Synthesis of Oxetanes

Zhicheng Fu; Jiaxi Xu

doi:10.7536/PC200758

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (6) : 895-906 DOI: 10.7536/PC200758

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Synthesis of Oxetanes

Zhicheng Fu
, Jiaxi Xu ^*

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Abstract

Oxetanes are a class of saturated four-membered cyclic ether compounds. They are not only an important class of organic synthetic intermediates, but also crucial active structural units of natural and synthetic biological and medicinal active compounds possessing anti-cancer, inhibition of human immunodeficiency virus, as well as inhibiting glutamine synthetase in clinical practice. Thus, it is in high demand to develop efficient methods for constructing oxetane structural motifs. In this review, the intramolecular cyclization reaction via C—C bond formation, the intramolecular Williamson etherification by the formation of C—O bond, the [2+2] photocycloadditions of alkenes with aldehydes and ketones(named as Paternò-Büchi reaction), transition metal catalyzed formal [2+2] cycloadditions, sulfide ylide-mediated epoxide ring expansion, and the C—H bond oxidative cyclization are reviewed with a focus on new progress in the synthesis of oxetanes during the last five years. It is hoped that this review can provide some valuable information for the organic chemists who are interested in the construction of the oxetane skeleton and promote the development on the synthesis and application of oxetanes.

Contents

1 Introduction

2 Cyclization through the C—C bond formation

3 Cyclization through the C—O bond formation

4 Ring expansion reaction of epoxides

5[2+2]Cycloadditions

5.1 Paternò-Büchi[2+2]photocycloadditions

5.2 Formal[2+2]cycloadditions

6 C—H bond oxidative cyclizations

7 Conclusion

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Keywords

oxetane / ring expansion / cyclization / cycloaddtion / C—H oxidative cyclization

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Zhicheng Fu, Jiaxi Xu. Synthesis of Oxetanes. Progress in Chemistry, 2021, 33(6): 895-906 DOI:10.7536/PC200758

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1 Introduction

The parent structure of oxetane compounds was first synthesized by Reboul in 1878^[1]. In 1909, Patern Paternò et al. Found that benzophenone 1 and norbornene 2 could react under light to give a new compound^[2]. In 1954, B Büchi et al. Confirmed that the [2 + 2] cycloaddition reaction occurred in this reaction, resulting in oxetanes, which is the classic Patern Paterní-B Büchi reaction^[3]^[4,5]. Later, after nearly 70 years of development, it was found that the important four-membered cyclic ether oxetane skeleton is not only a key pharmacophore in natural products such as paclitaxel or drugs and an important intermediate in organic synthesis, but also an important raw material for the production of ether polymers, which also have very important applications in polymer chemistry and other fields^[6,7]^[8⇓~10].

In the field of medicinal chemistry, the oxetane structure is often used as a substitute for gem-dimethyl and carbonyl groups to improve the physicochemical properties of the parent molecule^[11⇓~13]. In the field of organic synthesis, oxetane can undergo nucleophilic ring-opening, rearrangement, ring expansion and other functional group conversion reactions to construct organic compounds with diverse structures because of its high ring tension^{[14⇓⇓⇓⇓⇓~20]}. In natural products, the oxetane skeleton shows unique biological activity. Natural products with oxetane structure, such as taxol, have played an important role in the history of fighting cancer and promoting the development of organic chemistry.The complex ring system and excellent biological activity of taxol have attracted great interest of synthetic chemists and pharmaceutical chemists. In 1971, scientists isolated Taxol from the stem bark of the western Pacific purple shirt (purple shirt genus) and found that it could be used for cancer treatment. It was found that the oxetane structure acted as conformational locking, structural stabilization and hydrogen bond acceptor in the taxol structure^[21,22]. Later, many natural products containing oxetane fragments, such as Paclitaxel, Oxetin, Oxetanocin a, Mitrephorone a, Thromboxane A2, vitamin D3 analogues, Merrilactone A, Maoyecrystal I, Dict yo, which have anti-HIV, anti-cancer and glutamine synthetase inhibition effects, were isolated from soil bacteria, Streptomyces and spinach leaves^{[23⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓~40]}.

