Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition

Abstract

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.

Scheme 1. Design of a Complex Tetracyclic Scaffold on the Basis of Fragments Derived from Azepino/Cycloheptaindoles and Pyrrolidine-Containing Natural Products

Scheme 2. Scope of the (3 + 2) Cycloaddition of Indole-2-carbaldehydes

Reactions were carried out on 0.03–0.3 mmol scale, and combined isolated yields were reported unless otherwise stated. Scale-up: 1 mmol. Minor diastereomer was not isolated. Reaction was performed at 60 °C. Unseparable mixture of diastereomers.

Scheme 3. (3 + 2) Cycloaddition of Nitrone-Containing Substrates

Scheme 4. (3 + 2) Cycloaddition of In Situ Generated Nitrile Oxide-Containing Substrates