Asymmetric Syntheses of Stavudine (d4T) and Cordycepin by Cycloisomeri/ation of Alkynyl Alcohols to Endocyclic Enol Ethers

摘要

Various deoxynucleosides show potent antiviral activity, particularly against the human immunodeficiency virus (HIV), which is the causative agent for acquired immunodeficiency syndrome (AIDS). Stavudine (2,3'-didehydro-3'-deoxythymidine; d4T) retainsthe high antiviral activity of 3'-azido-3'-deoxy-thymidine (AZT) while exhibiting significantly lower bone marrow loxicity and reduced inhibition of mitochondrial DNA synthesis. Cordycepin (3'-deoxyadenosine) has been widely used as a probe for messenger RNA transcription and also exhibits antibiotic activity. These compounds have been clas-siealh prepared by functional group manipulation of naturally occurring ribo- and 2'-deoxyribonudeosides or from carbons-draie precursors. but more recently the synthesis of d4T has been reported from amino acid precursors. We envisioned that a shorter synthesis of deoxynucieosides might he obtained bv molybdenum pentacarbonyl catalyzed cxcloisoinerization of acvclic alkynyl aicohols to end'icyclic enol ethers. Given the p-adv availabiliu of chiral nonruceir.ic alkvnyl alcohols from achiral precursors as well as the demonstrated utility of endocvclic enol ethers in the synthesis of glvcasides and nu-cleosides. we set otit to establish the viability of the cy-cloisomerizatipn strategy for asymmetric synthesis of deoxynu-cleosides.