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Review

Macrocyclic Organic Peroxides: Constructing Medium and Large Cycles with O-O Bonds

by
Yana A. Barsegyan
,
Vera A. Vil’
* and
Alexander O. Terent’ev
*
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, Moscow 119991, Russia
*
Authors to whom correspondence should be addressed.
Chemistry 2024, 6(5), 1246-1270; https://doi.org/10.3390/chemistry6050072
Submission received: 10 September 2024 / Revised: 10 October 2024 / Accepted: 12 October 2024 / Published: 15 October 2024
(This article belongs to the Section Molecular Organics)
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Abstract

:
Macrocycles bridge the gap between conventional small molecules and polymers. Drawing inspiration from successful carbon heteroatom-containing macrocycles, peroxide-containing macrocycles are gaining attention for enhanced bioactivity, potential chelating properties, and applications in energetic materials. This review presents the following strategies for the construction of cyclic peroxides with 10- to 36-membered frameworks: (1) the intramolecular iodocyclization of hydroperoxides, (2) the intermolecular cyclization of hydroperoxides with alkyl dihalides or carbonyls, (3) the acid-catalyzed rearrangements of ozonides or 11-membered cyclic triperoxides via oxy- or peroxycarbenium ions, and (4) the peroxidation of carbonyls targeting macrocyclic peroxides. The specific agents that allow for the selective construction of the medium and large cycles are also analyzed.

1. Introduction

Traditionally, a macrocycle is defined as a molecule with a cyclic framework comprising at least twelve atoms. In nature, macrocycles are commonly found with 14-, 16-, or 18-membered rings [1]. Charles Pederson’s pioneering discovery of crown ethers [2] ignited the rapid development of fully synthetic macrocyclic chemistry, catalyzing the growth of host–guest [3] and the broader field of supramolecular chemistry [4]. Later, the synthesis of cryptands [5], cavitands [6], and spherands [7]—macrocycles featuring cavities and heteroatoms—expanded their application to binding alkali and alkaline earth metal cations, as well as small molecules. This work culminated in the 1987 Nobel Prize in Chemistry, awarded jointly to Donald J. Cram [8], Jean-Marie Lehn [9], and Charles J. Pedersen [10] for their contribution “to the development and use of molecules with structure-specific interactions of high selectivity”. Another significant class of macrocycles, cyclodextrins, are useful molecular chelating agents and have been instrumental in the development of numerous drug formulations [11,12,13]. Synthetic macrocycles such as calixarenes [14,15,16] and cucurbiturils [17,18,19] also play crucial roles in molecular recognition and self-assembly processes. As pharmaceutical targets become increasingly complex, the limitations of traditional small molecules become evident. As a result, macrocycles have emerged as the preferred scaffolds in modern drug discovery [20,21,22,23,24]. For example, macrocyclic peptides are valued as chemical tools for recognizing protein surfaces and probing protein–protein interactions, owing to their synthetic accessibility and high specificity in binding [1,25].
Organic peroxides have a long history of use in various industrial applications, such as oxidants [26,27,28,29], radical initiators in polymer manufacturing, and reagents in the vulcanization of rubber [30,31,32]. Various cyclic peroxides have been extensively used as initiators for the polymerization of styrene and methyl methacrylate [33,34,35]. The discovery of the antimalarial properties of the natural cyclic peroxide artemisinin (Qinghaosu), highlighted by the 2015 Nobel Prize in Physiology or Medicine, spurred interest in the medicinal chemistry of organic peroxides (Figure 1) [36]. Cyclic organic peroxides have been shown to exhibit high antimalarial [37,38,39,40,41,42,43,44,45], antihelminthic [46,47,48], cytotoxic [49,50,51], and antiviral [52,53,54] activities. Additionally, a number of stable cyclic organic peroxides have recently been found to possess fungicidal [55,56] and growth-regulating [57,58] properties.
This growing body of research shows that the O-O bond in peroxides can serve as a valuable structural element in pharmaceuticals. Not only was the general perception that the inherent instability of the O-O bond prevents the broader applications of peroxides challenged by the surprising stability of peroxides with acceptor substituents [59,60,61,62,63], but it was also found that peroxides exhibit unique conformational profiles that set them apart from more common chemical functionalities. While alkanes and ethers have a clear preference for staggered conformations, peroxides are much more flexible. The energy difference between the trans and perpendicular conformations of the O-O bond is minimal, leading to a greater range of accessible geometries (Scheme 1). This flexibility suggests that macrocycles incorporating O-O units may also display unusual and potentially beneficial conformational behaviors and molecular shapes.
Chemistry 06 00072 sch001
Scheme 1. The differences in rotation around the O-O and C-C bonds. The figure is adopted from Alabugin, I. V.; Kuhn L. Oxygen: the Key to Stereoelectronic Control in Chemistry. ACS in Focus, 2023 [64].
Scheme 1. The differences in rotation around the O-O and C-C bonds. The figure is adopted from Alabugin, I. V.; Kuhn L. Oxygen: the Key to Stereoelectronic Control in Chemistry. ACS in Focus, 2023 [64].
Chemistry 06 00072 sch001
This review provides an overview of both the synthetic approaches and potential pharmaceutical applications that make the 10–36-membered organic macrocyclic peroxides a unique class of molecules (Scheme 2). The task of synthesizing macrocycles with a defined structure is challenging and not always solvable because of thermodynamic and kinetic difficulties and a preference for oligomeric or polymeric products. Special catalysts or high-dilution methods are often required for the synthesis of large ring products. Moreover, approaches to the preparation of cyclic peroxides are further complicated by the instability of the O-O fragment to the many reagents used in organic synthesis [65,66,67,68,69,70,71,72]. The direction of the reaction towards the assembly of the macrocyclic scaffold also depends to a large extent on the stereoelectronic interactions. It is well known that the peroxide bond has an influence on the reactivity of the adjacent molecular sites [73,74]. For example, the peroxide fragment dramatically reduces the nucleophilicity of the NH group in aminoperoxides [75]. The unusual nature of anomeric effects in peroxides (i.e., the inverse α-effect of α-oxygen functionalities on stability) including ozonides [76] and peroxylactones [77,78,79] was also revealed. The thermal stability and state of matter of the peroxides studied vary according to the size of the ring and the heteroatoms represented in the cycle; the melting points for some of them are shown in Scheme 2.
Previous reviews devoted to cyclic organic peroxides have mostly been limited to cycles with five to nine members [80,81,82,83,84,85,86,87,88]. A number of review articles discuss artemisinin chemistry [42], biologically active peroxides [89], and natural peroxides with bioactivity [90,91,92]. However, no comprehensive papers on macrocyclic peroxides have yet been published.
The classification of this review is made according to the approach used to construct the macrocycle because the same synthetic methods were utilized for various peroxides. The material within the sections is organized mainly in chronological order, taking into account the proximity of structures by type, i.e., the total number of O-O bonds, framework, and the presence of heteroatoms.
To date, common approaches to macrocyclic organic peroxides are based on intra- and intermolecular cyclization of hydroperoxides and the acid-catalyzed rearrangement of cyclic peroxides (Scheme 3). In Section 2.1, the intramolecular iodocyclization processes of hydroperoxides are considered. The intermolecular nucleophilic substitution reactions of organic halides, chloro- and methoxymethylene-silanes with hydroperoxides, and condensations of hydroperoxides with aldehydes (especially formaldehyde), ketones, and azines are presented in Section 2.2. The third section is devoted to the acid-catalyzed rearrangement of ozonides or 11-membered cyclic triperoxides via oxy- or peroxycarbenium ions. The peroxidation of carbonyl compounds with hydrogen peroxide is considered in Section 2.4. Miscellaneous reactions are summarized in the last section.

