SYNOPSIS
The work carried in my research tenure has been compiled in the form of a
thesis
entitled
“Synthesis
c][1,4]benzodiazepine
of
Hybrids
DNA-interactive
and
C2/C8-Linked
Combinatorial
Pyrrolo[2,1-
Synthesis
of
its
Dimers/Hybrids and Bioactive Fused [2,1-b]quinazolinones” The main aim of this
work
is
to
design
and
synthesize
biologically
active
molecules
like
pyrrolobenzodiazepines, which are known for their DNA-binding ability and potent
anticancer activity. The biologically active pyrrolobenzodiazepine dimers/hybrids
and bioactive fused [2,1-b]quinazolinones namely vasicinone and deoxyvasicinone
have been synthesized by solid-phase combinatorial methods. The thesis has been
divided into four chapters.
CHAPTER I: This chapter gives the general introduction about cancer
chemotherapy, covalent interactions of drug-DNA, particularly of pyrrolo[2,1c][1,4]benzodiazepine (PBD) antitumour antibiotics, combinatorial chemistry, the
aim and objectives of the present work.
CHAPTER II: This chapter has been divided into two sections.
SECTION-A: Consists of the synthesis and DNA-binding affinity of novel 6chloropurine linked pyrrolo[2,1-c][1,4]benzodiazepine hybrids and their antitumour
activity against eight human tumour cell lines.
SECTION-B: Consists of the design, synthesis and DNA-binding affinity of novel
C2/C8-linked 1,2,3-triazene-pyrrolo[2,1-c][1,4]benzodiazepine conjugates.
CHAPTER III: This chapter describes the development of solid-phase synthetic
strategies for pyrrolo[2,1-c][1,4]benzodiazepine dimers, its hybrids and this chapter
has been divided in to three sections. SECTION-A: This section consists of the
selective reduction of aromatic azides to amines in solution as well as on solid-phase
and resin cleavage employing BF3. OEt2/EtSH. This reagent system has been utilized
for
the
synthesis
of
pyrrolo[2,1-c][1,4]benzodiazepines
and
fused
[2,1-
b]quinazolinones. SECTION-B: This section describes the combinatorial synthesis of
I
SYNOPSIS
C8-linked chalcone-pyrrolobenzodiazepine congugates and chalcone-napthalimide
hybrids have been synthesized for the first time on solid-support, which are
potential DNA-binding agents. SECTION-C: The biologically important DNAinteractive pyrrolo[2,1-c][1,4]benzodiazepine dimers (DSB-120) and their C2fluorinated analogues have been synthesized on solid-support.
CHAPTER IV: This chapter deals with the synthesis of fused [2,1-b]quinazolinones
namely vasicinone and deoxyvasicinone also for the first time on solid-phase. One of
the methods is resin attached to amino functionality while the other is an aza-Wittig
reductive cyclization approach. This methodology is amenable to the generation of
combinatorial libraries with diversity in both A- and C-rings to afford a variety of
fused [2,1-b]quinazolinones.
CHAPTER-I
INTRODUCTION
This chapter describes the general introduction about pyrrolobenzodiazepines and combinatorial chemistry..
PYRROLO[2,1-c][1,4]BENZODIAZEPINES
Cancer is a diseases characterized by uncontrolled growth or spread of
abnormal cells. It involves the conversion of any normal cell to a cancerous cell
showing tandem replication and cell division at much faster rate in comparison to
the normal cells and thus provides a potential target area for the development of
chemotherapeutic agents. It is now clear that chemotherapy’s most effective role in
solid tumours is as an adjuvant to initial therapy by surgical or radiotherapeutic
procedures. Chemotherapy becomes critical to effective treatment because only
systemic therapy can attack micrometastases. These agents can be categorized into
functional subgroups like alkylating agents, antimetabolites, antibiotics, and
antimitotics. The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) belonging to the class of
DNA-interactive antitumour antibiotics have the potential as regulators of gene
II
SYNOPSIS
expression with possible therapeutic application in the treatment of genetic
disorders including cancer. The first PBD antitumour antibiotic anthramycin has
been described by Leimgruber et. al., in 1963, and since then a number of
compounds have been developed on PBD ring system leading to DNA binding
ligands.
H3C
8
OH H
9
N
OCH 3
H
11
10
7
N
5
6
N
HO
H
1
11a
2
4
3
O
Anthramycin
N
H
O
N
N
H3CO
CONH 2
O
Tomaymycin
O
N
N
OCH 3 H3CO
O
SJG-136
H
O
Figure 1
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of potent naturally
occurring low molecular weight antitumour antibiotics originally isolated from
various Streptomyces species. Their common interaction with DNA has been
extensively investigated and it is considered unique since they bind within the
minor groove of DNA forming a covalent aminal bond between the C11-position of
the central B-ring and the N2 amino group of guanine base. A number of naturally
occurring and synthetic compounds based on PBD ring system, such as
anthramycin, tomaymycin, DC-81 and its dimers (presently, SJG-136 is under
clinical evaluation), have shown varying degrees of DNA binding affinity and
anticancer activity.
O
O
N
HN
H2N
N
H
N
HN
H
N
HH N
N
H
N
DNA
N
N
O
11R/S aminal
O
N10-C11 imine
Figure 2.
PBD-DNA interaction
III
N
N
DNA
SYNOPSIS
COMBINATORIAL CHEMISTRY
Combinatorial chemistry is a new methodology developed by researchers in
the pharmaceutical industry to reduce the time and costs associated with producing
effective and competitive new drugs. By accelerating the process of chemical
synthesis, this method is having a profound effect on all branches of chemistry,
especially on drug discovery. Through the rapidly evolving technology of
combinatorial chemistry, it is now possible to produce libraries of small molecules to
screen for novel bioactivities. This powerful new technology has begun to help
pharmaceutical companies to find new drug candidates quickly, save significant
money in preclinical development costs and ultimately change their fundamental
approach to drug discovery.
Combinatorial chemistry is used to synthesize large number of chemical
compounds by combining sets of building blocks. Each newly synthesized
compound’s composition is slightly different from the previous one. In this way the
bench chemists can single handedly prepare many hundreds or thousands of
compounds in the time usually taken to prepare only a few by routine
methodologies. Over the last few years, the combinatorial chemistry has emerged as
an exciting new paradigm for the drug discovery. In a very short time the topic has
become the focus of considerable scientific interest and research efforts.
