
THF at 0oC - r.t for 12 hr yielded diol 20. Compound 20 as treatment with MsCl in the
presence of Et3N in DCM at 0oC under nitrogen atmosphere afforded compound 21,
which was unstable to column chromatography. Immediately therefore treatment with
liq. NH3 in MeOH (6:4) afforded compound 3 in 27% yield.
Synthesis of chlorolactone 4:
Furfuryl alcohol was treated with propargyl bromide in presence of aq. NaOH
and tetra butylammonium hydrogensulfate (PTC) to give the alkylated terminal alkyne
22 in 70% yield. The alkynyl group in Compound 22 on treatment with potassium tertbutoxide in tert-butanol at 83oC, underwent isomerization to on allene followed by an
intramolecular Diels-Alder reaction and base induced ring opening to afforded
uneventfully the cyclised compound 23. The double bond in compound 23 was reducted
using hydrazine hydrate and hydrogen peroxide in EtOH at –10OC
to obtained
compound 24. Protection of the secondary hydroxy group of compound 24 as its benzyl
ether using NaH yieded compound 25 in 70% yield.
The next objective was the conversion of furan ring to a hydroxy butenolide
system. This was achieved by treatment of compound 25 with rosebengal,
diisopropylethylamine under oxygen atmosphere in DCM at –78oC to yield the went
photo Diels-Alder product which underwent opening of peroxy ring to give the
compound 26 in 87% yield. Compound 4 on treatment with thionylchloride and cat.
Amount of DMF (Vilsmeyer conditions) in CHCl3 at room temperature afforded 4 as
the sole product in 80% yield (Scheme4).
V
Synopsis
OH +
O
1. aq. NaOH
CH2 Br
7
O
O
2. Bu4NHSO4
8
22
t -BuO
H
O
K+ t- BuO-
O (4+2)
t - BuOH, 83oC
O
H
O
O
.
HO
23
NH2. NH2. H2O
O
H2O2, EtOH
Rose bengal
NaH, THF
O
Bn Br
HO
i-Pr2NEt, DCM,
BnO
24
..
B
H
O
O
O
O
O
O
BnO
-78oC, O2
25
SOCl2 / DMF
BnO
O
BnO
Cl
OH
H
26
4
Scheme 4
Condensation of pyrroloquinoline (23) with chloro lactone (4):
The coupling reaction in between pyrroloquinoline 3 and chloro lactone 4 was
achieved by using pyridine anhydrous acetonitrile to afford aldehyde 27 which was
further treated with sodiumacetate and acetic anhydride to furnish the benzyl ether 28 in
a 25% overall yield. (Scheme 5).
The compound 28 was deprotected with 5% Pd-C under hydrogen atmosphere to
give the alcohol 29 in 80% yield.
VI
Synopsis
O
NH +
O
Py / CH3CN
O
OBn
N
N
N
OHC
Cl
3
OBn
O
CH3COONa
acetic anhydride
27
4
N
N
28
OBn
Scheme 5
The alcohol 29 was oxidized with IBX in dry DMSO and DCM to deliver the
keto compound 30 in 93% yield. The keto 30 was selectively alkylated at 4th position on
treatment with ethyliodide using K2CO3 and a phase transfer catalyst in acetone to give
compound 31. Compound 31 it was reduced by using NaBH4 in methanol at 0oC to give
the single isomer alcohol 32. The compound 32 was converted to the mesylated 33 with
MsCl and triethylamine in DCM. The compound 33 was transformed into the alkene 34
by refluxing in CHCl3 in the presence of Et3N. Dihydroxylation of 34 with OsO4 / NMO
in acetone/ water gave the diol 35. The diol 35 was treated with PDC or DMP in dry
DCM at room temperature under nitrogen atmosphere. I did not get the target molecule
2 and i tried to alternative oxidation methods IBX, DMP, Jones oxidation failed to
under above reaction conditions (Scheme 6).
