Recent synthesis of thietanes

Thietanes are important aliphatic four-membered thiaheterocycles that are found in the pharmaceutical core and structural motifs of some biological compounds. They are also useful intermediates in organic synthesis. Various synthetic methods of thietanes have been developed, including inter- and intramolecular nucleophilic thioetherifications, photochemical [2 + 2] cycloadditions, ring expansions and contractions, nucleophilic cyclizations, and some miscellaneous methods. The recently developed methods provide some new strategies for the efficient preparation of thietanes and their derivatives. This review focuses on the synthetic methods to construct thietane backbones developed during 1966 to 2019.


Synthesis via double nucleophilic displacements of 1,3dihaloalkanes:
Although the double nucleophilic displacements of 1,3-dihaloalkanes with sodium sulfide are the oldest methods for the preparation of thietane derivatives and have well been studied, they are widely applied till now. The development of this method before 1965 was reviewed by Sander [12] and this review contains new advances since 1965.
The double displacement cyclic thioetherification strategy was also utilized for the synthesis of thietane-containing spironucleosides. The easily available 5-aldo-3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose (36) was first treated with formaldehyde in the presence of NaOH followed by MsCl, affording the dimesylate derivative 38, which was reacted with Na 2 S to afford the spirothietane 39. The latter was further converted into the thietane-containing spironucleoside 40 [40] (Scheme 8).
intermediate. It was further applied in the total synthesis of four different natural products of Nuphar sesquiterpene thioalkaloids 58 and 59 [43] (Scheme 13).

Synthesis via the direct cyclic thioetherification of γ-mercaptoalkanols:
The direct cyclic thioetherification of γ-mercaptoalkanols was regarded as an efficient route to synthesize thietanes. Indeed, the direct cyclization of the 3-mercapto-propan-1-ol unit in 60 with Ph 3 P(OEt) 2 as a reagent was realized in the synthesis of the spirothietane derivative 61 [44] (Scheme 14).
The treatment of 2-(allylthio)benzimidazole 69 with iodine in CHCl 3 followed by aq. KOH gave (iodomethyl)thiazolobenzimidazole 70 which was converted to thiazolobenzimidazolium perchlorate 71 by methylation with dimethyl sulfate and addition of HClO 4 . After the treatment with KOH powder in MeCN and subsequent hydrolysis it gave thietanylbenzimidazolone 75. In the last step, the hydroxide ion first nucleophilically added to the iminium 71 to generate an O,S-hemiacetal 72. Under the basic conditions, the hemiacetal 72 converted to the thiolate 74, which underwent an intramolecular substitution to give the final product thietanylbenzimidazolone 75 [46] (Scheme 16).
In 2004, Schulze and co-workers synthesized 3,5-anhydro-3thiopentofuranosides 104 from methyl α-and β-arabinosides 101 through a Mitsunobu reaction, mesylation, and hydrolysis sequence followed by an intramolecular displacement. The in situ generated thiolate nucleophilically attacked the mesylate to form the thietane ring [51] (Scheme 22).  In an alternative approach, the thietane ring was constructed more efficiently through a two-step displacement sequence from the D-xylose-derived dimesylate 114 (Scheme 24). The first step displacement involved the selective S N 2 reaction of the primary mesylate with KSAc to yield a monothioacetate 115 in 80% yield. The second displacement was an intramolecular S N 2 process performed under mild basic conditions, affording the desired thietane 116 in 92% yield. After deprotection, oxidative cleavage, and reduction, a thietanose 117 was obtained in 63% overall yield. The thietanose 117 was further applied to synthesize a series of thietanose nucleosides 118 [53]. Similarly, enatiomeric thietanose nucleosides 123 were prepared from L-xylose [53] (Scheme 24).
In 2010, Takahata and co-workers designed and synthesized thietane-fused nucleosides. They first prepared a key intermediate spiro acetal 125, which was converted into two different dimesylated nucleosides. After the deprotection with Hg(OAc) 2 in the presence of TFA, the dimesylated thiols 127 and 130 generated companied with the thietane-fused nucleoside 128 in one case. Further the treatment of the dimesylated thiols 127 and 130 with DBU gave rise to the corresponding mesylated thietane-fused nucleosides 128 and 131, which generated the final thietane-fused nucleosides 129 and 132 after the reactions with benzoic acid and CsF and subsequent aminolysis [54] (Scheme 25).

