Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

Summary The present review describes the current status of synthetic five and six-membered cyclic peroxides such as 1,2-dioxolanes, 1,2,4-trioxolanes (ozonides), 1,2-dioxanes, 1,2-dioxenes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes. The literature from 2000 onwards is surveyed to provide an update on synthesis of cyclic peroxides. The indicated period of time is, on the whole, characterized by the development of new efficient and scale-up methods for the preparation of these cyclic compounds. It was shown that cyclic peroxides remain unchanged throughout the course of a wide range of fundamental organic reactions. Due to these properties, the molecular structures can be greatly modified to give peroxide ring-retaining products. The chemistry of cyclic peroxides has attracted considerable attention, because these compounds are used in medicine for the design of antimalarial, antihelminthic, and antitumor agents.

Reviews published earlier on the chemistry of ozone [33][34][35][36] and on the chemistry and biological activity of natural peroxides, and cyclic peroxides [37][38][39][40][41][42][43][44][45][46] are closely related to this review. Generally speaking, state-of-the-art approaches to the synthesis of cyclic peroxides are based on three key reagents: oxygen, ozone, and hydrogen peroxide. These reagents and their derivatives are used in the main methods for the introduction of the peroxide group, such as the singlet-oxygen ene reaction with alkenes, the [4 + 2]-cycloaddition of singlet oxygen to dienes, the Mukaiyama-Isayama peroxysilylation of unsaturated compounds, the Kobayashi cyclization, the nucleophilic addition of hydrogen peroxide to carbonyl compounds, the ozonolysis, and reactions with the involvement of peroxycarbenium ions.
Each part of the review deals with a particular class of the above-mentioned peroxides in accordance with an increase in the number of oxygen atoms and the ring size. In the individual sections, the data are arranged mainly according to the common key step in the synthesis of the cyclic peroxides. Examples of the synthesis of peroxide derivatives via modifications of functional groups, with the peroxide bond remaining unbroken, are given in the end of each chapter. In most cases, the syntheses of compounds having high biological activity are considered.
Currently, the rapid progress in chemistry of organic peroxides is to a large degree determined by their high biological activity. In medicinal chemistry of peroxides, particular emphasis is given to the design of compounds having activity against causative agents of malaria and helminth infections. The World Health Organization (WHO) considers malaria as one of the most dangerous social diseases. Worldwide, 300-500 million cases of malaria occur each year, and 2 million people die from it [47,48].
Due to a high degree of resistance in malaria to traditional drugs as quinine, chloroquine, and mefloquine, an active search for other classes of new drugs is performed. In this respect, organic peroxides play a considerable role. In medicinal chemistry of peroxides, artemisinin a natural peroxide exhibiting high antimalarial activity, is the most important drug in use for approximately 30 years. Artemisinin was isolated in 1971 from leaves of annual wormwood (Artemesia annua) [49][50][51]; the 1,2,4trioxane ring V is the key pharmacophore of these drugs. A series of semi-synthetic derivatives of artemisinin were synthesized: artesunate, artemether, and artemisone ( Figure 2). Currently, drugs based on these compounds are considered as the most efficacious for the treatment of malaria .
The discovery of arterolane, a synthetic 1,2,4-trioxolane, is a considerable success in the search for easily available synthetic peroxides capable of replacing artemisinin and its derivatives in medical practice. Currently, this compound is currently in phase III clinical trials [77][78][79][80][81]. The mechanism of antimalarial action of peroxides is unusual for pharmaceutical chemistry. According to the commonly accepted mechanism, peroxides diffuse into Plasmodiuminfected erythrocytes, and the heme iron ion of the latter reduces the peroxide bond to form a separated oxygen-centered radical anion, which rearranges to the C-centered radical having a toxic effect on Plasmodium [82][83][84][85][86][87].

Review 1. Synthesis of 1,2-dioxolanes
The modern approaches to the synthesis of 1,2-dioxolanes are based on the use of oxygen and ozone for the formation of the peroxide moiety, the Isayama-Mukaiyama peroxysilylation, and reactions involving peroxycarbenium ions. Syntheses employing hydrogen peroxide and the intramolecular Kobayashi cyclization are less frequently used.