CHAPTER-II (SECTION-A)
DESIGN, SYNTHESIS OF NOVEL C2 AND C8-LINKED PURINE-PYRROLOBENZODIAZEPINE
HYBRIDS AS ANTITUMOUR ANTIBIOTICS
In the past few years design and synthesis of symmetrical cross-linking
agents, particularly based on pyrrolobenzodiazepines (PBDs) has been of
considerable interest. The PBDs are of current interest due to their ability to
recognize and subsequently form covalent bonds to specific base sequences of
double stranded DNA. These antitumour antibiotics bind covalently to the N2 of
IV
SYNOPSIS
guanine at Pu-Gu-Pu sites in the minor groove of DNA. All cancers are
characterized by an abnormal control of cell proliferation. This is caused by
mutation or mis-regulation of cell-cycle regulatory genes and proteins. Cyclindependent kinases (CDKs) are a family of serine/threonine kinases that become
active only when associated with regulatory partners called cyclins. The design and
development of selective CDK inhibitors is however, a serious challenge for
medicinal chemists for the target of anticancer agents. Further, chloro-purine
nucleoside ring systems are reported to have shown a variety of biological activities
particularly CDK inhibitors and selective adenosine receptors.
The objective of the present work is to combine the feature of CDK inhibitor
and adenosine receptor property in the purine nucleoside moiety. Therefore, it has
been of considerable interest to couple this moiety to the C2 and C8-position of
PBDs. In the present part of the chapter (Section-A) the design, synthesis of novel
C2 and C8-linked purine-pyrrolobenzodiazepine hybrids as antitumour antibiotics
has been described.
SYNTHESIS OF C8-LINKED PURINE-PBD HYBRIDS
Synthesis of C8-linked 6-chloropurine-PBD (11a,b) hybrids has been carried
out by employing the commercially available vanillin. Oxidation of vanillin
followed by benzylation and nitration by employing the literature methods provide
4-benzyloxy-5-methoxy-2-nitrobenzoic acid (1). This has been further coupled to Lproline methylester to afford the compound 2, which upon reduction with DIBAL-H
produces the corresponding aldehyde (3). The aldehyde group of this product has
been protected with EtSH/TMSCl to give 4. Compound 4 upon debenzylation
affords (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde
diethylthioacetal (5) which upon etherification by Boc-protected bromoalkanes
followed by deprotection provides 7a,b. These compounds have been coupled with
V
SYNOPSIS
2-amino-1,3-dichloropyrimidine
in
the
presence
of
Et3N
to
produce
the
corresponding 8a,b. The compounds 8a,b upon cyclization with CH(OEt)3 affordsScheme 1
BnO
NO 2
NO 2 CHO
BnO
ii)
OH
H3CO
NO 2 COOCH 3
BnO
i)
N
H3CO
O
1
N
H3CO
O
O
2
3
iii)
Boc
H
N
NO 2 CH(SEt)2
O
n
v)
N
H3CO
NO 2 CH(SEt)2
HO
N
H3CO
O
6a; n = 2
6b; n = 3 vi)
O
4
vii)
N
N
H3CO
N
H3CO
H
N
Cl
NO 2 CH(SEt)2
O
n
NO 2 CH(SEt)2
BnO
O
5
NH 2
H2N
iv)
N
O
n
NO 2 CH(SEt)2
N
H3CO
O
8a,b; n = 2,3
O
7a,b; n = 2,3
viii)
Cl
Cl
N
N
ix)
10a,b; n = 2,3
N
O
n
NO 2 CH(SEt)2
H3CO
N
H3CO
N
N
NH 2 CH(SEt)2
O
n
N
N
N
N
O
9a,b; n = 2,3
O
x)
Cl
N
N
N
N
O
n
N
H3CO
H
N
11a; n = 2 O
11b; n = 3
Reagents and conditions: (i) (a) SOCl2, C6H6, 1-3-drops DMF, rt, 2 h; (b) Et3N, L-proline
methylester hydrochloride, THF-H2O, 0 oC-rt, 2 h, 85%; (ii) DIBAL-H, CH2Cl2, -78 oC, 1 h,
71%; (iii) EtSH/TMSCl, CH2Cl2, rt, 8 h, 72%; (iv) BF3. OEt2, EtSH, CH2Cl2, rt, 12 h, 75%; (v)
K2CO3, DMF, Boc-protected aminobromoalkanes, rt, 48 h, 65-75%; (vi) TFA, CH2Cl2, rt, 6 h;
(vii) 2-amino-1,3-dichloropyrimidine, Et3N, n-BuOH, reflux, 48 h, 58%; (viii) CH(OEt)3, HCl
(10%), rt, 16 h, 62%; (ix) SnCl2. 2H2O, MeOH, reflux, 85-87%; (x) HgCl2-CaCO3, CH3CN-H2O
(4:1), 68-71%.
VI
SYNOPSIS
-9a,b. These purine-substituted nitrothioacetal intermediates 9a,b upon reduction
with SnCl2. 2H2O in methanol gives the aminothioacetal precursors 10a,b and these
on deprotection by HgCl2/CaCO3 affords the desired purine-PBD hybrids (11a,b) as
shown in Scheme 1.
SYNTHESIS OF C2-LINKED PURINE-PBD HYBRIDS
Synthesis of C2-linked 6-chloropurine-PBD hybrid (22a) has been carried out
by employing the commercially available 4,5-dimethoxy-2-nitrobenzoic acid (12a).
This has been further coupled to 4-hydroxy L-proline methylester to afford the
compound 13a. Mesylation of C2-hydroxy group followed by azidation (bimolecular
nucleophilic substitution reaction SN2) with NaN3 produces 15a. This upon
reduction with DIBAL-H produces the corresponding aldehyde 16a. The aldehyde
group of this product has been protected with EtSH/TMSCl to give 17a. The
compound 17a has been reduced with TPP followed by coupling with 2-amino-1,3dichloropyrimidine in the presence of Et3N produces the corresponding 19a. This
upon cyclization with CH(OEt)3 affords the cyclized product 20a. Further, the
purine-substituted nitrothioacetal intermediate 20a upon reduction with SnCl2.
2H2O in methanol gives the aminothioacetal precursors 21a and this on deprotection
by HgCl2/CaCO3 affords the desired purine-PBD hybrid (22a). Compound 22b has
also been obtained in the same manner by employing commercially available
vanillin. Oxidation of vanillin followed by benzylation and nitration by employing
the literature methods provides 4-benzyloxy-5-methoxy-2-nitrobenzoic acid (12b) as
shown in Scheme 2.