2.2.3
Synthesis via the nucleophilic ring-opening of threemembered heterocycles and subsequent displacement from halomethyloxirane derivatives: Chloromethyloxirane (142a) and its 2 and 3-phenyl derivatives 142b and 142c reacted with H 2 S in the presence of Ba(OH) 2 to give the corresponding thietane-3-ols 145. In this reaction H 2 S first was deprotonated to the hydrogensulfide anion ( − SH) by Ba(OH) 2 . The obtained anion nucleophilically attacked the less steric or benzylic ring carbon atom of the oxirane ring, giving mercaptoalkanolates 143. A proton transfer generated hydroxyalkanethiolates 144 because the acidity of the thiols is higher than that of alcohols, the newly generated thiolates 144 underwent an intramolecularly nucleophilic displacement to give thietane-3-ols 145 [56] (Scheme 28). In a similar approach, chloromethyloxirane (142a) was first converted into a thietan-3-ol 145a by treatment with H 2 S and Ba(OH) 2 . Compound 145a was further transformed to 3-aminothietane-3-carboxylic acid (146), a modulator of the N-methyl-D-aspartate (NMDA) receptor [57] (Scheme 29).  Paclitaxel (Taxol ® ) and docetaxel (Taxotere ® ) both are anticancer drugs of the taxoid series. They inhibit cell growth through the interaction with microtubules. In order to study the structure-activity relationships, the D-ring-modified deoxythiataxoid 154a was synthesized. For this, the iodomethyloxirane derivative 152 was first treated with lithium sulfide followed by reaction with carbonyldiimazole (CDI), yielding the thietane derivative 153 and byproduct. The thietane derivative 153 was then converted into 7-deoxy-5(20)-thiapaclitaxel 154a in a three steps sequence [59] (Scheme 31). Another member of taxoids, 10-deacetylbaccatin III (155) was isolated from the leaves of the European yew tree Taxus baccata L. in a significant yield and was applied as starting material for the semisynthesis of 5(20)-thiadocetaxel 158. First, the compound was converted into the corresponding bromomethyloxirane derivative 156, which generated the corresponding thietane-fused product 157 by the treatment with KSAc. Product 157 was finally transformed to 5(20)-thiadocetaxel 158 [6] (Scheme 32).