Oxetane, as a saturated four-membered heterocyclic ring containing oxygen, has a ring tension of 106 kJ/mol, which is slightly smaller than the ring tension energy of 112 kJ/mol of oxetane. Single crystal diffraction analysis shows that it has a nearly planar structure, and the presence of oxygen atoms significantly reduces the guache interaction in the structure, which weakens the ring tension^[41,42]. In addition, the presence of a lone pair of electrons on the oxygen allows the oxetane compound to act as a Lewis base and a hydrogen bond acceptor. Because of these unique structures, oxetanes are often used as bioisostere of dimethyl and carbonyl groups to improve the physicochemical and pharmacokinetic properties of drug skeletons^[43,44]. For example, in 2006, Carreira et al. Reported that 3,3-disubstituted oxetanes have the potential to replace gem-dimethyls in the field of medicinal chemistry^[11]. It was found that the introduction of the oxetane fragment avoided the defect of excessive lipophilicity of the gem-dimethyl, and improved the drug solubility, pharmacokinetic properties and metabolic stability. In addition, carbonyl compounds (aldehyde ketone esters) contained in drugs are vulnerable to enzyme attack, deprotonation and racemization of chiral centers in the human body. The introduction of oxetane structures with different chain length substituents improves this result and also increases the affinity of the drug for the target cell. In addition, the oxetane fragment also has an electron-withdrawing effect on the electron, which can improve the acidity and basicity of the parent compound^{[45⇓⇓⇓⇓~50]}.

It is of great significance to explore the synthesis method of oxetane. In 2016, Morgan et al published a Review in Chemical Review, which introduced the progress in the synthesis, reactivity and pharmaceutical chemistry of oxetane in the five years from 2010 to 2015, and also provided previous summary articles^[6]. In this paper, the latest achievements in the synthesis of oxetanes in the past five years from 2016 to 2020 are reviewed, including the cyclization of C — C bond formation, the cyclization of C — O bond formation, [2 + 2] cycloaddition reaction, ethylene oxide ring expansion reaction and C — H bond oxidative cyclization reaction.Including the application of each method in the synthesis of natural products and drugs, providing some valuable information for organic synthesis colleagues, especially for scholars studying the synthesis and application of oxetanes.

2 Intramolecular Cyclization Reaction of C-C Bond Formation

In recent years, there are few reports on the construction of oxa-four-membered ring structure by the formation of C-C bond. The conventional methods are mainly intramolecular substitution reactions, and no novel methods have been reported. In this paper, we will select some reports before 2016 and combine them with the development of the last five years to describe the latest achievements of this kind of method.

In 2013, Bull et al. Used the method of constructing the four-membered ring skeleton through C — C bond formation in the process of designing and synthesizing 2-sulfonyloxetane compounds based on the fragment-based drug discovery strategy^[51]. Namely, starting from a sulfone ether compound 3 as a raw material, a 2-sulfonyl oxetane compound 4 is obtained by intramolecular cyclization under the condition of strong base LiHMDS, wherein the sulfonyl group plays a role of stabilizing the carbanion (scheme 1).

In the second year, they continued to use the cyclization strategy of C-C bond formation to develop a mild and efficient method for the synthesis of multi-functional di-, tri- and tetra-substituted oxetanes^[52]. The most critical feature of this approach is the development of mild and widely applicable cyclization precursors. In order to construct the C — X (X = N, O, S) bond, the X — H bond was activated by the transition metal, and then the X — H insertion occurred with the diazotized carbene to form the C — X bond, and then the cyclization product was formed through the C — C bond. Diazopropionate 5 and ethylene glycol or a haloethanol compound 6 were reacted in the presence of a rhodium catalyst to give a cyclized precursor ether compound 7 in 77% yield. To facilitate rapid cyclization, the ethylene glycol moiety can be constructed as a leaving group by methanesulfonylation or halogenation, and finally construction of the oxetane skeleton 8 is achieved under basic conditions (Scheme 2).

