Stereoselective Synthesis of Fluoro-homoneplanocin A as a Potential Antiviral Agent

Abstract

Neplanocin A is one of the representative carbocyclic nucleosides that inhibit S-adenosylhomocysteine (SAH) hydrolase (EC 3.3.1.1). The inhibition of SAH hydrolase, causes accumulation of SAH within the cell, which results in inhibition of S-adenosyl-L-methionine (SAM)-dependent-transmethylase. Because SAM-dependent trans-methylase is essential for the formation of the capped methylated structure at the 5’-terminus of viral mRNA, SAH hydrolase is an attractive target for the development of broad-spectrum antiviral agent. However, the development of neplanocin A as a clinical agent was restricted due to its high cytotoxicity after phosphorylation. On the other hand, fluoro-neplanocin A, based on the structure of neplanocin A showed two times more potency, whilst another derivative, homoneplanocin A, a one-carbon homologated analog of neplanocin A, also exhibited potent inhibitory activity against SAH hydrolase. Based on the known discoveries, and on the search for new compounds which can be potential antiviral agents, fluoro-homoneplanocin A (4), which combines the properties of fluoro-neplanocin A (2) and homoneplanocin A (3) was designed and synthesized. In the synthesis of the target nucleoside, the enyne ring-closing metathesis (RCM), nucleophilic fluorination to epoxide, and simultaneous oxidation-elimination reactions were carried out as the key steps for the synthesis. ;SAH hydrolase를 효과적으로 억제하여 항바이러스 효과를 나타내는 neplanocin A에서부터 유도된 fluoro-neplanocin A와 homoneplanocin A의 두가지 성질을 모두 가지고 있을것으로 예상되는 fluoro-homoneplanocin A를 합성하였다. 합성과정에서 중요한 유도체서의 역할을 하는 cyclopentenol은 에틸렌 가스를 사용하는 enyne ring closing metathesis (RCM)으로 합성되었다. 이어서 선택적 epoxidation으로 fluorine을 유도체에 합성할 수 있었고, 연속적인 산화-환원 반응을 이용하여 선택적인 산화반응을 이끌어내어 뉴클레오사이드로 합성되기 위한 sugar form을 합성하였다