Homo-Mannich Reaction of Cyclopropanols: A Versatile Tool for Natural Product Synthesis

The Mannich reaction, involving the nucleophilic addition of an enol(ate) intermediate to an imine or iminium ion, is one of the most widely used synthetic methods for the synthesis of β-amino carbonyl compounds. Nevertheless, the homo-Mannich reaction, which utilizes a homoenolate intermediate as the nucleophilic partner and provides straightforward access to the valuable γ-amino carbonyl compounds, remains underexplored. This can be largely attributed to the difficulties in generation and manipulation of the homoenolate species, despite various homoenolate equivalents that have been developed. Among the homoenolate equivalents developed, cyclopropanol stands out due to its intriguing reactivities endowed by the highly strained cyclopropane. Upon activation by a metal, cyclopropyl alcohol is prone to undergo an endocyclic C(sp³)–C(sp³) bond cleavage to give a homoenolate intermediate or a β-keto radical intermediate, which sets the stage for a diverse range of transformations. This account outlines our recent progress in the development of homo-Mannich reaction of cyclopropanol and its applications in natural product total synthesis. This new methodology can be classified into two subtypes: 1) the homo-Mannich reaction of cyclopropanol with imines or iminium ions and 2) the homo-Mannich-type reaction of cyclopropanol with heteroarenes. Through different ways to generate imines or iminium ions, tandem or sequential reactions of C–H oxidation/homo-Mannich, Bischler–Napieralski/homo-Mannich, and asymmetric allylation/homo-Mannich have been developed, leading to the rapid assembly of core scaffolds of sarpagine, koumine, ibophyllidine, Aspidosperma, Melodinus, and Kopsia alkaloids. Besides the reactions with imines or iminium ions, cyclopropyl alcohol can undergo ring-opening addition to indole and pyrrole rings to deliver core scaffolds of schizozygane and indolizidine alkaloids. Based on these methodology advancements, we have accomplished the asymmetric synthesis of 29 alkaloids belonging to 8 families. In this Account, we present a complete picture of our works concerning synthetic design, method development, and applications in natural product total synthesis. It is anticipated that the development of new methodologies of cyclopropyl alcohol will find broad applications in the realm of natural product synthesis.