In 2017, Moody et al. Reported that the diazonium ester underwent rhodium carbene C-H insertion to form β-propiolactone under the catalysis of rhodium metal, and then reduced to obtain spirooxetane compounds^[53]. The carbene precursor 12 was obtained from the reaction of the easily available ketoester 9 with hydrazine 10 to form hydrazone, followed by diazotization in a packed column containing the oxidant PS-TsNIK 11. Then, without separation, the selective intramolecular C — H bond insertion reaction was carried out in the presence of rhodium (II) 13 under reflux in dichloromethane to give the structurally diverse spiro β — propanolactones 14 in 32% ~ 88% yields. This was followed by DIBAL-H low temperature reduction to give the diverse 3-spirooxetane product 15 in yields of 44% to 91%. The whole reaction process is simple and convenient to operate, the diazonium compound does not need to be separated, and the substrate has good universality and specific regioselectivity. A series of novel oxetane skeleton-containing compounds 15A to 15g (scheme 3) were obtained by functional group conversion of spirooxetane compounds.

The synthesis of oxetanes via intramolecular carbon-carbon bond formation cyclization is centered around transition metal-catalyzed O — H insertion followed by nucleophilic substitution cyclization. Or firstly preparing a diazoacetate cyclization precursor, and then realizing the construction of a multi-substituted four-membered ring skeleton by means of transition metal-catalyzed C-H bond insertion and reduction. However, the efficient and asymmetric synthesis of multi-substituted oxetanes has been a great challenge for this method, and how to achieve a novel C — C bond formation method with high efficiency, high enantioselectivity and wide substrate universality to synthesize oxetanes is still a goal worth exploring.

3 Intramolecular Cyclization Reaction of C-O Bond Formation

The intramolecular cyclization reaction formed by C — O bond is the earliest and most common method to construct the oxetane skeleton. Star from that earliest Williamson etherification reaction, the 2-substituted oxetane compound 17 (scheme 4) is obtain from the gamma-halohydrin starting material 16 by an intramolecular S_N2 nucleophilic substitution reaction under basic conditions^[54].

Later, after decades of development, Williamson etherification became more mature, and the raw materials became more accessible and diverse, from γ-halohydrins to γ-diols, β, γ-epoxy alcohols, γ-ester alcohols, γ-ether alcohols and so on. Although starting from different raw materials, the reaction mechanism is similar, that is, S_N2 substitution reaction. The hydroxyl group of the alcohol can be obtained by the ring opening of the corresponding aldehyde, ketone, ester, ether and epoxy, and the halogen is used as a leaving group in the intramolecular nucleophilic substitution reaction and can be replaced by other groups with better leaving ability, such as sulfonate OTf, OTs and the like (scheme 5)^{[55⇓⇓⇓⇓~60]}.

In 2019, Marini et al. Developed a novel method for the synthesis of spiroindolinones containing 3-oxetane, inspired by the cyclization of vinyl selenesulfone and the nucleophilicity of 3-hydroxyindolinones^[61]. Starting from compound 18 and phenylvinylselenesulfone 19, a novel spiroindolinone-containing oxetane compound 21 (Scheme 6) was obtained in moderate yield after a domino Michael addition and cyclization step under basic aqueous solution conditions. The formation of that Michael addition product 20 dure this reaction is a critical step. The method utilizes the double properties of the selenesulfone functional group with electron withdrawing and strong leaving ability, can promote the cyclization process in an alkaline aqueous solution, and has unique reactivity and practicability. In addition, phenyl vinyl sulfone reagents were also tried, but only 55% of the addition products were obtained, indicating that their reactivity was not as good as that of selensulfone compounds.

With the development of transition metal asymmetric catalysis, this method has shown its unique advantages of atom economy and high efficiency. Therefore, organic synthetic chemists have also attempted to synthesize novel oxetanes by metal-catalyzed intramolecular cyclization of C — O bond formation. Allyl or propargyl alcohol is used as a substrate, a transition metal is used for activating carbon-carbon double bonds and triple bonds to form an electron acceptor similar to a carbene intermediate, and then cyclization reaction is carried out to obtain a four-membered ring skeleton.

