Synthesis of Natural Products by C-H Functionalization of Heterocycless

Abstract

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C-H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C-H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C-H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.

Keywords: C−H activation; C−H functionalization; heterocycles; natural products; total synthesis.

Figure 1.

Selected Natural Products Synthesized by C–H Functionalization of Heterocycles.

Scheme 1.

Synthesis of (–)-Deoxoapodine by Pd-catalyzed C–H Alkylation of NH-Free Indoles by Tokuyama.

Scheme 2.

Synthesis of (–)-Lundurines A–C by Pd-catalyzed C–H Vinylation of Indoles by Zhai.

Scheme 3.

Synthesis of (±)-Strychnocarpine by Pd-catalyzed C–H Aminocarbonylation of Indoles by Xia.

Scheme 4.

Synthesis of (±)-Leuconodines D and E by Pd-catalyzed Oxidative Heck C–H Functionalization of Indoles by Han.

Scheme 5.

Synthesis of (±)-Deschloro-12-epi-fischerindole W Nitrile by Pd-catalyzed Oxidative Heck C–H Functionalization of Indoles by Maji.

Scheme 6.

Synthesis of (±)-Rhazinilam by Pd-catalyzed Oxidative Heck C–H Functionalization of Pyrroles by Blanc.

Scheme 7.

Synthesis of Aaptamine by Pd-catalyzed Reductive Cyclization of Nitroarenes with 1-Vinyl-Quinolines by Lin.

Scheme 8.

Synthesis of Lapidilectine and Grandilodine Natural Products by Au-catalyzed C–H Hydroarylation of Indoles by Echavarren.

Scheme 9.

Synthesis of (±)-Raputindole A by Au-catalyzed C–H Hydroarylation of Indolines by Lindel.

Scheme 10.

Synthesis of Dictyodendrins by Au-catalyzed C–H Hydroarylation Cascade of Pyrroles by Ohno.

Scheme 11.

Synthesis of Arboridinine by Ir-catalyzed Photoredox C–H Alkylation of Indoles by Snyder.

Scheme 12.

Synthesis of Aspidosperma Alkaloids by Ru-catalyzed Photoredox C–H Alkylation of Indoles by Dixon.

Scheme 13.

Synthesis of (+)-Actinophyllic acid by Ru-catalyzed Photoredox C–H Alkylation of Indoles by Qin.

Scheme 14.

Synthesis of Raputimonoindoles B and C by Ir-catalyzed C–H Borylation of Furans by Lindel.

Scheme 15.

Synthesis of Stemona Alkaloids by Ru-catalyzed C–H Isomerization of γ-Butyrolactones by Dai.

Scheme 16.

Synthesis of Tubulysins V and U by Transition-Metal-Free Radical C–H Acylation of Thiazoles by Nicolaou.

Scheme 17.

Synthesis of Aspidosperma Alkaloids by 1,5-Hydrogen Atom Transfer of Piperidin-2-ones by Beaudry.

Scheme 18.

Synthesis of (–)-Roseophilin by Electrophilic C–H Alkylation of Furans by Liang.

Scheme 19.

Synthesis of (–)-Cephalotaxine and (–)-Homoharringtonine by Electrophilic C–H Alkylation of Furans by Beaudry.

Scheme 20.

Synthesis of Carbazomycin A by Electrophilic C–H Annulation of Indoles by Mehta.

Scheme 21.

Synthesis of (–)-(3R)-Inthomycin C by Direct C–H Deprotonation of Oxazoles by Donohoe.

Scheme 22.

Synthesis of Ajudazol A by Direct C–H Deprotonation of Oxazoles by Menche.

Scheme 23.

Synthesis of Tryprostatin B by Direct C–H Deprotonation of Indoles by Hossain.