VII
Synopsis
O
O
Pd / C - H2
N
IBX
N
MeOH
DMSO, DCM
N
N
OH
OBn
29
28
O
N
PTC, dry acetone
N
O
30
N
O
31
O
NaBH4
MeOH, 0oC
O
EtI, K2CO3
N
O
Et3N, MSCl
N
DCM, 0oC
N
N
N
OH
OMs
33
32
O
TEA, CHCl3
0o
rt
O
OsO4, NMO
N
Acetone, H2O
N
N
N
reflux
35
34
O
N
N
2
OH
O
Scheme 6
VIII
OH
OH
Synopsis
CHAPTER-III
Microwave assisted organic reactions
The rapid heating of foodstuffs in microwave ovens is routinely used by a
significant proportion of mankind. However people have recognized other potential
applications for this method of heating and scientists engaged in a number of disciplines
have applied the rapid heating associated with microwave technology to a number of
useful processes. The technique has also found use in range of decomposition processes
including hydrolysis of proteins and peptides. Application to inorganic and solid state
synthesis has also been shown to have significant advantages. The purpose of this
review is to highlight the applications of microwave radiation to organic reactions,
organic synthesis is an area, which can benefit significantly from this technology
Section-A: Montmorillonite clay-catalyzed one-pot synthesis of -aminophosphonates
-aminophosphonates are an important class of biologically active compounds
and their synthesis has received an increasing amount of interest because of their
structural analogy to -amino acids. -Aminophosphonates act as peptide mimics,
enzyme inhibitors, antibiotics and pharmacology agents. Generally, they are prepared by
the addition of phosphorus nucleophiles to imines in the presence of either a base or an
acid. Lewis acids such as SnCl4, BF3. OEt2, ZnCl2, and MgBr2 have been used for this
transformation. However, these reactions cannot be carried out in a one-pot operation
with a carbonyl compound, amine and diethyl phosphite, because the amine and water
that exist during imine formation can decompose or deactivate the Lewis acids. In order
to circumvent some of these problems in one-pot procedures lanthanide triflates and
IX
Synopsis
indium triochloride have been used as catalysts. Clay catalysts make the reaction
processes convenient, more economic, and environmentally benign and act as both
Bronsted and Lewis acids in their natural and ion-exchanged forms. A novel and highly
efficient procedure for the synthesis of -amino phosphonates using an inexpensive and
reusable catalyst, montmorillonite KSF under microwave irradiation has been
developed (Scheme 7).
HN R2
O
R
C
1
Montmorillonite KSF
R1 + R2 NH2 + HOP (OEt)2
2
MW
3
P (OEt)2
R
C
4
R1 O
R = aryl, alkyl, naphthyl and cinnamyl
Scheme 7
Thus reaction of benzaldehyde, benzylamine and diethyl phosphite in the
presence of KSF clay resulted in the formation of -amino phosphonate in 90% yield
after 3 minutes irradiation under microwave. Similarly various aldehydes and amines
were reacted with diethyl phosphite to afford the corresponding -amino phosphonates
in high yields. The reactions proceeded smoothly under solvent-free conditions and was
completed within 3-5 min of reaction time. Both aromatic and aliphatic aldehydes
provided excellent yield of products (80-92%) in a short reaction time whereas ketones
gave phosphonates in good yields (65-80%) after a longer irradiation time (6-8 min)
several aromatic, ,-unsaturated, heterocyclic and aliphatic aldehydes worked well to
give the phosphonates in high yields (Table 1).
X
Synopsis
Table 1: Clay-catalyzed one-pot synthesis of a-amino phosphonates
Carbony
Compound
Entry
CHO
a
Microwave
irradiationa
time(min) Yield(%)
Amine
H2N
CH3
3 min
(85)
6h
(70)
3 min
(82)
8h
(75)
5 min
(90)
10h
(72)
6 min
(81)
8h
(70)
H2N
4 min
(89)
5h
(74)
H2N
5 min
(83)
7h
(80)
3 min
(90)
5h
(72)
5 min
(85)
7h
(70)
6 min
(80)
10h
(65)
5 min
(91)
8h
(75)
H2N Ph
4 min
(88)
6h
(77)
H2N
3 min
(92)
5h
(80)
H2N Ph
5 min
(87)
6h
(73)
H2N
Ph
8 min
(78)
12h
(68)
H2N
Ph
7 min
(75)
10h
(70)
H2N
Ph
5 min
(90)
6h
(75)
H2N Ph
4 min
(85)
6h
(78)
H2N
3 min
(87)
7h
(80)
CHO
Ph
Ph
b
H2N
Cl
CHO
Ph
H2N Ph
c
Ph
CHO
H2N
d
CHO
e
CHO
Conventional
heatingb
time(h) Yield(%)
Ph
f
Cl
CHO
g
H2N
CHO
H2N
h
O
i
j
CH3
Cl
H2N
CHO
MeO
Ph
Ph
H2N
MeO
CHO
k
Me
l
CHO
O
Ph
O
CHO
Cl
m
Cl
O
n
O
o
Cl
p
q
r
CHO
CHO
CHO
Ph
a) Microwave irradiation was carriedout 450 W using BPL, BMO, 700T microwave oven by pulsed irradiation
technique (20 s interval for each min.) b) Conventional heating in refluxing toluene.
