Synopsis
SYNOPSIS
The thesis entitled “ Synthetic studies towards the synthesis of
Amaryllidaceae
Alkaloids:
ent-7-deoxy
pancratistatin,
Pancratistatin
and
Conduramines” has been divided into three chapters.
Chapter-I: This chapter deals with an introduction to cancer and the approaches cited
in the literature towards the synthesis of pancratistatin, 7-deoxy pancratistatin and ent-7deoxy pancratistatin.
Chapter-II: This chapter deals with synthetic studies towards the stereoselective total
synthesis for ent-7-deoxy pancratistatin, Pancratistatin and ent-conduramines A-1, entconduramine C-4 derivatives.
Chapter-III: This chapter describes the development of a novel and highly efficient
procedure for the preparation of bis (indolyl) methanes catalyzed by lithium perchlorate.
CHAPTER-I: An introduction to cancer and the approaches cited in the literature
towards the synthesis of Amaryllidaceae alkaloids.
CHAPTER-II: Studies towards the synthesis of ent-7-deoxy pancratistatin,
Pancratistatin and Conduramine derivatives from D-ribose.
The Amaryllidaceae alkaloids () pancratistatin was first isolated from the roots
of pancratium littorate by Pettit and co-workers in 1984. This compound exhibits
anticancer activity and also a range of anti neoplastic properties, including activity
against murine p-5076 ovarian sarcoma and p-388 lymphocyctic leukemia. (+)
I
Synopsis
pancratistatin was tested against human cancer cell lines with GI50 values on the order
of 0.02 mg/ml. The promising biological activity and limited availability of this series
of highly oxygenated phenanthridone alkaloids has stimulated considerable synthetic
work in which the first total synthesis of () pancratistatin was recorded by Danishefsky
and co-workers in 1989 and subsequently by so many groups. Although little is known
about the precise mode of action of this compound, a great deal of effort has been
expended in the preparation and biological evalution of an natural derivatives of
Amaryllidaceae constituents including 7-deoxy pancratistatin and ent-7-deoxy
pancratistatin.
OH
HO
OH
HO
OH
OH
C
O
O
OH
A
O
R
H
B NH
OH
H
O
O
R
1. R=OH, Pancratistatin
2. R=H, 7-Deoxy Pancratistatin.
NH
O
3. R=H, ent-7-Deoxy pancratistatin.
Fig:1
Our retrosynthetic analysis involved the construction of BC ring system by
conjugate addition of aryl magnesium halide 6 to conduramine derivative 5. The
conduramine 5 was prepared from readily available starting material D-ribose, by using
strategies like Grubb’s cyclization , aziridine formation and oxidative opening of
aziridine (scheme 1).
II
Synopsis
R=H,ent 7-deoxy pancratistatin
R=OH,pancratistatin
O
O
O
HNCOOMe
O
4
R
OMs
Br
O
+
and
O
O
Br
O
O
O
HNCOOCH3
OMe
7
5
6
O-Vanillin
OCOCH3
O
O
N
COOCH3
8
OCOCH3
O
O
9
D + ribose
Scheme 1
III
Synopsis
Synthesis of sugar moiety:
Our initial attempts were based on an easily available sugar as the starting
material. Accordingly, D-ribose was converted to the O-methyl diisopropylidine
derivative 10 by treating with dry acetone in presence of 2% methanolic HCl and 2,2dimethoxy propane (scheme 2). Compound 10 was then treated with triphenylphosphine
and iodine in presence of imidazole in refluxing toluene to yield the iodo glycoside 11
in 92% yield.
O
D-ribose
HO
2,2-DMP, MeOH-HCl
O
,
0o
OMe
TPP,I2,PhCH3
H
to rt
O
O
10
OMe
H
O
O
11
OH
Br Zn
( ( ( ( , THF:H2O
Imidazole, 1 hr
O
I
O
O
12
Scheme:2
The iodofuranoside 11 on domino reaction with allyl bromide mediated by
activated zinc in a mixture of THF: H2O (4:1) under sonication conditions afforded
diene alcohol 12 as a inseparable diastereomeric mixture in 80% yield. Treatment of
diene alcohol 12 with 3 mol% of 1st generation Grubb’s catalyst under argon
atmosphere in dry dichloromethane at room temperature afforded an inseparable
mixture of alcohols 13 in almost quantitation yield. Compound 13 was then treated with
acetic anhydride, TEA and catalytic amount of DMAP in dry dichloromethane at 0oC
IV
Synopsis
afforded a separable mixture of diastereomeric acetates 9 and 14 in (4:1) ratio (scheme
3).