In 2010, Zhang et al. Used gold-catalyzed secondary propargyl alcohol 22 to produce oxetone compound 24 with 57% -82% yield in one step under the condition of pyridine oxynitride 23 as oxidant, and the latter was reduced to oxetane compound 25 (Scheme 7)^[62]. The method has the characteristics of simple operation, good substrate applicability, and reaction by open stirring.

In addition, the asymmetric reaction to realize this kind of method is also the development direction at present. However, the main challenge is how to obtain γ-diol or its analogues with high stereochemical specificity, and how to control the stereochemistry during the cyclization process to avoid racemization. In 2016, Krische et al. Designed and synthesized a class of rigid iridium catalysts 28, and completed the first asymmetric synthesis of spirooxetanes containing quaternary carbon centers^[63].

Using primary alcohol 26 and allyl oxirane 27 as substrates, a highly chemoselective and enantioselective isopentenediol intermediate 29 was obtained by asymmetric control strategy of C-C bond formation and transfer hydrogenation, and then 2,3,3-trisubstituted oxetane compound 30 (Scheme 8) was obtained by one-pot p-toluenesulfonylation and S_N2 cyclization. In order to prove the practicability of this method in the field of medicinal chemistry, it was also applied to the synthesis of haloperidol, an important antipsychotic drug^[64]. Starting from the substrate 31, the analog 33 was obtained by hydroboration oxidation and C-N coupling reaction, with a total yield of more than 80% (Scheme 9).

4 Oxirane ring enlargement reaction

Ring enlargement is one of the most important methods for the synthesis of heterocyclic compounds. The process of ring enlargement from nitrogen and thia-three membered rings to four-membered rings started late and has attracted much attention^{[65⇓⇓⇓⇓⇓⇓⇓⇓~74]}. The expansion of oxa-three membered rings into four-membered rings was discovered earlier and has been relatively more mature. In 1979, Welch et al. Reported that sulfoxide oxime anion, as a methylene transfer reagent, reacted with ketones in dimethyl sulfoxide at 40 ℃ to give oxetanes via ring expansion of the oxetane intermediate. However, the method has the problems of complex raw material preparation and low efficiency^[75]. In 1983, Ohta et al., by adjusting the methylene transfer reagent, developed the use of a common dimethyl sulfoxide methyl ylide 35 as a reagent to directly obtain 2-substituted and 2,2-disubstituted oxetanes 37 (Scheme 10) by in situ ring enlargement reaction with oxetanes 36 obtained by the Corey-Chaykovsky epoxidation of aldehydes and ketones 34 under one-pot conditions. The method has the characteristics of simplicity, high efficiency, mild conditions and wide substrate tolerance^[76].

After more than 20 years of development, people have a clearer understanding of the formation of oxirane from aldehydes and ketones and their ring expansion reactions, and a series of asymmetric catalytic methods have been developed^[77,78]^[6]. Before 2016, Fokin et al. And Shibasak et al. Mainly realized two asymmetric reaction modes: stereospecific reaction of optically active oxetanes to 2-substituted/2,2-disubstituted oxetane products; Stereospecific 2-substituted/2,2-disubstituted oxetane products were obtained from aldehydes and ketones by kinetic resolution of chiral metal complexes. Both methods are characterized by high yields and high ee values^[79,80].

In recent years, with the development of fluorine chemistry, it has been recognized that the introduction of fluorine atoms into drug molecules can change the lipophilicity, hydrogen bonding, metabolic stability and bioavailability of drugs, and can improve the activity of drugs^[81]. In 2017, am Ende et al. Found that the introduction of 2-trifluoromethyloxetane fragments into γ-secretase modulators for the treatment of Alzheimer's disease can improve the lipophilicity of drugs, which has potential application prospects^[82]. At that time, there was no report on the synthesis of oxetane substrates containing strong electron-withdrawing substituents such as trifluoromethyl, so trifluoromethyl ketones 38 were selected as substrates.Dimethyl sulfoxide methyl ylide is used as a nucleophilic methylene transfer reagent 35 to obtain 2-trifluoromethyloxetane compounds 39 (scheme 11) with 46% -78% yield and good substrate tolerance under mild conditions. In addition, this method was also used to synthesize a γ-secretase modulator analog 45 (Scheme 12), which showed good physicochemical properties and pharmaceutical activity through biological activity tests.