Use of oxygen for the peroxide ring formation
The singlet-oxygen ene reaction with alkenes provides an efficient tool for introducing the hydroperoxide function. The reaction starts with the coordination of oxygen to the double bond followed by the formation of hydroperoxides presumably by a stepwise or concerted mechanism [229,230]. The oxidation of α,β-unsaturated ketones 1a-c by singlet oxygen affords 3-hydroxy-1,2-dioxolanes 3a-c via the formation of β-hydroperoxy ketones 2a-c (Scheme 1) [231].
Dioxolane 6 was synthesized in 36% yield by the reaction of oxygen with hydroperoxide 4 in the presence of di-tert-butyl peroxalate (DTBPO) followed by the treatment of the reaction mixture with acetic anhydride and pyridine at room temperature (Scheme 2).
It should be emphasized that a mixture of dioxolanes 5 and 6 in a ratio of 7:3 is formed already in the first step [232].
An efficient method for the synthesis of 1,2-dioxolanes is based on the oxidation of cyclopropanes by oxygen in the presence of transition-metal salts as the catalysts. The reactions of bicycloalkanols 10a-e with singlet oxygen in the presence of catalytic amounts of Fe(III) acetylacetonate produce peroxides 12a-e, which can also be synthesized starting from silylated bicycloalkanols 11a-e with the use of Cu(II) acetylacetonate (Scheme 4, Table 1) [234].  Similarly, the reactions of silylated bicycloalkanols 13a-c with oxygen in the presence of the catalyst VO(acac) 2 yielded dioxolanes 14a-c, which made it possible to perform the oxidation without irradiation (Scheme 5, Table 2) [235].  This reaction gives β-hydroxyketones as by-products that are formed as a result of the decomposition of dioxolanes 14.
Presumably, the reaction proceeds via the intermediate formation of О-and С-centered radicals 16a-g and 17a-g, respectively. According to this method, dioxolanes 18a-g (exist in equilibrium with the open form 19a-g) were synthesized in 60-80% yields.
Like hydroxycyclopropanes, aminocyclopropanes are transformed into 1,2-dioxolanes. For example, N-cyclopropyl-Nphenylamines 20a-c form dioxolanes 21a-c in the presence of atmospheric oxygen (Table 3). It was found that the reaction rate substantially increases in the presence of catalytic amounts of [(phen) 3 Fe(III)(PF 6 ) 3 ] or equimolar amounts of benzoyl peroxide or di-tert-butyl peroxide. The possible mechanism of the oxidation is shown in Scheme 7 [237].
A series of 1,2-dioxolanes 27a-e containing various functional groups R were prepared by the oxidation of cyclopropanes 26a-e (Scheme 9, Table 4). The reaction was performed in the presence of Ph 2 Se 2 (10 mol %) and azobisisobutyronitrile (AIBN, 8 mol %) in air under irradiation for two days. The product was purified by Scheme 9: Synthesis of 1,2-dioxolanes 27a-e by the oxidation of cyclopropanes 26a-e. flash chromatography to obtain a mixture of cis and trans isomers, whose ratio depends primarily on the nature of the substituent in cyclopropanes 26a-e [240].
The oxidation of methylenecyclopropanes 28a and 28b under photoinduced electron-transfer conditions is described by a similar scheme (Scheme 10). Dioxolane 33 was synthesized in the highest yields (91% from 30 and 100% from 31) in acetonitrile with the use of 9,10dicyanoanthracene (DCA) as the sensitizer [242].
After irradiation of diazene 34 in an argon matrix at 10 K, biradical 35 was detected by IR spectroscopy and the reaction of the latter with oxygen at 10 K proceeded regioselectively to give dioxolane 36 (Scheme 12) [243].
The oxidation of arylacetylenes 37a-h with atmospheric oxygen in the presence of catalytic amounts of Mn(OAc) 3 34 11 The reaction was performed at 23 °С in glacial acetic acid in air; the 37/acetylacetone/Mn(OAc) 3 molar ratio was 1/10/10. The reaction gave oxiranes 39 as by-products, which can also be synthesized in quantitative yields by the treatment of dioxolanes 38 with silica gel in methanol [245].

