Synthesis of 2,3 -dideoxy-3 ,3 -gem-dic-alkyl pyranonucleoside analogues

Other Title(s)

تحضير مماثلات النيوكليوسيدات من نوع بايرانو-2،3-ثنائي ديوكسي-3، 3-التوأم-ثنائي-C-الكيل

Dissertant

al-Mumin, Thana Mahdi Abd al-Karim

Thesis advisor

al-Araji, Suad Mustafa
al-Fattahi, Yusuf Ali

University

University of Baghdad

Faculty

College of Science

Department

Chemistry Department

University Country

Iraq

Degree

Ph.D.

Degree Date

2007

English Abstract

Branched-chain sugar nucleosides are present in a wide range of both naturally occurring and synthetic products, some having biological activites such as antitumor, antiviral or antibacterial.

The key step in the total synthesis of these nuclosides is the stereocontrolled formation of a new C-C bond at the branching point.

The present work is the synthesis of new 2/, 3/-dideoxy-3/, 3/-gem-di-Calkyl pyrano nucleoside analogues.

The designed multisteps synthetic route to these nucleosides start with 4,6-O-benzylidene glucoside (106), prepared in one step from methyl-α- D-glucopyranoside (105), then p-toluenesultfonylation in pyridine afforded 2, 3-trans-ditosyl (107) which was selectively suitable to prepare allo-epoxy sugar (108) via intramolecular nucleophilic displacement, since it was readily opened by hydride anion using sodium borohydride gave the desired 2-deoxy sugar (109), oxidation of (109)with DMSOAc2O afforded the 3-keto sugar derivative (110).

Nucleophilic addition of three different compounds containing active methylene groups, nitromethane, 1,3-propanedinitrile (malononitrile) and 2,4-pentanedione (acetylacetone), to the keto sugar (110) using phase transfer conditions (PTC) gave, 3-C-nitromethyl (111) and 3-C-dicyanomethyl (147), sugar derivatives, while acetylacetone gave 3,3-di-C-diacetyl methyl (139) in one step.

Dehydration of (111) and (147) with DMSO-Ac2O afforded the, 3-C-nitromethylene (112) and 3-C-dicyanomethylene (148), derivatives respectively.

These derivatives are the key synthetic intermediates as Micheal acceptor.

Treatment of (112) with nitromethane, malononitrile and acetylacetone using PTC afforded different types of 2, 3-deoxy-3, 3-gem-di-C-alkyl carbohydrate derivatives 3, 3-di-C-dinitromethyl (113), 3-C-dicyanomethyl-3-C-nitromethyl (123) and 3-C-diacetylmethyl-3-Cxviii nitromethyl (131) respectively, similarly (148) gave, after treatment with malononitrile and acetylaceton; 3,3-di-C-dicyanomethyl (149) and 3-Cdiacetylmethyl- 3-C-dicyanomethyl (157) respectively, while the other gem-di-C-alkyl carbohydrate (139) was synthesized in previous step.

To prepare the nucleosides target, the branched chain sugars converted to their active form (1-bromosugar derivatives).

This convertion comprised the hydrolysis of 4, 6-O-benzylidene group of the prepared sugar derivatives to the corresponding diol (114), (124), (132), (150), (158) and (140) respectively, acetylation with acetic anhydride/acetic acid with low percents of sulfuric acid furnished the acetylated sugar (115) (125), (133), (151), (159) and (141) respectively, bromination with HBr in glacial acetic acid, forming 1-bromo sugars (116), (126), (134), (152) (160) and (142) respectively, which were subjected to condensation with theophylline mercury salt (117) to give acetylated nucleosides (119) (127), (135), (153), (161) and (143) respectively.

Deblocking of these nucleosides with sodium methoxide in methanol afforded our target the free nucleoside analogues type of (2/,3/-dideoxy-3/,3/- gem-di-C-alkylpyrono) theophylline, (120), (128), (136), (154), (162) and (144) respectively.

In a similar manner indole mercury salt (118) were condensed with 1-bromo sugar derivatives mentioned above to give acetylated nucleoside analogues (121), (129), (137), (155), (163) and (145) respectively, which upon hydrolysis afforded the target free nucleoside analogues as (2/,3/- dideoxy-3/,3/-gem-di-C-alkyl-pyrano)indole (122), (130), (130), (138), (156), (164) and (146)respectively.

The prepared compounds were identified by elemental analysis, specific rotation ([α]D) measurements and by spectroscopic methods: FT-IR, UV, 1H-NMR and 13C-NMR.

Main Subjects

Chemistry

No. of Pages

193

Table of Contents

• APA
• MLA
• AMA

Language

English

Data Type

Arab Theses

Record ID

BIM-600277