Synthesis of (–)-N-Methylwelwitindolinone B Isothiocyanate

Key words

welwitindolinone alkaloids - chlorination - nitrenes - C–H insertion - kinetic isotope effect - Burgess reagent - Schwartz’s reagent

Significance

The family of the welwitindolinone natural products represents a formidable challenge for synthetic chemists. Structurally, the majority of these molecules consist of an indolinone imbedded into a [4.3.1]bicycle. While several efforts towards the synthesis of congeners have been reported to date, the challenge of (–)-N-methylwelwitindolinone B isothiocyanate has not been met. This compound is unique due to the ­alkyl chloride, which has been found to undergo various side reactions. The approach presented by Garg and co-workers relies on a chlorinative oxabicyclic ring opening culminating in the first ­total synthesis of the target molecule.

 

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Comment

The synthesis commenced with ­ketone A, which was generated using an elegant indoline cyclization (J. Am. Chem. Soc. 2011, 133, 15797; Synfacts 2011, 7, 1281). Diastereoselective reduction, followed by ring closure, generated oxabicyle B. The subsequent BCl₃-mediated chlorinative ring opening proved to be efficient only when the vinyl group was first converted into an aldehyde. Carbamate E, obtained in a few steps, underwent nitrene C–H insertion under conditions previously reported. Finally, carbamate cleavage, oxidation, dehydration, and sulfurization delivered (–)-N-methylwelwitindolinone B isothiocyanate.

 

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