Peroxidation of alkenes with the Co(II)/Et 3 SiH/ O 2 system (Isayama-Mukaiyama reaction)
Peroxysilylation of alkenes with molecular oxygen in the presence of triethylsilane catalyzed by cobalt(II) diketonates was described for the first time by S. Isayama and T. Mukaiyama in 1989 [246,247]. Currently, this approach is one of the main methods for the preparation of peroxides from alkenes.
The reaction was carried out in 1,2-dichloroethane at room temperature, and the reaction products were separated by column chromatography. 1-Hydroxy-1-phenylpentan-3-one (42) was isolated as a by-product in 16% yield [248].
The peroxidation of 1,4-dienes 43a,b with the Co(modp) 2 / Et 3 SiH/O 2 system according to a similar reaction scheme gave dioxolanes 44a,b. Acetophenone (45) was obtained as the by-product (Scheme 15, Table 6) [249]. The desilylation of the initially formed silicon peroxide followed by cyclization of the hydroperoxide accompanied by the attack on the electrophilic center is another example of the use   1,2-Dioxolanes can be produced from oxetanes 53a,b containing a double bond in the side chain according to a similar scheme. The first step afforded peroxysilanes 54a,b, which upon treatment with aqueous HF gave the target dioxolanes 55a,b (Scheme 17) [250].
A similar way to 1,2-dioxolanes used an oxirane cycle for the stages of ring opening followed by 1,2-dioxolane ring closing [251].
The synthesis of spirodioxolane 59 involved the peroxysilylation of 1,3-dicyclohexenylpropan-2-yl acetate (56) catalyzed by cobalt complexed with 2,2,6,6-tetramethylheptane-3,5-dione (Co(THD) 2 ) as the first step giving 1,3-bis(1-(triethylsilylperoxy)cyclohexyl)propan-2-yl acetate (57) that was subse- The ozonolysis of unsaturated compounds is a reliable and facile method for the introduction of the peroxide functional group. As in the above-considered studies, the intramolecular cyclization of ozonolysis products can be performed with the use of the hydroperoxide group provided that there is an appropriate electrophilic center.
The reaction of oxetanes 60a,b with ozone in methanol produced 3-alkoxy-1,2-dioxolanes 62a,b. The analysis of the reaction mixture (TLC, NMR) confirmed that cyclic peroxides are formed immediately in the reaction mixture rather than in the course of the treatment or purification of the reaction products. It was suggested that the reaction proceeds via the formation of hydroperoxy acetals 61a,b (Scheme 19) [250].

Methods for the synthesis of 1,2-dioxolanes from hydrogen peroxide and hydroperoxides
This section deals with reactions, in which hydrogen peroxide or hydroperoxides are used for the construction of the fivemembered peroxide ring. In all syntheses, the final (key) step involves the intramolecular cyclization of hydroperoxide with  the attack on the electrophilic center (an activated double bond or a carbon atom of a keto or ester group).
The desilylation of tert-butyldimethylsilylperoxy ketones 131a,b with HF followed by cyclization and subsequent reaction with monomethylethylene glycol afforded dioxolanes 132a,b in 75 and 88% yield, respectively. The intermediate hydroxydioxolanes 131'a,b were used in the second step without isolation (Scheme 30) [260]. A series of analogues of plakinic acids were synthesized by the modification of the peroxyketal moiety of dioxolanes 132a and 132b [260].
A simple method was developed for the synthesis of cyclopropane-containing oxodioxolanes 143a-j and is based on the hydroperoxidation of tertiary alcohols 142a-j in an acidic medium followed by cyclization of the intermediate hydroperoxides through the ester group (Scheme 34) [265].
This method allows for the use of a nonhazardous 30% hydrogen peroxide solution. However, the authors mentioned that structurally similar tertiary alcohols, without a cyclopropane substituent, are inert under the reported conditions. 1.6. Structural modifications, in which the 1,2-dioxolane ring remains intact The possibility of performing the Curtius and Wolff rearrangements to form 1,2-dioxolane ring-retaining products was exemplified by the synthesis of ethyl (3,5,5-trimethyl-1,2-dioxolan-3yl)methylcarbamate (152) and methyl 3- Dioxolane 155 that contains a free hydroxy group was synthesized by the oxidative desilylation of silicon-containing peroxide 124 with n-Bu 4 NF and H 2 O 2 (Scheme 38) [259].
Dioxolane 158 with the aminoquinoline antimalarial pharmacophore was synthesized in two steps by the oxidation of alcohol 156 with H 5 IO 6 /RuCl 3 followed by amidation of the acid 157 (Scheme 39) [88]. It was shown that compound 158 exhibits antimalarial activity comparable with that of artemisinin [88].
Plakinic acids belong to a large family of natural products, which were shown to be highly cytotoxic toward cancer cells and fungi. Diastereomers of plakinic acid A, 162a and 162b were synthesized starting from dioxolane ((R)-3- [260]. In the first step, dioxolane 159 was treated with (1-(ethylthio)vinyloxy)-trimethylsilane in the presence of TiCl 4 to obtain S-ethyl The subsequent reaction with sodium methoxide in methanol produced the corresponding esters 161a and 161b, which were hydrolyzed to prepare the target plakinic acids (Scheme 40).