The DNA binding ability of these compounds have also been investigated by thermal
denaturation studies using calf thymus (CT) DNA at pH 7.0, incubated at 37 °C. It is
observed that compound 11a,b elevates the helix melting temperature (∆Tm) of the CT-DNA
to 2.1 and 2.2 °C after incubation for 18 h while compounds 22a and 22b have not exhibited
any significant ∆Tm value. In the same experiment the naturally occurring DC-81 exhibits a
∆Tm of 0.7 °C.
VII
SYNOPSIS
Scheme 2
R1
NO 2
R1
i)
OH
R2
NO 2 COOCH 3
R2
N
O
1
N
R1
v)
O
S
O
CH 3
O
N
O
14a,b
NO 2 CHO
R2
N3
O
17a,b
NO 2 COOCH 3
iii)
NO 2 CH(SEt)2
R2
R1
R2
OH
O
13a,b
2
12a; R , R = OCH3
12b; R1 = OBn, R2 = OCH3
R1
ii)
N
iv)
N3
O
16a,b
R1
NO 2 COOCH 3
R2
N
N3
O
15a,b
vi)
R1
NO 2 CH(SEt)2
R2
N
O
18a,b
R1
vii)
NO 2 CH(SEt)2
R2
NH 2
N
Cl
viii)
R1
NH 2 CH(SEt)2
R2
ix)
Cl
N
N
N
O
21a,b
R1
N
Cl
N
N
O
20a,b
N
N
NO 2 CH(SEt)2
R2
N
NH 2
NH
O
19a,b
N
N
N
x)
R1
N
H
Cl
N
R2
N
N
O
1
2
N
N
22a; R , R = OCH3
22b; R1 = OBn, R2 = OCH3
Reagents and conditions: (i) SOCl2, C6H6, 4-hydroxy L-proline methylester hydrochloride,
THF-H2O, oC-rt, 2 h, 85%; (ii) mesyl chloride, Et3N, CH2Cl2, rt, 6 h, 85%; (iii) NaN3, DMF, 50-60
o
C, 6 h; 80%; (iv) DIBAL-H, CH2Cl2, -78 oC, 1 h, 71%; (v) EtSH/TMSCl, CH2Cl2, rt, 8 h, 72%; (vi)
TPP, THF-H2O, rt, 24 h, 75%; (vii) 2-amino-1,3-dichloropyrimidine, Et3N, n-BuOH, reflux, 48 h,
58%; (viii) CH(OEt)3, HCl (10%), rt,16 h, 62%; (ix) SnCl2, 2H2O, MeOH, reflux, 6 h, 85-87%; (x)
HgCl2-CaCO3, CH3CN-H2O (4:1), 12 h, 68-72%.
The C8-linked purine-PBD hybrids (11a,b) have been evaluated against eight
human tumour cell lines derived from eight cancer types that are MCF7 (breast
VIII
SYNOPSIS
cancer), Hop62 (non-small cell lung cancer), KB, Colo205, PC3 (prostate cancer),
Gurav, Zr-75-1 and A549. These compounds exhibited in vitro anticancer activity in
selected human cancer cell lines.
CHAPTER-II (SECTION-B)
SYNTHESIS OF NOVEL C2/C8-LINKED 1,2,3-TRIAZENE SUBSTITUTED PYRROLO[2,1C][1,4]BENZODIAZEPINES AS ANTICANCER AGENTS
The development of hybrid molecules comprising of two types of cytotoxic
moieties represent a new approach in the discovery of new antitumour agents. DNA
is the major cause of cytostatic activity of antitumour agents such as the
methyltriazenes, temozolomide and dacarbazine in guanosine residues of Omethylation. In light of the high mortality rates associated with these cancers, the
role of cytotoxic chemotherapeutic drugs continues to be investigated. One such
drug which in recent years has emerged as arguably the most effective anticancer
agent
for
the
treatment
of
malignant
brain
methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one
tumours
is
(temozolomide).
8-carbamoyl-3Several
DNA
alkylating and cross-linking agents are currently in clinical trials in combination
with temozolomide. Further, in literature a number of anticancer agents have been
developed in which triazene-alkylating agents have played a key role in their
biological activity.
The objective of the present work is to combine the feature of DNA alkylating
and cross-linking properties in the 1,2,3-triazene molecules. Therefore, it has been
considered of interest to couple this moiety at C2, C8 and C2/C8-position of the PBD
ring system. In the present part of the chapter (Section-B), the synthesis of novel
C2/C8-linked
1,2,3-triazene
substituted
pyrrolo[2,1-c][1,4]benzodiazepines
potential anticancer agents have been described.
IX
as
SYNOPSIS
SYNTHESIS OF C8-LINKED TRIAZENE-PBD HYBRIDS
Synthesis of C8-linked triazene-PBD hybrids (27a-c) has been carried out by
employing the commercially available vanillin. Oxidation of vanillin followed by
benzylation and nitration by employing the literature method provides 4-benzyloxy5-methoxy-2-nitrobenzoic
acid.
The
(2S)-N-(4-hydroxy-5-methoxy-2-
nitrobenzoyl)pyrrolidine-2-carboxaldehyde diethylthioacetal (5) has been carried
out by the same procedure as mentioned in Section-A (Scheme 1). Compound 5
upon etherification with dibromoalkanes followed by azidation with NaN3 provides
24a-c. These compounds have been cyclized with dimethyl acetylene dicarboxylate
to produce the corresponding 25a-c that is called a “click reaction” as the
biologically diverse molecules are obtained in one step. These triazene ester
substituted nitrothioacetal intermediates 25a-c upon reduction with SnCl2. 2H2O in
methanol gave the aminothioacetal precursors 26a-c which upon deprotection by
HgCl2/CaCO3 afford the desired C8-linked triazene-PBD hybrids (27a-c) as shown
in Scheme 3.
X
SYNOPSIS
Scheme 3
NO 2 CH(SEt)2
HO
Br
i)
N
H3CO
NO 2 CH(SEt)2
O
n
N
H3CO
O
O
23a; n = 3
ii) 23b; n = 4
23c; n = 5
5
H3CO 2C
N N
N
H3CO 2C
n
NO 2 CH(SEt)2
O
N3
iii)
N
H3CO
NO 2 CH(SEt)2
O
n
N
H3CO
O
O
24a-c; n = 3-5
25a-c; n = 3-5
iv)
H3CO 2C
N N
N
H3CO 2C
O
n
NH 2 CH(SEt)2
v)
N N
N
H3CO 2C
N
H3CO
H3CO 2C
O
26a-c; n = 3-5
n
O
H3CO
27a; n = 3
27b; n = 4
27c; n = 5
N
H
N
O
Reagents and conditions: (i) dibromoalkane specers, K2CO3, dry DMF, 12 h, rt, 78-82%; (ii)
NaN3 (0.5M) in DMSO, 80 oC, 6 h, 85-88%; (iii) dimethyl acetylenedicarboxylate, dry
benzene, reflux, 6 h, 87-92%; (iv) SnCl2.2H2O, MeOH, reflux, 5 h, 75-83%; (v) HgCl2-CaCO3,
CH3CN-H2O (4:1), rt, 6 h, 58-62%.