2. Strategies for Macrocyclic Organic Peroxides

2.1. Intramolecular Iodocyclization of Hydroperoxides

In 1999, the first example of a natural diterpene with a macrocyclic peroxide ketal ring, neovibsanin C 1 (isolated from the leaves of Viburnum awabuki), was first synthesized (Scheme 4) [93]. It was found that neovibsanin C can be synthesized directly from hydroperoxyneovibsanin B 2 under acidic conditions in a 68% yield.
The synthesis of 11-, 13-, and 16-membered triperoxides based on the intramolecular iodocyclization of hydroperoxides onto double bonds was developed by the McCullough group [94]. Alkylation of bishydroperoxide 3a by alkyliodide 4 in the presence of Ag2O led to the formation of peroxide 5 in a 22% yield (Scheme 5). Subsequent ozonolysis of 5 in MeOH-CH2Cl2 gave hydroperoxide 6 (20%), bishydroperoxide 7 (47%), and unreacted peroxide 5 (29%). Treatment of hydroperoxide 6 with 1.5 eq. of bis(sym-collidine)iodine(I) hexafluorophosphate (BCIH) in CH2Cl2 at room temperature for 12 h afforded the 13-membered macrocyclic triperoxide 8 in a 50% yield (an equimolar mixture of two isomers). Bis(sym-collidine)iodine(I) hexafluorophosphate (BCIH) plays a key role in the iodoperoxidation process [95].
Macrocyclic triperoxides 9 were synthesized in moderate yields through a similar methodology by the ozonolysis of diperoxides 10a,b followed by BCIH-mediated cyclization of hydroperoxyketals 11 (Scheme 6) [94].
Peroxide 12 was synthesized via BCIH-mediated cyclization of hydroperoxide 13, which was obtained through the oxidation of unsaturated peroxide 10b by the Et3SiH/O2/Co(acac)2 system for 16 h at room temperature in EtOH followed by hydrolysis (Scheme 7) [94].
A few years later, McCullough expanded the range of approaches to the macrocyclic mono-, di-, and triperoxides by intramolecular iodocyclization of hydroperoxides [96]. Ag2O-catalyzed alkylation of peroxyketal 14 with alkyl diiodides 15 afforded hemiperketals 16a–d in good yields (Scheme 8) [94,96]. Alkylation of hydroperoxide 17a with alkyl iodides 16a–d resulted in products 18a–d. Subsequent deprotection of 18a–d with AcOH/H2O followed by BCIH-mediated cyclization of 19a–d led to the macrocycles 20a–d in 50–68% yields. As the product yield in each step is acceptable and the length of the longer tether is readily variable, the approach can provide a convenient synthetic route to a variety of novel macrocyclic peroxide systems.
In the case of hydroperoxide 21, however, the Kornblum–DeLaMare reaction competed with the intramolecular iodocyclization process, thereby providing aldehyde 22 (38%) together with the expected macrocyclic peroxide 23 (33%) (Scheme 9). This could be related to the higher steric congesting at the double bond of hydroperoxide 21.
The reaction of iodide 16a,b with hydroperoxide 24 by the nucleophilic substitution mechanism followed by deprotection of 25a,b with acetic acid resulted in the formation of peroxides 26a,b (Scheme 10). Subsequent BCIH-promoted cyclization afforded diperoxides 27a,b in acceptable yields.
The two-step method for the synthesis of peroxides 28a,b consisted of the alkylation of bishydroperoxide 3b and subsequent BCIH-promoted cyclization of peroxides 17a,b (Scheme 11) [96]. Target macrocycles 28a,b were obtained in 52–57% yields. Previously, a similar protocol was used in the synthesis of analogous eight-membered cyclic peroxide [97].
The intramolecular cyclization of unsaturated hydroperoxides 29a,b, which can be synthesized in four steps, has also been studied (Scheme 12) [96]. The carbonyl oxide, cyclohexanone O-oxide, generated in situ by ozonolysis of the vinyl ether 30, was captured by alcohols 31a,b to give the peroxyketals 32a,b in good yields (60–63%). The subsequent Ag2O-promoted alkylation of 32a,b afforded the peroxides 33a,b in poor yields. Target unsaturated hydroperoxides 33a,b were then obtained by removal of the triethylsilyl group. The outcome of BCIH-promoted cyclization of 29a,b is significantly influenced by the ring size. From peroxide 29a, path a takes place, and macrocycle 34 was isolated in 37% yield, whereas peroxide 29b underwent peroxyketal cleavage with the elimination of 1,2-dioxolane 35 (path b).
BCIH-promoted cyclization of unsaturated hydroperoxide 36 resulted in 1,2-dioxecane 37 (28%) along with the 20-membered cyclic dimeric peroxide 38 (12%) (Scheme 13).
The cyclization reaction of unsaturated alcohols 39a,b was also investigated by the McCullough group (Scheme 14) [96]. The latter 39a,b were obtained by treating the corresponding hydroperoxides 19b,d with Ph3P in CH2Cl2. The reaction of hydroxyl-containing bisperoxides 39a,b with BCIH led to the formation of macrocycles 40a,b (path a, 14–29%) and 1,2-dioxolane 35 (path b, 14–37%) and cyclododecanone (path b, 29–44%) as by-products. This is in marked contrast to the fact that in the case of the unsaturated hydroperoxides 19b,d, only macrocyclic peroxides were obtained in good yields (Scheme 8). This fact can be explained by the higher nucleophilicity of the hydroperoxides in comparison with the alcohols.
The BCIH-promoted macrocyclization of unsaturated alcohols 41a–c provided 10- and 12-membered peroxides 42a–c in low yields (11–19%) (Scheme 15) [96]. In all cases, significant quantities of starting material 41a–c were recovered. The low activity of 41a–c can be explained by the Thorpe–Ingold effect [98] and the lower nucleophilicity of the OH group compared with the OOH group (see Scheme 10).

2.2. Intermolecular Cyclization of Hydroperoxides

In 1999, McCullough et al. [99] reported the synthesis of 1,2,5,6-tetraoxacycloalkanes. In the first step, photooxygenation of 2-phenylnorbornene 43 in the presence of 30% aq. H2O2 at 0 °C in acetonitrile afforded bishydroperoxide 44 in quantitative yield (Scheme 16). The reaction of the latter with 1,3-diiodobutane 15a in the presence of 1.1 eq. Ag2O (at r.t. in CH2Cl2) gave macrocyclic peroxide 45, containing 1,2,5,6-tetroxecane cycle, albeit in low yield (7%).
The CsOH·H2O-promoted cycloalkylation reaction between bishydroperoxide 3b and diiodoalkanes (n = 3, 4, 6) 15b,c,e was developed as an approach to the synthesis of 10-, 11- and 13-membered cyclic bisperoxides 46a–c in 13–18% yields (Scheme 17) [100]. Peroxide 46b showed substantial antimalarial activity in vitro with an EC50 1.0 × 10−8 value against P. falciparum and selectivity against mouse mammary FM3A cells, but the in vivo antimalarial activity of 46b was moderate.
In 2014, it was shown [101] that in the reactions of symmetrical dichlorodisilanes 47 with diperoxide compounds 48a–c, cyclization processes dominate over polymerization. This is a rare example of cyclizing reagents that are structurally suited for polymerization. The reaction of dichlorodisilane 47 with 1,1′-dihydroperoxyperoxides 48a–c led to twelve-membered cyclic silicon peroxides 49 with good selectivity (Scheme 18) [101]. Peroxides 49 were obtained by an imidazole-catalyzed reaction in Et2O at 20–25 °C for 3 h in 77–90% yields.
A method for the synthesis of 18-membered Si-containing peroxide cycle 50 is based on the reaction of 1,2-bis(dimethylchlorosilyl)ethylene 51 and geminal bishydroperoxide 3c (Scheme 19, (a)) [101]. The synthesis of the peroxide was performed at 20–25 °C under an argon atmosphere in the presence of imidazole in 90% yield. An approach to the preparation of 24-membered peroxide 52 was also described (Scheme 19, (b)) [101]. The imidazole-catalyzed cyclization of 1,2-bis(dimethylchlorosilyl)ethylene 51 with 1,1′-bis(hydroperoxy)bis(cycloheptyl)peroxide 48c in Et2O furnished macrocyclic peroxide 52 in 80% yield.
A mixture of 27- and 18-membered macrocyclic peroxides 53 (40%) and 54 (32%) was obtained by the reaction of geminal bishydroperoxide 3c with bis(dimethylchlorosilyl)ethyne 55 for 2–3 min (Scheme 20).
Moreover, a method for the synthesis of 36-membered organosilicon peroxide 56 was revealed (Scheme 21) [101]. The reaction of bis(dimethylchlorosilyl)ethyne 55 with 1,1′-bis(hydroperoxy)bis(cycloheptyl)peroxide 48c catalyzed by imidazole gave as main products a mixture of two macrocyclic peroxides as follows: 24-membered dimeric peroxide 57 and 36-membered trimeric peroxide 56 in 30% and 50% yields, respectively.
The nature of the base and the reaction conditions have a considerable effect on the selectivity of the ring formation. Aliphatic amines (Et3N, Et2NH, DABCO) and tetrahydroquinoline are less efficient than imidazole and other aromatic amines (pyridine, 2,6-dimethylpyridine, and DMAP). Imidazole plays a key role in the formation of the peroxide macrocycle (Scheme 22). In the first step, a Si-O bond is formed; then, imidazole coordinates with the Si atom and successively via a hydrogen atom with another peroxide group. Finally, the second Si-O bond is formed by cyclization.
Hexamethylene triperoxide diamine (HMTD) 58 has a cage-like structure, and its extreme sensitivity makes it unsafe for commercial applications. HMTD was synthesized from the reaction of urotropine with 30% H2O2 by Legler (Scheme 23) [102]. The reaction was catalyzed by acids, usually citric acid. The antimalarial activity of HMTD was also tested [103].
Three-component condensation of diamines 59, formaldehyde, and H2O2 in AcOH resulted in the formation of ten-membered cage aminoperoxides 60 in good and high yields (72–91%) (Scheme 24) [104].
In 2018, the synthetic route to spiroheptaoxacanes 61 was developed by Makhmudiyarova et al. (Scheme 25) [105]. Eleven-membered peroxides 61a–c were obtained through the Sm(NO3)3·6H2O-catalyzed condensation of 1,1′-dihydroperoxyperoxides 62a–c with formaldehyde for 6 h at 20 °C in THF in good yields (79–82%).
In 2019, a versatile method for the synthesis of bicyclic aminoperoxides 63 by the three-component reaction of geminal bishydroperoxides 64, glutardialdehyde, and primary arylamines 65 through lanthanide salts catalysis was developed (Scheme 26) [106]. In addition, it was demonstrated that synthesized peroxides 63 exhibit high cytotoxic activity against Jurkat, K562, and U937 tumor cultures and fibroblasts.
An efficient approach for Si-containing cyclic triperoxides 66 was developed in 2020 (Scheme 27) [107]. The reaction of 1,1′-dihydroperoxyperoxides 62a–c with silane 67 in the presence of 5 mol.% La(NO3)3.6H2O as the catalyst for 6 h at 20 °C in THF afforded the corresponding 11-membered macrocyclic peroxides 66a–c in 63–70% yields. The latter can be further reduced by Ph3P with the formation of nine-membered cyclic monoperoxides.
It was found that 1,1′-dihydroperoxyperoxides 62a–c effectively reacts with aldazine 68 in the presence of 5 mol.% Sm(NO3)3·6H2O with the formation of 12-membered diaminotriperoxides 69a–c in 68–84% yields (Scheme 28) [108]. It was also found that diaminotriperoxides 69b,c exhibit cytotoxic activity in vitro against Jurkat, K562, U937, and fibroblast cells.
Cyclocondensation of phenols 70 with 1,1′-dihydroperoxyperoxides 62a–c and H2CO catalyzed by SmCl3·6H2O resulted in the formation benzannelated 13- and 14-membered macrocyclic triperoxides (Scheme 29) [109]. Symmetrical peroxides 71 were obtained using resorcinol and hydroquinone, and unsymmetrical peroxides 72 were obtained using phenol and catechol. Peroxides 71,72 possess high cytotoxic activity against Jurkat, K592, and U937 tumor cells and fibroblasts. They also induce apoptosis and cause cell cycle arrest, thus affecting all phases of the cell cycle.
The plausible mechanism of peroxide 71,72 formation is presented in Scheme 30. The reaction starts with the addition of 1,1′-dihydroperoxide 62a–c to H2CO, followed by the coordination of the catalyst with intermediate A and the nucleophilic attack of the phenol. Benzoylated peroxides 71,72 are formed by the removal of water and catalyst.
Three-component condensation of 1,1-dihydroperoxycycloalkanes 73 with formaldehyde and α,ω-diols 74 furnished the spirocyclic 12-, 14-, 15-, and 17-membered diperoxides 75 in good yields (70–88%) (Scheme 31) [110]. The reaction proceeded in THF in the presence of Sm(NO3)3·6H2O (5 mol.%) at 20 °C for 6 h.