Synthesis of 1,2,4-trioxolanes (ozonides)
The currently most widely used methods for the synthesis of 1,2,4-trioxolanes are based on reactions of ozone with unsaturated compounds, such as the ozonolysis of alkenes, the crossozonolysis of alkenes with carbonyl compounds, and the crossozonolysis of О-alkylated oximes in the presence of carbonyl compounds (Griesbaum coozonolysis).

Ozonolysis of alkenes
According to the mechanism proposed by R. Criegee [268,269] the ozonolysis of alkenes 163 involves several steps: the 1,3dipolar cycloaddition of ozone to the double bond to form   [270] hexane, −78 °C 78 [256] unstable 1,2,3-trioxolane 164 (so-called molozonide) that is followed by its decomposition to a peroxycarbenium ion and a carbonyl compound (Criegee intermediates). The 1,3-dipolar cycloaddition of the intermediates with each other form the 1,2,4-trioxolane 165 (Scheme 41, Table 11). Generally, the ozonolysis is performed in aprotic solvents at low temperatures and in some cases, on polymeric substrates. Since various compounds containing a С=С group are easily available, a wide range of functionalized 1,2,4-trioxolanes can be synthesized in moderate to high yields.
The same bicyclic peroxide 180 was synthesized in good yield by the reaction of 2- (181) [93]. It should be emphasized that this method can be applied in spite of the use of triphenylphosphine, which is a strong reducing agent for peroxides.
The alkylation of the sodium salt of alcohol 183 with 2-chloropyrimidine in dimethylformamide gave ozonide 189 (Scheme 51). In this reaction, neither sodium hydride nor sodium salt 183 cleave the ozonide ring to a substantial degree. The resulting 1,2,4-trioxolanes 188 and 189 exhibit high in vitro antimalarial activity comparable with that of artemisinin and in vivo even higher activity than that of artemisinin [93].

Synthesis of 1,2-dioxanes
Modern approaches to the synthesis of 1,2-dioxanes are based on reactions with singlet oxygen, the oxidative coupling of carbonyl compounds and alkenes in the presence of manganese and cerium salts, the co-oxidation of alkenes and thiols with oxygen, the Isayama-Mukaiyama peroxidation, the Kobayashi cyclization of hydroperoxides, the reaction of 1,4-diketones with hydrogen peroxide, the intramolecular nucleophilic substitution by the hydroperoxide group, the cyclization with partici-Scheme 53: Synthesis of arterolane.
pation of halogenonium ion donors, acid-mediated rearrangements of peroxides, the palladium-catalyzed cyclization of compounds with С=С and -О-О-groups, and reactions with the participation of peroxycarbenium ions.

Methods for the synthesis of 1,2-dioxanes using singlet oxygen
The oxidation of diarylheptadienes 197a-c with singlet oxygen in acetonitrile afforded bicyclic peroxides 198a-c in 33-58% yields. 2,4,6-Triphenylpyrylium tetrafluoroborate was used as the sensitizer for singlet oxygen generation (Scheme 54) [301].  mediate formation of carbon-centered peroxide radicals. The reaction occurs in the presence of catalytic amounts of manganese or cerium salts, which are involved in a redox cycle. It is assumed that the oxidation of β-dicarbonyl compounds proceeds through a formation of an enol-containing complex with a metal ion (Scheme 57, Table 14).

Oxidation of 1,5-dienes in the presence of thiols
The co-oxidation of 1,4-dienes and thiols (thiol-olefin co-oxygenation, TOCO reaction) was described for the first time by Beckwith and Wagner as a method for the synthesis of sulfur-containing 1,2-dioxolanes [313,314]. More recently, it has been shown that under similar conditions, the oxidation of 1,5-dienes 208 affords the corresponding sulfur-containing 1,2dioxanes 209. The reaction proceeds under oxygen atmosphere in the presence of azobisisobutyronitrile (AIBN) or ditert-butyl peroxalate (DBPO) as radical initiators. The resulting unstable hydroperoxides are reduced with triphenylphosphine to hydroxy derivatives 209 (Scheme 58, Table 15).

