1, 5-Radical Translocation Approach To The Spironucleosides-Synthesis And Structure Study

Chapter one provides the background and significance of the thesis. Diseases of cancer and virus infection are life threatening with unmet needs in therapeutical treatment until now. With the recent advances in understanding molecular biology of the diseases, researches for new drugs with more potency and lower toxicity have been made impressive progresses. In particular, nucleoside derived drugs have played an essential role in therapy against epidemical diseases caused by virus infection. The development of methodologies for nucleoside synthesis and pharmacological study of the modified nucleosides have continueously been an important and promising area in drug discovery arena.Chapter two reviews the research progresses and the synthetic methods of spironucleosides in the literature. Introduction of cascade of radical translocation/cyclization reactions and methods for the preparation of spiro-compounds including a few examples of spironucleosides are summarized. Finally, we outline the ideas behind our interests of spironucleoside in synthesis and biological study.Most of nucleoside drugs on the market or drug candidates in clinical phases structurally belong to a category of modified nucleosides on sugar moiety. However, the modifications combined with spiro ring are rare, presumably due to the difficulty in synthesis. The spiro ring in spironucleosides shall have notable effects on the conformation of furanose and will produce profound impact toward their pharmacological profile. Some stimulate results from biological tests of spironucleoside have been revealed. Several synthetic methods have been developed for the preparation of these nucleoside analogues, including: 1) radical reaction; 2) nucleophilic addition or nucleophilic substitution reaction; 3) glycosididation between ribose and nucleobase; 4) condensation/polymerization reaction. Among those methods, 1, 5-radical translocation reaction which has extensive application in the synthesis of natural products with unusual structural features has not been explored in the synthesis of 2′, 3′, 4′-spironucleosides. Therefore, the research work in this thesis is to synthesize those spironucleosides and to study their molecular structure and biological activity.Chapter three deals with our research on the development of a new method for the preparation of 2′, 3′, 4′-spironucleosides via cascade of 1, 5-radical translocation/cyclization reaction. Through intensive examination under different conditions (such as changing solvent, temperature, concentration, bases, ratio of radical precursor and radical initiator in radical reactions), we find a novel synthetic method for the construction of spironucleosides by cascade radical translocation cyclization of N-allyl-N-(2′-bromophenyl) amide of 5′-carboxylic nucleoside derivatives and of the N-propynyl analogues.Thus, proper 5′-carboxylic acids of hydroxyl protected nucleosides were coupled with 2-bromo- or 4-methoxy-2-bromoaniline followed by N-alkylation with allyl bromide or propynyl bromide to afford radical precursors. This general synthetic method was introduced by us the first time. The precursors were then treated with tri-n-butyltin hydride in the presence of 2, 2′-azo-bis-iso-butyronitrile as radical initiator to lead 5-exo-trig or 5-exo-dig cascade cyclization via of 1, 5-radical translocation reaction, forming the desired 4′-spironucleosides alone with amount of byproduct from direct cyclization of primary aryl radical and unsaturated bond.For expansion of the methodology described above for the synthesis 2′, 3′- spironucleosides, many attempts have been made with different radical precursors in our research. Unfortunately, we could not achieve any successful outcome so far. Appropriate radical precursors and proper reaction conditions for the synthesis of 2′and 3′spironucleosides need to be investigated in the future.The synthesized 4′-spironucleosides 3-42a and 3-42b were fully characterized by ¹H NMR, ¹³C NMR, NOE, COSY and LC-MS. Compounds of 4′-spironucleosides 3-43, 3-44, 3′-spironucleosides 3-74 and byproducts 3-41 and 3-45 were characterized by ¹H NMR, ¹³C NMR and LC-MS. The structures of spironucleosides, by-products and the intermediates have been elucidated based on analytical data.The biological tests of the spironucleosides are to be investigated in the near future.