SYNTHESIS OF C2-LINKED TRIAZENE-PBD HYBRIDS
(2S,4S)-N-[2-nitrobenzoyl]-4-azidopyrrolidine-2-carboxaldehyde diethylthio-acetal (9a-c) has been prepared by employing the same procedure described in
earlier Section-A (Scheme 2). These compounds (28a-c) have been cyclized with
dimethyl acetylene dicarboxylate to provide the corresponding 29a-c. The triazene
ester substituted nitrothioacetal intermediates 29a-c by reduction with SnCl2. 2H2O
in methanol gave the aminothioacetal precursors 30a-c and these upon deprotection
by HgCl2/CaCO3 afford the desired C2-linked triazene-PBD hybrids (31a-c)
(Scheme 4).
XI
SYNOPSIS
Scheme 4
R1
NO 2 CH(SEt)2
i)
R2
N
N
R2
H
N
O
H3CO 2C
N
N
N
N
N
CO 2CH 3
H3CO 2C
ii)
iii)
N
N
29a-c O
28a; R1 = R2 = H
28b; R1 = R2 = OCH3
28c; R1 = OBn, R2 = OCH3
R1
NO 2 CH(SEt)2
R2
N3
O
R1
R1
NH 2 CH(SEt)2
R2
N
O
30a-c
CO 2CH 3
N
N
H3CO 2C
N
CO 2CH 3
31a; R1 = R2 = H
31b; R1 = R2 = OCH3
31c; R1 = OBn, R2 = OCH3
Reagents and conditions: (i) dimethylacetylene dicarboxylate, dry benzene, reflux, 6 h, 88-90%; (ii)
SnCl2.2H2O, MeOH, reflux, 5 h, 80-85%; (iii) HgCl2-CaCO3, CH3CN-H2O (4:1), rt, 6 h, 58-61%.
SYNTHESIS OF C2/C8-LINKED TRIAZENE-PBD HYBRIDS
Compound 29 has been prepared by employing the same procedure
described in earlier Scheme 4 (29c). This compound 29 upon debenzylation affords
the corresponding debenzylated product 32. This upon etherification with
dibromoalkanes followed by azidation with NaN3 provides the precursors 34a-c.
These compounds have been cyclized with dimethyl acetylene dicarboxylate to
produce the corresponding 35a-c. This triazene ester substituted nitrothioacetal
intermediates 35a-c by reduction with SnCl2. 2H2O in methanol gave the
aminothioacetal precursors 36a-c and these upon deprotection by HgCl2/CaCO3
afford the desired C2/C8-linked triazene-PBD hybrids (37a-c) as shown in Scheme
5.
XII
SYNOPSIS
Scheme 5
BnO
NO 2 CH(SEt)2
N
N
H3CO
N
H3CO
N
N
NO 2 CH(SEt)2
HO
i)
O
N
N
N
O
CO 2CH 3
H3CO 2C
29
32
CO 2CH 3
H3CO 2C
ii)
N3
O
n
Br
NO 2 CH(SEt)2
N
N
H3CO
N
NO 2 CH(SEt)2
O
n
iii)
N
H3CO
N
N
O
O
CO 2CH 3
H3CO 2C
N
N
33a; n = 3
33b; n = 4
33c; n = 5
34a-c; n = 3-5
H3CO 2C
CO 2CH 3
iv)
H3CO 2C
N N
N
H3CO 2C
NO 2 CH(SEt)2
O
n
H3CO 2C
NH 2 CH(SEt)2
O
n
H3CO 2C
O
n
H3CO
N
N
O
CO 2CH 3
H3CO 2C
vi)
N N
N
N
N
H3CO
36a-c; n = 3-5
H3CO 2C
N
CO 2CH 3
H3CO 2C
v)
H3CO 2C
N
O
35a-c; n = 3-5
N N
N
N
N
H3CO
N
H
N
N
37a; n = 3 O
37b; n = 4
H3CO 2C
37c; n = 5
N
N
CO 2CH 3
Reagents and conditions: (i) BF3. OEt2, EtSH, CH2Cl2, rt, 12 h, 75%; (ii) dibromoalkane spacers,
K2CO3, dry DMF, 12 h, rt, 78-80%; (ii) NaN3 (0.5M) in DMSO, 80 oC, 6 h, 89-92%; (iii) dimethyl
acetylenedicarboxylate, dry benzene, reflux, 6 h, 88-90%; (iv) SnCl2.2H2O, MeOH, reflux, 5 h,
78-85%; (v) HgCl2-CaCO3, CH3CN-H2O (4:1), rt, 6 h, 58-62%.
XIII
SYNOPSIS
The DNA binding ability of these compounds has also been investigated by
thermal denaturation studies using calf thymus (CT) DNA at pH 7.0, incubated at 37
°C. It is observed that compound 27a,c; 31a-c and 37a,c elevates the helix melting
temperature (∆Tm) of the CT-DNA to 2.0, 1.0, 1.0; 1.0, 1.1, 2.0 and 0.9, 5.9 °C
incubation of 0 oC and after 18 h while compounds 27b and 37b have not exhibited
any significant ∆Tm value. In the same experiment the naturally occurring DC-81
exhibits a ∆Tm of 0.7 °C.
CHAPTER-III
SYNTHESIS OF PYRROLOBENZODIAZEPINES, ITS DIMERS AND HYBRIDS ON SOLID-PHASE
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of potent,
naturally occurring, antitumour antibiotics produced by various Streptomyces
species. A number of naturally occurring and synthetic compounds based on this
PBD ring system, such as anthramycin, chicamycin, abbeymycin, DC-81 and its
dimers (DSB-120) have shown varying degrees of DNA binding affinity and
anticancer activity. Moreover, pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones (PBD5,11-diones) are known as non-covalent interactive minor groove binders. These are
also intermediates for the synthesis of structurally modified PBD-imines via
oxidation of secondary amines. There are many methods known for the solution
phase synthesis of PBD imines. However, there are only few reports on the solidphase synthesis of these PBD antitumour antibiotics and this chapter has been
divided into three sections.