Synthesis of 1,2-dioxanes by the Kobayashi method
The synthesis is based on the peroxidation of the carbonyl group of unsaturated ketones 228 with the urea-hydrogen peroxide complex followed by a Michael cyclization of the hydroperoxy acetals 229 under basic conditions. This method is suitable for the efficient synthesis of functionalized 1,2-dioxanes 230 in moderate to high yields (Scheme 65, Table 17). In early studies, scandium(III) triflate was used as the catalyst for the hydroperoxidation of ketones with the H 2 O 2 -H 2 NCONH 2 complex. More recently, it was shown that in some cases, cheaper catalysts such as p-toluenesulfonic and 10-camphorsulfonic acid can be used for this purpose (Table 17). It was found that cesium hydroxide can be used as a base for the cyclization to give 232 and 234. Compared to Scheme 65, the method is suitable for the cyclization of hydroperoxides 231 and 233, which are no ketone derivatives (Scheme 66) [264]. Et 3 N in MeOH can also be used as catalyst for this type of cyclization [263].
Spirodioxane 227, whose synthesis by the Isayama-Mukaiyama method was described above (Scheme 64), could also be synthesized via the ozonolysis of alkene 248 in the presence of hydrogen peroxide followed by the cyclization of bis(hydroperoxide) 249 with potassium tert-butoxide (Scheme 71) [252].
An approach to the cyclization based on an intramolecular nucleophilic substitution was used also for the synthesis of diastereomers of dioxanes 252a,b containing triple bonds. Hydroperoxides 251a,b that were synthesized by the ozonolysis of 250 were treated with potassium tert-butoxide. One of the diastereomers, 252a, was then modified first via the stereoselective hydrozirconation and iodination to 253a and then by the Negishi cross coupling to produce silylated product 254a, which was desilylated to obtain alcohol 255a (Scheme 72). 1,2-Dioxane 255a is structurally similar to natural peroxyplakoric acids having fungicidal and antimalarial activities [332].

Use of halonium ions in the cyclization
This approach to the synthesis of 1,2-dioxane rings is based on the intramolecular cyclization of hydroperoxides containing a C=C group. In the first step, the addition of a halonium ion to the double bond results in the formation of a carbocation, which is subjected to the intramolecular attack of the hydroperoxide group.

Pd(II)-catalyzed cyclization
The palladium-catalyzed cyclization of δ-unsaturated hydroperoxides 271 represents a new route to 1,2-dioxane cyclic compounds 272 (Scheme 75). The cyclization was performed in toluene, 1,4-dioxane, or 1,2-dichloroethane at 80 °C for 3 h in the presence of p-benzoquinone or silver carbonate as the oxidizing agent for Pd(0) that was formed in the catalytic cycle.
The original cyclization occurs during the oxidation of 1,4betaines 291a-d prepared from dienones 290a-d containing an azide group in the side chain. The reaction yields peroxidebridged indolizinediones 292a-d (Scheme 82) [339].
The enzymatic hydrolysis step was necessary because attempts to hydrolize ester 298 under alkaline conditions (LiOH in dimethyl sulfoxide) failed and led to peroxide ring-opening [110].

