Total Synthesis of (<i>S</i>)-(+)-Citreofuran by Ring Closing Alkyne Metathesis

A concise total synthesis of citreofuran 4 is described, a structurally unique octaketide derivative belonging to the curvularin family. Key steps involve the elaboration of orsellinic acid methyl ester 5 to acid 14, which converts, on attempted formation of the corresponding acid chloride, to the 3-alkoxyisocoumarin derivative 20. This heterocycle can be used as an activated ester to give ketone 21 on treatment with 3-pentynylmagnesium bromide in the presence of TMSCl as the activating agent. Ring- closing alkyne metathesis (RCAM) of diyne 21 catalyzed by (tBuO)3W⋮CCMe3 affords the strained cycloalkyne 22. Treatment with acid renders its triple bond susceptible to nucleophilic attack by the adjacent carbonyl group, thus leading to a transannular cycloaromatization with formation of the intact skeleton of citreofuran. An X-ray crystallographic study reveals conformational details about this natural product. Finally, it is shown that 4 as well as its protected precursor 23 are able to cleave double-stranded DNA under oxidative conditions.