Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Abstract

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at −10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pK a units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C–O interaction with the two antiperiplanar C–O bonds. Due to the weakness of the complementary nO→σ*C–N donation from the peroxide oxygens (a consequence of “inverse α-effect”), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

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).…”

“…In contrast, when ammonia serves as a nitrogen source, similar cyclic imines can transform into neutral forms by releasing H + . 18 Scheme 1. (A) Structures of Bioactive Azaperoxides and (B) Synthesis of N-Substituted Bridged Azaozonides But why does the assembly of azaozonides occur for hydrazides but fail for more nucleophililc primary amines and hydrazines?…”

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