Epihalohydrins in Organic Synthesis - Chemical Reviews (ACS

Review pubs.acs.org/CR

Epihalohydrins in Organic Synthesis Girija S. Singh,*,† Karen Mollet,‡,§ Matthias D’hooghe,*,‡ and Norbert De Kimpe*,‡ †

Chemistry Department, Faculty of Science, University of Botswana, Private Bag 0022, Gaborone, Botswana Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium

‡

4.2.2. Nitrogen-Containing Heterocycles 4.2.3. Oxygen- and Nitrogen-Containing Heterocycles 4.2.4. Sulfur-Containing Heterocycles and Oxygen- and Sulfur-Containing Heterocycles 4.2.5. Sulfur- and Nitrogen-Containing Heterocycles 4.3. Synthesis of Macrocyclic Compounds 5. Synthesis, Reactivity, and Applications of Substituted Epichlorohydrin and Epibromohydrin 5.1. 1′-Substituted 2-(Halomethyl)oxiranes or 2(1-Haloalkyl)oxiranes 5.2. 2-Substituted 2-(Halomethyl)oxiranes 5.3. 3-Substituted 2-(Halomethyl)oxiranes 5.4. Di- and Trisubstituted 2-(Halomethyl)oxiranes 6. Epifluorohydrin in Organic Synthesis 6.1. Introduction 6.2. Synthesis and Conformational Stability of Epifluorohydrin 6.3. Reactivity of Epifluorohydrin 6.3.1. Ring-Opening Reactions of Epifluorohydrin 6.3.2. Applications of Epifluorohydrin in the Synthesis of Cyclic Compounds 7. Epiiodohydrin in Organic Synthesis 7.1. Synthesis and Reactivity of Epiiodohydrin 7.2. Epiiodohydrin in the Synthesis of Natural Products 8. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Synthesis and Structural Studies 3. Reactivity of Epichlorohydrin and Epibromohydrin: Methods in Organic Synthesis 3.1. Ring-Opening Reactions of Epichlorohydrin and Epibromohydrin 3.1.1. Ring Opening with Nitrogen-Centered Nucleophiles 3.1.2. Ring Opening with Oxygen-Centered Nucleophiles 3.1.3. Ring Opening with Halogen-Centered Nucleophiles 3.1.4. Ring Opening with Sulfur- and SeleniumCentered Nucleophiles 3.1.5. Ring Opening with Phosphorus-Centered Nucleophiles 3.1.6. Ring Opening with Carbon-Centered Nucleophiles 3.1.7. Radical- and Electrophile-Initiated Ring Opening 3.1.8. Chemical and Enzymatic Enantioselective Ring Opening 3.2. Direct Halide Substitution Reactions 3.2.1. Applications in Medicinal Chemistry 4. Applications of Epichlorohydrin and Epibromohydrin in the Synthesis of Heterocyclic Compounds 4.1. Heterocycles Containing One Heteroatom 4.1.1. Oxygen-Containing Heterocycles 4.1.2. Nitrogen-Containing Heterocycles 4.1.3. Sulfur- and Selenium-Containing Heterocycles 4.2. Heterocycles Containing Two or More Heteroatoms 4.2.1. Oxygen-Containing Heterocycles

© XXXX American Chemical Society

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1. INTRODUCTION Epihalohydrins [2-(halomethyl)oxiranes, 1,2-epoxy-3-halopropanes] (Figure 1) are well-known versatile synthons and important reagents in the realm of organic synthesis. Epihalohydrins comprise a class of organic compounds with high synthetic potential due to the presence of three different electrophilic carbon atoms and the nucleophilicity of the oxygen atom (Figure 2). Furthermore, many of these synthons are

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Received: August 17, 2012

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dx.doi.org/10.1021/cr3003455 | Chem. Rev. XXXX, XXX, XXX−XXX

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(epiiodo-, epifluoro-, epichloro-, and epibromohydrins) in organic synthesis and medicinal chemistry, with a special focus on the recent literature. Because there are numerous reports, a careful selection of leading references has been made in each of the sections. The literature is arranged according to the different types of epihalohydrins, i.e., unsubstituted racemic and enantiopure epihalohydrins and substituted epihalohydrins.

2. SYNTHESIS AND STRUCTURAL STUDIES Although the primary objective of this review is to discuss the reactivity and synthetic applicability of epihalohydrins in modern organic synthesis, it is appropriate to summarize briefly the historical background of the production and structural studies. Epichlorohydrin (5) was first synthesized in 1856.1 According to a report on carcinogens, small-scale production of epichlorohydrin (5) began in the United States from 1937 and large-scale production from 1949.2 According to the same report, epichlorohydrin (5) was produced in 2009 by 27 manufacturers worldwide, and the U.S. export of epichlorohydrin (5) ranged from 15.8 million kg to 136 million kg between 1989 and 2008. (±)-Epichlorohydrin (5) is produced on an industrial scale via cyclization of a mixture of 1,3-dichloropropan-2-ol (3) and 2,3dichloropropan-1-ol (4), synthesized from propene (1) by photochemical allylic chlorination, subsequent electrophilic addition of hypochlorous acid, and final treatment with aqueous base (Scheme 1).3 A similar cyclization of 1,3-dibromopropan-2ol affords epibromohydrin (6).4 1,3-Dichloro-2-propanol (3), however, is also obtained by treatment of glycerol with hydrochloric acid in acetic acid.5 The kinetic aspects of this reaction have been investigated recently in efforts directed toward maximizing the yield for industrial purposes.6 The development of improved methodologies for the production of epichlorohydrin (5) is still under investigation. For example, epoxidation of allyl chloride with aqueous hydrogen peroxide (60%) using a divanadium-substituted phosphotungstate as a catalyst has been evaluated, affording epichlorohydrin (5) in 84% yield.7 Both (R)- and (S)-enantiomers of epichlorohydrin and epibromohydrin are commercially available and are versatile building blocks for the enantioselective synthesis of a broad variety of natural products and other compounds of biological interest. The development of a straightforward and convenient strategy for the synthesis of enantioenriched epihalohydrins comprised a challenging endeavor until the discovery of hydrolytic kinetic resolution of terminal epoxides by Jacobsen and co-workers in the late twentieth century.8,9 Presumably the first report on the synthesis of an enantioenriched epichlorohydrin (5) concerned the resolution to (S)-epichlorohydrin (11).10 The synthesis of (R)-epichlor-

Figure 1. Structures of different epihalohydrins.

Figure 2. Reactive sites in epihalohydrins.

commercially available, or they can be prepared in high yield and purity using simple and straightforward methodologies. These features, combined with the inherent reactivity of the threemembered oxirane ring (due to the ring strain) and of the halogenated carbon atom, render epihalohydrins excellent substrates for various transformations in organic synthesis. Indeed, epihalohydrins are highly prone to undergo ring opening and/or nucleophilic substitution reactions with various carbon and heteroatom nucleophiles. Moreover, unsymmetrical substitution of the epoxide moiety in epihalohydrins allows the introduction of chirality, making these molecules valuable substrates in enantioselective synthesis as well. As the concept of chirality has become an important issue and challenge in organic and medicinal chemistry, chiral epihalohydrins provide a convenient entry into a wide range of enantiomerically pure target molecules, including complex natural products. The difference in reactivity of the three electrophilic carbon atoms has been exploited in organic synthesis to produce different types of vicinally di- and trifunctionalized compounds. Usually these reactions are highly chemo-, regio-, and stereoselective (in the case of chiral substrates or asymmetric catalysis). A number of efficient, reusable, cost-effective, and green catalysts have emerged during these studies. Moreover, studies on the reactions of epihalohydrins have revealed interesting facets of mechanistic organic chemistry in many cases. The present paper aims to review the synthetic applicability of epihalohydrins Scheme 1

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ohydrin (8) in 74% yield and 99.5% ee by base-mediated cyclization of (S)-2,3-dichloro-1-propanol (7) at room temperature has been reported by Suzuki and co-workers (Scheme 2).11

Scheme 4

Scheme 2

The starting alcohol 7 was resolved from the corresponding racemic mixture using Pseudomonas sp. OS. K. 29. In a totally different approach, asymmetric epoxidation of allyl chloride by several alkene-consuming bacteria has also been described to be an efficient method in the synthesis of highly enantiopure epichlorohydrin (5).12 Resolution of racemic epichlorohydrin (5) has also been achieved using diastereomers of Dcamphorquinone derivatives with 3-chloropropane-1,2-diol.13 A convenient method for the synthesis of (R)-epichlorohydrin (8) and (S)-epichlorohydrin (11) from (R)-3-tosyloxy-1,2propanediol (9) has been realized by Baldwin and co-workers in 1978.14 Treatment of the starting diol 9 with triphenylphosphine in carbon tetrachloride/DMF and subsequent cyclization under basic conditions afforded (S)-epichlorohydrin (11) in 56% yield (Scheme 3). The synthesis of (R)-epichlorohydrin (8) was accomplished via 2-(hydroxymethyl)oxirane (12), 2(mesyloxymethyl)oxirane (13), and chlorohydrin (14), which finally cyclized to yield the premised (R)-epichlorohydrin (8) in 50% yield. As mentioned before, the Jacobsen’s hydrolytic kinetic resolution (HKR) technique constitutes a highly effective strategy for the preparation of optically pure epichlorohydrin (5) and epibromohydrin (6). Other features of HKR include the use of water as a nucleophile to induce ring opening, the low loadings and recyclability of the commercially available catalysts, and the ease of product separation due to significant boiling point and polarity differences.15 The hydrolytic kinetic resolution of terminal oxiranes has been reported for the first time using a Cosalen complex.8 In that initial report, the optically pure epichlorohydrin (5) was obtained in 44% yield and 98% ee, and the ring-opened diol in 38% yield and 86% ee.8 Later on, the protocol was improved to obtain both (R)- (8) and (S)enantiomers (11) in up to 50% yield and 99% ee (Scheme 4).15 In contrast to the slow rate of racemization observed for epichlorohydrin (5) under HKR conditions, epibromohydrin (6) was found to undergo racemization relatively rapidly (vide inf ra). At 50% conversion in the hydrolysis of epibromohydrin

(6), the epoxide was recovered in only 6% ee while the ringopened diol was obtained in 93% yield and 96% ee.15 This report was followed by several other studies on the hydrolytic kinetic resolution of epichlorohydrin (5) and epibromohydrin (6).16 Polymer-supported chiral Co- and Mn-salen complexes have been used to produce excellent resolution, and in addition, the catalysts were easily separated from the product mixture.17,18 Investigations are still underway to design even more efficient, recyclable, and environmentally friendly catalysts for hydrolytic kinetic resolution of epihalohydrins 5 and 6. The molecular structures of epichlorohydrin (5) and epibromohydrin (6) have been studied by electron diffraction.19,20 The C−C bond length in the epichlorohydrin (5) ring system was shown to be 1.46 ± 0.03 Å and the C−O bond length 1.44 Å. A C−CH2 bond length of 1.52 Å has been reported.19 The angle between C−CH2 and the C−C−O ring plane is about 58°. Almost the same data have been observed for epibromohydrin (6).20 IR spectra of epichlorohydrin (5)21 and epibromohydrin (6),22 dissolved in liquid xenon, have been recorded at several temperatures ranging from −40 °C to −105 °C. Additionally, the Raman spectrum of the liquid has been obtained from 23 to −39 °C. These spectra were consistent with three stable conformers existing in both phases at ambient temperature.21,22 These data indicated the conformer 3 as the most stable form, followed by the conformer 2 (most polar) in the xenon solution. In the liquid phase, however, the conformer 2 was the most stable form followed by the conformer 1 and the conformer 3 (Figure 3).

Scheme 3

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epichlorohydrin (5) with the potassium salt of 2-acetyl-7hydroxybenzo[b]furan in DMF using radiotracer techniques.24 In the reaction of epibromohydrin (6) with potassium pyrocatecholate in aqueous ethanol (1:1), the nucleophile attacked at both the ring and the exocyclic methylene carbon atoms, with attack at the ring methylene slightly favored.25 Acetolysis of epichlorohydrin (5) was also observed to take place by attack of the nucleophile mainly at the ring methylene carbon atom.26 These studies generated curiosity in mechanistic investigations. Recently, some computational studies have been carried out on the reactivity of epichlorohydrin (5) and epibromohydrin (6) under basic27 and acidic conditions28 in the gas phase and aqueous solution, which have been found to be in good agreement with the experimental observations. These calculations suggested that nucleophilic attack by water under acidic conditions occurred preferentially at the unsubstituted epoxy carbon atom in both the gas phase and aqueous solution. These results were in contrast to those found for nucleophilic attack under basic conditions. In the gas phase, it was determined that a direct displacement mechanism was operative for epibromohydrin (6), while an indirect pathway (nucleophilic ring opening and subsequent intramolecular displacement) was followed for epichlorohydrin (5). In an acetone solution, however, only the indirect displacement mechanism was found to occur.27,28 The following and succeeding subsections describe the ring-opening and nucleophilic substitution reactions of epihalohydrins, especially epichlorohydrin (5) and epibromohydrin (6), with various nucleophiles and their applications in organic synthesis and medicinal chemistry.

Figure 3. Conformational structures of epichlorohydrin.

