Design and synthesis of carbocyclic nucleoside inhibitors for methylthioadenosine/S-adenosyl homocysteine nucleosidase
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The aim of this project was to synthesize carbocyclic inhibitors for methylthioadenosine/S-adenosyl homocysteine (MTA/SAH) nucleosidase. This enzyme is present only in microbes. The human analogue called MTA phosphorylase, uses a similar substrate as MTA/SAH nucleosidase. However, structural studies have revealed significant differences between the microbial and human enzymes making the former an attractive pharmacological target. Two sets of inhibitors have been designed for MTA/SAH nucleosidase but both have serious drawbacks. Here, we synthesized carbocyclic nucleoside inhibitors for MTA/SAH nucleosidase taking advantage of a large hydrophobic region in the enzyme. The carbocyclic nucleosides overcome the drawbacks of the two inhibitors and in addition will be stable to phosphorylases. Some of the key reactions, which were used in the synthesis were ring-closing enyne metathesis, hydrogenation and the Mitsunobu reactions. The final products were achieved but with the wrong stereochemistry. The wrong stereochemistry was traced to the Crabtree catalyzed hydrogenated product. X-ray crystal structure of the Crabtree hydrogenated product indicated a counter directed product, which was also the minor. The major product formed from the Crabtree hydrogenation reaction was characterized to be a ketone, apparently formed from isomerization of the diene. The last chapter was devoted to studying the specific regiochemistry adopted by Grubbs type II (Rugen-2) when it reacts with enynes having allylic substituents. A mechanism for the ring-closing metathesis of such substrates has been proposed. Also it has been explained how ethylene could help facilitate ring-closing metathesis of such substrates.