key: cord-0930895-w81bkq81
authors: Belyakova, Yulia Yu.; Radulov, Peter S.
title: [Image: see text] Synthesis of cyclic aza-peroxides (microreview)
date: 2021-09-27
journal: Chem Heterocycl Compd (N Y)
DOI: 10.1007/s10593-021-02999-z
sha: 7133af6bf30d3d4735e410816446b9a20f3bb46b
doc_id: 930895
cord_uid: w81bkq81

[Image: see text][Image: see text] A summary of approaches developed for the synthesis of stable cyclic aza-peroxides is presented. [Image: see text]

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.

A summary of approaches developed for the synthesis of stable cyclic aza-peroxides is presented.

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 BF 3 ·Et 2 O condensation of aldehyde, amine and peroxide fragments.

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

Diene was converted to the endoperoxide upon treatment with singlet oxygen (O 2 , meso-tetraphenylporphyrin (TPP), UV light 500 W). Pure endoperoxide was isolated with the use of column chromatography. 11 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 %).

An efficient route to cyclic aza-diperoxides based on Sm salts (SmCl 3 ·6H 2 O, Sm(NO 3 ) 3 ·6H 2 O, SmCl 3 /γ-Al 2 O 3 , and Sm(NO 3 ) 3 /γ-Al 2 O 3 ) 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.

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

Peroxy-bridged indolizidinones were obtained by the intramolecular cyclization of cross-conjugated dienones with pendent azide side chain under the action of BF 3 ·Et 2 O/air system. The yield of aza-peroxides was 36-72%. 16 

Heterocyclization of terpene bishydroperoxides with N-aryl-N,N-bis(methoxymethyl)amines in the presence of EuCl 3 / γ-Al 2 O 3 as a catalyst afforded new spiro terpene azadiperoxides. 20 An efficient synthesis of N-substituted tetraoxazaspiroalkanes can be carried out on the basis of Sm(NO 3 ) 3 ·6H 2 Ocatalyzed transformation of pentaoxaspiroalkanes with primary arylamines, 17 

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 1,2,4,5,7,8- 

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