New aromatic annulation reactions and their application in total synthesis

Abstract

A new benzannulation reaction involving a tandem Horner-Emmons and Claisen condensation sequence was developed and applied to the syntheses of six arylnaphthalene ligands:  taiwanin C, justicidin E, chinensin, retrochinensin, justicidin B and retrojusticidin B.

The tin-mediated addition of aryl radicals to various electron-rich condensed heterocycles was also investigated, 5-Exo-trig additions of N-tethered aryl radicals to indoles were demonstrated and shown to be more efficient when the radical intermediate was flanked by substituents.

Addition of aryl radicals to C-2 and C-3 of indoles, benzo[b]thiophenes and benzo[b]furans were also studied and the course followed found to be strongly influenced by the nature of the constituent heteroatom. When as cis-alkene was used to tether the arene to the heterocycle a 6-endo-trig radical cyclisation pathway was followed, leading to the corresponding polyaromatic system.  A notable exception arose when the aryl radical was tethered to C-3 of a benzo[b]thiophene or benzo[b]furan.  In such cases, an addition-elimination-reduction pathway dominated, yielding the corresponding 2-(2-naphthyl)-(thio)phenol.

With an alkane or benzyl ether as the tether, cyclisations generally proceeded via 5-exo-trig addition of the aryl radical to the tethering carbon.  However, with benzo[b]furans and N-acetyl indoles, C-3 tethered aryl radicals preferentially underwent 6-endo-trig addition to C-2 of the heterocycle in a reductive fashion.  A total synthesis of demethylhomopterocarpin using this methodology is described.

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