Synthesis via the nucleophilic ring-opening of threemembered heterocycles and subsequent displacement from oxirane-2-methyl sulfonates:
Similar as for the halomethyloxirane derivatives, oxiranemethyl mesylate derivatives were also used as precursors for the synthesis of the corresponding thietane derivatives. After various protection-deprotection steps and mesylation, the oxiranemethyl mesylate derivatives 160 were prepared (Scheme 33). Following treatments with KSAc and NaOMe in methanol, respectively, the corresponding thietane-fused products 162 were obtained as the intermediates for the synthesis of deoxythiataxoids [60] (Scheme 33).
Taxine B (163a) and isotaxine B (163b) were obtained from the leaves of the European yew tree Taxus baccata L. in significant yields as well. The compounds were used for the semisynthesis of further sulfur derivatives of taxoids by first converting them into the acetal-protected oxiranemethyl mesylate derivative 164. After the treatment of compound 164 with KSAc, the mesylate 165 generated the corresponding thietane-fused product 166, which was finally converted into the D-ring-modified 7-deoxy 5(20)-thiadocetaxel 154b [6] (Scheme 34).
The mechanism for the formation of thietane rings 171 from oxiranes 167 with vicinal leaving groups was suggested as a nucleophilic ring-opening and intramolecular transesterification followed by an intramolecular displacement [6] (Scheme 35).
The same research group also performed the reaction mechanistic studies. The reactivity of the substituted allenes towards triplet aromatic thiones was investigated. The product analysis revealed the formation of thietanes and occasionally of [4 + 2] cycloadducts (thiopyrans) generally in high overall yields. Steady-state measurements showed that electron-donating substituents present in the allenes enhanced the overall reaction rate. There was little effect of the solvent polarity on the reaction rate. The formation of thietanes involved the excited triplet thiones and the π-bond of allenes [66].
Rao and Ramamurthy systematically investigated the intermolecular photocycloadditions of 1,1,3-trimethyl-2-thioxo-1,2dihydronaphthalene (268) with a series of electron-deficient olefins 187b,c, 189, 242a, and 269-272. The reactions afforded stereospecifically and regioselectively the 3-functionalized spirothietanes 273-285 as the major products. The stereospecific addition suggested either a concerted process or a pathway involving very short-lived diradicals as intermediates. To explain the regioselectivity, theoretical calculations were performed with thiochalcone and acrylonitrile as model substrates. For the frontier molecular orbital treatment, the largest coefficients in both HOMO and LUMO of thiochalcone existed on the sulfur atom, while the largest coefficients in both HOMO and LUMO of acrylonitrile were located at the β-carbon atom. These favored the overlapping between the sulfur atom and the β-carbon atom, deciding the regioselectivity [76,77] (Scheme 51).
Interestingly, the photochemical behavior of thioenones was obviously different from that of enones. The latter underwent the [2 + 2] annulation with olefins at their olefinic center to yield cyclobutane derivatives, and rarely undergo oxetane formation completely. The reaction parameters such as solvent affected the balance between the cyclobutane and oxetane formation. Whereas reactions of olefins with thioenones took place on the thiocarbonyl group to give stereospecific and regioselective thietane derivatives. The same group further studied the photo [2 + 2] cycloadditions of thiocoumarin (286) and alkenes 187, 215a,f, and 271, producing the corresponding spirothietane derivatives 287-291 [78] (Scheme 52).
In 2001, they performed the absolute asymmetric synthesis of highly rigid thietane-fused β-lactams 356 from achiral monothioimides 355 using a chiral crystal environment through a topochemically controlled intramolecular photochemical [2 + 2] cycloaddition in a benzene solution. Only the 2-methylacrylamide derivative 355a afforded the desired product 356a in 70% yield with 40% ee at −45 °C and 75% yield with 10% ee at 0 °C, respectively, in the solid state [98] (Scheme 73). Compared with cyclic thioetherification reactions, the photochemical cycloadditions of thiocarbonyl compounds and olefins are highly suitable for the preparation of multiple substituted thietanes, including fused and spirothietanes.

Synthesis via the ring expansions and contractions 4.1 Synthesis via ring expansion
The ring expansions of thiiranes are alternative ways to prepare thietane derivatives. The transformations included the nucleophilic ring expansion of (1-haloalkyl)thiiranes with various nucleophiles, nucleophilic ring expansion of thiiranes with sulfur ylides, and the electrophilic ring expansion of thiiranes with carbenes generated from sulfur ylides under the catalysis of transition-metal catalysts.