OH
OH
O
Grubb's
O
Catalyst, DCM
O
O
13
12
OAc
OAc
O
O
Ac2O,DMAP
+
TEA, DCM
0oC to rt
O
O
9
14
Scheme 3
Treatment
of
compound
9
with
N-bromosuccinimide and water in
dimethoxyethane at –10oC afforded separable bromohydrine 15 and its diastereomer 16
in (9.5:0.5) ratio (scheme 4).
OAc
OAc
O
O
O
NBS, H2O
DME, 0oC to
rt
OAc
O
+
O
HO
OH
Br
9
O
Br
15
16
K2CO3
CH3CN
OCOCH3
O
OCOCH3
O
NaN3,NH4Cl
O
EtOH, reflux
O
O
N3
OH
17
Scheme 4
V
18
Synopsis
Compound 15 was converted to an epoxide 17 in 92% yield by refluxing with 6
equivalents of anhydrous potassium carbonate in dry acetonitrile. The chiral epoxide 17
was opened by an azido functionality by using 2.5 equivalents of sodium azide and 2.5
equivalents of ammonium chloride in refluxing ethanol to afford azido alcohol 18
regioselective in 65% yield.
OCOCH3
N3
OCOCH3
OCOCH3
O
MsCl, TEA
O
DCM, 0oC
O
O
N3
OH
OMs
18
19
O
TPP, iPr2NEt
THF: H2O
(10:1)
O
N
H
20
OCOCH3
O
ClCOCH3
TEA, DCM
0oC to rt
O
N
COOCH3
8
Scheme 5
The secondary hydroxyl group of compound 18 was converted as its mesylate
19 using 1.1 equivalent of methane sulfonyl chloride and TEA in dry DCM at 0oC.
Compound 19 was immediately treated with triphenylphosphine and diisopropyl
ethylamine in tetrahydrofuran and water at reflux temperature to give aziridine 20 in
good yield. The NH group of aziridine 20 was protected using methyl chloroformate,
TEA in dry DCM at 0oC to afford carbamate 8 in 90% yield (scheme 5). The
nucleophilic ring opening of aziridine 8 with aryl cuprates and aryl lithium were not
successesful. Then we diverted our strategy towards oxidative opening of aziridine,
VI
Synopsis
accordingly acetyl group in compound 8 was hydrolyzed using catalytic amount of
K2CO3 in MeOH to afford alcohol 21. Oxidation of 21 with 2 equivalents of DessMartin periodonane in dry DCM at room temperature afforded ketone 22, which was
not stable and converted into allyl amine 24 during silicagel column chromatography
(scheme 6).
OH
OAC
N
COOMe
8
O
O
K2CO3
O
O
MeOH
rt
O
O
DMP, DCM
RT
O
N
N
COOMe
COOMe
21
22
Silca gel
O
OH
O
NaBH4
O
O
CeCl3 H2O
MeOH
O
HNCOOMe
HNCOOMe
23
24
Scheme 6
Lunche reduction of ketone functionality in allylamine 22 with ceriumchloride
heptahydrate and sodium borohydride in methanol at –10oC afforded a mixture of
alcohols 24 in 70% yield. The mixture 24 was acetylated with acetic anhydride and
TEA in dry methylene chloride to afford a separable mixture of diastereomers 25, 26 in
VII
Synopsis
OCOCH3
OH
O
AC2O, TEA
O
O
DCM, DMAP
0oC to rt
O
+
NHCOOCH3
24
rt
OMs
NHCOOCH3
NHCOOCH3
25
26
K2CO3
MeOH
O
MsCl
TEA, DCM
K2CO3
rt
MeOH
OH
OH
O
OCOCH3
O
O
O
O
NHCOOMe
NHCOOMe
NHCOOMe
5
27
28
Scheme 7
3:7 ratio. The optical purity of compound 25 was determined by comparing the optical
rotation value with the value of its enantiomer reported in literature. Compound 25 on
hydrolysis with potassium carbonate in methanol afforded ent-conduramine A-1
derivative 27. In the similar manner we synthesized ent-conduramine C-4 derivative 28
in good yield (scheme 7). Compound 27 was mesylated by using methanesulfonyl
chloride and TEA in dry dichloromethane at 0oC to afford enentio pure mesylate 5.