CHAPTER-III (SECTION-A)
SELECTIVE REDUCTION OF AROMATIC AZIDES IN SOLUTION/SOLID-PHASE AND RESIN
CLEAVAGE EMPLOYING BF3. OEt2/EtSH: PREPARATION OF DC-81
The selective reduction of aromatic azido functionalities to the corresponding
amines is an important transformation in synthetic organic chemistry, used to
construct a variety of biologically active molecules, especially in heterocyclic and
XIV
SYNOPSIS
medicinal chemistry. In recent literature, the reduction of aromatic nitro/azido
functionalities is readily accomplished with a wide variety of reagents. Many of
these methods, however, require heavy metal catalysts, acid conditions, high
temperatures or pressure, which renders most of them not suitable for application to
synthetic organic chemistry.
In recent years, Lewis acid based reagents have found wide applications in
synthetic chemistry because of their ready availability, easy handling and low costs.
In the present work in search of solution-phase and solid-phase compatible method
a process employing BF3. OEt2/EtSH reagent system has been developed for the
reduction of aromatic azides (1a-g) to the amines (2a-g) as illustrated in Scheme 1.
Scheme 1
N3
R
BF3. OEt2/EtSH
CH2Cl2, r,t. 1.5-2.5 h.
1a-g
NH 2
R
2a-g
PREPARATION OF PYRROLO[2,1-c][1,4]BENZODIAZEPINE-5,11-DIONES AND FUSED [2,1b]QUINAZOLINONES BY REDUCTIVE CYCLIZATION APPROACH EMPLOYING BF3.
OEt2/EtSH
This methodology has also been applied to the synthesis of pyrrolo[2,1c][1,4]benzodiazepin-5,11-diones as intermediates in the synthesis of naturally
occurring and synthetically modified PBD imines such as tomaymycin and
chicamycin. With a view to develop new efficient solution- and solid-phase
procedures, BF3. OEt2/EtSH reagent system has been employed for the azido
reductive cyclization process. The substrates 3a-f have been taken in CH2Cl2, BF3.
OEt2 and EtSH is added to provide the PBD-5,11-diones (4a-f) Similarly, it has been
considered
of
interest
to
synthesize
fused
[2,1-b]quinazolinones
(e.g.,
deoxyvasacinone) by using this reagent system for the azido reductive cyclization
protocol for the substrates 3g-i to afford the fused [2,1-b]quinazolinones (4g-i) as
shown in Scheme 2.
XV
SYNOPSIS
Scheme 2
R
N3 COOCH 3
N
O
3a-f
R
N3 O
N
R1
BF3. OEt2/EtSH
R
H
N
CH2Cl2, rt, 1.5-2.5 h.
O
H
N
O
4a-f
BF3. OEt2/EtSH
R
R1
N
N
CH2Cl2, rt, 1.5-2.5 h.
O
O
3g-i
4g-i
PREPARATION OF NATURALLY OCCURRING DC-81
This approach has been further applied to the preparation of the naturally
occurring PBD antibiotic DC-81 (9). This compound exerts its biological activity by
covalently binding to the N2 of guanine in the minor groove of DNA. Various
approaches towards compounds of this type have been investigated over the past
few years; most of these methods have met with varying degrees of success and
have different limitations. Herein, we report an efficient and simple method for the
synthesis of naturally occurring DC-81 by employing BF3. OEt2/EtSH.
4-Benzyloxy-5-methoxy-2-azidobenzoic acid (5) has been converted to acid
chloride by using oxalyl chloride. This azidobenzoyl chloride has been coupled with
L-proline methylester in presence of Et3N to give the coupled azido benzoyl proline
methylester (6). This upon reduction with DIBAL-H gave the aldehyde 7. The
selective reduction of the azido group of 7 with varying amounts of BF3. OEt2/EtSH
(10:20 eq or 2.5:5 eq) to give the ethanethiol protected intermediates 8 and 10. Then
deprotection with HgCl2-CaCO3 in CH3CN:H2O (4:1) produces the naturally
occurring DC-81 (9) and benzylated DC-81 (11) as shown in Scheme 3.
XVI
SYNOPSIS
Scheme 3
N3
BnO
OH
H3CO
O
iii)
O
BnO
7
NH 2 CH(SEt)2
v)
N
H3CO
N3 CHO
HO
O
7
iv)
N
H3CO
O
10
H
N
O
DC-81 9
NH 2 CH(SEt)2
BnO
N
H3CO
O
8
N
H3CO
N
H3CO
6
HO
N3 CHO
BnO
ii)
N
H3CO
O
5
N3 COOCH 3
BnO
i)
v)
BnO
H3CO
N
H
N
O
Benzylated DC-81 11
Reagents and Conditions: (i) (a) (COCl)2 , CH2Cl2, O oC-rt, 2 h; (b) Et3N, L-Proline methylester hydrochloride,
THF, O oC-rt, 6 h; ii) DIBAL-H, CH2Cl2, -78 oC, 1 h; (iii) BF3. OEt2/EtSH (10:20 eq), CH2Cl2, rt, 6 h; (iv)
BF3. OEt2/EtSH (2.5:5 eq), CH2Cl2, rt, 6 h; (v) HgCl2-CaCO3, CH3CN:H2O (4:1), rt, 12 h.
Interestingly, when this procedure has been used for the reduction of resinlinked aryl azides to the corresponding aminophenols have been obtained. There are
some reports in the literature on the Lewis acid assisted cleavage of resins have been
employed, however; to the best our knowledge this is the first report on cleavage of
a resin employing BF3. OEt2/EtSH.
SOLID-PHASE SYNTHESIS
REDUCTIVE CYCLIZATION
OF
PBD-5,11-DIONES EMPLOYING BF3. OEt2/EtSH
BY
During the course of our studies in this laboratory on the development of
solid-phase synthetic methods for the PBD ring system, a number of procedures
mainly based on reductive-cyclization approaches have been studied. In this
connection, the boron trifluoride diethyletherate reagent system has been reacted
with resin-linked aryl azido proline methylesters (16a-e) to afford PBD-5,11-diones
(17a-e) by the simultaneous reduction of the azido functionality and cleavage of the
resin as shown in Scheme 4. This method is advantageous as the reductive
XVII
SYNOPSIS
cyclization and the resin cleavage takes place in the same step, unlike in the
previous procedures.