XI
Synopsis
Section-B: InCl3-SiO2 catalyzed electrophilic amination of arenes: a facile and rapid
synthesis of aryl hydrazides
As a continuation of studies on surface mediated solid state reactions coupled
with microwave irradiation, an efficient and rapid method for the synthesis of aryl
hydrazides through the electrophilic amination of electron rich arenes with diethyl
azodicarboxylate using indium trichloride supported on SiO2 in solvent-free conditions
was developed.
R
+ EtOOC
1
N N
COOEt
InCl3-SiO2
mw
2
N
R
COOEt
NHCOOEt
3
Scheme 8
Aryl hydrazides were formed in high yields in short reaction time when the
reactants were admixed with InCl3-SiO2 in Erlenmeyer flask and exposed to microwave
irradiation at 450 W using BPL, BMO-7—T focused microwave oven (Scheme 8). The
reactions were clean and completed in 2-6 min with high regioselectivtiy. The less
reactive substrates like anisole, naphthalene, 3,4-dimethoxybromobenzene, 1,4dimethoxybenzene and xylene smoothly underwent electrophilic amination to afford
corresponding hydrazides in good yields under microwave irradiation. The electrophilic
amination reaction of arenes with diethyl azodicarboxylate in the presence of BF3.OEt2
or CF3SO3H, or TFA resulted in a complex mixture of products and also the amination
was much slower using LiClO4 as a catalyst compared to reactions carried out in the
presence of indium trichloride-SiO2 under microwave irradiation. The reaction rates and
yields were dramatically enhanced by microwave irradiation. This is due to the
absorption of microwave energy by the polar media as well as polar reactants, which
XII
Synopsis
generates heat energy as required to promote the amination reaction. The reaction is
highly regioselective affording high yields of products in a short reaction time.
The present study has unequivocally confirmed that the conventional heating in
1,2-dichloroethane and longer reaction times (8-22 h) required for the amination of
arenes are improved using microwave irradiation, which is becoming an alternate and
substitute heating source. For example, the treatment of 1,2-dimethoxybenzene with
diethyl azodiocarboxylate in the presence of indium triochloride-SiO2 (3 wt equiv of
arene) under microwave irradiation at 450 watts for 3 min gave the corresponding
hydrazide in 88% yield after filtration through a small silica gel column, whereas under
conventional heating conditions, the hydrazide was obtained in 75% yield after 10 h of
heating in 1,2-dichlroethane (Table-2). Invariably, the products obtained by microwave
irradiation were purified with more ease. The hydrazides thus obtained were easily
converted to their corresponding anilines by reduction with zinc dust in acetic acid.
XIII
Synopsis
Table 2: Indium(III) chloride-SiO2 catalyzed elcetrophilic amination of arenes with DEAD.
Entry
Hydrazidea
(25)
Arene
(23)
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
a
b
8 h (80)
3 min (87)
12 h (70)
3 min (81)
15 h (68)
3 min (85)
10 h (73)
OMe
N COOEt
NHCOOEt
OMe
2 min (90)
8 h (78)
N COOEt
NHCOOEt
Br
6 min (83)
14 h (71)
3 min (87)
12 h (78)
OMe
N COOEt
NHCOOEt
OMe
O
O
O
O
OMe
f
OMe
MeO
MeO
MeO
MeO
Br
MeO
OMe
N COOEt
NHCOOEt
OMe
N COOEt
NHCOOEt
h
j
2 min (92)
MeO
OMe
i
N COOEt
NHCOOEt
OMe
N COOEt
NHCOOEt
OMe
g
10 h (75)
OMe
d
MeO
3 min (88)
OMe
MeO
e
Coventional Heatingc
Time (Yield)
N COOEt
NHCOOEt
OMe
c
Microwaveb
Time (Yield)
OMe
NHCOOEt
NCOOEt
OMe
3 min (90)
12 h (78)
CH3
NHCOOEt
NCOOEt
CH3
4 min (72)
20 h (65)
k
N COOEt
NHCOOEt
6 min (78)
22 h (62)
l
N COOEt
NHCOOEt
6 min (75)
15 h (71)
N COOEt
NHCOOEt
6 min (68)
22 h (60)
MeO
MeO
m
H3 C
H3C
a. All products were charcterized by 1H NMR, IR and Mass spectra.12,
b. Microwave irradation was carried out at 450 W (BPL, BMO 700 T).
c. Conventional heating in 1,2-dichloroethane.