Synthesis via nucleophilic ring expansion of thiiranes:
The nucleophilic ring expansion of thiiranes was used for the synthesis of thietanes. Isocyanoalkanes 415 can be considered as nucleophiles. However, after the nucleophilic addition, they could become electrophiles. Thus, they can be applied in the nucleophilic ring expansion of thiiranes 416, in which the generated thiolates 417 as nucleophiles undergo a further intramolecular addition to form iminothietanes 418. 2-Iminothiiranes 416 underwent a nucleophilic ring expansion with isocyanoalkanes 415 as nucleophiles to give rise to 2,4diiminothietanes 418 in 33 to 52% yields [101] (Scheme 91). One carbon-containing nucleophiles with a good leaving group should be another reagent for the nucleophilic ring expansion of thiiranes. In the ring expansion, the nucleophiles first nucleophilically open the thiiranes and the generated thiolates then serve as nucleophiles to undergo a further intramolecular displacement to give the thietanes. Dimethyloxosulfonium methylide was demonstrated to be a suitable reagent for the nucleophilic ring expansion of three-membered heterocycles. It was successfully applied in the preparation of oxetanes and azetidines via the ring expansions of oxiranes [116][117][118] and aziridines [119,120]. However, both thiiranes and thietanes were less stable than the corresponding oxa and aza-analogs. Thiiranes 419 were readily prepared from the corresponding oxiranes [121][122][123]. The ring expansion reactions of trimethyloxosulfonium iodide (424) and various thiiranes 419 delivered the corresponding thietanes 425 in the presence of NaH in a mixture of THF and DMSO at 40 °C [22] (Scheme 93).
The reaction mechanism was proposed as following. The treatment of trimethyloxosulfonium iodide (424) with sodium hydride generated dimethyloxosulfonium methylide (426) as the one carbon-containing nucleophile with DMSO (379) as a good leaving group. The nucleophilic attack of 426 on thiiranes 419 from the least substituted ring carbon atom generated the zwitterionic intermediates 427, with a good regioselectivity following the general regioselectivity rule in nucleophilic ring opening reactions of aliphatic three-membered heterocycles [124][125][126][127][128][129][130][131][132]. The generated thiolate in the zwitterionic intermediates 427 then further underwent an intramolecular nucleophilic substitution to yield the desired thietanes 425 by loss of a molecule of DMSO [22] (Scheme 94).

Synthesis via electrophilic ring expansion of thiiranes:
To realize the synthesis of functionalized thietanes, electrondeficient sulfur ylides were investigated in the ring expansion of thiiranes. However, the reactions failed due to the poor nucleophilicity of the electron-deficient sulfur ylides. However, in the presence of rhodium catalysts, the electron-deficient sulfur ylides were converted into electrophilic metallocarbenes, which favorably reacted with the electron-rich sulfur atom in the thiiranes and further underwent an electrophilic ring expansion to afford thietanes.
The reaction mechanism was proposed as following. The nucleophilic acyl sulfur ylides 428 first reacted with the rhodium catalyst to generate the electrophilic metallocarbenes 434 by loss of dimethyl sulfide, realizing an umplung. Thiiranes 419 then reacted nucleophilically with the electrophilic metallocarbenes 434 to yield thiiranium intermediates 435, which were nucleophilically attacked by the released dimethyl sulfide, producing the ring-opened zwitterionic intermediates 436. The intermediates 436 further underwent an intramolecular substitution, affording the desired thietanes 429 by loss of dimethyl sulfide and the rhodium catalyst. In this transformation dimethyl sulfide worked as a transient nucleophile and leaving group in the reaction system [23] (Scheme 96).