3. REACTIVITY OF EPICHLOROHYDRIN AND EPIBROMOHYDRIN: METHODS IN ORGANIC SYNTHESIS A major and characteristic property of epihalohydrins is their high reactivity toward a wide variety of nucleophilic reagents, an effect undoubtedly resulting from the presence of three electrophilic carbon centers and the strain associated with the three-membered ring system (117 kJ/mol). In that respect, epihalohydrins, especially epichlorohydrin (5) and epibromohydrin (6), are susceptible to nucleophilic substitution and ringcleavage reactions, whether or not followed by ring transformations, leading to a wide variety of functionalized (heterocyclic) oxygen-containing target molecules. The specific reaction pathway, i.e., direct nucleophilic substitution or nucleophile-induced ring opening, depends on a number of factors, such as solvents, reaction conditions, and steric and electronic factors of the reagent and the type of leaving group. McClure et al. have examined the reactivity of epichlorohydrin (5) with phenols under a variety of reaction conditions.23 When epichlorohydrin (5) was allowed to react with phenols in acetone or dichloromethane, nucleophilic attack occurred predominantly at the ring methylene carbon atom. When the reaction was carried out with preformed potassium phenoxides in dimethylformamide or tetrahydrofuran, however, the phenoxides reacted with both the ring and the exocyclic methylene carbon atoms equally. A similar observation in DMF has been described by Ohishi and Nakanishi in their studies on the reaction of

3.1. Ring-Opening Reactions of Epichlorohydrin and Epibromohydrin

The nucleophilic ring opening of three-membered heterocycles is a basic tool in organic synthesis because of the favorable release

Figure 4. Selected ring-opening products from epihalohydrins. D


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triflate,46 and sodium azide in combination with oxone.47 The amido nitrogen of isatin (indole-1H-2,3-dione) is known to react with epichlorohydrin (5) at the unsubstituted carbon atom of the epoxide moiety.48 3.1.2. Ring Opening with Oxygen-Centered Nucleophiles. The reaction of epichlorohydrin (5) with different alcohols in the presence of zinc chloride49 or Amberlyst-1550 has been carried out, affording 3-alkoxy-1-chloropropan-2-ols (23; Scheme 7). β-Hydroxy ethers are valuable organic solvents and

of strain energy involved, and also epihalohydrins undergo ring cleavage with nitrogen, oxygen, halogen, sulfur, selenium, phosphorus, and carbon nucleophiles to form synthetically and/or biologically useful products (Figure 4). The nucleophiles react at the less-hindered position of the three-membered ring system with a few exceptions. Certain chiral metal complexes and enzymes have been employed as catalysts to achieve enantioselective ring opening, leading to enantioenriched products. 3.1.1. Ring Opening with Nitrogen-Centered Nucleophiles. In general, treatment of epihalohydrins 5 and 6 with aliphatic, aromatic, and heterocyclic amines provides an easy access to 3-amino-1-halopropan-2-ols (20) due to the preferential attack of the nitrogen-centered nucleophile at the lesshindered site of the oxirane moiety (Scheme 5). The formation

Scheme 7

Scheme 5 versatile organic synthons and intermediates.51 β-Hydroxy ethers are also present in some naturally occurring compounds, e.g., citreoviral, asteltoxin, macrolide lactone FK506, and several others.52 In addition, regioselective alcoholysis, hydrolysis, and acetolysis of epichlorohydrin (5) in quantitative yields using alcohols, water, and acetic acid, respectively, have been achieved in the presence of catalytic amounts of electron-deficient tin(IV) porphyrin,53 ammonium decatungstocerate(IV),54 aluminum dodecatungstophosphate,55 iron(III) reagents,56,57 and carbon tetrabromide.58 Acetolysis using Ac2O has also been studied under solvent-free conditions using ammonium 12-molybdophosphate.59 Furthermore, the synthesis of 1,2-diacetates has been evaluated using Ac2O in the presence of metal hydrides.60 A very efficient and highly regioselective ring opening of epihalohydrins 5 and 6 with benzoic acid in the presence of a catalytic amount of tetrabutylammonium bromide (TBAB) has been developed in anhydrous acetonitrile to form monobenzoylated 1,2-diols 24 (Scheme 8).61 The reaction of epichlorohydrin

of the other regioisomers, i.e., 2-amino-3-halopropan-1-ols (19), is not observed. It is noteworthy to mention that 3-amino-1halopropan-2-ols (20) are important building blocks in organic synthesis.29 Regioselective aminolyses of epichlorohydrin (5) affording βamino alcohols have been reported using a number of catalysts, such as Bi(TFA)3 or Bi(OTf)3 in the presence of molten TBAB,30 indium(III) bromide,31 copper(II) tetrafluoroborate,32 erbium(III) triflate,33 ytrium nitrate hexahydrate,34 montmorillonite K10,35 titanosilicate molecular sieves,36 calcium trifluoromethanesulfonate,37,38 and silica nanoparticles.39 Quaternization of tertiary amines has been achieved by reaction with epichlorohydrin (5).40 Ring opening of epichlorohydrin (5) by azepinone has been studied in dimethylsulfoxide using potassium carbonate as an additive.41 In a rare case, nucleophilic attack at the epoxide ring carbon atom bearing the chloromethyl group has been observed as a side reaction to form the corresponding 2-amino-3-halopropan-1-ols as the minor constituents. For example, zinc(II) perchlorate hexahydrate has been described as an efficient catalyst for the ring opening of epichlorohydrin (5) with aniline, resulting in γ-chloro amine 21 as the major compound (85%), together with β-chloro amine 22 as the minor (6%) constituent (Scheme 6).42 A few other approaches toward regioselective ring opening of epihalohydrins with nitrogen nucleophiles include the magnesium sulfate/methanol/sodium nitrite system to form β-nitro alcohols, which were used for the synthesis of an immunosuppressive agent FTY-720,43 and sodium azide to yield 1-azido-3chloropropan-2-ol in 97% yield using acetonitrile as the solvent.44 Other reagents used for azidolysis include trimethylsilyl azide and aluminum(III) isopropoxide45 or erbium(III)

Scheme 8

(5) with acetyl chloride in the presence of a catalytic amount of indium(III) bromide has been employed to give the corresponding acetate in 80% yield.62 As a final example, a hydroformylation−acetalization reaction of epichlorohydrin (5) has been reported by trimethoxymethane in the presence of cobalt(II) octacarbonyl as a catalyst.63 3.1.3. Ring Opening with Halogen-Centered Nucleophiles. The halogen-induced regioselective ring opening of

Scheme 6

E


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furnish β-hydroxythiocyanates. Furthermore, the ring opening of epichlorohydrin (5) with 4-fluorobenzene sulfinic acid (29) has been carried out to form 3-(4-fluorophenylsulfonyl)prop-2-ene1-ol (30) by subsequent nucleophilic substitution and eliminative ring opening (Scheme 12).89 A catalyst-free efficient

epihalohydrins 5 and 6 toward β-halohydrins 25, a reaction where Y3− (Y = I, Br) is proposed to be the reactive species, has been described to be catalyzed by thiourea64 (Scheme 9), 2,6Scheme 9

Scheme 12

bis[2-(o-aminophenoxy)methyl]-4-bromo-1-methoxybenzene (BABMB),65 isoniazide,66 and phenylhydrazine.67 Also, reactions with hydrogen or lithium halides over β-cyclodextrin,68 lithium halides over silica gel,69 and (bromodimethyl)sulfonium bromide70 lead to similar β-halohydrins 25. The ring opening of epichlorohydrin (5) with bromotrimethylsilane has been proposed to proceed through a four-membered cyclic transition state.71 1,2-Ferrocenediylazaphosphinines have been used as catalysts in the regioselective ring opening of epichlorohydrin 5 with trimethylsilyl chloride.72 The synthetic utility of vicinal halohydrins as versatile building blocks has been emphasized in many reports.73 They have been employed in the synthesis of several halogenated marine natural products, unnatural amino acids, and various chiral auxiliaries.74 3.1.4. Ring Opening with Sulfur- and SeleniumCentered Nucleophiles. β-Hydroxy sulfides and β-hydroxy selenides are valuable intermediates in organic synthesis and medicinal chemistry,75 especially in the construction of both synthetic and naturally occurring pharmaceuticals, e.g., leukotrienes,76 pancratistatin,77 and schweinfurthin B.78 Highly regioselective thiolysis of epichlorohydrin (5) by thiophenols has been explored using a number of catalysts, such as borax (Scheme 10), 79 β-cyclodextrin,80 iodine,81 zinc perchlorate

regioselective ring opening of epichlorohydrin (5) and epibromohydrin (6) has been accomplished by thiobenzoic acid in water to form the corresponding 3-halo-2-hydroxypropylbenzothioates in quantitative yields.90 On the basis of the same methodology, the selenolysis of epichlorohydrin (5) with aryl selenols using the ionic liquid [Bmim]BF4 as a catalyst has been demonstrated to form βhydroxyselenides in excellent yields.83 Some other methods for the synthesis of β-hydroxyselenides involve the reaction of epichlorohydrin (5) with benzeneselenol in water under supramolecular catalysis in the presence of β-cyclodextrin91 or in dichloromethane using ammonium 12-molybdophosphate (Scheme 13),92 and with diselenides mediated by Zn/AlCl3.93 Scheme 13

As a final example, the ring opening of (R)-epichlorohydrin (8) with 2-mercaptobenzothiazole (32) has been described to afford (R)-1-(benzothiazol-2-ylsulfanyl)-3-chloropropan-2-ol (33) in 90% yield (Scheme 14), a precursor for drugs with potential β-blocker activity.94

Scheme 10

Scheme 14 hexahydrate,82 ionic liquid [Bmim]BF4,83 and (bromodimethyl)sulfonium bromide.84 Another example in that respect is a TBAF-catalyzed reaction of epichlorohydrin (5) with hexamethyldisilathiane to afford the corresponding β-mercapto alcohol in a highly regio- and stereoselective fashion.85 In another study, thiolate ions, generated from Rongalite-promoted cleavage of disulfides 27, induced ring opening of epichlorohydrin (5) in the presence of K2CO3 to afford the corresponding products 28 in high to excellent yields (Scheme 11).86 Similar regioselective ring opening of epichlorohydrin 5 by its reaction with ammonium thiocyanate using tetraarylporphyrins87 and thioxanthenonefused azacrown ethers88 as catalysts has been demonstrated to

3.1.5. Ring Opening with Phosphorus-Centered Nucleophiles. As a first example, the regioselective ring opening of epihalohydrins 5 and 6 with triethyl phosphate in the presence of chlorotrimethylsilane has been reported in the early 1980s to form 2-(trimethylsilyloxy)alkanephosphonates.95 Similarly, the reaction of epichlorohydrin (5) and epibromohydrin (6) with trialkyl phosphites and dialkyl phosphorochloridate in the presence of zinc(II) chloride afforded dialkyl 2(dialkoxyphosphinyloxy)alkanephosphonates.96 Recently, the ring opening of epichlorohydrin (5) to β-hydroxyphosphonate (35) has been explored, catalyzed by Al(OTf)3 as an efficient and reusable catalyst (Scheme 15).97 Among phosphonates, βhydroxyphosphonates constitute an important class of com-

Scheme 11

F


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44. This reaction has later been used in the synthesis of R(−)-carnitine, a natural product which plays an important role in human energy metabolism.104 Furthermore, the reaction of epichlorohydrin 5 with the conjugate base of a chromium−carbene complex, generated by treatment of the latter with n-butyllithium, has been described to yield the corresponding chlorohydrin containing the chromium−carbene complex moiety in 75% yield if the reaction was carried out in the presence of BF3·OEt2.105 In the absence of the Lewis acid, however, a chromium−carbene complex bearing the oxirane moiety was formed as the end product in 34% yield. Hodgson and co-workers have studied an efficient method to synthesize cyclopropanes fused to five- or six-membered carbocycles, such as bicycle 52, by intramolecular cyclopropanation of unsaturated chlorohydrins, for example, chlorohydrin 50, using lithium 2,2,6,6-tetramethylpiperidide, thus creating bicyclic motifs found widely in natural products.106,107 These unsaturated chlorohydrins were easily prepared from epichlorohydrin 11 and allylic and homoallylic Grignard reagents. Among others, this reaction pathway has been used to prepare (−)-sabinol (Scheme 19).106,107 Grignard reagents have also been used frequently for the regioand enantioselective ring opening of optically pure epibromohydrin (6) and epichlorohydrin (5) as the key intermediate step in the asymmetric synthesis of natural products.108,109 For example, coupling of (R)-epichlorohydrin (8) with vinylmagnesium bromide in the presence of CuBr has been described to afford the corresponding homoallylic alcohol 53 in 84% yield (Scheme 20).110 This reaction was later employed in the synthesis of (R)carnitine (56).111 The quaternary ammonium hydroxide 55, obtained from quaternary ammonium chloride 54 using an ionexchange resin, underwent oxidative removal of the terminal carbon atom with formation of a carboxyl functionality by ozonolysis in acetic acid followed by treatment with an excess of hydrogen peroxide to afford (R)-carnitine (56) (Scheme 21).111 In a second example, Blechert and co-workers have described the CuCN-catalyzed ring opening of (R)-epichlorohydrin (8) with n-butylmagnesium chloride as a key intermediate step in the synthesis of (+)-calvine.112 The Grignard reagent-mediated nucleophilic ring opening of (R)-epichlorohydrin (8) has also been employed by Kishi and co-workers in the synthesis of the metabolite 58, present in the lipid extract of the frog pathogen Mycobacterium lif landii.113 In this study, the reaction of (R)-epichlorohydrin (8) with vinylmagnesium bromide in the presence of a catalytic amount of CuI, followed by treatment with potassium hydroxide, afforded oxirane 57, which was used as a building block in the synthesis of macrolactone 58 (Scheme 22).113 In another example, (S)-3-hydroxytetradecanoic acid (62), a compound of interest in glycobiochemistry, has been synthesized in an overall yield of 27% starting from (S)-epichlorohydrin (11) by initial regio- and chemoselective Cu(I)-catalyzed ring opening with n-decylmagnesium bromide followed by consecutive epoxide formation. Subsequently, regioselective epoxide ring opening of (S)-1,2-epoxytridecane (60) with cyanide under pH controlled conditions followed by consecutive nitrile hydrolysis with alkaline H2O2 gave, after purification, pure (S)-3hydroxytetradecanoic acid (62) as its N,N-dicyclohexylammonium salt (Scheme 23).114 Kumar and co-workers have reported an efficient enantioselective synthesis of (3S,6R)-3,6-dihydroxy10-methylundecanoic acid115 and herbarumin III116 from epichlorohydrin (5) employing Jacobsen’s HKR, Sharpless

