2 Synopsis Title of the Thesis: Synthesis of Triazolylated Nucleosides, Coumarins and Coumarinyldihydropyrimidinones and Selective Biocatalytic Acylation & Antifungal Activity Studies on Coumarins. The thesis is divided into three chapters, i.e. Chapter I, Chapter II and Chapter III. Chapter II is further divided into two Sections, i.e. Section-A and Section-B. Chapter I: Synthesis of 3'-substituted Triazolylnucleosides Chapter II: Synthesis and Antifungal Activity of Novel Azido and 1,2,3-Triazole containing Coumarins & their Enzymatic Stereoselective Acylation Studies This Chapter is divided into two Sections: Section A: Synthesis and Antifungal Activity of Novel Azido and 1,2,3-Triazole containing Coumarins Section B: Enzymatic Stereoselective Acylation Studies on Novel Azido and 1,2,3-Triazole containing Coumarins Chapter III: Synthesis of Novel Coumarinyldihydropyrimidinones and their N-Acylates A brief account of each Chapter is given below: Chapter I Synthesis of 3'-substituted Triazolylnucleosides The copper (I)-catalyzed Huisgen-Sharpless-Meldal click reaction has gained significant importance because of its wide range of applications in the synthesis of drugs and drug like molecules, bioconjugates and useful materials. Further, triazolyl nucleosides, which can be
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2
Synopsis
Title of the Thesis: Synthesis of Triazolylated Nucleosides, Coumarins and
Coumarinyldihydropyrimidinones and Selective Biocatalytic Acylation
& Antifungal Activity Studies on Coumarins.
The thesis is divided into three chapters, i.e. Chapter I, Chapter II and Chapter III. Chapter II
is further divided into two Sections, i.e. Section-A and Section-B.
Chapter I: Synthesis of 3'-substituted Triazolylnucleosides
Chapter II: Synthesis and Antifungal Activity of Novel Azido and 1,2,3-Triazole containing
Coumarins & their Enzymatic Stereoselective Acylation Studies
This Chapter is divided into two Sections:
Section A: Synthesis and Antifungal Activity of Novel Azido and 1,2,3-Triazole containing
Coumarins
Section B: Enzymatic Stereoselective Acylation Studies on Novel Azido and 1,2,3-Triazole
containing Coumarins
Chapter III: Synthesis of Novel Coumarinyldihydropyrimidinones and their N-Acylates
A brief account of each Chapter is given below:
Chapter I
Synthesis of 3'-substituted Triazolylnucleosides
The copper (I)-catalyzed Huisgen-Sharpless-Meldal click reaction has gained significant
importance because of its wide range of applications in the synthesis of drugs and drug like
molecules, bioconjugates and useful materials. Further, triazolyl nucleosides, which can be
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generated using click reaction, are of special interest because of their pronounced biological
activities.
A very promising area for the preparation of new bioconjugates is the synthesis of
azidonucleosides. In general, azido analogs have been used mostly as intermediates in the
preparation of aminonucleosides. But discovery of 3'-azido-3'-deoxythymidine (AZT) as an
inhibitor of HIV reverse transcriptase triggered explosive developments in the synthetic
chemistry of azidonucleosides. In order to discover new derivatives potentially endowed with
biological activity, the copper-catalyzed azide/alkyne 1,3-dipolar cycloaddition reaction has
also been applied to the functionalization of sugar and base moieties of nucleosides. A
number of reports have demonstrated the potency of triazole linked nucleosides. Triazole
moiety can be linked on nucleoside at various positions such as 2', 3', 5' and also at anomeric
position of sugar part as well as base. Based on these compounds, the most common
application of the Cu-catalyzed azide–alkyne 1,3-cycloaddition reaction has been the
condensation of azido sugar moiety with various alkynes in order to form modified
nucleosides bearing a substituted 1,2,3-triazole. In this context, it has to be mentioned that the
potency of of all azido derivatives of nucleosides in such cycloaddition reactions has been
explored (Figure 1) except of 3'-azido-3'-deoxy-5-methyluridine.
Figure 1
Coumarin derivatives are widely used as fluorescent probes, labels and pigments,
laser dyes and signalling units in sensors. They are also attractive molecules due to their
extended spectral range, high emission quantum yields and photo stability.
In the present work, we have achieved the synthesis of a series of coumarin, aryl and
alkyl conjugated triazolylnucleosides by using click chemistry. One of the precursor moieties
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3'-Azido-3'-deoxy-5-methyluridine 8 required for the synthesis of the targeted compound was
prepared in seven steps from readily available D-xylose (Scheme 1). D-xylose (1) was
selectively protected as a monoketal, 1,2-O-isopropylidene-α-D-xylofuranose 2 in a two step
reaction in 90 % yield. The primary hydroxyl group of compound 2 was selectively protected
with benzoyl chloride and pyridine to produce the benzoyl derivative 1,2-O-isopropylidene-
5-O-benzoyl-α-D-xylofuranose 3 in 85% yields. In order to introduce a 3-azido group,
compound 3 was converted into 1,2-O-isopropylidene-5-O-benzoyl-3-O-
trifluoromethanesulfonyl-α-D-xylofuranose 4 by reaction with trifluoromethanesulfonic
anhydride in 85 % yield, which was subsequently converted into a 3-azido-1,2-O-
isopropylidene-5-O-benzoyl-3-deoxy-α-D-xylofuranose derivative 5 in approximately 45%
yield with sodium azide in DMF at 60 oC. The azide 5 was converted into 3-azido-1,2-di-O-
acetyl-5-O-benzoyl-3-deoxy-β-D-ribofuranose 6 in 75% yield as an epimeric mixture with
acetic acid, acetic anhydride in pyridine. The 3-deoxy-3-azidoribofuranoside 6 was then
coupled with thymine as base by using trimethylsilyl triflate as lewis acid (Vorbruggen
coupling) to afford the corresponding azido nucleoside 3'-azido-2'-O-acetyl-5'-O-benzoyl-3'-
deoxy-5-methyluridine 7 in 83 % yield. Removal of acetate and benzoate esters of the azido
nucleoside gave the key intermediate 3'-azido-3'-deoxy-5-methyluridine 8 in 79 % yield.
The mild reaction conditions and high fidelity of Cu (I)-catalysed process allowed the
1,3-dipolar cycloaddition of 3'-azido-3'-deoxy-5-methyluridine 8 with commercially available
alkynes phenylacetylene (9a), propargyl alcohol (9b) and 5-Chloro-1-pentyne (9c) by using
0.15 molar equiv. of CuI in mixture of THF: H2O:EtOH (1:1:1) solution at 60 oC to afford the