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Abstract

Synthetic routes to several novel series of nucleoside analogues, bearing modifications at the 2'- and 3'-positions, are presented. Attempts at preparing 23'-dihalogenated uridine nucleosides are described first, followed by the application of various organometallic reactions, on both purine and pyrimidine nucleosides, to afford a number of 3'- and 2'-alkylated derivatives.

The preparation of a number of 2',3'-dihalogenated-23'-dideoxy-uridines was attempted by several routes but without success. Two majo^ side reactions were encountered which lead to 5'-O-trityl-3'-0-mesyl-0 ,2'- anhydro-uridine and 5'-0-trityl-2'-halo-2',3'-didehydro-2',3'-dideoxy-uridines. It proved possible to select the reaction conditions, so as to afford either one of the above two types of compounds as the sole product, in good overall yield. The 5'-0-trityl-2'-halo-2',3'-didehydro-2',3'- dideoxy-uridines are a class of compounds which have received limited attention in the literature, therefore a study of their reactions was undertaken (see below).

The application of some organometallic reactions on a uridine- 2' , 3-lyxo-epoxide, to give 3-alk.ylated-3' -deox.y-ara-uridines, in good overall yields from uridine, is described. The use of three types of organometallic reagents was explored. These were the organolithiums, Grignards and lithium dialkylcuprates, which lead to the direct introduction of an alkynyl, alkenyl and alkyl side-chain respectively, at the 3'-position of the uridine molecule. Attack was shown to occur predominantly at the 3'-position by n.m.r. techniques. A limited amount of attack at the 2'-position was noted in most of the epoxide-opening reactions to yield a 2'-alkylated-2'-deoxy-xylo-uridine, although it proved possible to isolate this minor product in only one case. Attack at C-6 of the uridine molecule was observed only when the uridine-2',3'-lyxo-epoxide was treated with lithium 1,3-dithian-2-yl, in which case it was the sole course of reaction. With the most basic organometallic reagents (e.g. butyl lithium), abstraction of the l'-proton occured to give a 1',2'-unsaturated nucleoside. Some of the 3'-alk.ylated-3'-deox.y-ara-uridines were converted to the corresponding ara-c.ytidine, ara-thymidine and 5-halo-ara-uridine derivatives by known methodology. A brief investigation of the reactions of the 3'-unsaturated side-chains (e.g. hydrogenation, hydroboration and epoxidation) is described. An attempt at inverting the configuration at 02', in 5'-O-trityl-3'-ethynyl-2'-0-mesyl-3'-deoxy-ara-uridine was made. However, the sole product of reaction, isolated in high yield, was 5'-O-trityl-3'-ethynyl-2',3' didehydro-2',3'-dideoxy-uridine.
Some reactions of the 5'-0-trityl-2'-halo-2',3'-didehydro- 2*,3'-dideoxy-uridines (mentioned earlier) were explored. A variety of electrophilic reagents (e.g. MCPBA, BH^, Br2) did not react with the 2',3'-double bond. However, the 2'-bromo analogue reacted with lithium dimethylcuprate to undergo metal-halogen exchange and give a 2'-lithiated derivative. This could be protonated, to afford 5'-0-trityl-2',3'- didehydro-2',3'-dideoxy-uridine, as well as alkylated (with Mel) to give 5'-O-trityl-2'-C-methyl-2',3'-didehydro-2',3'-dideoxy-uridine; both obtained in good yield. Application of this reaction to the 2'-chloro analogue afforded the above mentioned 2'-C-methyl derivative, together with 5'-0-trityl-2'-keto- 3'-deoxy-uridine. A mechanism by which the latter two compounds might arise from a common intermediate is presented.

Finally, the application of some organometallic reactions on a 5'-protected adenosine-2',3'-lyxo-epoxide is described. This lead to a good synthetic route to 3'-methyl-3-deoxy-ara-adenosine from ara-adenosine.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science Q Science > QD Chemistry
Departments:	School of Science & Technology School of Science & Technology > School of Science & Technology Doctoral Theses Doctoral Theses

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