A mild and efficient synthesis of oxindoles: progress towards the synthesis of welwitindolinone A isonitrile.

Recently, Moore and co-workers reported the isolation and structural elucidation of several oxindole-containing natural products from blue-green algae. Termed the welwitindolinones, this structurally intriguing class of alkaloids displays diverse and valuable biological properties, including multiple drug resistance (MDR) reversing, insecticidal, and antifungal activities. To date, ten congeners have been identified, nine of which contain a 3,4-bridged oxindole core as exemplified by N-methyl welwitindolinone C isothiocyanate (1). Welwitindolinone A isonitrile (2) accounts for the antifungal activity associated with the extracts and is the proposed biosynthetic precursor to welwitindolinones B–D. Motivated by its antifungal activity, topological complexity, and the possibility of accessing other welwitindolinones (e.g. 1), we targeted 2 for total synthesis. Herein we report a novel method for the preparation of spiro-oxindoles and its application in a synthesis of an advanced intermediate that contains the complete welwitindolinone A carbon framework. Recognizing that the sensitive vinyl isonitrile region found in 2 could potentially derive from a ketone, we began devising a synthetic approach that targeted 3 as a key intermediate (Scheme 1). For the construction of 3 we envisioned routes that, in a retrosynthetic sense, involved disconnection of either the C3 Caryl bond (Scheme 1, bond a), or the C3 Ccarbonyl bond (bond b). Although ring formation by closure of bond a (i.e., 4 ! 3) was well precedented in either radical or metal catalyzed modes, concern over the thermal stability of the proposed cyclobutene intermediate and the likelihood that bond formation would occur on the convex face (thus delivering the incorrect stereochemistry at C3) led us to focus on strategies involving formation of bond b (i.e., 5!3). To this end, Pd-catalyzed carbonylative cyclization of aniline 5a (R=NH2) [5] or radical cyclization of isonitrile 5b (R=NC) held potential; however, remaining