Scheme 15

pounds exhibiting useful biological properties leading to applications as herbicides, antibiotics, pesticides, antioxidants, and horticulture agents. The reaction of epichlorohydrin (5) and epibromohydrin (6) with trialkylphosphites and trimethylsilyl chloride in the presence of lithium perchlorate in diethyl ether, however, afforded γ-halo-α-(trimethylsilyloxy)phosphonates (37) (Scheme 16)98 via carbonyl products 36 that are favored by the presence of LiClO4 in the reaction.99 Scheme 16

3.1.6. Ring Opening with Carbon-Centered Nucleophiles. Haynes and co-workers have prepared pent-2-en-4-yn-1ol (39) from epichlorohydrin (5) as a 9/1 mixture of E- and Zstereoisomers by reaction with sodium acetylide in liquid ammonia (Scheme 17).100 The reaction mechanism involved Scheme 17

was explained by nucleophilic attack of the acetylide at the chlorinated carbon center, followed by eliminative oxirane ring opening.100 This reaction was employed for the synthesis of 1(Z)-atractylodinol, a natural product isolated from the dried rhizomes of Atractylodes lancea, widely used in China and Japan against rheumatic diseases, digestive disorders, night blindness, and influenza.101 An interesting method for the synthesis of methylene- or alkylidenecyclopropane carbinols 48 via Wittig olefination has been developed by Turcant and Le Corre. The key intermediate ylide 46 in this synthesis was formed by sequential nucleophilic substitution/cyclization of methylenephosphorane with epichlorohydrin (5) (Scheme 18).102 However, a slight change in the reaction conditions (solvent and base) brought about the formation of isomeric alkylidenecyclobutanols 44 in good yields, as studied by Okuma and co-workers (Scheme 18).103 According to the proposed reaction mechanism, initial attack of the Wittig reagent 40 across epichlorohydrin (5) resulted in the formation of the ring-opened intermediate 41, which underwent an αproton abstraction to form γ-oxide ylide 42. Intramolecular substitution gave the corresponding cyclobutane 43, which finally reacted with aldehydes to form 3-alkylidenecyclobutanols G


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Scheme 18

Scheme 19

Scheme 22

Scheme 20

TFA-protected tert-butyl glycinate in the presence of zinc chloride and BF3·Et2O.119 The nucleophilic ring opening of epichlorohydrin (5) by active methylene compounds under solvent-free conditions by using polystyrene-supported bases as catalysts has been evaluated by Pizzo and co-workers. The best results were obtained by using 5 mol % of the very strong Schwesinger’s phosphazene base 2-tertbutylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP), resulting in a mixture of products 64 and 65 (Scheme 24).120 The formation of product 65 was explained by nucleophilic attack of the oxygen atom of the acetylacetone anion and subsequent ring closure by intramolecular Michael addition. β-Hydroxy nitriles have been obtained from the regioselective ring opening of epichlorohydrin (5) and epibromohydrin (6) by trimethylsilyl cyanide using lithium perchlorate121 or solid bases such as MgO or CaO as catalysts.122 The synthetic utility of the sulfonyl dianion 67 in the annelation reaction with epibromohydrin (6) resulted in the formation of cyclopropane (68) and cyclobutanol (69) in a molar ratio of 92/8 (Scheme 25).123

Scheme 21

asymmetric dihydroxylation, and regioselective epoxide ring opening with the appropriate Grignard reagents as the key steps. Another regioselective ring opening at the less-substituted site of epichlorohydrin 5 has been achieved by using trimethylsilyl enol ethers in the presence of TiCl4,117 2-(trialkylsilyl)allyl organometallic reagents (Sn, Si, Li, Cu),118 and the enolate of H


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Scheme 23

Scheme 24

Scheme 25

Scheme 26

followed by cyclization. However, [(phenylsulfonyl)methylene]dilithium was supposed to open first the oxirane ring, followed by attack at the carbon−bromine bond to afford the corresponding cyclobutanol. In another approach, the ring opening of (S)-epichlorohydrin (11) with lithiobutyne in the presence of BF3·Et2O led to the formation of chlorohydrin (70) (Scheme 26), which served as a precursor for the synthesis of the tetrahydropyran ring of

These results are in contrast to those observed in the reaction of epibromohydrin (6) with [(phenylsulfonyl)methylene]dilithium, which afforded exclusively the corresponding cyclobutanol derivative.124 This different behavior of both dilithiated sulfones was explained by the different initial attack of the two dianions. In the case of sulfonyl dianion 67, the formation of cyclopropane 68 as the major reaction product was rationalized by the initial nucleophilic substitution of the bromine atom, I


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Scheme 27

Scheme 28

the lithium salt of TMS-acetylene is also the first step in a multistep synthesis of the natural product furanocembrane bisdeoxylophotoxin.128 Reduction of ketone 76 with NaBH4/ Et2BOMe in THF/MeOH and NaBH(OAc)3 in MeCN/AcOH, respectively, followed by a Pd-catalyzed hydrogenation, and subsequent acid-mediated cyclization led to the preparation of euscapholide D (81) and euscapholide C (78), respectively, which served as precursors for the preparation of tarchonanthus lactone D (82) and tarchonanthus lactone C (79) (Scheme 27).126,127

bistramide D, a natural product isolated from the marine ascidian Lissoclinum bistratum.125 A versatile and facile synthetic route to all the stereoisomers of tarchonanthus lactone and euscapholide, natural products containing an α,β-unsaturated δ-lactone moiety, has been described using chiral epichlorohydrin (11) as the source of all chiral centers.126,127 The key reaction involved the enantioselective epoxide ring opening with the lithium salt of TMSacetylene in the presence of BF3·Et2O (Scheme 27). The enantioselective ring opening of (R)-epichlorohydrin (8) with J


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Recently, C-alkylation of 2-lithio-1,3-dithiane (84), reported earlier by Seebach and co-workers,129 has been carried out using commercially available (R)-epichlorohydrin (8) as a key intermediate step in the synthesis of a macrolactone natural product, leucascandrolide A.130 2-Lithio-1,3-dithiane (84), prepared in situ, reacted with (R)-epichlorohydrin (8) to furnish (R)-2-(1,3-dithian-2-ylmethyl)oxirane (85) in 86% yield (Scheme 28).130 This reaction proceeded with complete inversion of configuration via initial opening of the oxirane ring and subsequent intramolecular displacement of chloride. As a final example, Langer and co-workers have investigated the formation of cyclopropanes and several heterocyclic compounds through reactions of epichlorohydrin (5) and epibromohydrin (6) with lithiated dianions. 2-Aryl-substituted 2-(hydroxymethyl)cyclopropane carbonitriles (89) were formed by reaction of dilithiated aryl-substituted acetonitriles with epibromohydrin (6) in the presence of lithium perchlorate (Scheme 29).131 For all products (except for R = Nmethylpyrrol-2-yl), good diastereoselectivities were observed in favor of the cis-configured products (dr = 5/1 to 8/1).

Scheme 30

93 to the corresponding allylic alcohols 96 in good yields involving radical removal of the bromo atom by indium hydride (HInCl2), generated by transmetalation between InCl3 and NaBH4, followed by selective C−O bond cleavage through a radical process. Several aromatic, cyclic, and open-chain 2(bromomethyl)oxiranes successfully participated in this reaction (Scheme 31).136

Scheme 29

Scheme 31

Iranpoor and co-workers have introduced the use of Ph3P in the presence of Br2 or NBS in DMF for the conversion of epichlorohydrin (5) to the corresponding dihaloformate 97 in good yields (Scheme 32).137 Later on, the yield of β3.1.7. Radical- and Electrophile-Initiated Ring Opening. Reactions of epichlorohydrin (5) with cerium(IV) ammonium nitrate (CAN) alone or in the presence of an excess of nitrateeither as its ammonium or tetrabutylammonium salthave been described to proceed smoothly and efficiently under mild reaction conditions using dry or aqueous acetonitrile to yield the corresponding β-hydroxy nitrate 92 with excellent regioselectivity (Scheme 30).132 The reaction was proposed to occur through a one-electron transfer process with the formation of an epoxonium radical cation 90, followed by nucleophilic attack of the nitrate anion to produce the corresponding alkoxy radical 91. Finally, regeneration of Ce(IV) occurred through reaction of Ce(III) with the latter alkoxy radical 91.132 Epichlorohydrin (5) was also cleaved efficiently and regioselectively to the corresponding β-hydroxy nitrate 92 in the presence of zirconyl nitrate133 or tetranitromethane.134 The radical-initiated reductive ring opening of epihalohydrins 5 and 6 has been achieved with triphenyltin hydride135 and with the sodium borohydride−indium(III) chloride system136 to yield the corresponding allylic alcohols. A combination of sodium borohydride and a catalytic amount of indium(III) chloride in acetonitrile has been investigated to reduce 2,3-epoxybromides

Scheme 32

bromoformate (97) has been improved to 88% using Br2/ Silphos.138 The use of NBS or TABCO (2,4,4,6-tetrabromo-2,5cyclohexadiene-1-one) as efficient catalysts provided a highly selective method for the alcoholysis of epichlorohydrin (5) (Scheme 32).137 In the presence of Ph3P/I2 (Scheme 32)137 or ZrCl4/NaI,139 epichlorohydrin (5) was quantitatively deoxyK


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Scheme 33

genated to allyl chloride 2. Yadav and co-workers have reported on the regioselective ring opening of epichlorohydrin (5) with acetyl chloride using iodine under mild conditions to form the corresponding bromo ester.140 3.1.8. Chemical and Enzymatic Enantioselective Ring Opening. A first example comprises the Jacobsen’s hydrolytic kinetic resolution as a highly effective technique for the preparation of enantiopure epichlorohydrin (5) and epibromohydrin (6) on the one hand and enantioenriched halogenated diols on the other hand (Scheme 4). A stereoselective kinetic resolution of oxiranes by aminolysis using secondary amines in the presence of a chiral Lewis acid has been developed by Brunner and co-workers in the early 1990s.141 Furthermore, a recyclable Co(III)−salen complex has been used by Kureshy and co-workers142 as a catalyst in an environmentally benign protocol for the highly enantioselective aminolytic kinetic resolution of racemic epichlorohydrin (5) with various amines in the presence of ionic liquids at room temperature, yielding the corresponding N-protected 1,2-amino alcohols with high regioand enantioselectivity (ee >99%) together with the simultaneous formation of the chirally pure oxirane (ee >99%). Dynamic kinetic resolution has been identified as an attractive strategy for the generation of enantiomerically enriched compounds for organic synthesis.143 Such a process requires racemization of the slower reacting enantiomer under conditions compatible with a kinetic resolution reaction. This mechanism has been illustrated by Jacobsen and co-workers in the reaction of racemic epichlorohydrin (5) with trimethylsilyl azide in the presence of Cr(III)−salen complex 16 (Scheme 33).144 Similarly, an enantioselective azidolysis has been accomplished using chiral binuclear Co−salen complexes bearing Lewis acid metal chlorides and hydrazoic acid as the azide source.145 Cr(III)Cl−salen complexes146 and Co(III)OAc−salen complexes147 are known to catalyze the regio- and stereoselective ring opening of epichlorohydrin (5) with aliphatic carboxylic acids. In another study, the enantioselective ring opening of epichlorohydrin (5) and epibromohydrin (6) with aliphatic acids has been achieved using chiral binuclear Co−salen complexes bearing Lewis acids of Al and Ga (Scheme 34).148 The reaction of (±)-epibromohydrin (6) with phenol in the presence of Co(III)−salen complex 104 and lithium bromide in acetonitrile has been described to lead to the formation of (R)bromohydrin (105) in 74% yield and excellent enantiomeric excess (Scheme 35).149 The dynamic kinetic resolution of epibromohydrin (6) via phenolic ring opening provided a highly efficient route to enantiopure aryl glycidyl ether derivatives. An analogous reaction of epichlorohydrin (5) has been evaluated by Kirschning and co-workers using Co(III)−salen complexes