2.3. Cyclic Peroxide Rearrangement via Oxy- or Peroxycarbenium Ions

Miura and Nojima, together with co-workers, studied the acid-catalyzed rearrangements of bridged ozonides in detail [111,112,113,114,115,116,117]. Initially, the conversion of ozonides 76 to 10-membered bicyclic peroxides 77 in the presence of catalytic amounts of SbCl5 or ClSO3H was reported (Scheme 32) [111,112].
The ClSO3H-catalyzed reaction of ozonides 78 with ketones 79 and H2O2 in AcOH afforded macrocyclic peroxides 80 in 7–35% yields (Scheme 33, (a)) [113]. Ozonides 78 reacted with peroxide 81 [114] (Scheme 33, (b)) or underwent cross-reactions with ozonides 82 [115] (Scheme 34, (c)) under acidic conditions to form macrocyclic products 83–85 up to 33% yield.
Treatment of indene ozonide 86 with 0.1 eq. of ClSO3H at 0 °C in CH2Cl2 afforded cyclic tetramer 87 in a 20% yield (Scheme 34) [118]. The structure of peroxide 87, containing a 20-membered dodecaoxacycloicosane ring system, was confirmed by X-ray analysis.
Later, it was shown that ClSO3H-mediated acidolysis of indene ozonides 88a–d or their CF3CH2O-containing derivatives 89a–d [119] provided symmetrical cyclic dimers 90 (14–60%), which have a hexoxecane ring structure (Scheme 35) [120]. However, 1H and 13C NMR, mass, and crystal data were presented only in the case of 90a.
The plausible mechanism of peroxide 90a formation is shown in Scheme 36. Acid-catalyzed ring-opening of ozonide 88a or elimination of trifluoroethanol from 89a produces carbocation A, which is captured by a second molecule of 88a or 89a from the least sterically hindered face to give B or C. Ring closure of B via intramolecular attack of OOH group results in the formation of 90a.
Over the last 5 years, the Dzhemilev group has reported a cycle of works dedicated to the rearrangements of macrocyclic peroxides with N-, P-, and S-reagents, which proceed via peroxycarbenium ion formation [105,121,122,123,124,125,126]. Sm-catalyzed ring transformation of heptaoxadispiroalkanes 61 with N-aryl(o-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, and p-methylphenyl)amines 91 provided access to 11-membered aminotriperoxides 92 in 70–87% yields (Scheme 37, (a)) [105]. An approach to the synthesis of N-substituted hexaoxaazadispiroalkanes 93 through the reaction of heptaoxadispiroalkanes 61 with hydrazines (R2 = t-Bu, Ph, m-ClC6H4, 2,4-O2NC6H3) 94 was reported with good yields (70–87%) (Scheme 37, (b)) [121]. It was found that N-substituted cycloaminotriperoxides 93 exhibit a high cytotoxic activity against Jurkat, K562, and U937 tumor cell lines and normal fibroblast cell lines. Furthermore, methods for the synthesis of 11-membered N-substituted hexaoxaazadispiroalkanes 95,96 from corresponding heptaoxadispiroalkanes 61 and aminoacids 97 [124] or ureas 98 [125] have been developed (Scheme 37, (c),(d)). In 2020, a two-step approach to phosphorous-containing macrocyclic triperoxides 99 was reported (Scheme 37, (e)) [122]. The first step involved the rearrangement of peroxide 61, while the second step concerned the oxidation of phosphorus by H2O2. Sm-catalyzed rearrangement of heptaoxadispiroalkanes 61 using H2S resulted in the formation of hexaoxathiocanes 100 in 83–86% yields (Scheme 37, (f)) [123]. These S-containing triperoxides 100 exhibit high cytotoxic activity against Jurkat, K562, U937, and HL60 tumor cultures and fibroblasts. Remarkably, sulfur or phosphorous functionalities did not reduce the O-O bond in these processes.
It was shown that N-substituted aminotriperoxides 101 underwent Sm(NO3)3·6H2O-catalysed rearrangement via peroxycarbenium ion generation and subsequent addition of 2-chloroaniline 102 to form aminotriperoxides 103 (Scheme 38) [126].
Recently, the Sm-catalyzed rearrangement of heptaoxadispiroalkanes 61 with the participation of diamines 104 [127] or urea/thiourea 105 [125] was utilized in the synthesis of dimeric aminoperoxides 106 or 107, respectively (Scheme 39). Products 106 are efficient apoptosis inducers with Jurkat, K562, U937, and Hek293 [127].
The reaction of heptaoxadispiroalkanes 61 with malonates 108 under Sm(NO3)3·6H2O catalysis led to the corresponding 11-membered triperoxides 109a–i in 75–86% yields (Scheme 40) [128].
Probably, triperoxides 92,93,95,96,99–101,103,106,107,109 are formed as a result of the opening of the triperoxide 61 ring by the action of a catalyst, nucleophilic addition of NuH, and intramolecular cyclization (Scheme 41). This process is similar to the Yuryev reaction, which allows the interconversion of five-membered O-, S-, N-, and Se-containing heterocyclic compounds [129]. The selectivity of the transformation can be explained by an inverse α-effect [62,64], which determines the reaction pathway via the peroxycarbenium ion.

2.4. Peroxidation of Carbonyl Compounds

In 1962, the reaction of 2,5-hexanedione 110 with H2O2 to form a mixture of peroxides, including macrocycle 111, was published (Scheme 42) [130]. Product 111 was identified by IR spectroscopy and elemental analysis.
SnCl4·5H2O catalyzed peroxidation of acetone with 30% aqueous H2O2 at room temperature led to the formation of tetrameric acetone peroxide 112 in 44% yield (Scheme 43) [131]. Product 112 was identified by elemental analysis, FTIR, NMR spectroscopy, and MS.
Ozonolysis of hydroperoxides 113 at 0 °C in TFE-CH2Cl2, proceeding via the peroxycarbenium ion and carbonyl compound formation, afforded the corresponding 10- and 12-membered macrocyclic peroxides 114a,b in low yields (Scheme 44) [132]. Significant quantities of polar oligomeric products were also obtained. The Kornblum–DeLaMare reaction of α-hydroperoxy-substituted tetraoxacycloalkanes 114a,b using an Ac2O-Et3N mixture resulted in the formation of macrocyclic peroxylactones 115a,b in high yields (80–83%).

2.5. Miscellaneous Methods

The unstable 10-membered peroxylactone 116 (35%) was synthesized through the radical β-fragmentation of steroidal cyclic peroxyhemiacetal 117 and was further used for the preparation of 1,2-dioxolane 118 (Scheme 45) [133]. Although peroxylactone 116 decomposed quickly, it was fully characterized by 1H and 13C NMR and IR spectroscopy.
In 1994, the Chou group [134] found that 2,5-dimethylene-2,5-dihydrothiophene 119, the product of flash vacuum pyrolysis (FVP) of 5-methylthenyl benzoate 120, reacted with O2 at −78 °C in CH2Cl2 with the formation of S-containing 14-membered cyclic peroxide 121 in 83% yield (Scheme 46). The structure of 121 was determined by 1H and 13C NMR spectroscopy and CIMS spectral data.

3. Conclusions

The analysis of published data indicates that common approaches to the macrocyclic organic peroxides typically involve three key strategies as follows: (1) intramolecular iodocyclization of unsaturated hydroperoxides; (2) intermolecular reactions such as nucleophilic substitution of organic halides and silanes with hydroperoxides, as well as condensations of hydroperoxides with aldehydes, ketones, and azines; and (3) rearrangement of ozonides or 11-membered cyclic triperoxides via oxy- or peroxycarbenium ion generation.
The intramolecular iodocyclization of unsaturated hydroperoxides was carried out using a special iodonium source and afforded a wide range of macrocyclic iodoperoxidation products. Intermolecular cyclization of hydroperoxides with organic halides into macrocyclic peroxides resulted in poor yields because of undesirable oligomerizaton side processes. However, Lewis or Brønsted acid-catalyzed condensations of hydroperoxides with aldehydes in the absence or presence of a third component (O- or N-nucleophile) proved to be a reliable route to macrocycles. Access to Si-containing macrocyclic peroxides with cycle sizes ranging from 12 to 36 was provided by imidazole-catalyzed reactions of acyclic bisperoxides and chlorosilanes. Acid-catalyzed rearrangement of bridged ozonides via the peroxycarbenium ion resulted in macrocyclic peroxides. Lanthanide salts played a key role in the rearrangement of 11-membered triperoxides, which made it possible to obtain C-, N-, S-, and P-containing cyclic triperoxides and dimeric aminoperoxides. Some of the 11-membered triperoxides showed a high cytotoxic activity against Jurkat, K562, and U937 tumor cell lines and normal fibroblast cell lines. Macrocyclic peroxide synthesis via the peroxidation of carbonyl compounds with H2O2 has been poorly studied but may be greatly expanded in the near future in view of the development of the field and the availability of starting reagents.
The focus of synthetic chemists’ efforts is currently on the development of methods for the synthesis of peroxides with high biological activity. To achieve this goal, approaches to peroxides containing two or more O-O bonds in the macrocycle are being developed. Attempts have also been made to introduce other heteroatoms (such as nitrogen, silicon, sulfur, and phosphorus) into the cycle.
Because of the application of both macrocyclic compounds and organic peroxides in medicinal chemistry, we can expect a breakthrough in the synthesis of biologically active macrocyclic peroxides in the near future.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