XIV
Synopsis
Section-C: Montmorillonite clay-catalyzed stereoselective synthesis of aryl- substituted
(E)-and (Z)-allyl iodides and bromides
The Baylis-Hillman reaction continues to attract organic chemists as it
constructs a novel cabon-carbon bond between the -position of activated alkenes and
carbon electrophiles leading to the formation of synthetically attractive and useful class
of molecules with chemospecific functional groups.
Several methods have been developed for the direct conversion of 3-hydroxy-2methylene alkanoates to 2-(halomethyl) alk-2-enoates, including those using HBrH2SO4, NBS-Me2S, PBr3, MsCl-Et3N and CuBr2-silica gel. Recently, the synthesis of 2(halomethyl) alk-2-enoates has been reported from the acetyl derivative of BaylisHillman adducts using MgBr2-THF and AlCl3-CH2Cl2. however, there is no report of
the synthesis of allyl iodides from Baylis-Hillman adducts.
In continuation of studies on the applications of clays for various
transformations, the remarkable catalytic activity of montmorillonite clay for the
synthesis of 2-(iodo or bromomethyl) aryl-2-enoates from 3-hydroxy-2-methylene
alkanoates (Scheme 9). In addition, microwave irradiation, which has become a
powerful tool for the rapid synthesis of a variety of organic compounds, is used to
enhance the rates of reaction.
OH
EWG
Ar
EWG
KSF-NaX
MW
X
Ar
2
1
A = aryl; EWG = COOMe, X = I, Br
Scheme 9
XV
Synopsis
The treatment of Baylis-Hillman adducts, derived from acrylate esters, such as
3-hydroxy-2-methylene alkanoates with clay-supported NaI and NaBr under microwave
irradiation led to the formation of the corresponding (Z)-allyl iodides and bromides in
high yields (Table 3). The irradiation was carried out a 450W using a BPL, BMO-700T
domestic microwave oven. The reaction temperature reached 110oC after 3 min pulsed
irradiation (1 min on with 20 s off interval) at constant power. The same reaction, under
thermal conditions, at 110oC took 5-8 h to afford yields comparable with those that are
obtained by microwave irradiation. The reactions of Baylis-Hillman adducts derived
from acrylonitrile, that is 3-hydroxy-2-methylene alkanenitriles with NaI and NaBr in
the presence of KSF clay, produced the corresponding (E)- amd (Z)-allyl iodides and
bromides in high yields (Scheme 10 and table 3).
OH
EWG
Ar
KSF-NaX
MW
1
X
H
CN
H
+
CN
Ar
3
(E)
Scheme 10
XVI
X
Ar
4
(Z)
Synopsis
Table 3: Microwave-assisted synthesis of allyl iodides and bromides
Reaction time (yield (%)
Substrate
Entry
Nucleophile
Irradiationa/min
Conventionalb/h
E : Zc
OH O
OMe
NaBr
4 (87)
6 (73)
0 : 100
OMe
NaI
3 (89)
5 (81)
0 : 100
OMe
NaI
3 (80)
7 (74)
0 : 100
NaBr
5 (78)
8 (65)
0 : 100
OMe
NaI
4 (85)
7 (70)
0 : 100
CH3
NaBr
5 (81)
8 (83)
0 : 100
CH3
NaI
4 (90)
6 (77)
0 : 100
CH3
NaBr
5 (84)
8 (75)
0 : 100
CH3
NaI
4 (87)
6 (80)
0 : 100
NaI
3 (85)
5 (78)
87 : 13
CN
NaBr
4 (78)
6 (65)
89 : 11
CN
NaI
3 (83)
5 (71)
91 : 09
CN
NaBr
4 (80)
7 (68)
93 : 07
CN
NaI
3 (88)
5 (70)
95 : 05
a
OH O
b
OH O
c
NO2
OH O
d
OMe
O2N
OH O
e
Cl
Cl
OH O
f
Cl
Cl
OH O
g
Cl
Cl
OH O
h
Cl
OH O
i
Cl
OH
CN
j
OH
k
Cl
Cl
OH
l
Cl
Cl
OH
m
OPh
OH
n
OPh
a. Pulsed irradiation (1 min with 20 s interval).b. Conventional heating at 110 oC. c. E : Z ratio was based
on integration ratios of isomeric allylic and vinyl protons in 1H NMR spectra.
XVII