Scheme 34

Scheme 35

covalently immobilized on polymer carriers.150 The latter reaction of phenol with 4 equiv of epichlorohydrin (5) yielded a mixture of two products in a 1:1 ratio that were identified as (R)-1-chloro-3-phenoxypropan-2-ol and (S)-glycidyl phenyl ether; the latter product formed after ring closure of the former product. Treatment of (R)-1-chloro-3-phenoxypropan-2-ol with KOH in Et2O led to formation of (S)-glycidyl phenyl ether in 86% yield and 93.2% ee.150 Next to chemocatalysis, microbial enzymes are also known to perform enantioselective conversions of epihalohydrins. For example, Weijers and co-workers have studied the enantioselective hydrolysis of epichlorohydrin (5) by Rhodotorula glutinis.151 The haloalcohol dehalogenase from Agrobacterium radiobacter AD1 and the lipase Amano PS from Pseudomonas L


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cepacia were used for the dynamic kinetic resolution of epichlorohydrin (5) and epibromohydrin (6).152,153 Recently, Candida rugosa lipase (CRL) has been demonstrated to catalyze the enantioselective aminolysis of (±)-epichlorohydrin (5). Incubation of an equimolar mixture of (±)-epichlorohydrin (5) and aromatic amines in diisopropyl ether for 8−12 h led to the enantioselective formation of (S)-3-arylamino-1-chloropropan2-ols 106 (Scheme 36).154

Scheme 38

pure oxiranes which serve as versatile building blocks in organic synthesis. As depicted in Scheme 39, (2S)-2-(chloromethyl)oxirane (11) can undergo a direct SN2 nucleophilic substitution at the halogenated carbon atom toward (2S)-oxirane (111) (pathway a, retention of configuration), or alternatively, the nucleophile can attack the unsubstituted oxirane carbon atom, resulting in a ring-opened intermediate 110, which is prone to undergo ring closure toward the substituted (2R)-oxirane 109 (pathway b, inversion of configuration).23 If both pathways are competitive, a mixture of both enantiomers 109 and 111 will be obtained. Applying this methodology, the reaction of (R)-epichlorohydrin (8) or (S)-epichlorohydrin (11) with different substituted phenols in the presence of potassium carbonate in boiling acetone has been shown to result in 87−97% inversion of configuration, whereas the reaction in NaH−DMF produced 30−50% inversion of configuration.23 Huerou and co-workers have reported similar observations.157 In the reaction of (S)epichlorohydrin (11) with alcohol 112 under phase-transfer conditions, only one O-alkylated product 113 was obtained in 78% yield (Scheme 40), whereas the reaction of the same epichlorohydrin 11 with a catechol derivative 114 in NaH−DMF afforded both enantiomers 115 and 116 (70% inversion and 30% retention of configuration) (Scheme 41).157 Recently, nucleophilic substitution of epichlorohydrin 5 with substituted phenols and benzyl alcohols has been discussed to yield the corresponding O-alkylated products as precursors for enantiopure β-aminoalcohols,158 chlorohydrins,159 and 4benzyloxy-3-hydroxybutanenitriles.160 The nucleophilic substitutions with various alcohols161 and diols162 have been studied in the presence of NaOH or KOH as a base and tetrabutylammonium hydrogen sulfate as a phase-transfer catalyst. Nakatsuji and co-workers have accomplished a facile synthesis of polyglycidyl ethers from polyols and epichlorohydrin (5) in the presence of KOH in DMSO.163 For example, the reaction of epichlorohydrin (5) with benzene-1,3,5-triol (117) afforded the corresponding 1,3,5-tris(oxiran-2-ylmethoxy)benzene (118) (Scheme 42). In addition, Kameyama and co-workers have evaluated the synthesis of polycyclic ortho-esters by a one-pot reaction of potassium perfluoroalkanoates with epibromohydrin (6) in the presence of quaternary ammonium salts.164 Nucleophilic substitution reactions of epichlorohydrin (5) with thiophenols 119 have led to the formation of the corresponding 2-(arylthiomethyl)oxiranes 120 in 80−85% yield (Scheme 43).165 In a following example, the C-alkylation of lithiated tetrahydropyrimidine (122) with epibromohydrin (6) has been studied (Scheme 44).166 Similarly, the reaction of epibromohydrin (6) with 1,3-dithiane (83) using n-butyllithium and 1,3dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) in THF has been evaluated to afford the corresponding alkylated product 1,3-(dithian-2-yl)methyloxirane (124) in 67% yield (Scheme 45).167 More recently, Tsuda and co-workers have employed the nucleophilic substitution of epichlorohydrin (5) with piperidine to yield 2-(piperidinomethyl)oxirane in the preparation of ionic liquids.168 The reaction of (2,2-dimethyl-

Scheme 36

In conclusion, the interest in epihalohydrin derivatives can (partially) be explained by their well-known applicability in organic synthesis for the preparation of a variety of ring-opened oxygen-containing target compounds. It is clear from the above paragraphs that this powerful synthetic utility resulted in numerous reports on the regioselective ring opening of epihalohydrins by N-, O-, halogen-, S-, Se-, P- and C-centered nucleophiles, as well as by radicals and electrophiles. Furthermore, the development of chiral metal complexes enabled the highly enantioselective ring opening of epihalohydrins, leading to enantiomerically pure compounds. In addition, in almost all cases, the ring-opening reactions proceeded in a highly regioselective manner through addition at the lesshindered epoxide carbon atom. Indeed, the epoxide part of epihalohydrins is susceptible toward ring cleavage because of the favorable release of ring strain involved. Next to this reactivity, the presence of a halogenated carbon atom renders epihalohydrins excellent substrates for direct nucleophilic substitution reactions leading to diversely substituted oxiranes, which will be discussed in the next section. 3.2. Direct Halide Substitution Reactions

In 1908, Boyd and Marle have reported on the reaction between epichlorohydrin (5) and phenol to form 3-phenoxy-1,2epoxypropane.155 This result led to speculation about the reaction mechanismwhether the product was formed by direct displacement of the chloride ion (Scheme 37) or by initial attack Scheme 37

of the nucleophile at the less-hindered epoxide carbon atom to form an intermediate alkoxide ion 108, which subsequently underwent cyclization by displacement of the chloride to form a new oxirane ring (Scheme 38). In principle, both reaction pathways are possible and their feasibility has been demonstrated by carrying out reactions of differently substituted epibromohydrins with ethoxide and methoxide ions,156 which will be discussed in the section on substituted epihalohydrins (section 5). Enantiopure epichlorohydrins have been subjected to nucleophilic substitution leading to 2-alkyl-substituted enantioM


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Scheme 39

Scheme 40

Scheme 42

Scheme 43

1,3-dioxolan-4-yl)methanol, commonly known as (S)-solketal, with epichlorohydrin (5) has led to the synthesis of a linker scaffold required for the preparation of fluorinated chiral polar lipids.169 Nucleophilic substitution reactions of epihalohydrins are of paramount importance in medicinal chemistry. The reactivity of epihalohydrins toward O-, N-, and S-centered nucleophiles has been explored extensively in the design and the synthesis of diverse bioactive compounds. 3.2.1. Applications in Medicinal Chemistry. The nucleophilic substitution products of epichlorohydrin (5) and epibromohydrin (6) with alcohols and amines have been employed in medicinal chemistry for the synthesis of different types of target compounds with potential biological activity (Table 1). Usually, the new oxirane ring obtained underwent a subsequent ring opening by nucleophilic attack to form the desired bioactive products. For example, alkylation of α-naphthol (125) with epichlorohydrin (5) in the presence of K2CO3 afforded the corresponding oxirane 126, which subsequently underwent hydrolytic kinetic resolution to afford the corresponding chiral expoxide 128 in 47% yield and 96% ee and chiral 1,2-diol 127 in 43% yield.170 Ring opening of the former compound 128 with isopropylamine led to the enantioselective synthesis of (S)-propranolol (129), a β-adrenergic blocking agent (Scheme 46).170 Table 1 demonstrates that nucleophilic substitution reactions of epihalohydrins have been employed amply in medicinal chemistry in order to synthesize new target compounds with biological activity, such as antibacterials, antituberculars, antimalarials, antioxidants, enzyme inhibitors, hypoglycemics, β3-adrenergic receptor antagonists, uterine relaxants, calcium blockers, dopamine uptake inhibitors, etc. Apart from applications in medicinal chemistry, the reactivity of epihalohy-

Scheme 44

Scheme 45

Scheme 41

N


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Scheme 46

heterocycles. As a first example, Langer and co-workers have performed considerable work on the reactions of epichlorohydrin (5) and epibromohydrin (6) with various dianions to synthesize different types of heterocyclic compounds. The reaction of epichlorohydrin (5) and epibromohydrin (6) with 1,3-bis(trimethylsilyloxy)-1,3-butadienes214 or with dilithiated 1,3-dicarbonyl compounds215 has been reported to form 2alkylidenetetrahydrofurans. For example, the titanium(IV) chloride-mediated cyclization of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (134) with epichlorohydrin (5) afforded 2-alkylidene-5-(chloromethyl)tetrahydrofuran (135) in 66% yield (Scheme 48).216 Subsequent hydrogenation occurred with very good diastereoselectivity to afford the corresponding tetrahydrofuran 136 in quantitative yield (Scheme 48).216 Epibromohydrin (6) reacted in a similar manner with the dilithiated dianions of ethyl acetoacetate to afford 2-alkylidene-5-(hydroxymethyl)tetrahydrofurans.217 It is worth mentioning that the (tetrahydrofuran-2-yl)acetate framework is present, for example, in the polyether antibiotics lasalocid A,218 ferensimycin A and B, and lysocellin.219 The same authors have prepared methyl 5-(chloromethyl)dihydrofuran-2(3H)-ylidene acetates 137 and 138 in excellent enantiomeric excess by reaction of enantiopure (S)-11 and (R)epichlorohydrin (8), respectively (Scheme 49).220 No loss of enantiomeric purity was observed during the cyclization, which proceeded with very good chemo-, regio-, and E-selectivity. Similarly, titanium(IV) chloride-promoted reactions of epichlorohydrin (5) and epibromohydrin (6) with silyl ketene acetals 139 followed by acidic workup have led to the formation of γ-(halomethyl)butanolides 140 (Scheme 50).221 On the basis of the same methodology, the base-induced coupling reactions of epihalohydrins 5 and 6 with ethyl acetoacetate (141) have led to the formation of three types of reaction products depending on the reaction conditions and the halogen (Schemes 51 and 52).222 With epichlorohydrin (5), exclusive formation of lactone 144 was observed (Table 2, entry 1: NaOEt as base in ethanol at 50 °C). In contrast, the use of epibromohydrin (6) led to the formation of a mixture of dihydrofuran (142) and tetrahydropyran (143) (Table 2, entries 2−7). The formation of O-heterocycles 142, 143, and 144 was rationalized as follows (Scheme 52). The enolate of ethyl acetoacetate 141 induces direct nucleophilic substitution at the

drins has been further investigated in order to develop new synthetic methodologies toward the efficient and convenient synthesis of novel heterocyclic and macrocyclic compounds, which will be the topic of the following section.

