No abstract

The Petasis-type reaction, which couples an imine and boronic acid, is an important tool for CÀ C bond formation in organic synthesis. However, the generality of this transformation has been limited by the requirement for a directing heteroatom to enable reactivity. Herein, we report the development of a nondirected Petasis-type reaction that allows for the coupling of trifluoroborate salts with α-hydroxyindoles. By disrupting aromaticity to generate a reactive iminium ion, in conjunction with using trifluoroborate nucleophiles, the method generates a new CÀ C bond without the need for a directing group. This reaction is operationally simple, providing α-functionalized indoles in up to 99 % yield using sp, sp 2 , and sp 3 -hybridized trifluoroborate nucleophiles. Finally, this reaction is applied as a novel bioconjugation strategy to link biologically active molecules and toward the convergent synthesis of non-natural heterodimeric bisindole alkaloid analogs.

Strempeliopidine is a member of the monoterpenoid bisindole alkaloid family, a class of natural products that have been shown to elicit an array of biological responses including modulating protein−protein interactions in human cancer cells. Our synthesis of strempeliopidine leverages palladium-catalyzed decarboxylative asymmetric allylic alkylations to install the requisite allcarbon quaternary centers found in each of the two monomeric natural products, aspidospermidine and eburnamine. Initial studies employing Suzuki−Miyaura cross-coupling followed by diastereoselective hydrogenation provided evidence for a structural reassignment of the natural product. Our final synthetic sequence employs a diastereoselective Petasis borono−Mannich reaction to couple eburnamine to a trifluoroborate aspidospermidine derivative. These convergent approaches enabled the synthesis of eight diastereomers of this heterodimer and offer support for the reassignment of the absolute configuration of strempeliopidine.

The Petasis‐type reaction, which couples an imine and boronic acid, is an important tool for C−C bond formation in organic synthesis. However, the generality of this transformation has been limited by the requirement for a directing heteroatom to enable reactivity. Herein, we report the development of a non‐directed Petasis‐type reaction that allows for the coupling of trifluoroborate salts with α‐hydroxyindoles. By disrupting aromaticity to generate a reactive iminium ion, in conjunction with using trifluoroborate nucleophiles, the method generates a new C−C bond without the need for a directing group. This reaction is operationally simple, providing α‐functionalized indoles in up to 99 % yield using sp, sp2, and sp3‐hybridized trifluoroborate nucleophiles. Finally, this reaction is applied as a novel bioconjugation strategy to link biologically active molecules and toward the convergent synthesis of non‐natural heterodimeric bisindole alkaloid analogs.