Scheme 4
N3
N3 COOCH 3
i)
R
R
N
COOH
OH
O
13a-c
12a-c
NH
ii)
OH
O
Wang resin
15
14
N3 COOCH 3
H
N
N3 COOCH 3
15 iii)
R
CCl 3
iv)
R
N
R
N
OH
O
13a-c
O
O
17a-c
N3 COOCH 3
iv)
N
H3CO
O
16d,e
N
O
O
16a-c
O
H
HO
H3CO
R
H
N
OH
O
H
N
R
O
17d,e R = H, OH
Reagents and conditions: (i) (a) (COCl)2, CH2Cl2, 0 oC-rt, 2 h; (b) Et3N, hydroxy-L-proline methylester
hydrochloride,THF, 0 oC-rt, 1 h; (ii) trichloroacetonitrile, DBU, CH2Cl2, 40 min, 0 oC; (ii) trifluoromethane
sulphonic acid, CH2Cl2, 40 min; (iii) CH2Cl2:BF3. OEt2:EtSH (2:1:0.25), 2 h.
The DBU has been added to a suspension of Wang resin (14) and
trichloroacetonitrile to give TCA resin (15), which has been coupled with azidoesters
(13a-c) in presence of trifluoromethane sulphonic acid to provide the precursors 16ac. The compounds 13a-c has been prepared from substituted 2-azidobenzoic acids
through their acid chlorides on coupling with hydroxy-L-proline methylester
hydrochloride. Similarly, 16d,e has been prepared by the coupling of bromomethyl
Wang resin and hydroxy azidobenzoyl proline methylester in presence of Cs2CO3NaI. Reductive cyclization and resin cleavage of 16a-e employing BF3. OEt2/EtSH in
CH2Cl2 to gave PBD-5,11-diones (17a-e) as illustrated in Scheme 4 (Tetrahedron Lett.
2006, 47, 4253-4257).
XVIII
SYNOPSIS
CHAPTER-III (SECTION-B)
SOLID-PHASE SYNTHESIS AND DNA BINDING AFFINITY OF C8-LINKED CHALCONEPYRROLOBENZODIAZEPINE CONJUGATES AND CHALCONE-NAPTHALIMIDE HYBRIDS
Chalcones are a class of anticancer agents that have shown promising
therapeutic efficacy for the management of human cancers. Chalcones, considered as
the precursor of flavonoids and isoflavonoids, are abundant in edible plants.
Chemically they consist of open-chain flavonoids in which the two aromatic rings
are joined by a three-carbon α,β-unsaturated carbonyl system. The objective of the
present work is to combine the feature of anticancer property in the chalcone
molecule. Therefore, it has been considered of interest to couple to C8-position of
PBD through alkyl spacer. In the present part of chapter (Section-B), the solid-phase
synthesis, DNA binding affinity of C8-linked chalcone-pyrrolobenzodiazepine
conjugates and chalcone-napthalimide hybrids have been described.
SOLID-PHASE SYNTHESIS OF A CHALCONE LIBRARY
2-Hydroxyacetophenone (18) has been coupled to commercially available
Merrifield resin (19, 2.00 mmol/g) with Cs2CO3 and NaI to give the resin-bound 2hydroxyacetophenone (20). This reaction has been confirmed by IR spectrum, which
showed
the
keto
group
absorption
at
1739
cm-1.
The
resin-bound
2-
hydroxyacetophenone (20) has been condensed with vanillin (21) employing
NaOMe (as a 0.5M solution in MeOH) to give the resin-bound enone product 22.
This reaction has also been monitored by FT-IR, which showed a strong peak of the
carbonyl absorption at 1747 cm-1 (Scheme 5).
Scheme 5
OH
Cl
OH
CH 3
18
O
OHC
O
19
i)
21
CH 3
OCH 3
O
OH
ii)
OCH 3
O
O
20
22
Reagents and conditions: (i) Cs2CO3, NaI, DMF, rt, 24 h; (ii) NaOMe/THF/MeOH, rt, 4 days.
XIX
SYNOPSIS
SOLID-PHASE SYNTHESIS OF A C8-LINKED CHALCONE-PBD LIBRARY
The derivatized resin (22) has been coupled with bromo-substituted
azidobenzoyl proline methyl esters (23a-c) in presence of K2CO3 to afford the resin
24a-c as indicated by IR spectra that shows strong azide stretching vibrations
between 2106 and 2110 cm-1. After that the derivatized resins (24a-c) have been
reduced selectively with DIBAL-H to give the corresponding resin-bound azido
aldehyde 25a-c. These azido aldehyde chalcone-resins (25a-c) have been reduced
and cyclized via Staudinger reaction by employing TPP to produce 26a-c. This step
has been confirmed by IR analysis (the azido peak disappeared). Finally, the resins
26a-c have been cleaved by employing TFA/CH2Cl2 (1:1) to afford the products 27ac. The resin-bound chalcone PBD dilactams (28a-c) have been obtained by the
reduction of 24a-c employing TPP and followed by cleavage with TFA to afford 29ac (62-73%) as shown in Scheme 6.
The DNA binding ability of these compounds has also been investigated by
thermal denaturation studies using calf thymus (CT) DNA at pH 7.0, incubated at 37
°C. It is observed that compounds 27a-c elevates the helix melting temperature of
the CT-DNA to 7.9, 2.1 and 5.0 °C after incubation of 18 h. In the same experiment
the naturally occurring DC-81 exhibits a ∆Tm of 0.7 °C.
XX
SYNOPSIS
Scheme 6
O
OH
Br
+
N
O
23a-c; n = 1-3
O 22
i)
O
n
N3
O
24a-c; n = 1-3
COOCH 3
N
OCH 3 H3CO
O
N3 COOCH 3
O
H3CO
OCH 3
O
n
O
ii)
iii)
O
O
n
O
N3
N
OCH 3 H3CO
O
O
O
n
O
O
O
25a-c; n = 1-3
O
H
H
N
N
OCH 3 H3CO
iii)
O
28a-c; n = 1-3
O
O
iv)
n
O
N
O
n
O
26a-c; n = 1-3
H
N
OCH 3 H3CO
O
OH
CHO
O
O
H
H
N
iv)
N
OCH 3 H3CO
O
29a-c; n = 1-3
O
OH
O
n
O
N
N
OCH 3 H3CO
O
27a-c; n = 1-3
H
O
Reagents and conditions: (i) K2CO3/DMF, 50 oC, 48 h; (ii) DIBAL-H, CH2Cl2, -78 oC, 2 h; (iii) TPP/toluene,
rt, 16 h; (iv) TFA/CH2Cl2 (1:1), rt, 2 h;
XXI
SYNOPSIS
SOLID-PHASE SYNTHESIS OF A CHALCONE-NAPTHALIMIDE LIBRARY
The resin-coupled chalcone-napthalimides (32a-c) have been prepared by a
similar procedure as shown in Scheme 6. Further, the resins have been cleaved with
TFA/CH2Cl2 (1:1) to afford the compounds 32a-c as shown in Scheme 7.