4. APPLICATIONS OF EPICHLOROHYDRIN AND EPIBROMOHYDRIN IN THE SYNTHESIS OF HETEROCYCLIC COMPOUNDS As described in the previous sections, epihalohydrins are important intermediates in organic synthesis. In terms of synthetic transformations, ring opening of these strain-loaded three-membered rings allows for regio- and stereoselective installation of a wide range of functional groups in a 1,2relationship to oxygen. In addition, nucleophilic substitution at the halogen-containing electrophilic carbon center comprises a key intermediate step in the synthesis of a broad variety of biologically important products. In the next section, this review will focus on the applicability of epihalohydrins in the synthesis of heterocyclic compounds of synthetic and biological interest (Figure 5). Indeed, in order to release their ring strain, ring expansions of epihalohydrins are favorable from a thermodynamic and kinetic viewpoint, and ring rearrangements can lead to five-, six-, seven-, eight-, and nine-membered heterocycles. The reactions covered in this section will be classified according to the number and type of heteroatom(s) present in the heterocycle. 4.1. Heterocycles Containing One Heteroatom

4.1.1. Oxygen-Containing Heterocycles. An efficient and straightforward approach to synthesize the smallest possible oxygen-containing heterocycles, i.e., substituted oxiranes, involves nucleophilic substitution of epihalohydrins either by direct displacement of the halide or by initial nucleophileinduced ring opening followed by intramolecular cyclization in the presence of a base. An excellent example in that respect is the asymmetric synthesis of glycidyl butyrate 133 by the Lewis acidcatalyzed regio- and enantioselective ring opening of epichlorohydrin (5) with butanoic acid (131) in the presence of catalyst (R,R)-102 followed by cyclization in tert-butyl methyl ether (TBME) in the presence of a base and a catalyst (Scheme 47).148 Next to the synthesis of differently substituted oxirane derivatives, epihalohydrins have also been employed in the synthesis of a variety of five-membered oxygen-containing O


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Table 1. Bioactive Products Prepared from Epihalohydrins

P


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Table 1. continued

Q


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Table 1. continued

R


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Table 1. continued

S


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Table 1. continued

T


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Table 1. continued

U


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Table 1. continued

V


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Table 1. continued

halogenated carbon atom or ring opening at the less-hindered site of epihalohydrins 5 and 6 to furnish intermediates 145 and 146, respectively. Subsequent proton abstraction of oxirane 145, followed by intramolecular cyclization has been described as the most feasible pathway toward dihydrofuran 142. Intermediate 146 has several opportunities to cyclize, i.e., intramolecular nucleophilic substitution as an alternative route toward epoxide 145, intramolecular nucleophilic substitution toward lactone 144, or enolate formation to intermediate 148 and subsequent 6exo-tet-cyclization to form tetrahydropyran 143 (Scheme 52).222 Another important illustration, based on a similar methodology, comprises the reaction of (R)-epibromohydrin (150) with 1,3-dicarbonyl dianions 151, generated in situ by treatment of 1,3-dicarbonyl compounds 149 with NaH and then nBuLi, resulting in the chemo-, regio-, and stereoselective formation of functionalized 2-alkylidene-5-(hydroxymethyl)tetrahydrofurans 153. These products are of pharmacological relevance and comprise versatile building blocks for the synthesis of natural products223 via initial nucleophilic substitution by the terminal carbon atom of dianions 151, followed by regioselective intramolecular ring opening of the oxirane ring (Scheme 53).224

Recently, Moon and co-workers have demonstrated the synthesis of a novel class of bicyclonucleosides as synthetic analogues of the known antiviral drugs used in the treatment of herpes viruses.225 In this synthesis, (S)-epichlorohydrin (11) acted as the starting compound to form the corresponding cyclopropane-fused lactone ester 154 via a tandem alkylation− lactonization protocol on treatment with diethyl malonate. The latter compound led to the synthesis of a bicyclic compound 155, bearing an oxabicyclo[3.1.0]hexane unit, as a template for the preparation of thiamine and uracil nucleosides (Scheme 54).225 Analogously, the same authors used (R)-epichlorohydrin (8) in a multistep synthesis of enantiopure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides with antiviral activity.226 The formation of a similar cyclopropane-fused γ-lactone, bearing a phenylsulfonyl group at C3, has been demonstrated by the reaction of (R)-epichlorohydrin (8) with phenylsulfonylacetonitrile227 and has been employed in the synthesis of NMDA receptor antagonists.228 Roy and co-workers have reported a titanocene(III) chloridemediated 8-endo radical cyclization toward the synthesis of an eight-membered cyclic ether.229,230 Epichlorohydrin (5) initially W


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Figure 5. Selected heterocyclic systems synthesized from epihalohydrins as substrates.

Scheme 47

4.1.2. Nitrogen-Containing Heterocycles. Epihalohydrins are involved in the selective synthesis of biologically important nitrogen-containing heterocycles such as pyrrolidin-2ones, pyrrolidin-2-thiones, azetidinols, and pyrroles. A number of 5-(hydroxymethyl)pyrrolidin-2-ones 169 (X = O) and 5-(hydroxymethyl)pyrrolidin-2-thiones 170 (X = S) have been prepared by the coupling of dianions of amides or thioamides, generated in situ upon treatment with n-butyllithium, with epibromohydrin 6 (Scheme 57).232 The mechanism was explained by nucleophilic attack of the carbanionic center in intermediate 166 at the bromine-containing electrophilic carbon atom of epibromohydrin 6, followed by nucleophilic attack of the nitrogen anion at the oxirane ring, resulting in ring enlargement

reacted with 2-allylphenol (156) under basic conditions to form an O-alkylated product 157 in 72% yield (Scheme 55). Subsequently, this product underwent radical cyclization toward the eight-membered cyclic ether 158 in 44% yield upon treatment with Cp2TiCl. Next to the reductive ring-opening product 159, two other unidentified products were obtained. In a last example, the Friedel−Crafts alkylation of mesitylene 160 with epichlorohydrin 5 resulted in the alkylation of the phenyl ring followed by oxirane ring opening to yield 1-chloro-3mesitylpropan-2-ol (161) (Scheme 56).231 The oxidation of the alcohol moiety to the corresponding α-chloroketone 162 followed by reaction with salicylaldehyde 163 led to the synthesis of 2-acetylbenzofuran derivative 164. X


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Scheme 48

Scheme 49

Scheme 50

Scheme 51

pioneering work on the preparation of azetidinols from epichlorohydrin (5) was limited to sterically hindered amines,236 some important progress has been made toward more productive synthesis of these compounds. Okutani et al. have decreased the reaction time for ring closure substantially and increased the yields conducting the reactions in acetonitrile,237 and Gaj has described a modified synthetic method toward N-alkylazetidin-3ols from sterically less hindered amines.238 Jenkins and Higgins have reported on an improved method for the preparation of the ether derivatives of azetidinols with nonbulky N-alkyl substituents.239 More recently, Oh and co-workers have further

toward pyrrolidin-2-one/pyrrolidin-2-thione derivatives 169 and 170 (Scheme 57). Tverdokhlebov and co-workers have investigated the coupling of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles (171) with epichlorohydrin (5) in the presence of K2CO3 to yield 1,2-dihydrofuro[2,3-c]-2,7-naphthyridine derivatives 173 via a domino heterocyclization reaction (Scheme 58).233 In the next example, different attempts have been made toward the selective synthesis of azetidin-3-ols from epichlorohydrin (5), as 3-azetidinols attract considerable attention due to their synthetic234 and biological properties.235 Although Gaertner’s Y


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Scheme 52

Scheme 53

Scheme 54

Scheme 55

Table 2. Base-Induced Coupling Reactions of Ethyl Acetoacetate 141 with Epihalohydrins 5 and 6 entry

X

solvent

base

T (°C)

t (d)

result

yield % (ratio)

1 2 3 4 5 6 7

Cl Br Br Br Br Br Br

EtOH EtOH DMF EtOH DMF DMF DMF

NaOEt NaOEt Li2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3

50 50 50 50 50 20 50

1 1 2 2 2 2 2

144 142/143 142/143 142/143 142/143 142/143 142/143

42 54 (64/36) 44 (100/0) 60 (63/37) 19 (100/0) 33 (100/0) 13 (88/12)

Scheme 56

improved the synthesis of N-alkylazetidin-3-ols (175) by the regioselective rearrangement of N-alkyl-2,3-epoxypropylamines (174), formed from primary alkylamines and epichlorohydrin (5). During these transformations, a solution of the primary amines and epichlorohydrin (5) was stirred in isopropanol at room temperature to give the corresponding N-alkyl-2,3epoxypropylamines 174 in good yields (81−98%). When these 2-(aminomethyl)oxiranes (174) were heated under reflux in acetonitrile in the presence of triethylamine as a base, they were smoothly transformed into the premised N-alkylazetidin-3-ols (175) (Scheme 59).240 Interestingly, the regioselective ring opening of epichlorohydrin (5) with α-C-silylated amines 176 has been employed in the synthesis of N-(trimethylsilyl)alkyl-3-azetidinols (179) in good yields (Scheme 60).241 As a final example, Katritzky and co-workers have explored the reactivity of epibromohydrin (6) toward allylbenzotriazole (180) (Bt = benzotriazole) in the presence of nBuLi (Scheme 61).242 The substituted oxirane 181 obtained was employed in the

synthesis of 1-benzyl-2-ethylpyrrole 185 by treatment with benzylamine followed by a palladium-catalyzed cyclization. 4.1.3. Sulfur- and Selenium-Containing Heterocycles. The oxirane ring in epichlorohydrin (5) has been transformed efficiently into a thiirane ring 186 in one step by treatment with ammonium thiocyanate in the presence of catalytic cerium(IV) Z


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Scheme 57

Scheme 58

Scheme 59

Scheme 61

Scheme 60

Scheme 62

The reaction of epichlorohydrin (5) with dithiocarbamates 187 has been described to effect an intramolecular rearrangement yielding S-[(2,3-epithio)propyl]-N,N-dialkylthiocarbamates (188) (Scheme 63).247 Subsequent ring opening with secondary amines, followed by treatment with tartaric acid led to the formation of tartrate salts 190 as nondetergent spermicidal agents.248 In addition, Plenkiewicz and co-workers have developed a simple method for the preparation of optically active thiiranes

ammonium nitrate (Scheme 62)243 or a Ru(III)244 catalyst. In recent years, solvent-free conversions of epichlorohydrin (5) toward the corresponding thiirane ring 186 using 2,4,6-trichloro1,3,5-triazine245 or fluoroboric acid absorbed on silica gel246 as catalysts have been developed. AA


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Scheme 63

Scheme 64

195 in excellent enantiomeric excess from racemic epichlorohydrin (5) by a microbiological reduction of intermediate thiocyanatoketones 193 and subsequent treatment with lithium hydroxide in aqueous THF (Scheme 64).249 Finally, the reaction of epichlorohydrin (5) with lithium selenide, prepared from lithium triethylborohydride and gray selenium in THF, has led to the formation of 3-hydroxyselenetane (196) in 75% yield (Scheme 65).250

Scheme 66

plastics. In addition, chemical CO2 fixation is a challenging and important synthetic goal, as CO2 is an inexpensive and abundant C1 feedstock, and in terms of “green chemistry” and “atom economy”, the chemistry of carbon dioxide has garnered much attention in recent years. A wide range of catalysts has been employed for the generation of cyclic carbonates by the reaction of CO2 with epichlorohydrin (5), including Co(III) porphyrin/DMAP,251 metal phthalocyanines,252 tetraalkylammonium/phosphonium halides-CaCl2,253 zinc-substituted polyoxometalate,254 ZnCl2/[BMIm]Br,255 (Salen)AlX-n-Bu4NI,256 zeolite-based organic−inorganic hybrids,257 MCM-41,258 Cu and Mn peraza macrocyclic complexes,259 tungstate-based solid catalysts,260 hexabutylguanidinium salt/zinc bromide,261 SnCl4-5DBU,262 zinc phenosulfonate octahydrate-Bu4NBr,263 hydroxyl-functionalized ionic liquid,264 immobilized ionic liquid/ZnCl2,265 silica-supported polyvinylpyridine,266 PEG-supported quaternary ammonium salts,267 silica-supported quaternary ammonium salts,268 ZnBr2− Ph4PI,269 InBr3−Ph3P,270 and some others.271

Scheme 65

4.2. Heterocycles Containing Two or More Heteroatoms

4.2.1. Oxygen-Containing Heterocycles. The reaction of epichlorohydrin (5) with carbon dioxide catalyzed by a Co(III) porphyrin/DMAP-system has led to the synthesis of a fivemembered cyclic carbonate, 4-chloromethyl-1,3-dioxolan-2-one (197) (Scheme 66).251 An enantioselective insertion of CO2 toward enantiomerically enriched cyclic carbonates has been achieved by applying chirally modified Zr- and Ti-complexes.141 Cyclic carbonates are valuable products finding use as organic synthetic intermediates, aprotic polar solvents, precursors for biomedical applications, and raw materials for engineering AB


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2,3-dihydro[1,4]dioxino[2,3-b]pyridine derivatives 207 and 208.274 The ring-opened alcohols 206 underwent cyclization by intramolecular nucleophilic aromatic substitution and Smiles rearrangement to yield two isomeric products 207 and 208, respectively (Scheme 69). Similarly, reaction of epichlorohydrin (5) with 2-iodophenol (209) catalyzed by copper over alumina has been described to yield 2-chloromethyl-1,4-benzodioxane (210) (Scheme 70).275 Epichlorohydrin (5) and o-bromobenzylic ether (211) have been used as substrates in a multistep synthesis toward spiroperoxide 214 as a potential antimalarial agent (Scheme 71).276 The initial step in this synthesis comprises a direct nucleophilic substitution at the chlorinated carbon atom of epichlorohydrin (5) with a lithium species prepared in situ from bromide 211 in the presence of nBuLi and BF3·Et2O (Scheme 71).276 Recently, Wang and co-workers have elaborated a novel Lewis acid-catalyzed intermolecular [4 + 3]-cycloaddition of epichlorohydrin (5) and benzylideneacetone (215) to yield the corresponding 7-membered oxacycle 217 in 73% yield (Scheme 72).277 According to the proposed reaction mechanism, benzylideneacetone 215 reacted with epichlorohydrin (5) in the presence of BF3-etherate to give zwitterionic intermediate 216, stabilized by both the phenyl group and the double bond, which subsequently coupled with epichlorohydrin (5) through an intermolecular [4 + 3]-cycloaddition and simultaneous removal of BF3. In the next example, the reaction of epibromohydrin (6) with 6,6′-bis(diphenylphosphino)biphenyl-2,2′-diol (218) has been directed to the formation of a nine-membered fused heterocycle 219, albeit in low yield (Scheme 73).278 As a final example, the stereoselective synthesis of both enantiomers of ketoconazole, a potent orally active broadspectrum antifungal agent, from commercially available (R)epichlorohydrin (8) and (S)-epichlorohydrin (11) has been investigated by Garciá and co-workers.279 Treatment of (S)epichlorohydrin (11) with acetone in the presence of BF3·Et2O led to the selective formation of (R)-4-chloromethyl-2,2dimethyl-1,3-dioxolane (220) (Scheme 74), which subsequently underwent selective substitution at the chlorinated carbon atom by sodium benzoate in DMSO to yield acetal ester 221. Both (R)- and (S)-enantiomers of epichlorohydrin (5) were used to synthesize isomeric ketoconazoles.279 4.2.2. Nitrogen-Containing Heterocycles. In a first example, the coupling reaction of epibromohydrin (6) with guanidine 223 in the presence of tBuOK followed by treatment with trifluoroacetic acid in methanol has been evaluated to yield imidazoline derivative 224 (Scheme75).280 In a second approach, Yadav and co-workers have studied a direct and efficient one-pot synthesis of β-hydroxytriazole (226) through a three-component reaction of epichlorohydrin (5),

