Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing Thiophenol-N-Iodosuccinimide Leads to 4′-Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins on the Basis of Substitution of the Phenylsulfanyl Leaving Group

Upon reaction of the 3′,4′-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4′-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N 6-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4′-α-alkoxycordycepins 15a–21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4′-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon–carbon bond construction was also applicable to 7, giving 4′-α-allylcordycepin (24a) and 4′-α-cyanoethylcordycepin (25) derivatives.