Funding

This research was financially supported by the Ministry of Science and Higher Education of the Russian Federation by the project FFZZ-2024-0001.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AcOHacetic acid
Ac2Oacetic anhydride
acacacetylacetonate
DABCO1,4-diazabicyclo[2.2.2]octane
DCE1,2-dichloroethane
DIB(diacetoxyiodo)benzene
DMAP4-dimethylaminopyridine
DMFdimethylformamide
FTIRFourier-transform infrared spectroscopy
LALewis acid
TEStriethylsilyl
THFtetrahydrofuran
TPPtetraphenylporphyrin

References

  1. Yudin, A.K. Macrocycles: Lessons from the distant past, recent developments, and future directions. Chem. Sci. 2015, 6, 30–49. [Google Scholar] [CrossRef] [PubMed]
  2. Pedersen, C.J. Cyclic polyethers and their complexes with metal salts. J. Am. Chem. Soc. 1967, 89, 7017–7036. [Google Scholar] [CrossRef]
  3. Cram, D.J.; Cram, J.M. Host-Guest Chemistry: Complexes between organic compounds simulate the substrate selectivity of enzymes. Science 1974, 183, 803–809. [Google Scholar] [CrossRef] [PubMed]
  4. Lehn, J.-M. Supramolecular Chemistry: Concepts and Perspectives; Wiley-VCH: Weinheim, Germany, 1995. [Google Scholar]
  5. Zhang, M.; Yan, X.; Huang, F.; Niu, Z.; Gibson, H.W. Stimuli-responsive host-guest systems based on the recognition of cryptands by organic guests. Acc. Chem. Res. 2014, 47, 1995–2005. [Google Scholar] [CrossRef]
  6. Hooley, R.J.; Rebek, J., Jr. Chemistry and catalysis in functional cavitands. Chem. Biol. 2009, 16, 255–264. [Google Scholar] [CrossRef] [PubMed]
  7. Cram, D.J. Preorganization—From Solvents to Spherands. Angew. Chem. Int. Ed. Engl. 1986, 25, 1039–1057. [Google Scholar] [CrossRef]
  8. Cram, D.J. The Design of Molecular Hosts, Guests, and Their Complexes (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27, 1009–1020. [Google Scholar] [CrossRef]
  9. Lehn, J.M. Supramolecular Chemistry—Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27, 89–112. [Google Scholar] [CrossRef]
  10. Pedersen, C.J. The Discovery of Crown Ethers (Noble Lecture). Angew. Chem. Int. Ed. Engl. 1988, 27, 1021–1027. [Google Scholar] [CrossRef]
  11. Del Valle, E.M.M. Cyclodextrins and their uses: A review. Process Biochem. 2004, 39, 1033–1046. [Google Scholar] [CrossRef]
  12. Loftsson, T.; Duchene, D. Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 2007, 329, 1–11. [Google Scholar] [CrossRef] [PubMed]
  13. Kurkov, S.V.; Loftsson, T. Cyclodextrins. Int. J. Pharm. 2013, 453, 167–180. [Google Scholar] [CrossRef] [PubMed]
  14. Rodik, R.V.; Boyko, V.I.; Kalchenko, V.I. Calixarenes in Bio-Medical Researches. Curr. Med. Chem. 2009, 16, 1630–1655. [Google Scholar] [CrossRef] [PubMed]
  15. Böhmer, V. Calixarenes, Macrocycles with (Almost) Unlimited Possibilities. Angew. Chem. Int. Ed. Engl. 2003, 34, 713–745. [Google Scholar] [CrossRef]
  16. Antipin, I.S.; Alfimov, M.V.; Arslanov, V.V.; Burilov, V.A.; Vatsadze, S.Z.; Voloshin, Y.Z.; Volcho, K.P.; Gorbatchuk, V.V.; Gorbunova, Y.G.; Gromov, S.P.; et al. Functional supramolecular systems: Design and applications. Russ. Chem. Rev. 2021, 90, 895–1107. [Google Scholar]
  17. Assaf, K.I.; Nau, W.M. Cucurbiturils: From synthesis to high-affinity binding and catalysis. Chem. Soc. Rev. 2015, 44, 394–418. [Google Scholar] [CrossRef]
  18. Gerasko, O.A.; Samsonenko, D.G.; Fedin, V.P. Supramolecular chemistry of cucurbiturils. Russ. Chem. Rev. 2002, 71, 741–760. [Google Scholar] [CrossRef]
  19. Kim, K.; Selvapalam, N.; Ko, Y.H.; Park, K.M.; Kim, D.; Kim, J. Functionalized cucurbiturils and their applications. Chem. Soc. Rev. 2007, 36, 267–279. [Google Scholar] [CrossRef]
  20. Marsault, E.; Peterson, M.L. Macrocycles are great cycles: Applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J. Med. Chem. 2011, 54, 1961–2004. [Google Scholar] [CrossRef]
  21. Mallinson, J.; Collins, I. Macrocycles in new drug discovery. Future Med. Chem. 2012, 4, 1409–1438. [Google Scholar] [CrossRef]
  22. Yu, X.; Sun, D. Macrocyclic drugs and synthetic methodologies toward macrocycles. Molecules 2013, 18, 6230–6268. [Google Scholar] [CrossRef] [PubMed]
  23. Mortensen, K.T.; Osberger, T.J.; King, T.A.; Sore, H.F.; Spring, D.R. Strategies for the Diversity-Oriented Synthesis of Macrocycles. Chem. Rev. 2019, 119, 10288–10317. [Google Scholar] [CrossRef] [PubMed]
  24. Liu, Z.; Nalluri, S.K.M.; Stoddart, J.F. Surveying macrocyclic chemistry: From flexible crown ethers to rigid cyclophanes. Chem. Soc. Rev. 2017, 46, 2459–2478. [Google Scholar] [CrossRef] [PubMed]
  25. Gao, M.; Cheng, K.; Yin, H. Targeting protein-protein interfaces using macrocyclic peptides. Biopolymers 2015, 104, 310–316. [Google Scholar] [CrossRef]
  26. Wu, X.-F.; Gong, J.-L.; Qi, X. A powerful combination: Recent achievements on using TBAI and TBHP as oxidation system. Org. Biomol. Chem. 2014, 12, 5807–5817. [Google Scholar] [CrossRef]
  27. Schmidt, R.J. Industrial catalytic processes—Phenol production. Appl. Catal. A General 2005, 280, 89–103. [Google Scholar] [CrossRef]
  28. Zhu, Y.; Wang, Q.; Cornwall, R.G.; Shi, Y. Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications. Chem. Rev. 2014, 114, 8199–8256. [Google Scholar] [CrossRef]
  29. Fisher, T.J.; Dussault, P.H. Alkene ozonolysis. Tetrahedron 2017, 73, 4233–4258. [Google Scholar] [CrossRef]
  30. Gaylord, N.G.; Mandal, B.M.; Martan, M. Peroxide-induced polymerization of norbornene. J. Polym. Sci. Polym. Lett. Ed. 1976, 14, 555–559. [Google Scholar] [CrossRef]
  31. Emami, S.H.; Salovey, R.; Hogen-Esch, T.E. Peroxide-mediated crosslinking of poly(ethylene oxide). J. Polym. Sci. Part A Polym. Chem. 2002, 40, 3021–3026. [Google Scholar] [CrossRef]
  32. Russell, K.E. Free radical graft polymerization and copolymerization at higher temperatures. Prog. Polym. Sci. 2002, 27, 1007–1038. [Google Scholar] [CrossRef]
  33. Islamova, R.M.; Ishkinina, O.I.; Nazarova, S.V.; Chupakhin, O.N.; Utepova, I.A.; Andriyashina, N.M.; Terent’ev, A.O. Cyclic peroxides and related initiating systems for radical polymerization of methyl methacrylate. Russ. Chem. Bull. 2014, 62, 1282–1285. [Google Scholar] [CrossRef]
  34. Cerna, J.R.; Morales, G.; Eyler, G.N.; Cañizo, A.I. Bulk polymerization of styrene catalyzed by bi- and trifunctional cyclic initiators. J. Appl. Polym. Sci. 2002, 83, 1–11. [Google Scholar] [CrossRef]
  35. Sheng, W.-C.; Wu, J.-Y.; Shan, G.-R.; Huang, Z.-M.; Weng, Z.-X. Free-radical bulk polymerization of styrene with a new trifunctional cyclic peroxide initiator. J. Appl. Polym. Sci. 2004, 94, 1035–1042. [Google Scholar] [CrossRef]
  36. Su, X.Z.; Miller, L.H. The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. Sci. China Life Sci. 2015, 58, 1175–1179. [Google Scholar] [CrossRef]
  37. Zhou, W.-S.; Xu, X.-X. Total Synthesis of the Antimalarial Sesquiterpene Peroxide Qinghaosu and Yingzhaosu A. Acc. Chem. Res. 1994, 27, 211–216. [Google Scholar] [CrossRef]
  38. White, N.J. Qinghaosu (Artemisinin): The Price of Success. Science 2008, 320, 330–334. [Google Scholar] [CrossRef]
  39. Haynes, R.K.; Vonwiller, S.C. From Qinghao, Marvelous Herb of Antiquity, to the Antimalarial Trioxane Qinghaosuand Some Remarkable New Chemistry. Acc. Chem. Res. 1997, 30, 73–79. [Google Scholar] [CrossRef]
  40. Kumar, V.; Mahajan, A.; Chibale, K. Synthetic medicinal chemistry of selected antimalarial natural products. Bioorg. Med. Chem. 2009, 17, 2236–2275. [Google Scholar] [CrossRef]
  41. Meshnick, S.R.; Jefford, C.W.; Posner, G.H.; Avery, M.A.; Peters, W. Second-generation antimalarial endoperoxides. Parasitology Today 1996, 12, 79–82. [Google Scholar] [CrossRef]
  42. Vil’, V.A.; Yaremenko, I.A.; Ilovaisky, A.I.; Terent’ev, A.O. Synthetic Strategies for Peroxide Ring Construction in Artemisinin. Molecules 2017, 22, 117. [Google Scholar] [CrossRef] [PubMed]
  43. Tang, Y.; Dong, Y.; Vennerstrom, J.L. Synthetic peroxides as antimalarials. Med. Res. Rev. 2004, 24, 425–448. [Google Scholar] [CrossRef] [PubMed]