The formation of cyclic carbonates has been explained by different reaction mechanisms depending mainly on the catalyst. According to the mechanism for the Co(III) porphyrin/DMAPcatalyzed reaction (Scheme 67),251 the epoxide was first activated Scheme 67

via binding to a coordinatively unsaturated Lewis acidic metal center, followed by nucleophilic ring opening to produce the requisite metal alkoxide intermediate 200, which subsequently coupled with CO2. A similar initial mechanistic step for the Cr(III) salen/1-methylimidazole-catalyzed coupling of CO2 and cyclohexene oxide to form the corresponding polycarbonate has been proposed by Darensbourg and co-workers.272 Finally, intramolecular cyclization of intermediate 201 leads to the formation of 4-chloromethyl-1,3-dioxolan-2-one (197).251 In a second example, Getautis and co-workers have developed an efficient synthetic method for the preparation of [1,5]dioxocines 205 via condensation of salicylaldehydes 203 and epichlorohydrin 5 in the presence of benzyltriethylammonium chloride as a catalyst (Scheme 68).273 The initial O-alkylated products 204 underwent intramolecular cyclization upon prolonged heating to afford the final products 205 in good yields. On the basis of the same methodology, nucleophilic substitution of epichlorohydrin (5) with 2-substituted 3pyridinols and subsequent ring opening with amines, alcohols, and azide has been used in the synthesis of 2- and 3-substitutedScheme 68

AC


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Scheme 69

intramolecular displacement of chloride and a subsequent “click reaction” with terminal alkynes 229 to furnish epoxytriazoles 230. On the other hand, ring opening of 2-(azidomethyl)oxiranes 228 by azide followed by a “click reaction” led to the selective synthesis of bis(triazoles) 232 (Scheme 77). The “click reaction” has also been employed in the synthesis of triazolyl polymers starting from polymeric azidoalcohols.284 An interesting application of 2-alkylidenetetrahydrofurans 233, prepared via coupling of epichlorohydrin (5) or epibromohydrin (6) with dilithiated acetone, has been reported in the synthesis of pyrimidine derivatives 235 by reaction with amidines 234 (Scheme 78).285 Finally, Patil and co-workers have explored the synthesis of 2oxazolidinone/imidazolinone (236) using a polyethylene glycol (PEG)-functionalized phosphonium salt as an efficient homogeneous recyclable catalyst via addition of CO2 to epichlorohydrin (5), followed by treatment with 2-aminoethanol and 1,2diaminoethane, respectively (Scheme 79).286 4.2.3. Oxygen- and Nitrogen-Containing Heterocycles. Different attempts have been made in order to synthesize substituted oxazolidinone derivatives, compounds which have been shown to exhibit various pharmacological activities in the areas of drug development, leading to applications as antibacterials, cytokine modulators, antiallergy agents, intermediates in the synthesis of renin inhibitors, β-lactam and macrolide antibiotics, immunosuppressants, and many others.287 A first reaction comprises the cycloaddition of phenylisocyanate 237 to epichlorohydrin (5), catalyzed by an organotin iodide− Lewis base complex under mild conditions (40 °C, 2 h) (Scheme 80).288 Later on, Y(III), Yb(III), and Er(III) chlorides have been investigated as catalysts for this reaction,289 and more recently, this cycloaddition has been carried out with different arylisocyanates using MgI2·etherate as a catalyst in tetrahydrofuran to yield 3-aryl-2-oxazolidinones.290 Next, epichlorohydrin (5) and epibromohydrin (6) have been observed to react with primary amines and carbonate salts (Na2CO3, K2CO3, Cs2CO3, and Ag2CO3) in the presence of a base such as DBU/TEA to give 5-hydroxymethyl-2-oxazolidinones, 291 and the reaction of epibromohydrin (6) or epichlorohydrin (5) with benzylamine in the presence of K2CO3 and TEA in methanol under reflux afforded 3-benzyl-5(hydroxymethyl)oxazolidin-2-one (239) in 81% and 88% yield, respectively (Scheme 81).291 This reaction was explained by an oxazinanone 242 to oxazolidinone 239 rearrangement via a bicyclic intermediate 244 (pathway I) or via initial nucleophilic attack of methanol (pathway II) (Scheme 82). An approach toward enantiopure 3-substituted 5-hydroxymethyl-2-oxazolidinones 247 has been developed as well by the same authors starting from enantiopure (S)-epichlorohydrin 11 (Scheme 83).291 Furthermore, Madhusudhan and co-workers have also investigated the use of (S)-epichlorohydrin (11) in the synthesis of enantiopure oxazolidinones.287 In this synthetic strategy, (S)-

Scheme 70

Scheme 71

Scheme 72

Scheme 73

NaN3, and 1-octyne (225) (Scheme 76).281 However, in the presence of a copper(I)−zeolite catalyst (Cu(I)-USY) (Scheme 77),282,283 β-azido alcohol 227, derived in situ from epichlorohydrin (5) and NaN3, underwent a smooth ring closure through AD


Chemical Reviews

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Scheme 74

epibromohydrin (6) and subsequent ring opening of the resulting oxirane to chlorohydrins.294 As illustrated by Martin and co-workers,295 (S)-epichlorohydrin (11) has been converted into the enantiopure isoxazolidin4-ol (260) by treatment with N-hydroxyphthalimide (258) in the presence of triethylamine and subsequent reaction with triethylamine in methanol (Scheme 87). According to a recent report, epichlorohydrin (5) and epibromohydrin (6) exhibit different reactivities toward 2chloroindole-3-carboxaldehyde (261) under basic conditions (Scheme 88).296 Reaction with epibromohydrin (6) led to the selective formation of the corresponding 1-(oxiran-2-ylmethyl) derivative 262 by direct nucleophilic displacement of bromide, whereas the analogous reaction with epichlorohydrin (5) afforded the oxazolo[3,2-a]indole skeleton 264 by initial epoxide ring opening, followed by a nucleophilic aromatic substitution. Another important illustration of the ring transformation of epihalohydrins comprises the synthesis of morpholine derivatives through nucleophilic ring opening of epichlorohydrin (5) or epibromohydrin (6) by 2-aminoethanols, followed by acid- or base-promoted intramolecular cyclization. Loftus and co-workers, for example, have pursued this strategy successfully in the synthesis of 2-chloromethyl-4-benzylmorpholine through sulfuric acid-mediated cyclization.297 Furthermore, Buriks and coworkers have prepared a 2-(hydroxymethyl)morpholine and a 3hydroxyoxazepine derivative in 9:1 ratio.298 In a similar way, Breuning and co-workers have reported a one-pot procedure for the synthesis of 4-benzyl-2-(hydroxymethyl)morpholine (266) by reaction of epichlorohydrin (5) with 2-(N-benzylamino)ethanol (265) in the presence of lithium perchlorate, followed by addition of a base.299 Among many bases, solvents, and reaction conditions studied for this reaction, the highest yield (62%) of morpholine derivative 266 was obtained using NaOMe in toluene at 60 °C. The oxazepane 267 was formed as a minor product (8−24%) under all conditions investigated. The reaction using NaOMe in toluene at 20 °C afforded 55% of the morpholine derivative 266 and 14% of the oxazepane derivative 267 (Scheme 89).299

Scheme 75

epichlorohydrin (11) was stereoselectively ring opened with NaN3 in aqueous ethanol, while maintaining mild acidic conditions using NH4Cl, to give (2S)-1-azido-3-chloropropan2-ol (248) without racemization. The latter compound, upon treatment with Ph3P and carbon dioxide in toluene under reflux, gave (S)-5-chloromethyl-2-oxazolidinone (251), which was further treated with NaN3 to afford (S)-5-azidomethyl-2oxazolidinone (252) (Scheme 84). The mechanism was explained via the reaction of an intermediate iminophosphorane 249 with carbon dioxide to generate an intermediate isocyanate 250, which subsequently cyclized to afford the corresponding oxazolidinone 251 (Scheme 84).287 The corresponding (R)-enantiomer 255 was obtained by converting azido alcohol 248 into tert-butyl carbamate derivative 253, which further reacted with NaN3 using tetrabutylammonium chloride to give azido compound 254. This azido alcohol 254 was then cyclized through SN2 inversion in Ph3P/CCl4/Et3N (1/2/2) to furnish (R)-oxazolidinone 255 (Scheme 85).287 Later on, the same authors developed a convenient synthesis of (R)-5-chloromethyl-2-oxazolidinone in 75% yield and 90% ee by heating commercially available (R)-epichlorohydrin (8) under reflux with potassium cyanate in water over magnesium sulfate for 15 h.292 Su and co-workers have elaborated an efficient [3 + 2]cycloaddition of N-arylimines 256 and epichlorohydrin (5) catalyzed by ytterbium(III) triflate under solvent-free conditions to afford substituted 1,3-oxazolidines 257 in good yields (Scheme 86).293 Also, a solid-phase multistep synthesis of 1,3oxazolidines has been elaborated starting from O-alkylation of the phenolic hydroxyl group of p-hydroxybenzylalcohol by Scheme 76

AE


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Scheme 77

Scheme 78

Scheme 79

synthesis of (S)-N-Boc-2-(hydroxymethyl)morpholine and (S)N-Boc-morpholine-2-carboxylic acid using (R)-epichlorohydrin (8) and 2-N-benzylaminoethanol has been reported by Henegar.301 The synthesis of (S)-[(4-(3,4-dichlorobenzyl)morpholin-2-yl)]methanamine has been achieved through enantioselective ring opening of (R)-epichlorohydrin (8) with neat 2-(3,4-dichlorophenyl)aminoethanol.302 Finally, epibromohydrin (6) has been employed in the synthesis of 6-hydroxymethyl-5,6-dihydro-4H-1,2-oxazines.303 In that respect, the reaction of epibromohydrin (6) with dilithiated oximes 277, generated from oximes 276 with nbutyllithium, led to the selective formation of 1,2-oxazines 279 in 30−81% yield by initial nucleophilic substitution of epibromohydrin (6) to form intermediate 278, which cyclizes to the dihydro1,2-oxazine derivatives 279 (Scheme 92). 4.2.4. Sulfur-Containing Heterocycles and Oxygenand Sulfur-Containing Heterocycles. The combined use of the bimetallic aluminum(salen) complex [Al(salen)]2O and tetrabutylammonium bromide or tributylamine has been found to catalyze the reaction between epichlorohydrin (5) and carbon disulfide to yield 1,3-oxathiolane-2-thione (280) and 1,3dithiolane-2-thione (281) in varying ratios and yields, depending on the catalytic system and the temperature (Scheme 93).304 In most cases, at 50 °C, the reaction produced 1,3-oxathiolane-2thione (280) as the major product, while, at 90 °C, 1,3dithiolane-2-thione (281) has been observed to be the major constituent. According to the proposed reaction mechanism, tributylamine (a decomposition product of Bu4NBr) reacted as a

Scheme 80

Scheme 81

The same authors have also investigated the reaction of commercially available (S)-epichlorohydrin (11) with enantiopure β-amino alcohols 268 to perform the stereoselective synthesis of enantiopure morpholine derivatives 269 in good yields (57−77%) (Scheme 90).299 Later on, this study has been extended to the one-pot synthesis of enantiomerically pure 2phenyl-9-oxabispidines 275 by a sequence of reactions involving epoxide ring opening, cyclization, activation of hydroxyl groups, and finally cyclization by heating with benzylamine in toluene under reflux (Scheme 91).300 A one-pot procedure for the AF


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Scheme 82

Scheme 83

Scheme 84

Scheme 85

Lewis base with CS2 to form a dithiocarbamate which, in turn,

Yavari and co-workers have utilized an efficient threecomponent reaction of epichlorohydrin (5), carbon disulfide, and malononitrile (282) in the presence of triethylamine to furnish 2-(1,3-oxathiolan-2-ylidene)malononitrile (286) in 87% yield (Scheme 94).306 4.2.5. Sulfur- and Nitrogen-Containing Heterocycles. The most important representatives in this class of heterocyclic

acted as a nucleophile to induce ring opening of the aluminumcoordinated epoxide. This mechanism stands in contrast to the one proposed for the reaction of oxiranes with CO2, in which metal-coordinated oxiranes underwent ring opening by the nucleophilic amine followed by reaction with CO2.305 AG