The synthesis of oxetanes by ring enlargement of oxetanes is one of the most important methods for the synthesis of 2,2-disubstituted oxetanes, which has been well developed and has shown good application value in both the regulation of methylene transfer reagent sulfur ylide and the modification of substrate structure by cheap and readily available ketone substrates. However, how to develop more asymmetric catalytic synthesis methods of optically active oxetanes and apply them to the synthesis of natural products or drug molecules is also one of the important directions of its next exploration.

5 [2 + 2] cycloaddition

5.1 Patern Paterní-B Büchi [2 + 2] photoreaction

Since the discovery by Patern Paternò and Chieffi in 1909 of the first photomediated cycloaddition of a carbonyl compound 1 to an alkene compound 2 to give an oxetane compound 46 (Scheme 13), this reaction has been studied without interruption^[2]. In order to determine the structure of the product as an oxetane derivative, scientists have been exploring for nearly half a century. In 1954, B Büchi et al repeated the experiment and confirmed that it was an oxa-four-membered ring structure^[3]. In 1964, Yang et al. First discovered the general law of its chemoselective cyclization, and since then the Patern PaternⅡ-B Büchi reaction has become famous^[4]. A mechanistic study of the reaction found that the diradical intermediate 47 was mainly involved^[83]. The ketone carbonyl is excited by light and undergoes intersystem crossing to form a triplet, which then reacts with the C = C double bond to form a triplet radical intermediate 48, which then undergoes rapid intersystem crossing to form a singlet diradical intermediate, and then undergoes cyclization to construct a four-membered ring or breaks the C — O bond back to the raw material (Scheme 14). The Patern PaternⅡ-B Büchi reaction has obvious substrate limitation, and the more stable the diradical intermediate is, the higher the activity of the olefin is, and the more favorable the cyclization is to obtain the oxa-four-membered ring compound. This reaction is suitable for the construction of oxetane structures from aromatic ketones or aldehydes and electron-rich olefins. For alkyl ketone substrates, ultra-high pressure irradiation and quartz reactor are mostly needed, which are not practical and friendly to operate.

After a century of development, organic synthesis chemists have been committed to solving the problem of substrate versatility in this reaction. In 1964, it was discovered that an unsubstituted cumene 49 reacted with a ketone 50 under light conditions to give an exocyclic olefinically substituted oxetane structure 51 (Scheme 15)^[84]. However, this method has obvious disadvantages: firstly, it requires the use of excessive cumulated dienes; secondly, there are unavoidable side reactions in the cycloaddition process; and thirdly, the selectivity of ring closure is poor.

In 2012, Schmidt et al. Used the method of transition metal catalysis to activate olefins by charge transfer between the central metal and the ligand under the condition of light radiation to obtain active metal species, which were then captured in situ by alkyl aldehyde ketone carbonyl to obtain [2 + 2] oxetane products (Scheme 16)^[85]. The optimum reaction conditions were as follows: ketone 52 reacted with norbornene 2 in a molar ratio of 1 ∶ 3 in the presence of 10 mol% tripyrazolylboron-copper (Ⅰ) complex (TpCu) 53 in diethyl ether under 100 W mercury lamp for 12 ~ 48 H to give the target compounds in 41% ~ 85% yields with high selectivity (exo: endo > 95 ∶ 5). It is worth mentioning that TpCu- (Norb) 54 produced by the system is an important photoactive species, which plays a vital role in the smooth reaction. The mechanism of this reaction is that the TpCuI compound 55 coordinates to the alkene 2 to form TpCu (Norb) 54 (fig. 2), which undergoes metal-ligand charge transfer under illumination at 280-300 nm to give the Cu (II) metal center and the radical anion species of the alkene 56, which is then captured by the carbonyl group to give the target compound 57 (fig. 17).

