Toward the Synthesis of Daphniphyllum Alkaloids using Radical Chemistry

Abstract

The manuscript of this Doctoral Thesis has been divided into five main parts: a general introduction into the calyciphylline A-type alkaloids followed by three research chapters and conclude by a review about the radical cyclization of trichloroacetamides.

The general introduction provides an overview of the calyciphylline A-type alkaloids, the partial syntheses previously reported and as well as the group precedents in the field of the calyciphylline A-type alkaloids.

The second chapter titled “Toward the Synthesis of Calyciphylline A-type alkaloids” describes our synthetic efforts toward the calyciphylline A-type alkaloids with a new synthetic approach. The synthesis started from the cyclohexanedione monoethylene acetal, followed by the 5-endo-trig radical cyclization of trichloroacetamides using Bu3SnH and AIBN as the initiator to give access to 3a-methyloctahydroindoles, the cornerstone of our strategy. After derivatization, several advanced tricyclic intermediates (ABC and ACD ring systems) were synthetized using Pd a-alkenylation of enolates, radical cyclization of trichloroacetamides and aldol condensation. Further functionalization allowed the synthesis of the tetracyclic ABCD ring core of calyciphylline A-type alkaloids via a 6-exo radical cyclization of a trichloroacetamide upon an enol acetate embedded in a tricyclic synthetic intermediate.In summary, it highlights the synthetic usefulness of radical cyclization procedures in structural demanding substrates with the formation of carbon-carbon bonds using dichloromethylcarbamoyl radicals upon electron-rich acceptors.

The third chapter titled “Radical Cyclization in the Synthesis of cis-3-Methyloctahydroindol-6-ones” describes a generalization of the 5-endo-trig radical cyclization of trichloroacetamides to other haloacetamides and enynes showing the versatility of this process. It allowed an express synthesis of cis-3-methyloctahydroindoles, a motif embedded in. yuzurimine- and daphniglaucine-type alkaloids, by 5-endo-trig radical cyclizations of alkynes or methylhaloacetamides. The results obtained were interesting from the mechanistic point of view, since some unexpected reaction pathways were found in the radical cyclization processes. This project was performed in collaboration with Sergi Jansana.

The fourth chapter titled “Synthesis of a-Chlorolactams by Cyanoborohydride-Mediated Radical Cyclizations of Trichloroacetamides” describes a new methodology to access a-chlorolactams in a simple and an efficient way using cheap NaBH3CN and

easily available allylic and homoallylic secondary amines as starting materials. The standard conditions favored the diastereoselectivity toward the formation of the thermodynamic trans a-chlorolactam products and can be applied to non-activated, electron rich or electron poor alkenes. The process can be performed in a gram scale.

And this methodology allowed the synthesis of a library of compounds sent for biological testing. This project was performed in collaboration with Bayer CropScience (Frankfurt am Main, Germany) under the supervision of Dr. Stephen Lindell and Dr. Harald Jakobi.

The fifth chapter titled “Radical Cyclization of Trichloroacetamides: Synthesis of Lactams” gathers all the published results and methodologies involving trichloroacetamides in radical chemistry. Trichloroacetamides can act as radical precursors to synthesize nitrogen-containing heterocycles such as β-, γ-, and δ-lactams which are highly useful building blocks in the synthesis of nitrogen-containing natural products and bioactive molecules, in a variety of processes, mainly involving atom transfer radical cyclizations (ATRC), mediated by Cu(I) or Ru(II) catalysts, and the hydride reductive method, employing either Bu3SnH or (Me3Si)3SiH, or recently NaBH3CN. Additionally, amine-mediated single electron transfer cyclizations, as well as radical processes promoted by Ni, Fe, Mn, Ti, and Ag, have been developed.