Synthesis of cyclic aza-peroxides (microreview).

A summary of approaches developed for the synthesis of stable cyclic aza-peroxides is presented. © Springer Science+Business Media, LLC, part of Springer Nature 2021.

Introduction

Now there is no doubt that cyclic organic peroxides are a promising class of compounds for the development of drugs. Stable cyclic peroxides like artemisinin for discovery of which the Nobel Prize was awarded, possess high antimalarial activity.[1] Drugs based on artemisinin are recommended by WHO for the treatment of malaria. Over the past two decades, a whole spectrum of biological activity has been identified for organic peroxides.[2] Furthermore, artemisinin,[3] artesunate, OZ418, and OZ277 have an inhibitory ability to SARS-CoV-2.[4] However, for a long time, azaperoxides were kept in the shadow of organic peroxides because of their instability associated with self-oxidation due to the presence of both oxidizing and reducing moieties in one molecule. Discovery of two natural cyclic azaperoxides verruculogen[5] and fumitremorgin A[6] as well as the synthesis of 6(11)-azaartemisinins, which exhibit promising antimalarial[7] and anticancer[8] activity, gave impetus to the development of methods for the synthesis of nitrogencontaining peroxides.[9] However, the synthesis of stable and readily available cyclic peroxides fused with a nitrogen heterocycle is a challenge. This microreview describes recent achievements in the synthesis of cyclic azaperoxides: 1,2,4-dioxazolidines, 1,2,4-dioxazinanes, peroxybridged indolizidinones, 1,2,4-dioxazepanes, 1,2,4,5,7-tetraoxazocanes, 1,2,4,5,7,8-hexaoxa-10-azacycloundecanes.

Yulia Yu. Belyakova graduated from the D. Mendeleev University of Chemical Technology of Russia in 2018. At present, she is a graduate student under the supervision of Prof. A. O. Terent'ev (N. D. Zelinsky Institute of Organic Chemistry RAS). Her research interest is the chemistry of organic peroxides.

Peter S. Radulov received PhD in organic chemistry in 2020 under the supervision of Prof. A. O. Terent'ev. At present, he is a researcher in the N. D. Zelinsky Institute of Organic Chemistry RAS. His research interest is the chemistry of organic peroxides, medicinal and agrochemistry.

Synthesis of verruculogen

Only two bioactive natural aza-peroxides verruculogen and fumitremorgin A are known (isolated from Aspergillus fumigatus in the 1970s). First total synthesis of verruculogen and fumitremorgin A was developed only in 2015 by the Baran group.[10] The final step included catalyzed by BF3·Et2O condensation of aldehyde, amine and peroxide fragments.

Synthesis of 1,2,4-dioxazepanes

Diene was converted to the endoperoxide upon treatment with singlet oxygen (O2, meso-tetraphenylporphyrin (TPP), UV light 500 W). Pure endoperoxide was isolated with the use of column chromatography.[11]

The Schenck ene reaction of 1-benzazepines in the presence of rose bengal as a photosensitizer provided endoperoxides in high yields. Several obtained endoperoxides are valuable precursors for the synthesis of d-fused 1-benzazepines with antitumor activity.[12]

Synthesis of bridged 1,2,4-dioxazolidines

A selective and atom-efficient method for the synthesis of stable cyclic bridged 1,2,4-dioxazolidines (azaozonides) without the use of a catalyst through the three-component condensation of 1,5-diketones, hydrogen peroxide, and aqueous ammonia or ammonium salts as NH group source was described.[13] Azaozonides were obtained in high yield (up to 96 %).

N-Methoxy-1,2,4-dioxazolidines can be obtained by the ozonolysis of O-methylated dioximes.[14]

Synthesis of 1,2,4-dioxazinanes

A diastereoselective synthesis of 1,2,4-dioxazinanes based on acid-catalyzed intramolecular cyclization of the corresponding hydroperoxides was carried out. The desired products were obtained in 52–71% yields.[15]

Synthesis of peroxy-bridged indolizidinones

Peroxy-bridged indolizidinones were obtained by the intramolecular cyclization of cross-conjugated dienones with pendent azide side chain under the action of BF3·Et2O/air system. The yield of aza-peroxides was 36–72%.[16]

Synthesis of 1,2,4,5,7-tetraoxazocanes

An efficient synthesis of N-substituted tetraoxazaspiroalkanes can be carried out on the basis of Sm(NO3)3·6H2Ocatalyzed transformation of pentaoxaspiroalkanes with primary arylamines,[17] diamines,[18] or amino acids.[19]

Heterocyclization of terpene bishydroperoxides with N-aryl-N,N-bis(methoxymethyl)amines in the presence of EuCl3/γ-Al2O3 as a catalyst afforded new spiro terpene azadiperoxides.[20]

An efficient route to cyclic aza-diperoxides based on Sm salts (SmCl3·6H2O, Sm(NO3)3·6H2O, SmCl3/γ-Al2O3, and Sm(NO3)3/γ-Al2O3) catalyzed three-component condensations of 1,1-bis(hydroperoxy)cycloalkanes with formaldehyde[21] or pentanedial[22] and primary arylamines was developed. The chemoselectivity of this reaction depends on the position of the substituent (F, Cl, Br) in the phenyl ring of the primary amine.

Synthesis of 1,2,4,5,7,8-hexaoxa-10-azacycloundecanes

Sm salts catalyzed the reaction of heptaoxaspiroalkanes with arylamines affording N-arylhexaoxazadispiroalkanes.[23] The reaction of heptaoxacycloundecanes with hydrazine derivatives (3-chlorophenylhydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, and tert-butylhydrazine)[24] or amino acids[19] in the presence of Sm-containing catalysts gave the corresponding N-substituted hexaoxazaspiroalkanes in high yields. It was found that cycloaza-triperoxide-substituted amines possessed high cytotoxicity against Jurkat, K562, and U937 tumor cell lines and normal fibroblast cell line. A useful one-pot synthesis of tetra(spirocycloalkane)-substituted α,ω-(1,2,4,5,7,8-hexaoxa-10-azacycloundecan-10-yl)-alkanes via the reaction between heptaoxacycloundecanes and α,ω-alkanediamines (1,4-butane-, 1,5-pentane-, 1,7-heptane-, 1,8-octane-, and 1,10-decanediamines) catalyzed by Sm compounds was developed. It was shown that synthesized dimeric aza-triperoxides exhibited high cytotoxic activity against Jurkat, K562, and U937 tumor cultures.[25]

Authors are grateful for the support of the Russian Foundation for Basic Research according to the research project №18-53-15010 and Projects de Recherche Conjoints (PRC) – CNRS, PRC Russie 2017 CNRS.