In addition to the above [2 + 2] reaction using photo-excited metal-olefin complexes, Ouyang et al. reported another novel and simple reaction mechanism to promote the reaction^[86]. Under the induction of visible light, the compound 59 of diphenyl ketone 1 and unsaturated lipid 58 combined by non-covalent force can promote the ring closure of C = C bond and C = O bond to form an oxa four-membered ring product 60. The first [2 + 2] reaction of ketones and alkenes promoted by visible light was found through mass spectrometry and calculation. The mechanism study found that the proton pair promoted the electron transfer from the C = C double bond in fat to the carbonyl group, forming a dimer species of double bond and carbonyl group by non-covalent bond, and oxetane could be obtained under visible light conditions (Scheme 18).

5.2 Formal [2 + 2] cycloaddition reaction

In addition to the photocatalytic [2 + 2] cycloaddition reaction, the formal [2 + 2] cycloaddition reaction has also been reported. From 2010 to 2011, Mikami et al. Developed the Lewis acid-catalyzed activation of alkenes and trifluoro pyruvate ester 61 to form the formal [2 plus 2] Cycloaddition reaction to construct polysubstituted oxetane compounds^[87,88]. Different transition metal catalysts are selected according to different substrates. When the olefin is vinyl silyl ether 62, Cu (II) bis oxazoline complex 63 is selected; When the olefin is vinyl acetate 64, the Pd (II) -BINAP complex 65 is selected. When the vinyl substrate is replaced by an alkynylsilane 66, high yields and enantioselectivity of the oxa-four-membered ring compounds 67 and 68 can be obtained under the conditions of the chiral cationic BINAP-Pd complex 65 (Scheme 19).

In addition to Lewis acid catalysis, Lewis base catalyzed forms of [2 + 2] cycloaddition have recently been reported. In 2011, Ye et al. Catalyzed this kind of cycloaddition reaction with DABCO. The unsubstituted cumulate dienoate 70 reacted with trifluoromethyl ketone 71 in the presence of 20 mol% DABCO to afford the 2-alkenyloxetane compound 72 (Scheme 20) in high diastereoselectivity and moderate yield,The mechanism is shown in Scheme 21: the chiral tertiary amine 73 selectively adds to the cumulated diene bond to give zwitterionic intermediates 74 and 75, which in turn add to trifluoromethyl ketone 71 to give intermediate quaternary ammonium salt 76, which in turn undergoes intramolecular cyclization to give intermediate 77, followed by quaternary ammonium salt elimination to release the tertiary amine catalyst and give the target compound^[89]. On this basis, in 2012, Shi et al. realized the asymmetric [2 + 2] cycloaddition reaction of cumulate dienoate 70 with trifluoromethyl ketone 78 using chiral tertiary amines (Scheme 22)^[90]. Through the screening of chiral amine catalysts, it was found that the reaction could be successfully carried out under the conditions of 20 mol% β-ICD 79, 10 EQ. Water and low temperature, and good yields and ee values were obtained. The hydrogen bonds in the transition state of the system played a vital role in the enantioselectivity control.

In 2013 and 2015, Chi et al. And Smith et al. Reported that the [2 + 2] cycloaddition of aldehydes and trifluoromethyl ketones could be asymmetrically catalyzed by azacyclocarbene to produce unsaturated esters containing oxetane structure, which could be reduced to oxetane compounds with diverse structures and optical activity^[91,92]. Inspired by this, in 2018, Scheidt et al. First reported the formal [2 + 2] cyclization of an azacyclocarbene (NHC) 81-catalyzed gamma-substituted cyclopentadienoate 82 with trifluoromethylketone 83 to give 2-alkenyl-substituted oxetanes 84 and 85 in excellent yields and good diastereoselectivity in one step (Scheme 23)^[93]. A further functional group conversion of that carbon-carbon double bond of the olefin 86 gave the diverse oxetane compound 87 and 88 (scheme 24). The systematic mechanism study showed that the N-heterocyclic carbene catalyst 89 attacked the β-carbon position of the cumulate diene and produced the zwitterionic intermediate 90 by nucleophilic addition, which then reacted with the ketone to produce the intermediate 91 by nucleophilic addition at the γ-position.The oxygen anion then attacks the beta carbon of compound 91 to yield the enol intermediate 92, and finally the NHC is regenerated by reductive elimination and the target compound is released to complete the catalytic cycle (Scheme 25).

