Inverse α-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities

Abstract

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of β,δ′-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the “stereoelectronic frustration” of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

Cascade Assembly of Bridged N-Substituted Azaozonides: The Counterintuitive Role of Nitrogen Source Nucleophilicity

“…For example, 11-aza-artemisinin and 6-aza-artemisinin (Scheme A) can be more potent than artemisinin. , However, the synthesis of azaperoxides remains challenging as illustrated by the >40-year delay between the discovery of natural azaperoxides verruculogen and fumitremorgin A and their total synthesis by Baran’s group . Recently, we expanded access to bridged and tricyclic aminoperoxides (Scheme B) via cascade condensations of di- and tricarbonyl precursors using ammonia and ammonium salts as the N components. , Paradoxically, the peroxide moiety offers the NH moiety intramolecular protection against electrophiles and oxidants by depleting nitrogen electron density via stereoelectronic n N → σ* CO interactions.…”

“…17 Recently, we expanded access to bridged and tricyclic aminoperoxides (Scheme 1B) via cascade condensations of diand tricarbonyl precursors using ammonia and ammonium salts as the N components. 18,19 Paradoxically, the peroxide moiety offers the NH moiety intramolecular protection against electrophiles and oxidants by depleting nitrogen electron density via stereoelectronic n N → σ* CO interactions.…”

“…In our recent studies, we applied 15 N NMR chemical shifts as an experimental probe of the stereoelectronic effects that correlated well with computational analysis. 18,19 Therefore, we have compiled a full experimental map of 15 N chemical shifts in all synthesized azaozonides in Scheme 2 (see Figure S2).…”

“…Similar effects in bicyclic and tricyclic azaperoxides were reported by us recently. 18,19 As we have shown previously, 18,19 the assembly of polycyclic aminoperoxides usually starts with the formation of a cyclic iminium, which is attacked by H 2 O 2 at the C�N bond. We propose that N-substituted azaozonides are assembled via a similar mechanism outlined in Figure 2.…”

“…18,19 Calculated free energies of formation for the intermediates relative to starting materials are colored cyan.…”