  44. Jefford, C.W. New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discov. Today 2007, 12, 487–495. [Google Scholar] [CrossRef] [PubMed]
  45. Opsenica, D.M.; Šolaja, B.A. Antimalarial peroxides. J. Serb. Chem. Soc. 2009, 74, 1155–1193. [Google Scholar] [CrossRef]
  46. Keiser, J.; Utzinger, J. Food-borne trematodiasis: Current chemotherapy and advances with artemisinins and synthetic trioxolanes. Trends Parasitol. 2007, 23, 555–562. [Google Scholar] [CrossRef]
  47. Muraleedharan, K.M.; Avery, M.A. Progress in the development of peroxide-based anti-parasitic agents. Drug Discov. Today 2009, 14, 793–803. [Google Scholar] [CrossRef]
  48. Panic, G.; Duthaler, U.; Speich, B.; Keiser, J. Repurposing drugs for the treatment and control of helminth infections. Int. J. Parasitol. Drugs Drug Resist. 2014, 4, 185–200. [Google Scholar] [CrossRef]
  49. Dembitsky, V.M. Bioactive peroxides as potential therapeutic agents. Eur. J. Med. Chem. 2008, 43, 223–251. [Google Scholar] [CrossRef]
  50. Chaturvedi, D.; Goswami, A.; Pratim Saikia, P.; Barua, N.C.; Rao, P.G. Artemisinin and its derivatives: A novel class of anti-malarial and anti-cancer agents. Chem. Soc. Rev. 2010, 39, 435–454. [Google Scholar] [CrossRef]
  51. Liu, D.-Z.; Liu, J.-K. Peroxy natural products. Nat. Prod. bioprospect. 2013, 3, 161–206. [Google Scholar] [CrossRef]
  52. Efferth, T.; Marschall, M.; Wang, X.; Huong, S.-M.; Hauber, I.; Olbrich, A.; Kronschnabl, M.; Stamminger, T.; Huang, E.-S. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J. Mol. Med. 2002, 80, 233–242. [Google Scholar] [CrossRef] [PubMed]
  53. Efferth, T.; Romero, M.R.; Wolf, D.G.; Stamminger, T.; Marin, J.J.G.; Marschall, M. The Antiviral Activities of Artemisinin and Artesunate. Clin. Infect. Dis. 2008, 47, 804–811. [Google Scholar] [CrossRef] [PubMed]
  54. Jia, M.; Zhao, R.; Xu, B.; Yan, W.; Chu, F.; Gu, H.; Xie, T.; Xiang, H.; Ren, J.; Chen, D.; et al. Synthesis and biological activity evaluation of novel peroxo-bridged derivatives as potential anti-hepatitis B virus agents. MedChemComm 2017, 8, 148–151. [Google Scholar] [CrossRef] [PubMed]
  55. Phillipson, D.W.; Rinehart, K.L. Antifungal peroxide-containing acids from two Caribbean sponges. J. Am. Chem. Soc. 1983, 105, 7735–7736. [Google Scholar] [CrossRef]
  56. Oh, D.-C.; Scott, J.J.; Currie, C.R.; Clardy, J. Mycangimycin, a Polyene Peroxide from a Mutualist Streptomyces sp. Org. Lett. 2009, 11, 633–636. [Google Scholar] [CrossRef]
  57. Cusati, R.C.; Barbosa, L.C.A.; Maltha, C.R.A.; Demuner, A.J.; Oliveros-Bastidas, A.; Silva, A.A. Tetraoxanes as a new class of efficient herbicides comparable with commercial products. Pest Manag. Sci. 2015, 71, 1037–1048. [Google Scholar] [CrossRef]
  58. Antolínez, I.V.; Barbosa, L.C.A.; Maltha, C.R.A.; Pereira, G.A.M.M.; Silva, A.A. Synthesis and phytotoxic profile of a new tetraoxane designed from a commercial auxin. Química Nova 2020, 43, 901–908. [Google Scholar] [CrossRef]
  59. Nissen, J.H.; Drews, T.; Schroder, B.; Beckers, H.; Steinhauer, S.; Riedel, S. Perfluoro Alkyl Hypofluorites and Peroxides Revisited. Chem.—Eur. J. 2019, 25, 14721–14727. [Google Scholar] [CrossRef]
  60. Nissen, J.H.; Stuker, T.; Drews, T.; Steinhauer, S.; Beckers, H.; Riedel, S. No Fear of Perfluorinated Peroxides: Syntheses and Solid-State Structures of Surprisingly Inert Perfluoroalkyl Peroxides. Angew. Chem., Int. Ed. 2019, 58, 3584–3588. [Google Scholar] [CrossRef]
  61. Afonso, M.A.S.; Cormanich, R.A. The preferred geometry of hydroperoxides is the result of an interplay between electrostatic and hyperconjugative effects. Phys. Chem. Chem. Phys. 2020, 22, 27173–27177. [Google Scholar] [CrossRef]
  62. Juaristi, E.; Dos Passos Gomes, G.; Terent’ev, A.O.; Notario, R.; Alabugin, I.V. Stereoelectronic Interactions as a Probe for the Existence of the Intramolecular alpha-Effect. J. Am. Chem. Soc. 2017, 139, 10799–10813. [Google Scholar] [CrossRef] [PubMed]
  63. Gomes, G.D.P.; Vil, V.; Terent’ev, A.; Alabugin, I.V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 6783–6791. [Google Scholar] [CrossRef] [PubMed]
  64. Alabugin, I.; Kuhn, L. Oxygen: The Key to Stereoelectronic Control in Chemistry; American Chemical Society: Washington, DC, USA, 2023; pp. 1–390. [Google Scholar]
  65. He, Z.; Moreno, J.A.; Swain, M.; Wu, J.; Kwon, O. Aminodealkenylation: Ozonolysis and copper catalysis convert C(sp3)-C(sp2) bonds to C(sp3)-N bonds. Science 2023, 381, 877–886. [Google Scholar] [CrossRef] [PubMed]
  66. Dehnert, B.W.; Dworkin, J.H.; Kwon, O. Dealkenylative Functionalizations: Conversion of Alkene C(sp3)–C(sp2) Bonds into C(sp3)–X Bonds via Redox-Based Radical Processes. Synthesis 2023, 56, 71–86. [Google Scholar] [PubMed]
  67. Dworkin, J.H.; Dehnert, B.W.; Kwon, O. When all C-C breaks LO-Ose. Trends Chem. 2023, 5, 174–200. [Google Scholar] [CrossRef]
  68. Swain, M.; Bunnell, T.B.; Kim, J.; Kwon, O. Dealkenylative Alkynylation Using Catalytic Fe(II) and Vitamin C. J. Am. Chem. Soc. 2022, 144, 14828–14837. [Google Scholar] [CrossRef]
  69. Smaligo, A.J.; Wu, J.; Burton, N.R.; Hacker, A.S.; Shaikh, A.C.; Quintana, J.C.; Wang, R.; Xie, C.; Kwon, O. Oxodealkenylative Cleavage of Alkene C(sp3)-C(sp2) Bonds: A Practical Method for Introducing Carbonyls into Chiral Pool Materials. Angew. Chem., Int. Ed. 2020, 59, 1211–1215. [Google Scholar] [CrossRef]
  70. Vil, V.A.; Gorlov, E.S.; Bityukov, O.V.; Barsegyan, Y.A.; Romanova, Y.E.; Merkulova, V.M.; Terent’ev, A.O. C−O coupling of Malonyl Peroxides with Enol Ethers via [5+2] Cycloaddition: Non-Rubottom Oxidation. Adv. Synth. Catal. 2019, 361, 3173–3181. [Google Scholar] [CrossRef]
  71. Vil’, V.A.; Barsegyan, Y.A.; Kuhn, L.; Terent’ev, A.O.; Alabugin, I.V. Creating, Preserving, and Directing Carboxylate Radicals in Ni-Catalyzed C(sp3)–H Acyloxylation of Ethers, Ketones, and Alkanes with Diacyl Peroxides. Organometallics 2023, 42, 2598–2612. [Google Scholar] [CrossRef]
  72. Bityukov, O.V.; Skokova, K.V.; Vil, V.A.; Nikishin, G.I.; Terent’ev, A.O. Electrochemical Generation of Peroxy Radicals and Subsequent Peroxidation of 1,3-Dicarbonyls in an Undivided Cell. Org. Lett. 2024, 26, 166–171. [Google Scholar] [CrossRef]
  73. Alabugin, I.V.; Kuhn, L.; Medvedev, M.G.; Krivoshchapov, N.V.; Vil, V.A.; Yaremenko, I.A.; Mehaffy, P.; Yarie, M.; Terent’ev, A.O.; Zolfigol, M.A. Stereoelectronic power of oxygen in control of chemical reactivity: The anomeric effect is not alone. Chem. Soc. Rev. 2021, 50, 10253–10345. [Google Scholar] [CrossRef] [PubMed]
  74. Alabugin, I.V. Stereoelectronic Effects: A Bridge Between Structure and Reactivity; Wiley: Hoboken, NJ, USA, 2016; pp. 1–400. [Google Scholar]
  75. Yaremenko, I.A.; Belyakova, Y.Y.; Radulov, P.S.; Novikov, R.A.; Medvedev, M.G.; Krivoshchapov, N.V.; Korlyukov, A.A.; Alabugin, I.V.; Terent Ev, A.O. Inverse alpha-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities. J. Am. Chem. Soc. 2022, 144, 7264–7282. [Google Scholar] [CrossRef] [PubMed]
  76. Gomes, G.D.P.; Yaremenko, I.A.; Radulov, P.S.; Novikov, R.A.; Chernyshev, V.V.; Korlyukov, A.A.; Nikishin, G.I.; Alabugin, I.V.; Terent’ev, A.O. Stereoelectronic Control in the Ozone-Free Synthesis of Ozonides. Angew. Chem. Int. Ed. 2017, 56, 4955–4959. [Google Scholar] [CrossRef] [PubMed]
  77. Vil, V.A.; Dos Passos Gomes, G.; Bityukov, O.V.; Lyssenko, K.A.; Nikishin, G.I.; Alabugin, I.V.; Terent’ev, A.O. Interrupted Baeyer-Villiger Rearrangement: Building A Stereoelectronic Trap for the Criegee Intermediate. Angew. Chem. Int. Ed. 2018, 57, 3372–3376. [Google Scholar] [CrossRef] [PubMed]
  78. Vil, V.A.; Barsegyan, Y.A.; Barsukov, D.V.; Korlyukov, A.A.; Alabugin, I.V.; Terent’ev, A.O. Peroxycarbenium Ions as the “Gatekeepers” in Reaction Design: Assistance from Inverse Alpha-Effect in Three-Component beta-Alkoxy-beta-peroxylactones Synthesis. Chem.—Eur. J. 2019, 25, 14460–14468. [Google Scholar] [CrossRef]