Acid-base catalyzed [2 + 2] cycloaddition reaction has great potential for development because of its simple operation, high efficiency and selectivity, and good tolerance of substrate functional groups.

6 Oxidative cyclization of C-H bond

As mentioned earlier, oxetane-containing structures are widely found in natural products, such as taxol, oxetanocin A, oxetinoxetin, merrilactone A, etc., in which the introduction of oxetane is the core of the synthetic strategy. However, the conventional methods of ring enlargement, [2 + 2] cycloaddition reaction and nucleophilic substitution reaction to form oxetanes have great substrate limitations. How to realize the construction of this core fragment in natural products has been a challenging work.

(-) -Mitrephorone A93 is a diterpenoid isolated from the Borneo shrub Mitrephora glabra by Oberlies et al. In 2005. (-) -Mitrephorone A has a compact six-ring skeleton with highly substituted oxetane and cyclopropane modifications, five consecutive stereocenters, four quaternary carbon centers, and a rare 1,2-dione structure (Fig. 3). The natural product has potent and broad-spectrum inhibitory activity against various tumor cell lines (KB, MCF-7, NCI-H460, SF-268) in addition to antibacterial activity^[94].

After 13 years of hard exploration, scientists finally achieved the first asymmetric total synthesis of it. Carreira et al. Constructed all the carbon rings quickly by three [4 + 2] cycloadditions, and the key oxetane structure was constructed by the later oxidative cyclization of the hydroxybutol structure and the Koser's reagent^[95]. Selenium dioxide is oxidized to form a diketone (Riley oxidation) 94, which is isomerized to an enol 95 while removing the silicon protecting group with TABF, and the enol is further subjected to the action of a trivalent iodine reagent PhI (OH) OTs (Koser's reagent) to obtain an intermediate 96, which is subjected to 4-exo-trig oxidative cyclization to finally complete the synthesis of the natural product (-) -Mitrephorone A 93 (Scheme 26).

In recent years, biogenic synthesis strategy has been paid more and more attention by scientists. Inspired by this, Austrian scientist Magauer et al. First reported the total synthesis of mitrephorone B 97 in 2020, and mitrephorone A was synthesized through iron-catalyzed oxidative cyclization of C-H bond, electrochemical oxidation and photochemical oxidation, and highly substituted oxetane was obtained in only one step (scheme 27)^[96]. This is of great significance for the total synthesis and diversity synthesis of this kind of natural products.

Through the screening of oxidants and the study of structure-related substrates, it was found that the yield of this oxidation step was not high, which indicated that the current C — H bond oxidative cyclization methods still had limitations and development space, and the biogenic synthesis pathway needed further study.

7 Conclusion

Oxetane is a kind of saturated oxa small ring compound, which plays an important role as a structural unit in natural products, pharmaceutical chemistry, material chemistry and organic synthesis. In this paper, the synthesis methodology of oxetanes in the past five years was systematically reviewed, which has important guiding significance for the study of the construction of oxetane four-membered ring skeleton. Reviewing the development history of the synthesis of oxetanes in the past one hundred years, it is found that the cyclization via C — C bond and C — O bond is the earliest and more mature among the existing methods, such as cyclization via C — C bond, cyclization via C-O bond, [2 + 2] cycloaddition reaction, ring enlargement reaction and oxidative cyclization of C — H bond. However, [2 + 2] cycloaddition reaction, ring enlargement reaction and C — H bond oxidative cyclization reaction have more research space, because these methods generally have the disadvantages of limited substrates, many steps and few asymmetric methods. In recent years, with the rapid development of photochemistry, electrochemistry and biomimetic synthesis, how to combine the characteristics and advantages of new synthesis methods to broaden the asymmetric synthesis methodology of oxetanes and overcome the above limitations will be the next research goal of organic synthesis workers.

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