Synthesis of 1,2-dioxenes 4.1. Reaction of 1,3-dienes with singlet oxygen
The reaction of singlet oxygen with the 1,3-diene system can proceed by the following pathways: the [4 + 2]-cycloaddition, the singlet-oxygen-ene reaction, and the [2 + 2]-cycloaddition to form dioxetanes. The reaction pathway depends on the nature of the solvent, and on electronic and steric factors. However, the [4 + 2]-cycloaddition (302 + 1 O 2 ) occurs in most cases, and this reaction is frequently used for the synthesis of the 1,2dioxene system 303 (Scheme 86). Table 18 gives examples of 1,2-dioxenes synthesized by the reaction of singlet oxygen with 1,3-diene systems.
Scheme 86: Reaction of singlet oxygen with the 1,3-diene system 302.   (+)-Premnalane A is a natural compound of plant origin exhibiting pronounced antimicrobial activity. The synthesis of this compound includes the following steps: oxidation of the furan ring of compound 304, the singlet-oxygen-ene reaction of the double bond-containing bicyclic compound 305, and acidinduced ketalization (Scheme 87) [362].
6-Epiplakortolide Е is a bicyclic peroxylactone that was isolated in low yield (0.0003%) from the marine sponge Plakortis sp. The structurally related plakortolide Е (Figure 4) exhibits high cytotoxicity against cancer cells and shows also activity against Toxoplasma gondii, which is the causative agent of toxoplasmosis [184,185]. 6-Epiplakortolide Е was synthesized by the multistep synthesis involving the oxidation of diene 310 with singlet oxygen to give two isomeric 1,2-dioxenes 311a,b, the isolation of dioxene 311a, its silyl deprotection to form alcohol 312, the oxidation of the latter to 1,2-dioxenic acid 313, the I + -induced lactonization to produce 314, and the deiodination to obtain the target product (Scheme 89) [184,185]. It should be noted that the cyclic peroxide compound 314 remains intact under the reductive conditions in the presence of tributylstannane; this step occurs in good yield (68%) [184,185].
More recently, a similar approach was used for the preparation of tetrahydrofuran-containing bicyclic peroxides 318a,b. It involves the synthesis of 1,2-dioxenes 316 from dienes 315, the cation-initiated cyclization to give bicyclic compounds 317, and the reduction with Bu 3 SnH. N-Bromoand iodosuccinimides (NBS and NIS, respectively) were used as donors of halogenide ions. Additionallay, the cyclization was successfully performed with the use of phenylselenyl chloride as the donor of PhSe + cation (Scheme 90) [364]. Acids 307a and 307b were synthesized by oxidation of the corresponding alcohols with the bis(acetoxy)iodobenzene/ 2,2,6,6-tetramethyl-1-piperidinyl oxyl (BAIB/TEMPO) system. The cyclization to bicyclic peroxides 319a-f containing the lactone ring was performed with the use of N-bromo-and iodosuccinimides and PhSeCl (Scheme 91) [364]. As in the above-considered case, the peroxide ring remains unchanged upon the reduction of the С-X bond in compounds 319a-f with Bu 3 SnH [364].
The cyclopropanation of the double bond in endoperoxides 327 was performed by the reaction with diazomethane in the presence of Pd(OAc) 2 to produce 328a,b (Scheme 94) [368].

Synthesis of 1,2,4-trioxanes
This part is devoted to methods for the synthesis of the 1,2,4trioxane ring by the singlet-oxygen ene reaction with unsaturated alcohols, the photooxidation of enol ethers and vinyl sulfides, the [4+2]-cycloaddition of singlet oxygen to the pyran system, the Isayama-Mukaiyama peroxysilylation of unsatu- rated alcohols, reactions with hydrogen peroxide, and the intramolecular Kobayashi cyclization.

Use of singlet oxygen in the synthesis of 1,2,4trioxane
One of the widely used approaches to the synthesis of the 1,2,4trioxane ring 337 is based on the hydroperoxidation of unsaturated alcohols 335 with singlet oxygen (the singlet-oxygen ene reaction) and the acid-catalyzed condensation of the resulting vicinal hydroxy hydroperoxides 336 with ketones or aldehydes (acetals, orthoesters) (Scheme 96, Table 19).
The formation of peroxyketals 342a-g from vicinal hydroxyhydroperoxides 341 (oxidation products of unsaturated alcohols 340) in the presence of boron trifluoride is a convenient approach to the synthesis of the 1,2,4-trioxane ring (Scheme 98) [385].
The approach to the synthesis of 1,2,4-trioxanes proposed by Jefford and co-workers in 1993 [394] is based on the photooxidation of enol ethers or vinyl sulfides 343 with oxygen followed by the rearrangement of the resulting 1,2-dioxetanes in the presence of trialkylsilyl triflates. The resulting bicyclic compound 344 is structurally similar to artemisinin. Another version of this synthesis is based on the use of the ozone/triphenylphosphite in the oxidation step 1) (Scheme 99, Table 20).
It was shown that in this reaction the starting pyran can serve as the sensitizer for the formation of singlet oxygen [402].

Synthesis of 1,2,4-trioxanes by the Isayama-Mukaiyama method
The Isayama-Mukaiyama peroxysilylation of unsaturated alcohols 352 is a new route to hydroxy silyl peroxides 353, whose condensation with ketones in an acidic medium affords 1,2,4trioxanes 354 (Scheme 103, Table 22). the hydroperoxidation of the keto group in 358 and the epoxidation of the double bond occur followed by the acid-induced intramolecular cyclization to form bicyclic compound 359 [408].