Scheme 7
O
Br
O
OH
n
O
O
30a-c; n = 1-3
OCH 3
O
N
O
O
N
n
O
OCH 3
i)
22
O
31a-c; n = 1-3
ii)
O
OH
O
n
N
O
OCH 3
O
32a-c; n = 1-3
Reagents and conditions: (i) K2CO3/DMF, 50 oC, 48 h; (ii) TFA/CH2Cl2 (1:1), rt, 2 h.
CHAPTER-III (SECTION-C)
SOLID-PHASE SYNTHESIS OF BIOLOGICALLY IMPORTANT DNA-INTERACTIVE
PYRROLO[2,1-c][1,4]BENZODIAZEPINE DIMERS (DSB-120) AND THEIR C2-FLUORINATED
ANALOGUES
As part of our continuing effort to develop new heterocyclic solid-phase
strategies for synthesizing nitrogen-rich heterocyclic compounds based on
pyrrolobenzodiazepines,
we
required
libraries
of
the
dimers
of
pyrrolobenzodiazepines for lead generation against certain disease targets,
particularly cancer. In continuation of earlier efforts in this laboratory on the
structural modifications of PBDs and their dimers we were interest to develop solidphase methodologies, particularly for the PBD dimers. The solid-phase synthesis of
PBD dimers such as DSB-120 and its C2-fluoro substituted analogues has been
carried out for the first time. It has been observed that in most solution-phase
XXII
SYNOPSIS
procedures for the preparation of PBD dimers there are problems relating to
solubility. Therefore, the development of solid-phase protocols for PBD dimers is of
immense importance and this could address the solubility difficulties encountered
during work-up.
The 4-hydroxy-3-methoxybenzaldehyde (vanillin) (21) has been oxidized
with sulphamic acid and sodium chlorite in ice-cold water to give 33. Further,
esterification followed by dimerization with dibromo alkanes in presence of K 2CO3
gave 35a-c. These 35a-c upon nitration with freshly prepared mixture of
SnCl4/HNO3, followed by subsequent reduction with SnCl2. 2H2O produce the
starting materials (37a-c) as shown in Scheme 8.
Scheme 8
HO
HO
i)
H3CO
OH
H3CO
CHO
21
33
HO
ii)
OCH 3
H3CO
O
34
O
iii)
O2N
H3CO
O
n
O
NO 2
OCH 3
OCH 3 H3CO
O
36a-c; n = 1-3
O
iv)
H3CO
O
n
O
OCH 3
OCH 3 H3CO
O
35a-c; n = 1-3
O
v)
H2N
H3CO
O
n
O
NH 2
OCH 3
OCH 3 H3CO
O
37a-c; n = 1-3
O
Reagents and conditions: i) NaClO2, sulphamic acid, H2O, 1 h, rt; ii) MeOH, H2SO4, reflux, 2 h;
iii) dibromo alkanes, K2CO3, DMF, 12 h, rt; iv) SnCl4/HNO3, CH2Cl2, -35 oC, 10 min; v) SnCl2. 2H2O,
MeOH, reflux, 5 h.
The starting materials (37a-c) have been treated with p-nitrophenyl carbonate
Wang resin (38) using 1-hydroxybenzotriazole (HOBt) and diisopropylethylamine
(DIPEA) in CH2Cl2:DMF (2:1) to give 39a-c. Hydrolysis of the methyl esters (39a-c)
afforded the corresponding acids in presence of 1N NaOH to give 40a-c. These have
XXIII
SYNOPSIS
O
Scheme 9
37a-c; n = 1-3
O
O
38
i
NO 2
O
O
HN
O
H3CO
O
O
n
O
NH
OCH 3
OCH 3 H3CO
O
O
39a-c; n = 1-3
O
ii
O
HN
O
HO
O
O
O
n
NH
OH
OCH 3 H3CO
O
O
HO
40a-c; n = 1-3
iii
41 R = H
NH 42 R = F
R
O
HO
O
HN
O
N
R
n
N
OCH 3 H3CO
N
R
iv
O
O
N
R
O
43a-f; n = 1-3
O
OH
NH
O
O
HO
H
O
O
O
n
O
O
N
OCH 3 H3CO
O
OH
H
N
R
O
44a-f; n = 1-3
v
N
H
N
R
O
n
O
N
N
OCH 3 H3CO
O
45a-c, R = H
45d-f, R = F
H
O
R
Reactions and conditions: i) HOBt, DIPEA, CH2Cl2:DMF (2:1) 6 h, rt; ii) 1N NaOH, 1,4-dioxane, 80
o
C,12 h; iii) EDCI, HOBt,15-24 h, rt; iv) DMSO, (COCl)2, Et3N, CH2Cl2, -78 oC, 2 h; v) TFA/CH2Cl2
(1:1), 2 h, rt.
XXIV
SYNOPSIS
-been coupled with 2-pyrrolidinemethanol (41) in the presence of EDCI and HOBt to
provide 43a-c. Similarly, 4-fluoro-2-pyrrolidinemethanol (42) has also been coupled
same as mentioned above procedure to give 43d-f. Swern oxidation of 43a-f then
gave 44a-f via an oxidative cyclization process in presence of COCl2 and Et3N.
Finally, the resins (44a-f) have been cleaved by using TFA/CH2Cl2 (1:1) to afford the
target products 45a-f via loss of the hydroxyl groups as shown in Scheme 9
(Tetrahedron Lett. 2006, 47, 6553-6556).
CHAPTER-IV
SOLID-PHASE COMBINATORIAL SYNTHESIS OF
ALKALOIDS (VASICINONE AND DEOXYVASICINONE)
FUSED
[2,1-b]QUINAZOLINONE
Combinatorial chemistry has become an extremely powerful technique for
the generation of drug-like small organic molecule libraries in medicinal chemistry
programmes. Solid-phase organic synthesis (SPOS) is especially useful in creating
large numbers of hit and lead compounds in combinatorial libraries for use in highthroughput screening. As a result, an increasing range and number of
pharmaceutically useful heterocyclic compounds have been prepared. In this
investigation, we have developed new solid-phase strategies for synthesizing
nitrogen-containing heterocyclic compounds based on fused [2,1-b]quinazolinones,
employing Wang resin and polymer-supported (PS) 4-nitrophenyl carbonate linkers.
