Synthetic Explorations to Sinefungin Analogs
Type of DegreeDissertation
DepartmentChemistry and Biochemistry
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Sinefungin, a natural complex nucleoside, has been isolated from the cultures of Streptomyces griseolous, and from that of Streptomyces incarnatus. It is a structural analog of S-adenosylmethionine (AdoMet) and since its discovery, its biological activities have been thoroughly studied, including antifungal, antitumor, antiparasitic, antiviral and amoebicidal activities. The nature of these biological activities results from its inhibition of a variety of AdoMet-dependent methyltranferase enzymes. These methylation reactions are crucial in many biochemical processes, including virus-encoded mRNA cap methyltransferases, of which sinefungin is a selective inhibitor. As a consequence of the latter observation, sinefungin and related compounds have attracted the attention of synthetic chemists in the design of antiviral chemotherapeutic agents. However, the clinical usefulness of sinefungin has been precluded by its toxicity in in vivo assays. To seek a novel approach to toxic-free sinefungin-based compounds, the main body of this dissertation research considers the design and possible synthetic routes to the analog of carbocyclic sinefungin (target I) and related intermediates (47, 53, 55 and 79, 81, 86) for other sinefungin-based compounds. In this research, the key synthetic steps that have been investigated are the installment of the C-6' and C-9' stereocenters by efficient asymmetric synthetic methods. In the C-6' case, a highly diastereoselective allylborating agent, (+) and/or (-)-B-allydiisopinocampheylborane (Ipc2BCH2CH=CH2) has been called forth. The requisite C-9' amino acid stereochemistry has been established by alkylation reactions with the Schöllkopf reagent. Finally, coupling of cyclopentyl or ribosyl units with the heterocyclic base (adenine) has been evaluated by standard SN2 substituted reactions. These synthetic approaches are adaptable to a number of structural investigations relevant to analogs of carbocyclic sinefungin and the parent sinefungin.