VIII
Synopsis
Synthesis of aromatic moiety:
Commercially available o-vanillin 29 was brominated regioselectively by using
2 equivalents of potassium bromide and 2 equivalents of bromine in acetic acid at
110oC to give 5-bromo vanillin 30 in 50% yield after two recrystalization. Bromide 30
was then subjected to Baeyer-Villiger oxidation conditions using 2 equivalents of
mCPBA in dry dichloromethane at reflux temperature to afford catachol derivative 31
after base hydrolysis (scheme 8). Compound 31 was treated with 1.2 equivalents of
dibromometane and 1.2 equivalents of K2CO3 in dry DMF at 100oC to afford bromide 7
in good yield.
CHO
AcOH, 110oC
H2O
OH
OMe
29
Br
Br
KBr, Br2
CHO
OMe
30
CH2Br2, DMF
O
OH
K2CO3, 100oC
O
Br
OMe
7
Scheme 8
IX
CH2Cl2
OH
OH
OMe
31
mCPBA
Synopsis
Coupling of sugar and aromatic moieties:
With enantiopure mesylate derivative 5 in hand, the stage were set for regio and
diastereo controlled introduction of aryl group 7 by SN2 chemistry via organocuprates.
All attempts to perform the organocuprate led to disappointing results, which we
attributed to the instability of the organocuprate.
On the other hand, addition of the Grignard reagent of aryl bromide 6 to a
mixture of the mesylate derivative 5 and cuprous cyanide in THF at 0oC gave the
desired adduct 4 (scheme 9) in good yield, whose spectral properties are in full
agreement with those of the product reported by Hudlicky et al.
O
OMs
MgBr
O
O
CuCN
+
THF,
O
O
O
O
0oC
HNCOOMe
O
HNCOOCH3
6
4
5
Scheme 9
X
Synopsis
Chapter III: Lithium perchlorate catalyzed reactions of indoles: An expeditious
synthesis of Bis (indolyl) methanes.
The acid-catalyzed reaction of electron-rich heterocyclic compounds with pdimethylamino benzaldehyde is known as Ehrlich test for -electron excessive
heterocycles such as pyroles and indoles. The analogous reaction of indoles with other
aromatic or aliphatic aldehyde and ketones produces azafulvenium salts. The
azafulvenium salts can undergo further addition with the second indole molecule to
afford bis (indolyl) methanes. Protic acids as well as Lewis acids are known to promote
these reactions. Lanthanide triflates are also found to catalyze these reactions.
Indoles and their derivatives are used as antibiotics in the field of
pharmaceuticals, moreover bis (indolyl) methanes are versatile building blocks for the
synthesis so many alkaloids. Because the synthesis of bis (indolyl) methanes is an
important synthetic goal, we have developed a novel methodology for the preparation of
bis (indolyl) methanes using lithium perchlorate as a Lewis acid.
In recent years, lithium perchlorate in diethyl ether has received considerable
attention as a powerful reaction medium for effecting various organic transformations.
LPDE medium offers a convenient procedure to carry out the reactions under essentially
neutral reaction and work-up conditions. These special properties inherent to LPDE
medium prompted us to disclose a mild and efficient procedure for the synthesis of bis
(indolyl) methanes.
XI
Synopsis
R
O
+
N
H
R
R1
LiClO4
1
R
CH3CN, r.t
N
H
1(a-o)
N
H
2(a-o)
Scheme 10
Bis (indolyl) methanes were formed in high yields when indole was treated with
aldehydes or ketones in the presence of 5 M lithium perchlorate in diethyl ether. The
electrophilic substitution reactions of indole with aldehydes or ketones proceeded
smoothly at room temperature to afford the corresponding bis (indole) derivatives in
high yields in a short reaction time. The reactions were carried out in diethyl ether as
well as in acetonitrile. The reactions proceeded with 10% lithium perchlorate in
acetonitrile at room temperature. The catalyst is effective in both solvent systems. The
results, summarized in the table, clearly indicate the scope of the reaction with respect
to various substituted aldehydes and ketones
In conclusion, we have described a novel and highly efficient procedure for the
preparation of bis (indolyl) methanes through the electrophilic substitution reactions of
indoles with aldehydes and ketones using lithium perchlorate under essentially neutral
reaction and work-up conditions.
Table: LiClO4- catalyzed Synthesis of Bis (indolyl) methane Derivatives
Entry
Indole
Aldehyde or Ketone
5 M LPDE
Time (h)
Yield (%)
CHO
a
XII
N
H
O
b
N
O
CHO
10% LiClO4
Time(h)
(h)
Yield (%)
2.5
95
5.0
90
3.0
92
5.5
88
Synopsis
XIII