Vasicinone is a fused [2,1-b]quinazolinone alkaloid isolated from the aerial
parts of Adathoda vasica Nees (family: Acanthacea; Sanskrit-Vasaka), which is an
evergreen subherbaceous bush used extensively in indigenous medicine for
treatment of colds, coughs, bronchitis and asthma. The leaves of this plant are rich in
essential oil and quinazoline alkaloids viz,. (–)-vasicinone, (–)-vasicine, vasicinolone,
deoxyvasicinone, vasicoline, adathaodine, luotonin A and anisotine. Vasicinone and
related alkaloids have also been reported to be present in other plants namely,
Peganum harmala and Sida cordifolia. Fitzgerald et al., isolated mackinazolinone and
XXV
SYNOPSIS
6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline,
analogues
of
vasicinone
and
vasicine analogues respectively from Mackinlaya macrosciadia and Mackinlaya subulata
of the family Araliaceae.
The present work describes the solid-phase combinatorial synthesis of fused
[2,1-b]quinazolinones including vasicinone for the first time on solid-phase, starting
from different anthranilic acids, substituted 2-azidobenzoic acid and coupling with
various lactams.
The lactams have been synthesized starting from γ-butyrolactone (1a) and δvelarolactone (1b). The synthesis involves use of red phosphorus and bromine at 80
C to obtain the corresponding tribromo compounds (2a,b) which upon treatment
o
with ammonia followed by cyclization using NaH afforded the 3-bromo-lactams
(4a,b) as shown in Scheme 1.
Scheme 1
O
O
i)
n
O
Br
n
Br
Br
Br
n = 1; 1a
n = 2; 1b
n
iii)
NH 2
Br
n = 1; 2a
n = 2; 2b
Br
O
ii)
n = 1; 3a
n = 2; 3b
n
O
N
H
n = 1; 4a
n = 2; 4b
Reagents and conditions: i) Red P/Br2, 0-80 oC, 3 h; ii) NH3, H2O/CHCl3, 10-30 oC, 1 h; iii) NaH,
THF, 0-10 oC-rt, 1 h.
A stirred solution of commercially available substituted anthranilic acids
(6a-c) have been coupled to the activated polymer-supported p-nitrophenyl
carbonate (5) (1.00 g, 0.93 mmol/g) by using 1-hydroxybenzotriazole (HOBt) and
diisopropylethylamine (DIPEA) in DMF-CH2Cl2 (1:2) to give 7a-c. Then 7a-c has
been coupled to different lactams (8a,b and 4a,b) using dicyclohexylcarbodiimide
(DCC) and catalytic amount of 4-dimethylaminopyridine (DMAP) in CH2Cl2 to
afford 9a,b; 10a,b and 11a-c; 12a-c. The solid-supported bromides have been reacted
with potassium acetate and catalytic amount of 18-crown-6-ether to afford acetates
(13a-c) and (14a-c). These upon deacetylation with K2CO3 in THF-MeOH (1:1) gave
XXVI
SYNOPSIS
15a-c and 16a-c. Finally, 9a,b; 10a,b and 15a-c; 16a-c have been treated with TFACH2Cl2 (1:1) for the effective cleavage from the resin followed by cyclization to
produce 17; 18a-b; 19a-c and 20, 21; 22 and 23 as shown in Scheme 2.
Scheme 2
O
O
O
R1
O
R2
O
X
OH
O
R1
NH 2
i)
R2
6a; R1 = H, R2 = H
6b; R1 = H, R2 = Cl
6c; R1 = OMe, R2 = OBn
NO 2
5
O
HN
R1
n
ii)
OH
8a; n = 1
8b; n = 2
NH
O
R2
X=H
7a-c
O
1
n
N
20; n
21; n
22; n
23; n
iii)
v)
O
N
n
R2
=1
=1
=2
=2
O
N
N
OH
R2
17
18a,b; n = 1
19a-c; n = 2
O
N
R2
R1
X
11a-c; n = 1
12a-c; n = 2 X = Br
O
O
n
9a,b; n = 1
10a,b; n = 2 X = H
v)
R1
NH O
4a; n = 1
4b; n = 2 X = Br
O
R
N
NH O
n
iv)
OH
O
O
15a-c; n = 1
16a-c; n = 2
R1
N
R2
NH O
n
OAc
O
O
13a-c; n = 1
14a-c; n = 2
Reagents and conditions: i) HOBt, DIPEA, CH2Cl2:DMF (2:1), 6 h, rt; ii) DCC, DMAP, CH2Cl2, 0 oC, 12 h, rt; iii)
KOAc, 18-crown-6-ether, CH3CN, 80 oC, 6 h or DMF, 8 h, rt; iv) K2CO3, THF:MeOH (1:1), rt, 6 h; v) TFA, CH2Cl2
(1:1), 2 h, rt.
Similarly, in Scheme 3 the compound 24 has been attached to bromomethyl
Wang resin (25) (1.0 g, 0.8-1.0 mmol/g) with Cs2CO3 and NaI. This upon hydrolysis
with 1N NaOH and coupling with 4a,b gave 27a,b as indicated by IR spectrum that
showed a strong azide peak in the range 2110 cm-1. Azides 27a,b have been cyclized
by
an
aza-Wittig
mediated
reductive-cyclization
approach
by
using
triphenylphosphine (TPP) in dry toluene to give 28a,b. Intermediates 28a,b have
XXVII
SYNOPSIS
been converted to 31a,b by employing reactions similar to those described in
Scheme 2. These transformations have been monitored by FT-IR spectroscopy of the
resin beads (Tetrahedron Lett. 2006, 47, 9025-9028).
Scheme 3
O
Br
H3CO
OCH 3
HO
O
O
H3CO
OH
25
O
i)
N3
HN
H3CO
O
n
N
n
ii)
4a; n = 1
4b; n = 2
N3
26
24
O
Br
N3 O
Br
27a; n = 1
27b; n = 2
iii)
O
H3CO
O
O
O
N
v)
H3CO
N
N
n
n
O
30a; n = 1
30b; n = 2
iv)
N
n
H3CO
O
N
OH
29a; n = 1
29b; n = 2
OAc
N
Br
28a; n = 1
28b; n = 2
vi)
O
H3CO
HO
N
n
N
31a; n = 1 OH
31b; n = 2
Reagents and conditions: i) (a) Cs2CO3, NaI, DMF, 24 h, rt; (b) 1N NaOH, 1,4-dioxane, 100 oC, 12 h; ii) DCC,
DMAP, CH2Cl2, 12 h, 0 oC-rt; iii) TPP, toluene, 3 h, rt; iv) KOAc, 18-crown-6-ether, CH3CN, 80 oC, 6 h or DMF,
8 h, rt; v) K2CO3, THF:MeOH (1:1), 6 h, rt; vi) TFA, CH2Cl2, (1:1) 1 h, rt.
XXVIII