  79. Vil, V.A.; Barsegyan, Y.A.; Kuhn, L.; Ekimova, M.V.; Semenov, E.A.; Korlyukov, A.A.; Terent’ev, A.O.; Alabugin, I.V. Synthesis of unstrained Criegee intermediates: Inverse alpha-effect and other protective stereoelectronic forces can stop Baeyer-Villiger rearrangement of gamma-hydroperoxy-gamma-peroxylactones. Chem. Sci. 2020, 11, 5313–5322. [Google Scholar] [CrossRef]
  80. Terent’ev, A.O.; Borisov, D.A.; Vil, V.A.; Dembitsky, V.M. Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products. Beilstein J. Org. Chem. 2014, 10, 34–114. [Google Scholar] [CrossRef]
  81. Pinet, A.; Nguyen, L.T.; Figadère, B.; Ferrié, L. Synthesis of 3,5-Disubstituted 1,2-Dioxolanes. Eur. J. Org. Chem. 2020, 2020, 7407–7416. [Google Scholar] [CrossRef]
  82. Belyakova, Y.Y.; Radulov, P.S. Synthesis of cyclic aza-peroxides (microreview). Chem. Heterocycl. Cmpd. 2021, 57, 908–910. [Google Scholar] [CrossRef]
  83. Radulov, P.S.; Yaremenko, I.A. Application of BF3·Et2O in the synthesis of cyclic organic peroxides (microreview). Chem. Heterocycl. Cmpd. 2020, 56, 1146–1148. [Google Scholar] [CrossRef]
  84. Radulov, P.S.; Vil’, V.A. Metal-based Lewis acids in the synthesis of cyclic organic peroxides (microreview). Chem. Heterocycl. Cmpd. 2020, 56, 299–301. [Google Scholar] [CrossRef]
  85. Yaremenko, I.A.; Radulov, P.S.; Belyakova, Y.Y.; Fomenkov, D.I.; Tsogoeva, S.B.; Terent’ev, A.O. Lewis Acids and Heteropoly Acids in the Synthesis of Organic Peroxides. Pharmaceuticals 2022, 15, 472. [Google Scholar] [CrossRef] [PubMed]
  86. McCullough, K.; Nojima, M. Recent Advances in the Chemistry of Cyclic Peroxides. Curr. Org. Chem. 2001, 5, 601–636. [Google Scholar] [CrossRef]
  87. McCullough, K.J. Synthesis and use of cyclic peroxides. Contemp. Org. Synth. 1995, 2, 225–249. [Google Scholar] [CrossRef]
  88. Ferrié, L. Chapter Two—Advances in the synthesis of 1,2-dioxolanes and 1,2-dioxanes. Adv. Heterocycl. Chem. 2021, 135, 57–146. [Google Scholar]
  89. Vil, V.A.; Yaremenko, I.A.; Ilovaisky, A.I.; Terent’ev, A.O. Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions. Molecules 2017, 22, 1881. [Google Scholar] [CrossRef]
  90. Tolstikov, G.A.; Tolstikov, A.G.; Tolstikova, O.V. Natural peroxides. Chemistry and biological activity. Russ. Chem. Rev. 1996, 65, 769–783. [Google Scholar] [CrossRef]
  91. Vil, V.A.; Terent’ev, A.O.; Savidov, N.; Gloriozova, T.A.; Poroikov, V.V.; Pounina, T.A.; Dembitsky, V.M. Hydroperoxy steroids and triterpenoids derived from plant and fungi: Origin, structures and biological activities. J. Steroid Biochem. Mol. Biol. 2019, 190, 76–87. [Google Scholar] [CrossRef]
  92. Vil, V.A.; Gloriozova, T.A.; Poroikov, V.V.; Terent’ev, A.O.; Savidov, N.; Dembitsky, V.M. Peroxy steroids derived from plant and fungi and their biological activities. Appl. Microbiol. Biotechnol. 2018, 102, 7657–7667. [Google Scholar] [CrossRef]
  93. Kubo, M.; Minami, H.; Hayashi, E.; Kodama, M.; Kawazu, K.; Fukuyama, Y. Neovibsanin C, a macrocyclic peroxide-containing neovibsane-type diterpene from Viburnum awabuki. Tetrahedron Lett. 1999, 40, 6261–6265. [Google Scholar] [CrossRef]
  94. McCullough, K.J.; Ito, T.; Tokuyasu, T.; Masuyama, A.; Nojima, M. The synthesis and crystal structure analysis of novel macrocyclic peroxides. Tetrahedron Lett. 2001, 42, 5529–5532. [Google Scholar] [CrossRef]
  95. Rousseau, G.; Homsi, F. Preparation of seven and larger membered heterocycles by electrophilic heteroatom cyclization. Chem. Soc. Rev. 1997, 26, 453–461. [Google Scholar] [CrossRef]
  96. Ito, T.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K.J. Synthesis of novel macrocyclic peroxides by bis(sym-collidine)iodine (I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols. Tetrahedron 2003, 59, 525–536. [Google Scholar] [CrossRef]
  97. Nonami, Y.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K.J.; Kim, H.-S.; Wataya, Y. Synthesis, crystal structure and anti-malarial activity of functionalized spiro-1,2,4,5-tetraoxacycloalkanes from unsaturated hydroperoxy peracetals. Tetrahedron Lett. 2000, 41, 4681–4684. [Google Scholar] [CrossRef]
  98. Jung, M.E.; Piizzi, G. gem-disubstituent effect: Theoretical basis and synthetic applications. Chem. Rev. 2005, 105, 1735–1766. [Google Scholar] [CrossRef] [PubMed]
  99. McCullough, K.J.; Nonami, Y.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Wataya, Y. Synthesis, crystal structure and antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes from 2,3-dihydroperoxy-2-phenylnorbornane. Tetrahedron Lett. 1999, 40, 9151–9155. [Google Scholar] [CrossRef]
  100. Kim, H.S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K.J. Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes. J. Med. Chem. 2001, 44, 2357–2361. [Google Scholar] [CrossRef]
  101. Arzumanyan, A.V.; Novikov, R.A.; Terent’ev, A.O.; Platonov, M.M.; Lakhtin, V.G.; Arkhipov, D.E.; Korlyukov, A.A.; Chernyshev, V.V.; Fitch, A.N.; Zdvizhkov, A.T.; et al. Nature Chooses Rings: Synthesis of Silicon-Containing Macrocyclic Peroxides. Organometallics 2014, 33, 2230–2246. [Google Scholar] [CrossRef]
  102. Legler, L. Ueber Producte der langsamen Verbrennung des Aethyläthers. Ber. Dtsch. Chem. Ges. 1885, 18, 3343–3351. [Google Scholar] [CrossRef]
  103. Vennerstrom, J.L. Amine peroxides as potential antimalarials. J. Med. Chem. 1989, 32, 64–67. [Google Scholar] [CrossRef]
  104. Edward, J.T.; Chubb, F.L.; Gilson, D.F.R.; Hynes, R.C.; Sauriol, F.; Wiesenthal, A. Cage peroxides having planar bridgehead nitrogen atoms. Can. J. Chem. 1999, 77, 1057–1065. [Google Scholar] [CrossRef]
  105. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Tyumkina, T.V.; Ibragimov, A.G.; Dzhemilev, U.M. Synthesis of N-aryl-hexaoxazadispiroalkanes using lanthanide catalysts. Tetrahedron Lett. 2018, 59, 3161–3164. [Google Scholar] [CrossRef]
  106. Makhmudiyarova, N.N.; Shangaraev, K.R.; Dzhemileva, L.U.; Tyumkina, T.V.; Mescheryakova, E.S.; D’yakonov, V.A.; Ibragimov, A.G.; Dzhemilev, U.M. New synthesis of tetraoxaspirododecane-diamines and tetraoxazaspirobicycloalkanes. RSC Adv. 2019, 9, 29949–29958. [Google Scholar] [CrossRef] [PubMed]
  107. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Ibragimov, A.G. Lanthanide-Catalyzed Synthesis of Cyclic Silicon-Containing Di- and Triperoxides. Russ. J. Org. Chem. 2020, 56, 1685–1690. [Google Scholar] [CrossRef]
  108. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Dzhemileva, L.U.; Dyakonov, V.A.; Ibragimov, A.G. Synthesis of Macrocyclic Diazatriperoxides and Their Cytotoxic Activity. Vestnik Bashkirskogo Universiteta 2021, 26, 717–722. (In Russian) [Google Scholar] [CrossRef]
  109. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Shangaraev, K.R.; Dzhemileva, L.U.; D’yakonov, V.A.; Ibragimov, A.G.; Dzhemilev, U.M. Catalytic synthesis of benzannelated macrocyclic di- and triperoxides based on phenols. New J. Chem. 2021, 45, 2069–2077. [Google Scholar] [CrossRef]
  110. Mahmudiyarova, N.N.; Ishmukhametova, I.R.; Dzhemilev, U.M. Catalytic synthesis of spiromacrocyclic diperoxides based on α,ω-diols. Russ. Chem. Bull. 2023, 72, 1161–1165. [Google Scholar] [CrossRef]
  111. Miura, M.; Nojima, M. Formation of 3,6-dialkyl-1,2,4,5-tetraoxans and related cyclic bis(peroxides) by the action of antimony pentachloride or chlorosulphonic acid on ozonides. J. Chem. Soc., Chem. Commun. 1979, 467–468. [Google Scholar] [CrossRef]
  112. Miura, M.; Nojima, M. Reaction of ozonide with antimony pentachloride or chlorosulfuric acid. Participation of antimony pentachloride-complexed or protonated carbonyl oxide. J. Am. Chem. Soc. 1980, 102, 288–291. [Google Scholar] [CrossRef]
  113. Miura, M.; Ikegami, A.; Nojima, M.; Kusabayashi, S. Synthesis of 1,4-disubstituted (or 1,4,4-trisubstituted) 2,3,5,6,11-pentaoxabicyclo[5.3.1]undecanes. J. Chem. Soc., Chem. Commun. 1980, 1279–1281. [Google Scholar] [CrossRef]
  114. Miura, M.; Ikegami, A.; Nojima, M.; Kusabayashi, S.; McCullough, K.J.; Walkinshaw, M.D. Synthesis and X-ray analysis of 2,3,5,6,11-pentaoxabicyclo[5.3.1]undecanes. J. Chem. Soc., Perkin Trans. 1 1983, 1657–1664. [Google Scholar] [CrossRef]