Chemical Reviews

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Scheme 86

Scheme 88

systems are substituted (hydroxymethyl)thiazolidines, as this scaffold is present in a variety of pharmacologically relevant compounds. In the recent literature, two principal synthetic pathways involving epihalohydrins are described. 2-Arylimino-3-aryl-1,3-thiazolidines 288 and 289 have been successfully obtained from epichlorohydrin (5) and thioureas 287 in DMF catalyzed by ytterbium(III) triflate (Scheme 95).307 Less bulky, electron-donating substituents at the phenyl rings in thioureas 287 (R1, R2) were observed to increase the nucleophilicity of the nitrogen atom, leading to a relatively higher reactivity in comparison with more bulky and electronwithdrawing groups. When similar reactions with alkylsubstituted thioureas were carried out, no desired products were detected.307 The reaction of (R)-epichlorohydrin (8) with 1,3-diphenylthiourea (291) has led to the stereoselective formation of (R)thiazolidinimine 293 with inversion of configuration at the chiral center of the starting epoxide 8 (Scheme 96).307 According to the proposed reaction mechanism (Scheme 96), (R)-epichlorohydrin (8) first coordinated to Yb(OTf)3 to form intermediate 290, which was subsequently attacked by the thiol group of thiourea 291 to generate a highly reactive intermediate 292. The nucleophilic attack occurred at the β-carbon atom of epoxide 290 and led to an inversion of configuration. Finally, intramolecular nucleophilic displacement of chloride by the nitrogen atom afforded the final thiazolidinimine 293.307 Another effective method for the preparation of substituted 4(hydroxymethyl)thiazolidine derivatives comprises a threecomponent reaction of nitriles 86, isothiocyanates 294, and epibromohydrin (6) in the presence of n-butyllithium in THF to furnish 2-cyanomethylidene-4-hydroxymethyl-1,3-thiazolidines 297 (Scheme 97).131,308 The formation of the latter compounds was explained by attack of the dianion of nitriles 86 at the electrophilic carbon atom of isothiocyanates 294 to give the dianionic intermediates 295, followed by nucleophilic displacement of bromide by the sulfur atom or, alternatively, sulfurmediated nucleophilic ring opening of epibromohydrin 6 and subsequent Payne rearrangement. Finally, intramolecular cyclization via nitrogen-induced epoxide ring opening in intermediates 296 afforded 4-hydroxymethyl-1,3-thiazolidines 297 in

good to high yields. This cyclization proceeded with very good regioselectively and good E-stereoselectivity (E/Z: 5/1). The regioselectivity is a result of the higher nucleophilicity of sulfur compared to nitrogen.308 From the above-described reactions, it is clear that epichlorohydrin and epibromohydrin serve as important substrates for the synthesis of diverse types of heterocyclic compounds. Three- to nine-membered heterocycles bearing one or more heteroatoms have been synthesized using epichlorohydrin or epibromohydrin as the starting material. These heterocycles include oxiranes, thiiranes, alkylidenetetrahydrofurans, pyrrolidines, cyclic carbonates/thiocarbonates, imidazoles, triazoles, pyrroles, oxazolidines, thiazolidines, pyrimidines, oxazines and morpholines, etc. A Lewis acid-catalyzed [4 + 3]cycloaddition of epichlorohydrin with benzylideneacetone has been discussed to form seven-membered heterocyclic 1,4dioxepine derivatives. Cyclizations involving dilithiated anions and different cycloadditions constitute principal strategies for direct syntheses of heterocylic compounds from epihalohydrins. In some cases, the roles of solvents and the halogen atom in epihalohydrins have been observed as crucial in governing the formation of the final product. The reactions of epichlorohydrin with suitably substituted nucleophiles have been employed in the synthesis of macrocyclic compounds as well, which will be discussed in the following section.

Scheme 87

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Scheme 89

Scheme 90

Scheme 92

4.3. Synthesis of Macrocyclic Compounds

The reaction of epichlorohydrin (5) with the dipotassium salt of the bisamide of salicylic acid and ethylenediamine (298) in aqueous medium has been described to afford macrocyclic diamide 299 by subsequent nucleophilic substitution and nucleophile-induced ring opening.309,310 Acylation with chloroacetyl chloride in DMF and subsequent reaction with piperidine and morpholine in acetone gave the corresponding macrocycles 301 (Scheme 98), which are of interest in supramolecular chemistry for their complexing properties. Alternatively, the potassium salt of salicylaldehyde (302) has been investigated to react with epichlorohydrin (5), and subsequent condensation with 1,ω-bis(4-amino-1,2,4-triazol-3-ylsulfany)alkanes 304 in acetic acid led to the formation of crown macrocycles 305 (Scheme 99).311 In another approach, epichlorohydrin (5) has been employed in the synthesis of bis[aminomethyl]crown ethers 310 (Scheme 100).312 The reaction of epichlorohydrin (5) with appropriate glycol derivatives 306 led to the formation of oligoethylene glycol diglycidyl ethers 307, which, in their turn, were treated with an excess of aqueous amine solution to form bis[aminomethyl]oligoethylene glycols 308. Subsequent reaction

Scheme 93

with oligoethylene glycol bis[p-toluenesulfonates] 309 furnished bis[aminomethyl]crown ethers 310. Crown ethers in which two aminomethyl groups are directly linked to the rings can be converted to crown polymers with high complexing activities, hence the interest in their preparation.312 A final example comprises the preparation of an optically active proton-ionizable crown ether 313 by modification of crown ether 312 as the key starting material.313 The latter was synthesized in two steps from commercially available (S)-binaphthol (311) and epichlorohydrin (5) (Scheme 101).314

Scheme 91

AI


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Scheme 94

Scheme 96

5. SYNTHESIS, REACTIVITY, AND APPLICATIONS OF SUBSTITUTED EPICHLOROHYDRIN AND EPIBROMOHYDRIN As a general strategy, Concellón and co-workers have described a useful method for the preparation of 1′-substituted [i.e., 2-(1haloalkyl)oxiranes], 3-substituted, 1′,2-disubstituted, and 2,3disubstituted 2-(chloromethyl)oxiranes (Figure 6) by reaction of α-bromo- or α-chlorocarbonyl compounds with chloro- or iodomethyllithium, respectively.315 The reaction of different αbromoketones 316 with chloromethyllithium 315 (generated in situ upon treatment of chloroiodomethane 314 with methyllithium at −78 °C) led to the diastereoselective preparation of 3substituted and 2,3-disubstituted 2-(chloromethyl)oxiranes 318 (Scheme 102). A similar reaction of α-chloroketones 321 with iodomethyllithium 320 gave the corresponding 1′-substituted and 1′,2-disubstituted 2-(chloromethyl)oxiranes 323 (Scheme 103).315 The nature and position(s) of substituent(s) present in substituted epihalohydrins (Figure 6) often have profound implications on their chemical reactivity, regiochemistry, and stereochemistry. The synthesis, reactivity, and applications of these epihalohydrins are described in the present section by dividing them into four types depending upon the substitution pattern (Figure 6).

Scheme 97

initial attack of the acetylide on epihalohydrins was not restricted to the halogen-bearing carbon center but instead was controlled by steric requirements. Later on, Overman and Renhowe also reported the nucleophilic ring opening of 3-bromo-1,2epoxybutane (328) through nucleophilic attack at C3.118 In another approach, Karikomi and co-workers have investigated the ring opening of diastereomerically enriched 2(α-bromobenzyl)oxirane (332) in the presence of MgBr2, yielding the corresponding dibromo alcohols 333 in ratios of 55−92/8−45 (Scheme 106).318 The reaction was carried out in different solvents, which were observed to influence the yield and diastereomeric ratio. A radical-induced ring opening of isomeric 2-(1-chloroethyl)oxiranes by triphenyltin hydride has been realized to form the corresponding allylic alcohols,135 and the reductive ring opening of 2-(α-bromobenzyl)oxirane with sodium borohydride in the

5.1. 1′-Substituted 2-(Halomethyl)oxiranes or 2-(1-Haloalkyl)oxiranes

Krosley and co-workers have prepared a diastereomeric mixture of 2-(1-chloroethyl)oxiranes 325 and 326 by epoxidation of the corresponding allylic chloride 324 using mCPBA (Scheme 104).316,135 Separation of both diastereomers was achieved by preparative GC. Furthermore, the ring opening of 3-bromo-1,2-epoxybutane (328), synthesized by cyclization of 2,3-dibromobutanol (327) in alkaline medium, with sodium acetylide in liquid ammonia has been carried out to yield hex-3-en-5-yn-2-ol (329) (Scheme 105),317 obtained earlier from 1-bromo-2,3-epoxybutane (330) under the same reaction conditions,100 thus demonstrating that Scheme 95

AJ


Chemical Reviews

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In general, the electrophilic reactivity of the constrained heterocycle of epihalohydrins can be assessed relative to the haloalkyl moiety, meaning that nucleophiles can discriminate between three different electrophilic carbon atoms. The regioand chemoselectivity of nucleophilic attack is of particular importance in the design of synthetic protocols toward the preparation of valuable target compounds. In the case of substituted epihalohydrins, initial nucleophilic attack can be influenced by steric factors. For example, Waters and Vander Werf have investigated the reactivity of 3-bromo-1,2-epoxybutane (328) and 1-bromo-2,3-epoxybutane (330) toward the methoxide and ethoxide anions.156 Nucleophilic substitution occurred via different mechanisms, pointing to the conclusion that the nucleophilic attack is directed by sterical hindrance. 3Bromo-1,2-epoxybutane (328) underwent initial nucleophilic attack at the unhindered epoxide carbon atom, whereas 1-bromo2,3-epoxybutane (330) underwent a direct nucleophilic displacement of the halide. This study clearly illustrated that the nucleophile reacted at the least hindered site. Interestingly, the reaction of both oxiranes 328 and 330 with phenol under basic conditions took place by the same mechanism (Scheme 107) that is, initial attack of the phenoxide ion at the ring carbon (C3) farthest from the bromomethyl groupthus indicating that not only the steric factor but also the nature of the nucleophile was important in the chemoselectivity of the reaction.319 Interestingly, the reaction of 1-bromo-2,3-epoxy-1-phenylpropane (332a) with several aliphatic amines has been described to form 1-alkyl-3-hydroxy-2-phenylazetidines 336 (Scheme 108).320,321 A similar reaction of the isomeric 1-bromo-2,3epoxy-1-phenylpropane (332b) with benzylamine, however, afforded only 2-(N-benzylamino)methyl-3-phenyloxirane (337) (Scheme 109). The difference in reactivity of both diastereomers 332a and 332b was explained by different conformations of the intermediates formed after nucleophilic attack (Scheme 110). Conformation 338 led to the formation of the corresponding azetidines 336, whereas conformation 339 was responsible for the formation of the corresponding oxirane 337.321 In a following example, the reaction of 2-(1-bromoethyl)oxirane (340) with the dianion of ethyl acetoacetate (141) has been shown to result in the stereoselective formation of 2alkylidenetetrahydrofuran (341) in 38% yield with complete Zselectivity and good stereoselectivity (9/1) (Scheme 111).224 As a final example, the diastereoselective synthesis of 2-(1bromoalkyl)oxiranes 346 has been evaluated by a four-step

Scheme 98

Scheme 99

presence of indium(III) chloride has been observed to afford cinnamyl alcohol.136 Scheme 100

AK


Chemical Reviews

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Scheme 101

selenium, in THF at room temperature, leading to the selective synthesis of 3-substituted 3-hydroxyselenetanes 352 in 55−67% yield (Scheme 114).250 The same reaction at reflux in THF, however, furnished the corresponding 2-substituted propenols 353 in 48−70% yield (Scheme 114).250 Analogous reactions with telluride have been reported to give only the allylic alcohols, even at room temparature.324 The formation of 2-substituted allylic alcohols from 2-substituted 2-(halomethyl)oxiranes has also been achieved by utilizing sodium iodide in acetone.325 In another example, Bravo and co-workers have studied the enantioselective synthesis of (R)-356 and (S)-2-chloromethyl-2(sulfinylmethyl)oxiranes (357) via transfer of methylene from diazomethane to the carbonyl group of enantiomerically pure 1chloro-3-p-toluenesulfinylacetone (354) (Scheme 115).326 To exploit the reactivity of the sulfinyl moiety, the Pummerer rearrangement has been used to remove the sulfinyl group in (R)2-chloromethyl-2-(sulfinylmethyl)oxirane (356) with the introduction of an oxygen functionality in its place to yield 2formyl-2-(chloromethyl)oxirane (358). The latter compound was further transformed into 2-hydroxymethyl-2(chloromethyl)oxirane (360) and glycidyl acid (359) by reduction and oxidation, respectively (Scheme 116).326

Figure 6. Substituted epihalohydrins.

sequence involving Wittig reaction, ester reduction, electrophilic bromine addition, and intramolecular dehydrobromination (Scheme 112).221 Subsequent titanium(IV) chloride-promoted reaction of the latter substituted epibromohydrins 346 with silyl ketene acetals 139 followed by acidic workup led to the formation of syn-5-(1-bromoalkyl)dihydrofuran-2(3H)-ones 347 (Scheme 112).221 5.2. 2-Substituted 2-(Halomethyl)oxiranes

