The Wood Synthesis of Welwitindolinone A Isonitrile

Welwitindolinone A Isonitrile 3 is the first of a family of oxindole natural products isolated from the cyanobacteria Hapalosiphon welwischii and Westiella intricate on the basis of their activity for reversing multiple drug resistance (MDR). A key transformation in the total synthesis of 3 reported (J. Am. Chem. Soc. 2008,130, 2087) by John L. Wood, now at Colorado State University, was the chlorination of 1, that in one step established both the axial secondary chloro substituent and the flanking chiral quaternary center. 

The starting material for the s mthesis of 3 was the diene acetonide 5, readily prepared from the Birch reduction product 4. Intermolecular ketene cycloaddition proceeded with high regio- and diastereoselectivity, to give the bicyclooctenone 6. 

Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by P-ehmination gave the enone 13. Direct reductive amination of 13 failed, hut reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3. 

The starting diene 5 used in this synthesis was prochiral, leading to racemic 3. Now that the route to 3 is established, it would he interesting to devise a method for preparing enantiomerically-enriched 6. EnantiomericaUy-pure variants of 5 have been prepared, inter alia by fermentation of halogenated aromatics. Alternatively, an enantioselective version of the [2-1-2] cycloaddition to the prochiral 5 could be developed. 

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