  115. Miura, M.; Nojima, M.; Kusabayashi, S.; Nagase, S. Formation of the crossed product 1,4-disubstituted 2,3,5,6,11-pentaoxabicyclo[5.3.1]undecane from a mixture of two kinds of ozonides in the presence of an acid catalyst. Elucidation of the intermediates in the acidolysis of an ozonide. J. Am. Chem. Soc. 1981, 103, 1789–1796. [Google Scholar] [CrossRef]
  116. Miura, M.; Ikegami, A.; Nojima, M.; Kusabayashi, S.; McCullough, K.J.; Nagase, S. Synthesis, X-ray analysis, and acidolysis of exo- and endo-1-methylindene ozonides. J. Am. Chem. Soc. 1983, 105, 2414–2426. [Google Scholar] [CrossRef]
  117. Miura, M.; Nagase, S.; Nojima, M.; Kusabayashi, S. Acidolysis of ozonides. An ab initio study. J. Org. Chem. 1983, 48, 2366–2370. [Google Scholar] [CrossRef]
  118. McCullough, K.J.; Teshima, K.; Nojima, M. Unprecedented formation of a cyclic tetramer from the acidolysis of indene ozonide. Isolation and characterisation of a novel dodecaoxacycloicosane derivative. J. Chem. Soc. Chem. Commun. 1993, 931–933. [Google Scholar] [CrossRef]
  119. Teshima, K.; Kawamura, S.-i.; Ushigoe, Y.; Nojima, M.; McCullough, K.J. Ozonolyses of Indene and of 1-Alkyl- and 1,1-Dialkyl-Substituted Indenes in Protic Solvents. Remarkable Effects of the Substituent Steric Bulk and the Solvent Nucleophilicity on the Direction of Cleavage of the Primary Ozonides and on the Mode of Capture of the Carbonyl Oxide Intermediates by the Solvents. J. Org. Chem. 1995, 60, 4755–4763. [Google Scholar]
  120. Ushigoe, Y.; Kawamura, S.-i.; Teshima, K.; Nojima, M.; McCullough, K.J. Transformation of 1-alkyl-substituted indene ozonides and the corresponding solvent-derived ozonolysis products to tricyclic peroxides: Isolation and characterization of novel hexoxecane derivative. Tetrahedron Lett. 1996, 37, 2093–2096. [Google Scholar] [CrossRef]
  121. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Dzhemileva, L.U.; D’yakonov, V.A.; Ibragimov, A.G.; Dzhemilev, U.M. Hydrazines in the Synthesis of Cytotoxic N-Aryl(alkyl)-N-(hexaoxazadispiroalkyl)amines. Russ. J. Org. Chem. 2020, 56, 797–801. [Google Scholar] [CrossRef]
  122. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Ibragimov, A.G.; Dhzemilev, U.M. Synthesis of a New Class of Macrocyclic Phosphorus-Containing Tri- and Diperoxides in the Presence of Lanthanide Catalysts. Dokl. Chem. 2020, 492, 93–98. [Google Scholar] [CrossRef]
  123. Makhmudiyarova, N.; Ishmukhametova, I.; Dzhemileva, L.; D’yakonov, V.; Ibragimov, A.; Dzhemilev, U. First Example of Catalytic Synthesis of Cyclic S-Containing Di- and Triperoxides. Molecules 2020, 25, 1874. [Google Scholar] [CrossRef]
  124. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Shangaraev, K.R.; Meshcheryakova, E.S.; Ibragimov, A.G. Synthesis of N-Substituted Tetra(hexa)oxazaspiroalkanes Using Amino Acids and Samarium Catalysts. Russ. J. Org. Chem. 2021, 57, 64–70. [Google Scholar] [CrossRef]
  125. Makhmudiyarova, N.N.; Ishmukhametova, I.R. Urea and Thiourea Derivatives in the Synthesis of Hexaoxaazadispiroalkanecarboxamides. Russ. J. Org. Chem. 2022, 58, 1959–1962. [Google Scholar] [CrossRef]
  126. Makhmudiyarova, N.N.; Ishmukhametova, I.R. Recyclization of S- and N-Containing Cyclic Peroxides with Aromatic Amines. Russ. J. Org. Chem. 2022, 59, 47–53. [Google Scholar] [CrossRef]
  127. Makhmudiyarova, N.N.; Ishmukhametova, I.R.; Dzhemileva, L.U.; Tyumkina, T.V.; D’yakonov, V.A.; Ibragimov, A.G.; Dzhemilev, U.M. Synthesis and anticancer activity novel dimeric azatriperoxides. RSC Adv. 2019, 9, 18923–18929. [Google Scholar] [CrossRef]
  128. Makhmudiyarova, N.N.; Ishmukhametova, I.R. Synthesis of New Macrocyclic Triperoxides. Russ. J. Org. Chem. 2022, 58, 1909–1914. [Google Scholar] [CrossRef]
  129. Yuryev, Y.K. Catalytic transformations of heterocyclic compounds. Zh. Obshch. Khim. 1936, 6, 972–976. (In Russian) [Google Scholar]
  130. Milas, N.A.; Golubovic, A. Studies in Organic Peroxides. XXX. Organic Peroxides Derived from 2,5-Hexanedione and Hydrogen Peroxide1a. J. Org. Chem. 1962, 27, 4319–4323. [Google Scholar] [CrossRef]
  131. Jiang, H.; Chu, G.; Gong, H.; Qiao, Q. Tin Chloride Catalysed Oxidation of Acetone with Hydrogen Peroxide to Tetrameric Acetone Peroxide. J. Chem. Res. 1999, 23, 288–289. [Google Scholar] [CrossRef]
  132. McCullough, K.J.; Tokuhara, H.; Masuyama, A.; Nojima, M. New approaches to the synthesis of spiro-peroxylactones. Org. Biomol. Chem. 2003, 1, 1522–1527. [Google Scholar] [CrossRef]
  133. Boto, A.; Hernández, R.; Velázquez, S.M.; Suárez, E.; Prangé, T. Stereospecific Synthesis of 1,2-Dioxolanes by Alkoxy Radical β-Fragmentation of Steroidal Cyclic Peroxyhemiacetals. J. Org. Chem. 1998, 63, 4697–4705. [Google Scholar] [CrossRef]
  134. Huang, C.-S.; Peng, C.-C.; Chou, C.-H. Reaction of 2,5-dimethylene-2,5-dihydrothiophene with triplet oxygen. Tetrahedron Lett. 1994, 35, 4175–4176. [Google Scholar] [CrossRef]
Chemistry 06 00072 g001
Figure 1. Biologically active cyclic organic peroxides.
Figure 1. Biologically active cyclic organic peroxides.
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Scheme 2. Reviewed macrocyclic peroxides.
Scheme 2. Reviewed macrocyclic peroxides.
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Chemistry 06 00072 sch003
Scheme 3. Main strategies for macrocyclic organic peroxide synthesis.
Scheme 3. Main strategies for macrocyclic organic peroxide synthesis.
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Chemistry 06 00072 sch004
Scheme 4. Synthesis of neovibsanin C 1 from hydroperoxyneovibsanin B 2.
Scheme 4. Synthesis of neovibsanin C 1 from hydroperoxyneovibsanin B 2.
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Chemistry 06 00072 sch005
Scheme 5. Synthetic route to the 13-membered macrocyclic triperoxide 8.
Scheme 5. Synthetic route to the 13-membered macrocyclic triperoxide 8.
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Chemistry 06 00072 sch006
Scheme 6. Synthesis of hydroperoxyketals 9.
Scheme 6. Synthesis of hydroperoxyketals 9.
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Chemistry 06 00072 sch007
Scheme 7. Synthesis of peroxide 12.
Scheme 7. Synthesis of peroxide 12.
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Chemistry 06 00072 sch008
Scheme 8. Synthetic route to the macrocyclic peroxides 20a–d.
Scheme 8. Synthetic route to the macrocyclic peroxides 20a–d.
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Chemistry 06 00072 sch009
Scheme 9. Synthesis of cyclic peroxide 23.
Scheme 9. Synthesis of cyclic peroxide 23.
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Chemistry 06 00072 sch010
Scheme 10. Synthesis of macrocyclic diperoxides 27a,b.
Scheme 10. Synthesis of macrocyclic diperoxides 27a,b.
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Chemistry 06 00072 sch011
Scheme 11. Transformation of bishydroperoxide 3b into macrocycles 28a,b.
Scheme 11. Transformation of bishydroperoxide 3b into macrocycles 28a,b.
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Chemistry 06 00072 sch012
Scheme 12. Cyclization of hydroperoxides 29a,b with the formation of macrocyclic peroxide 34 or 1,2-dioxolane 35.
Scheme 12. Cyclization of hydroperoxides 29a,b with the formation of macrocyclic peroxide 34 or 1,2-dioxolane 35.
Chemistry 06 00072 sch012
Chemistry 06 00072 sch013
Scheme 13. Synthesis of 1,2-dioxecane 37 and 20-membered diperoxide 38.
Scheme 13. Synthesis of 1,2-dioxecane 37 and 20-membered diperoxide 38.
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Chemistry 06 00072 sch014
Scheme 14. Macrocyclization of unsaturated alcohols 39a,b with the formation of macrocyclic peroxides 40a,b.
Scheme 14. Macrocyclization of unsaturated alcohols 39a,b with the formation of macrocyclic peroxides 40a,b.
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Chemistry 06 00072 sch015
Scheme 15. Synthesis of 10- and 12-membered peroxides 42a–c.
Scheme 15. Synthesis of 10- and 12-membered peroxides 42a–c.
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Chemistry 06 00072 sch016
Scheme 16. Synthesis of 1,2,5,6-tetroxecane 45.
