An unexpected C–C bond cleavage was observed in trichloroacetamide-tethered ketones under amine treatment and exploited to develop a new synthesis of normophans from 4-amidocyclohexanones. The reaction involves an unprecedented intramolecular haloform-type reaction of trichloroacetamides promoted by enamines (generated in situ from ketones) as counter-reagents. The methodology was applied to the synthesis of compounds embodying the 6-azabicyclo[3.2.1]octane framework.

Synthesis of the tetracyclic cores of madangamines D–F was achieved, featuring a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.

The ABC-ring system of calyciphylline A-type alkaloids has been synthesized. The key steps of the synthetic approach are an atom transfer radical cyclization of a trichloroacetamide upon an enol acetate to generate the B ring, and a sulfone-based conjugated addition upon a β-methyl-α,β-unsaturated ketone to give the target azatricyclic ketone. Selecting the cation (K+ or Cs+) of the carbonate in the C ring-forming intramolecular Michael addition gives stereodivergent access to both epimers of the cyclized product.

Intramolecular Kharasch-type additions of trichloroacetamides on anisole and enol acetates catalyzed by Grubbs’ ruthenium carbenes are described. This protocol provides access to highly functionalized 2-azaspiro[4.5]decanes, morphan compounds, and the azatricyclic core of FR901483.

An atom transfer radical dearomatizing spirocyclization from N-benzyltrichloroacetamides using CuCl regioselectively leads to 2-azaspiro[4.5]decadienes, in which the labile allylic chlorine atom is easily replaced by a hydroxyl group in aqueous medium or by quenching with methanol or allylamine. After oxidation of the target compound, the N-tert-butyl group can be removed from the resulting spirocyclohexanedienone.

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.

The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.

The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.