Synthesis of 1,2,4-trioxanes by the Kobayashi method
A convenient method for the synthesis of bicyclic trioxanes 362 was developed based on the hydroperoxidation of polyfunctional compounds 360 with the urea-hydrogen peroxide complex followed by the base-mediated intramolecular cyclization of 361 (Scheme 106). The yield of hydroperoxides 361 was 86-90%. In the second step, the intramolecular cyclization was performed in the presence of a catalytic amount of diethylamine. The yields of trioxanes 362 are in the range of 10-35% [409,410]. Trioxaquines are hybrid compounds containing the 1,2,4trioxane and aminoquinoline moieties. They attracted interest because of a dual mode of action on Plasmodium. One of these compounds, PA1103/SAR116242, was selected as a drug candidate. The final step of its synthesis involves the reductive amination of keto-containing 1,2,4-trioxane 370 with N 1 -(7chloroquin-4-yl)cyclohexane-1,4-diamine (371) (Scheme 110) [86].
Trioxaferroquines, ferrocene-containing compounds, belong to a new type of hybrid molecules exhibiting high antimalarial activity. The last step of the synthesis of one of these com- 6. Synthesis fo 1,2,4,5-tetraoxanes The most widely used approaches to the synthesis of 1,2,4,5tetraoxanes are based on the reaction of ketones and aldehydes with hydrogen peroxide or gem-bishydroperoxides catalyzed by protic or aprotic acids, MeReO 3 , Re 2 O 7 , and iodine. These methods were used for the synthesis of a wide range of symmetrical and unsymmetrical 1,2,4,5-tetraoxanes.

Acid-catalyzed cyclocondensation of ketones and aldehydes with hydrogen peroxide
This cyclocondensation is the simplest route to some symmetrical (containing identical substituents in positions 3 and 6) 1,2,4,5-tetraoxanes 375 starting from ketones 374 (Scheme 112, Table 24). The acid-catalyzed reactions of hydrogen peroxide with dialkyl ketones, cycloalkanones, and substituted mediumsize cycloalkanones produce symmetrical 1,2,4,5-tetraoxanes in  [416] moderate to high yields. The drawback of this method is the high sensitivity of the yields of the target peroxides to the structure of the starting carbonyl compounds.  Structurally more simple ketones, for example, acetone, are also involved in the cyclocondensation with bishydroperoxide 400 [141]. The synthesis of keto-containing tetraoxane 403 was also performed in two steps [144]. Thus the intermediate 1,1-dihydroperoxycyclohexane 402 was prepared from cyclohexanone in a neutral medium, and its condensation with 1,4-cyclohexanedione was carried out in the presence of HBF 4 (Scheme 123).

Cyclocondensation of bishydroperoxides with acetals and enol ethers
The method for the synthesis of 1,2,4,5-tetraoxanes 407 and 408 is based on the boron trifluoride etherate-catalyzed reaction of gem-bishydroperoxides 404 with enol ethers 405 and acetals 406 under mild conditions. More than two dozens of tetraoxanes were synthesized in yields from 45 to 95% according to this method (Scheme 124). The advantage of this method is the use of readily available starting compounds, such as acetals, enol ethers, and boron trifluoride etherate [424,425].

Iodine-catalyzed one-pot synthesis of symmetrical and unsymmetrical tetraoxanes
The reaction of substituted benzaldehyde 412 with hydrogen peroxide in the presence of the Lewis acid I 2 produced geminal bishydroperoxide, whose condensation with the starting or another substituted benzaldehyde gave tetraoxane 413 (Scheme 126, Table 26) [426,427].
The iodine-catalyzed one-pot synthesis of symmetrical and unsymmetrical tetraoxanes from substituted benzaldehydes has some advantages over other methods. Thus, it can be performed with the use of mild reagents (which do not decompose peroxide) and it does not need an excess of hydrogen peroxide and substituted benzaldehyde.

