Journal of Organic Chemistry 2003-02-21

Total synthesis of (s)-(+)-citreofuran by ring closing alkyne metathesis.

Alois Fürstner, Anne-Sophie Castanet, Karin Radkowski, Christian W Lehmann

Index: J. Org. Chem. 68(4) , 1521-8, (2003)

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Abstract

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)(3)W[triple bond]CCMe(3) 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.