Weires NA, Styduhar ED, Baker EL, Garg NK * University of California, Los Angeles,
USA
Total Synthesis of (–)-
N-Methylwelwitindolinone B Isothiocyanate via a Chlorinative Oxabicycle Ring-Opening
Strategy.
J. Am. Chem. Soc. 2014;
136: 14710-14713
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.
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.