Scheme 16. Synthesis of 1,2,5,6-tetroxecane 45.
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Chemistry 06 00072 sch017
Scheme 17. The CsOH·H2O-promoted cycloalkylation reaction between bishydroperoxide 3b and diiodoalkanes 15b,c,e.
Scheme 17. The CsOH·H2O-promoted cycloalkylation reaction between bishydroperoxide 3b and diiodoalkanes 15b,c,e.
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Chemistry 06 00072 sch018
Scheme 18. Synthesis of cyclic silicon peroxides 49.
Scheme 18. Synthesis of cyclic silicon peroxides 49.
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Chemistry 06 00072 sch019
Scheme 19. Synthesis of 18- and 24-membered organosilicon peroxides 50 and 52.
Scheme 19. Synthesis of 18- and 24-membered organosilicon peroxides 50 and 52.
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Chemistry 06 00072 sch020
Scheme 20. Synthesis of 24- and 18-membered organosilicon peroxides 53 and 54.
Scheme 20. Synthesis of 24- and 18-membered organosilicon peroxides 53 and 54.
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Chemistry 06 00072 sch021
Scheme 21. Synthesis of 24- and 36-membered organosilicon peroxides 57 and 56.
Scheme 21. Synthesis of 24- and 36-membered organosilicon peroxides 57 and 56.
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Chemistry 06 00072 sch022
Scheme 22. Possible mechanism of Si-containing peroxide cycle formation.
Scheme 22. Possible mechanism of Si-containing peroxide cycle formation.
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Chemistry 06 00072 sch023
Scheme 23. Synthesis of HMTD 58.
Scheme 23. Synthesis of HMTD 58.
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Chemistry 06 00072 sch024
Scheme 24. Synthesis of cage aminoperoxides 60.
Scheme 24. Synthesis of cage aminoperoxides 60.
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Chemistry 06 00072 sch025
Scheme 25. Transformation of 1,1′-dihydroperoxyperoxides 62a–c into corresponding spiroheptaoxacanes 61.
Scheme 25. Transformation of 1,1′-dihydroperoxyperoxides 62a–c into corresponding spiroheptaoxacanes 61.
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Chemistry 06 00072 sch026
Scheme 26. Synthesis of bicyclic aminoperoxides 63 by the three-component reaction of gem-dihydroperoxides 64, glutardialdehyde, and primary arylamines 65.
Scheme 26. Synthesis of bicyclic aminoperoxides 63 by the three-component reaction of gem-dihydroperoxides 64, glutardialdehyde, and primary arylamines 65.
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Chemistry 06 00072 sch027
Scheme 27. Synthesis of Si-containing 11-membered cyclic triperoxides 66.
Scheme 27. Synthesis of Si-containing 11-membered cyclic triperoxides 66.
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Chemistry 06 00072 sch028
Scheme 28. Synthesis of 12-membered diaminotriperoxides 69a–c.
Scheme 28. Synthesis of 12-membered diaminotriperoxides 69a–c.
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Chemistry 06 00072 sch029
Scheme 29. Cyclocondensation of phenols with 1,1′-dihydroperoxyperoxides 62a–c and H2CO with the formation of benzannelated 13- and 14-membered macrocyclic triperoxides 71 and 72.
Scheme 29. Cyclocondensation of phenols with 1,1′-dihydroperoxyperoxides 62a–c and H2CO with the formation of benzannelated 13- and 14-membered macrocyclic triperoxides 71 and 72.
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Chemistry 06 00072 sch030
Scheme 30. Plausible mechanism of peroxide 71,72 formation.
Scheme 30. Plausible mechanism of peroxide 71,72 formation.
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Chemistry 06 00072 sch031
Scheme 31. Synthesis of spirocyclic 12-, 14-, 15-, and 17-membered diperoxides 75.
Scheme 31. Synthesis of spirocyclic 12-, 14-, 15-, and 17-membered diperoxides 75.
Chemistry 06 00072 sch031
Chemistry 06 00072 sch032
Scheme 32. Rearrangement of ozonides 76 with the formation of macrocyclic peroxides 77.
Scheme 32. Rearrangement of ozonides 76 with the formation of macrocyclic peroxides 77.
Chemistry 06 00072 sch032
Chemistry 06 00072 sch033
Scheme 33. Synthesis of 10-membered peroxides 80,82–85.
Scheme 33. Synthesis of 10-membered peroxides 80,82–85.
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Chemistry 06 00072 sch034
Scheme 34. Synthesis of cyclic tetrameric peroxide 87.
Scheme 34. Synthesis of cyclic tetrameric peroxide 87.
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Chemistry 06 00072 sch035
Scheme 35. Synthesis of cyclic dimeric peroxides 90.
Scheme 35. Synthesis of cyclic dimeric peroxides 90.
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Chemistry 06 00072 sch036
Scheme 36. Probable mechanism of peroxide 90a formation.
Scheme 36. Probable mechanism of peroxide 90a formation.
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Chemistry 06 00072 sch037
Scheme 37. Reactions of macrocyclic peroxides 61 with N-, P-, and S-reagents.
Scheme 37. Reactions of macrocyclic peroxides 61 with N-, P-, and S-reagents.
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Chemistry 06 00072 sch038
Scheme 38. Rearrangement of aminotriperoxides 101 into aminotriperoxides 103.
Scheme 38. Rearrangement of aminotriperoxides 101 into aminotriperoxides 103.
Chemistry 06 00072 sch038
Chemistry 06 00072 sch039
Scheme 39. Synthesis of dimeric aminoperoxides 106 and 107.
Scheme 39. Synthesis of dimeric aminoperoxides 106 and 107.
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Chemistry 06 00072 sch040
Scheme 40. Synthesis of 11-membered triperoxides 109a–i.
Scheme 40. Synthesis of 11-membered triperoxides 109a–i.
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Chemistry 06 00072 sch041
Scheme 41. Proposed mechanism of rearrangement of heptaoxadispiroalkanes 61 via the generation of peroxycarbenium ion and the addition of NH-, PH-, SH-, and CH-nucleophiles.
Scheme 41. Proposed mechanism of rearrangement of heptaoxadispiroalkanes 61 via the generation of peroxycarbenium ion and the addition of NH-, PH-, SH-, and CH-nucleophiles.
Chemistry 06 00072 sch041
Chemistry 06 00072 sch042
Scheme 42. Synthesis of macrocycle 111.
Scheme 42. Synthesis of macrocycle 111.
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Chemistry 06 00072 sch043
Scheme 43. Synthesis of tetrameric acetone peroxide 112.
Scheme 43. Synthesis of tetrameric acetone peroxide 112.
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Chemistry 06 00072 sch044
Scheme 44. Synthesis of 10- and 12-membered macrocyclic peroxides 114a,b and 115a,b.
Scheme 44. Synthesis of 10- and 12-membered macrocyclic peroxides 114a,b and 115a,b.
Chemistry 06 00072 sch044
Chemistry 06 00072 sch045
Scheme 45. Synthesis of 10-membered peroxylactone 116.
Scheme 45. Synthesis of 10-membered peroxylactone 116.
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Chemistry 06 00072 sch046
Scheme 46. Synthesis of S-containing 14-membered cyclic peroxide 121.
Scheme 46. Synthesis of S-containing 14-membered cyclic peroxide 121.
Chemistry 06 00072 sch046
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Barsegyan, Y.A.; Vil’, V.A.; Terent’ev, A.O. Macrocyclic Organic Peroxides: Constructing Medium and Large Cycles with O-O Bonds. Chemistry 2024, 6, 1246-1270. https://doi.org/10.3390/chemistry6050072

AMA Style

Barsegyan YA, Vil’ VA, Terent’ev AO. Macrocyclic Organic Peroxides: Constructing Medium and Large Cycles with O-O Bonds. Chemistry. 2024; 6(5):1246-1270. https://doi.org/10.3390/chemistry6050072

Chicago/Turabian Style

Barsegyan, Yana A., Vera A. Vil’, and Alexander O. Terent’ev. 2024. "Macrocyclic Organic Peroxides: Constructing Medium and Large Cycles with O-O Bonds" Chemistry 6, no. 5: 1246-1270. https://doi.org/10.3390/chemistry6050072

APA Style

Barsegyan, Y. A., Vil’, V. A., & Terent’ev, A. O. (2024). Macrocyclic Organic Peroxides: Constructing Medium and Large Cycles with O-O Bonds. Chemistry, 6(5), 1246-1270. https://doi.org/10.3390/chemistry6050072

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