Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

Abstract

Tandem reactions of Pd‐catalyzed cross‐coupling of 3‐(2‐isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich‐type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich‐type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich‐type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

“…Liu designed a novel approach on SPA‐catalyzed Mannich‐ type cyclization toward the formation of enantiomerically enriched pentacyclic spiroindolines (Scheme 60). [ 64 ] 15 mol% of ( S )‐ SPA 6 was the optimal Brønsted acid catalyst to form the target product with good yields and enantioselectivities (up to 71% yield, up to 86% ee). Generally, no electronic effect was observed on this Mannich‐type cyclization reaction, which afforded the corresponding products in good yields with moderate to high enantioselectivity.…”

Synthesis of Azepinoindoles via Pd-Catalyzed C(sp2)–H Imidoylative Cyclization Reactions

“…The Ugi-type reaction of 3-(2-isocyanoethyl)­indoles is based on the nucleophilicity of the isocyanic group toward polarized double bonds such as imines, isocyanates, and Michael acceptors as well as activated meso-aziridines to form highly reactive nitrilium ion species followed by dearomative nucleophilic attack of the indole moiety to deliver spiroindoline scaffolds gracefully. Liu and Ji reported the carbenoid coupling between 3-(2-isocyanoethyl)­indoles and diazoacetates/organic azides to assemble spiroindoline skeletons, respectively. In 2021, we developed a Pd-catalyzed imidoylative spirocyclization of 3-(2-isocyanoethyl)­indoles for the construction of spiroindolines through dearomative spirocyclization (Scheme a) .…”

Can “Easy” Chemistry Produce Complex, Diverse and Novel Molecules?

“…There is also the risk that important, difficult-to-make compounds are not made if chemists resort to making easy compounds "just because they can". 7 Complicated synthetic schemes like Mannich-type spirocyclization 8 and complex natural product total synthesis 9 are often considered laudable, while common reactions (e.g. amide-formations) are frequently looked down upon.…”