Synthesis through the ring contraction of thiolanes:
Compared to the ring expansion reactions of thiiranes to thietanes, the ring contraction of thiolanes to thietanes was applied in only limited cases. As an example, 3-chloro-2- methylthiolane (441) underwent a ring contraction to give 2-(1hydroxyethyl)thietane (442) and 2-(1-acetoxyethyl)thietane (443), respectively, when it was treated with water in ethanol or sodium acetate in acetic acid. The ring contraction proceeded through a thiiranium intermediate 444, which was isolated as chloride salt from the reaction system, indicating that an intramolecular nucleophilic substitution occurred, followed by the nucleophilic ring opening of the thiiranium ring [32] (Scheme 98). The ring contraction of thiolanes to thietanes was also utilized in the synthesis of thietanoses. The ring contraction was realized by the DAST-mediated conversion of thiofuranose 445 derived from D-xylose into the protected fluorinated thietanose 447 through a thiiranium intermediate 446 [135,136] (Scheme 99). The similar DAST-mediated ring contraction of thiopentose 448 to thiotetraose 447 was also reported [20] (Scheme 100).
The DAST-mediated ring contraction of a thiopentose to a thiotetraose was realized in the direct conversion of the thiopentose in thionucleoside 450 to its thiotetraose analogue 451 [20] (Scheme 101).
To make the strategy more efficient, the same group developed a one-pot protocol. The one-pot three-component coupling reaction of O,O-diethyl hydrogen phosphorodithioate (463), aromatic aldehydes 476, and electron-deficient olefins 187b,c proofed as efficient method for the highly diastereoselective synthesis of functionalized thietanes 478 in high yields [141] (Scheme 110).
In 2013, Gates's group prepared a small analogue of the anticancer natural product leinamycin. They first synthesized 3-mercapto carboxylic acid 510 as a key intermediate and then cyclized it with DCC and DMAP as coupling reagents, affording the thietan-2-one derivative 511 which was further converted into a small analogue 512 of leinamycin [149] (Scheme 118).

Synthesis via nucleophilic addition
The reaction of bulky α,β-unsaturated trifluoromethyl ketone, adamantylmethylene trifluoromethyl ketone (545), and ammonium hydrosulfide generated a spiroadamantine-thietan-3-ol 548 in 86% yield. The reaction involved a thia-Michael addition, proton transfer, and nucleophilic addition [156] (Scheme 125). The de novo synthesis of the enantiopure thietane derivative 553, a four-membered ring thiosugar, was conducted from cisbut-2-ene-1,4-diol (47). The two asymmetric centers were generated first via the Sharpless asymmetric epoxidation. The epoxide 549 was then converted into the corresponding thiirane 550 through a cyclic xanthate intermediate generated by the treatment with CS 2 and KH. After the protection of the secondary hydroxy group, methanolysis of the xanthate afforded the desired thiirane 550 in 63% overall yield. The AgOAc-mediated regioselective ring opening of the thiirane 550 provided a thiol 551, which was converted to 1-O-ethyl-thietanoside 553 through the acid-catalyzed elimination of EtOH followed by the thiol nucleophilic addition induced by the treatment with CSA in refluxing benzene. The highly stereoselective conversion proceeded via an oxocarbenium intermediate 552, leading to the thermodynamically favored trans,trans-substituted thietane derivative 553 [157] (Scheme 126). (Z)-α-Silyl vinyl sulfides 554 were prepared from (Z)-α-silyl enethiols and chloromethyl ketones and further converted into 2-alkylidenethietan-3-ols 557 by the treatment with fluoride. The conversion included the desilylation, intramolecular nucleophilic addition, and protonation [158] (Scheme 127).

Conclusion
Thietanes are one class of important aliphatic four-membered thiaheterocycles. They are not only crucial pharmaceutical cores and structural motifs of some biological compounds, but also useful and versatile synthetic intermediates in organic chemistry. Various synthetic methods of thietanes have been developed to date. They mainly included the inter-and intramolecular nucleophilic thioetherifications and photochemical [2 + 2] cycloadditions of thiocarbonyl compounds with olefins, the ring expansions of aliphatic three-membered heterocycles and ring contractions of aliphatic five-and six-membered thiaheterocycles, the nucleophilic cyclizations, and some miscellaneous methods. Abundant synthetic methods are available for the preparation of different substituted thietanes, respectively. Although various cyclic thioetherification strategies have been applied in the synthesis of biologically important thietanose nucleosides and sulfur analogues of docetaxel and 7-deoxydocetaxel till now, it can be believed that some newly developed synthetic strategies will show wide applications in the preparation of sulfur-containing biologically active compounds and organic materials in the near future.

Funding
The project was supported by the National Natural Science Foundation of China (Nos. 21572017 and 21772010).