Acid-catalyzed condensation of β-diketones with hydrogen peroxide
The acid-catalyzed condensation of β-diketones 414a-l with hydrogen peroxide is a simple and facile method for the synthesis of bridged 1,2,4,5-tetraoxanes 415a-l. This method enables the synthesis of these compounds on the multigram scale in 47-77% yields (Scheme 127). The high concentration of a strong acid, such as H 2 SO 4 , HBF 4 , or HClO 4 (2 g of the acid per 5 mL of the solvent) is the key factor determining the yield and selectivity of the synthesis of 1,2,4,5-tetraoxanes. Under these conditions, the targeted compounds are produced selectively even in the presence of an excess of hydrogen peroxide [428]. Unlike many compounds with the O-O bond, which are rearranged in acidic media, the resulting cyclic peroxides are fairly stable under these reaction conditions. It was found that phosphomolybdic acid and phosphotungstic acid efficiently catalyze the addition of H 2 O 2 to β-diketones resulting in the selective formation of bridged 1,2,4,5-tetraoxanes. The use of these catalysts made it possible to obtain bridged tetraoxanes from easily oxidizable benzoylacetone derivatives and α-unsubstituted β-diketones [429]. For example, the ozonolysis of verbenone 419 via the formation of zwitterioninc structures 420 and 421 gives a mixture of two symmetrical 1,2,4,5-tetraoxanes 422 and 423 (Scheme 129) [430]. Peroxides 422 and 423 are unstable due to the presence of carbonyl groups adjacent to the O-O group, and they almost completely decompose as the temperature is raised.
The synthesis of unsymmetrical steroidal tetraoxane 429 in 19% yield was performed by the intramolecular cyclization of dialdehyde 428 with hydrogen peroxide under acidic conditions (Scheme 132) [434].
6.11. Structural modifications, in which 1,2,4,5tetraoxane ring remains intact In the last two decades, 1,2,4,5-tetraoxanes were considered as the most promising compounds for the design of antiparasitic drugs. This is due, first, to the high activity of their derivatives and, second, to a wide scope of structural modifications, in which the tetraoxane ring remains intact. An interesting feature of the synthesis according to Scheme 135 is the use of such strong reducing agents as LiAlH 4 and NaBH(OAc) 3 , with the products retaining the peroxide ring.
Steroidal tetraoxane 448, which is approximately six times more active that Artelinic acid and 2.4 times as active as arteether against P. falciparum, was also synthesized by the alkaline hydrolysis of ester 401g followed by the amidation of acid 447 (Scheme 136) [128].
Compounds containing a fluorescent moiety are of interest in terms of the mechanism of antiparasitic action of peroxides. For example, 1,2,4,5-tetraoxane 454 containing the 4-chloro-7methylbenzo[c] [1,2,5]oxadiazole moiety was synthesized according to Scheme 137. In the first step, ketone 449 was transformed in tetraoxane 450, whose ester group was subjected to the alkaline hydrolysis to form acid 451 followed by the amidation to give 452 and the hydrolysis to obtain hydrochlo-ride 453. Then the reaction of the latter with 4-chloro-7nitrobenzo[c] [1,2,5]oxadiazole afforded the target compound 454 [138].
The synthesis of tetraoxane 458 (RKA182) exhibiting the in vitro and in vivo activity comparable with that of artemisinin was performed on the kilogram scale according to Scheme 138. This compound is a promising malaria drug candidate [82,83].
The key steps in this synthesis are the preparation of adamantane-containing tetraoxane 456 from ethyl 2-(4oxocyclohexyl)acetate (455), the hydrolysis of 456, and the purification to obtain acid 457. The amidation of the latter affords target product 458.

Conclusion
The review summarizes and generalizes studies on the synthesis of five-and six-membered cyclic peroxides published last decade (since 2000 to present). Most of the currently established methods for the synthesis of these compounds are based on the use of such key oxidizing agents as oxygen, ozone, and hydrogen peroxide. The Isayama-Mukaiyama and Kobayashi methods are widely used in the synthesis of 1,2-dioxolanes, 1,2dioxanes, and 1,2,4-trioxanes. The reactions with the participation of peroxycarbenium ions play an important role in the synthesis of peroxides. The Griesbaum coozonolysis of ketones and O-alkyl oximes is the most flexible and efficient method for the synthesis of unsymmetrical 1,2,4-trioxolanes. The [4 + 2]-cycloaddition of oxygen to a 1,3-diene system is, in fact, the only route to 1,2dioxenes.
Methods for the synthesis of 1,2,4,5-tetraoxanes are based on reactions of ketones, aldehydes, and their dialkyloxy derivatives with hydrogen peroxide or gem-bishydroperoxides catalyzed by protic and aprotic acids, such as MeReO 3 , Re 2 O 7 , and iodine.
Modifications of functional groups to form peroxide ringretaining products are applicable to the synthesis of cyclic peroxides of various structural types. This approach can be used to prepare complex peroxides exhibiting antiparasitic and antitumor activities.
Carbonyl compound are generally employed as the starting reagents in the synthesis of cyclic peroxides. These methods can be used for the selective peroxidation of monocarbonyl compounds. In the case of dicarbonyl compounds, there are a limited number of efficient procedures for the synthesis of cyclic peroxides.