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.
A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).
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