The first example described here comprises the reaction of 2,2bis(chloromethyl)oxirane (348), synthesized by epoxidation of methallyl dichloride with mCPBA,322 with sodium azide in acetone/water to furnish the corresponding 1,3-diazido-2azidomethyl-2-propanol (349) (Scheme 113).323 This highly reactive triazido compound has been used in the synthesis of molecules that have a polyazido functionality on the periphery of a polyfunctionalized benzene ring (Scheme 113), cubane or adamantane nuclei, useful in the synthesis of dendritic structures.323 In a second approach, Polson and Dittmer have investigated the reaction of 2-substituted epichlorohydrins 351 with lithium selenide, prepared from lithium triethylborohydride and gray

5.3. 3-Substituted 2-(Halomethyl)oxiranes

The diastereoselective synthesis of trans-3-butyl- or trans-3hexyl-2-(chloromethyl)oxiranes has been achieved via the reaction of the appropriate α-bromoaldehydes with chlorome-

Scheme 102

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Scheme 103

Scheme 104

Scheme 106

thyllithium, generated in situ from chloroiodomethane and methyllithium.327 Chiral β-amino alcohol units are found in many biologically active compounds and chiral auxiliaries/ligands that are used in asymmetric synthesis.328 A direct and practical approach to βamino alcohols involves the ring opening of 1,2-disubstituted epoxides using amines as nucleophiles. For example, Bartoli and co-workers have investigated the highly regio-, diastereo-, and enantioselective aminolysis of racemic trans-2-bromomethyl-3phenyloxirane (361) with p-anisidine (362) catalyzed by a commercially available [Cr(Salen)Cl] complex (Scheme 117).329 The transformation of enantiomerically pure 3-alkyl-2(chloromethyl)oxiranes, obtained via Sharpless asymmetric epoxidation, to the corresponding chiral propargyl alcohols via double elimination upon treatment with lithium in ammonia or nBuLi, has been described as a key intermediate step in the total synthesis of different natural products, e.g. stagonolide A (Scheme 118),330 2,3-dihydroxytrinervitanes,331 azamacrolides,332 and leiocarpin C.333 In a following example, the reaction of 3-substituted 2(bromomethyl)oxiranes 367, prepared by nucleophilic substitution of 2,3-bis(bromomethyl)oxirane (366) with the appropriate diethyl malonates (Scheme 119), with the sodium salt of 2-mercaptopyridine-N-oxide (368) in DMF gave complex reaction mixtures, from which only episulfides 369 could be isolated in very low yield (Scheme 120).334 A similar reaction, however, using 3-phenyl-2-(bromomethyl)oxirane (370) resulted in the formation of episulfide 375 as the only isolable product (Scheme 121).334 The formation of the latter compound was rationalized by initial nucleophilic attack at the benzylic carbon atom to yield epoxide 371. Clason335 and Sander336

Scheme 107

Scheme 108

Scheme 109

noted that thioamides convert epoxides to episulfides, suggesting that the latter compound 371 rearranged via a 6-membered intermediate 372 to a spiro-fused compound 373. Subsequent

Scheme 105

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Scheme 110

Scheme 114

radical.338 In that respect, Ding and Bentrude have employed trimethyl phosphate as a trap for alkoxy radicals formed from the ring opening of oxiranyl carbinyl radicals.339 The radical cleavage of 2-bromo- or 2-iodomethyl-3-phenyloxiranes by the use of a zinc−copper couple under sonification afforded 1-phenylallylalcohol.340 Murphy and co-workers have observed the formation of allylic alcohol 380 and vinyl ether 382 as a result of a radical-initiated fragmentation of C−O and C−C bonds, respectively, in 2-bromomethyl-3-phenyloxirane (370) upon treatment with tributyltin hydride (Scheme 123).341 Finally, 2,3-disubstituted oxirane 385, a key intermediate for the synthesis of disubstituted oxepanes, has been synthesized by nucleophilic substitution of 3-substituted 2-(bromomethyl)oxirane (383) with an alkyne 384 in the presence of nBuLi as the key reaction step (Scheme 124).342 Oxepanes constitute a prominent structural feature of many natural products, such as (+)-isolaurepinnacin343 and regioloxepane.344

Scheme 111

Scheme 112

5.4. Di- and Trisubstituted 2-(Halomethyl)oxiranes

Azetidin-2-ones, commonly known as β-lactams, are the key structural motifs in the most widely used class of antibiotics, i.e., β-lactam antibiotics, such as penicillins, cephalosporins, carbapenems, etc. The development of novel synthetic methodologies for the preparation of functionalized β-lactams and the screening of their biological activity has occupied a pivotal position in medicinal chemistry for almost a century now.345 Also, the chemistry of spiro-fused 2-azetidinones has been explored in recent years for the synthesis of many biologically important compounds. 346 Benfatti and co-workers have described the treatment of 3-bromo-3-(1-butenyl)azetidin-2ones 386 with mCPBA to afford the corresponding epoxides 387 and 388 in a 1:1 mixture and in almost quantitative yield (Scheme 125).347 The diastereomeric mixture of epoxides 387 and 388 was separated by column chromatography. Subsequent treatment with Me2AlN3, prepared in situ from sodium azide and Me2AlCl, gave the corresponding azides 389 and 390 in good yield and complete stereo- and regioselectivity (Scheme 126). In addition, upon treatment of bromohydrins 389 and 390 with 1 equiv of NaH in dry THF at 0 °C, spiro-epoxides 391 and 392 were obtained in quantitative yields via bromide displacement (Scheme 127).347 In a second example, a double elimination reaction of enantiopure epichlorohydrin 393, synthesized via Sharpless asymmetric epoxidation, has been effected by treatment with nBuLi in THF at −40 °C to afford the corresponding optically

rearrangement, driven by the formation of a conjugated pyridone, afforded the final episulfide 375. The authors suggested that the mechanism of formation of episulfide 369 was the same, but with the initial nucleophilic displacement occurring at the bromine-bearing carbon atom.334 In another example, Wu and co-workers have reported on the stereoselective ring opening of enantiopure 3-phenyl-2(chloromethyl)oxirane (376) with nitric oxide, affording the corresponding syn-ring-opened β-hydroxy nitrate 377 (Scheme 122).337 The generation of a radical at the α-position of an oxirane ring is known to result in cleavage of the C−O bond to give an alkoxy Scheme 113

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Scheme 115

Scheme 116

Scheme 117

Scheme 120

Scheme 118

(Scheme 129), indanone (Scheme 130), and trimethylsilylindene (Scheme 131).349,350 Treatment of epoxybromide 395 with tributyltin hydride and AIBN as the initiator has led to the isolation of cyclic allylic alcohol 396 (21%), a product of C−O bond cleavage, and ω-hydroxyketone 398 (35%), a product of C−C bond cleavage (Scheme 129). Radical activation of epoxybromide 399 yielded chromene 402 (27%) as the only product, a result of C−C bond cleavage (Scheme 130). Similar treatment of indane epoxy bromide 403 afforded indanone 408 via C−O bond cleavage (Scheme 131). The authors inferred from these observations that C−C bond cleavage was possible in ring-fused 2-(bromomethyl)oxiranes, but at reflux temperature in benzene, stereoelectronic effects prevented this in those cases where the initial radical had restricted conformational mobility.349 Next, the reaction of diastereomeric 2-(α-bromobenzyl)-2methyloxirane (409) with benzylamine in methanol has led to the formation of 1-benzyl-3-hydroxy-3-methyl-2-phenylazetidine (410), a biologically important compound,345d and 2-(Nbenzylaminomethyl)-2-methyl-3-phenyloxirane (411) in 72% and 20% yield, respectively (Scheme 132).320 In the absence of the methyl group at the C2 position of the starting oxirane, the

Scheme 119

pure propargyl alcohol 394 in 85% yield (Scheme 128),348 which was employed in the synthesis of (S)-(+)-plakolide A, a marine natural product isolated recently from a shallow-water marine sponge of the genus Plakortis.348 The cleavage of epoxides by radical chemistry has been the subject of growing mechanistic and synthetic interest. Murphy and Patterson have studied the radical-induced ring transformation of ring-fused epoxides, derived from tetralone AO


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Scheme 121

Scheme 122

Scheme 125

Scheme 123 Scheme 126

Marshall and co-workers have studied a Zn-initiated triepoxide cascade cyclization reaction for the synthesis of the bistetrahydrofuran core segment of the polyether ionophore antibiotic ionomycin.351,352 In this cascade reaction, a Zn-initiated elimination of an in situ formed 2-(iodomethyl)epoxide

corresponding azetidine was obtained as the sole reaction product in 92% yield.320 Scheme 124

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Next to (substituted) epichlorohydrins and epibromohydrins, epifluorohydrin and epiiodohydrin derivatives have also been used in (medicinal) organic synthesis, which will be discussed in the next paragraphs.

Scheme 127

6. EPIFLUOROHYDRIN IN ORGANIC SYNTHESIS 6.1. Introduction

Although terminal and internal polyfluorinated epoxides have been thoroughly investigated in the literature as excellent building blocks for the synthesis of a large variety of heterocyclic and ring-opened compounds with potential biological activity,355 the study of their synthesis, reactivity, and synthetic applicability falls outside of the scope of this paper. Furthermore, numerous patents describing the synthesis and reactivity of (substituted) epifluorohydrin derivatives in (medicinal) organic chemistry have been granted, but this patent literature is also not covered in this literature overview.

Scheme 128

6.2. Synthesis and Conformational Stability of Epifluorohydrin

Bravo and co-workers have developed different strategies to synthesize chiral and enantiopure small fluorinated molecules as potential building blocks for biologically active organofluorine compounds. In that context, they have explored new synthetic pathways for the preparation of enantiomerically pure fluorosubstituted oxirane derivatives starting from fluoro-containing esters and sulfoxides as chiral auxiliaries. Thus, they have examined the synthesis of (2S,RS)-oxirane 424 from (R)-1fluoro-3-[(4-methylphenyl)sulfinyl]-2-propanone (423), prepared through acylation of the lithium derivative of (+)-(R)methyl-4-methylphenyl sulfoxide with ethyl fluoroacetate. Different reaction conditions have been tested, involving variation of the solvent (Et2O, MeOH, benzene) and the reaction temperature (−78 °C, −15 °C, 0 °C, 25 °C), and appropriate selection of the optimal experimental conditions (Scheme 136) has led to the preparation of (2S,RS)-oxirane (424), which could be isolated in pure form through fractional crystallization or column chromatography in good yield and with high diastereomeric excess (88%).356,357 The reaction mechanism involved was explained by the methylene transfer from diazomethane to the carbonyl group of β-keto-γ-fluorosubstituted sulfoxide (423), and the high chemo- and diastereoselectivity was considered to be controlled by the unique ability of the sulfinyl group to participate in diazomethane coordination and, simultaneously, in the facial selectivity control of the approaching reagent.356,357 Furthermore, the high diastereoselectivity in favor of (2S,RS)-oxirane (424) may also be related to the presence of a strong electron-withdrawing group such as fluorine in the α-position to the carbonyl functionality in the starting sulfoxide 423, because similar results were obtained when the corresponding bromo and chloro derivatives were used, whereas analogous methyl and hydroxymethyl carbonyl derivatives reacted with very low or no stereoselectivity.356,357 This methodology has been expanded by the same research group to enantiopure oxirane derivatives bearing an additional

Scheme 129

generated the requisite vinyl group with formation of a Lewisacidic iodozinc byproduct that catalyzed a subsequent internal 5exo cyclization, resulting in the desired bistetrahydrofurans 416 (Scheme 133) and 419 (Scheme 134). Starting from farnesol 412, the specific stereochemistry was obtained by subsequent Sharpless and double Shi asymmetric epoxidation (Scheme 133 and 134).352 Finally, the alkylation of alcohols using substituted epihalohydrins is of immense importance in natural products synthesis.353 For example, alcohol 420 has been alkylated with 2bromomethyl-3,3-dimethyloxirane (421) during the synthesis of a key intermediate of the natural product maxacalcitol, used for hyperparathyroidism and psoriasis (Scheme 135).354 This literature review on substituted epichlorohydrins and epibromohydrins reveals diverse reports on the synthesis, reactivity, and applications of different types of mono-, di-, and trisubstituted epihalohydrins, synthons of high importance in organic chemistry. Substituted epihalohydrins and their ringopening products have been used as building blocks in the synthesis of several natural products and heterocyclic systems, such as thiiranes, azetidines, β-lactams, and tetrahydrofurans. Scheme 130

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Scheme 131

oxirane oxygen and subsequent cleavage of the C−O bond to generate the corresponding ring-opened benzylic carbenium ion. Finally, although the formation of a diastereoisomeric mixture is expected, transfer of fluorine from BF3 to the carbenium ion and subsequent workup yielded syn-fluorohydrin 431 in 70% yield, which was converted into the desired (S)-2-[(S)-fluoro(phenyl)methyl]oxirane (432) in quantitative yield by intramolecular nucleophilic displacement induced by lithium tert-butoxide (Scheme 138).360,361 Ley and co-workers have reported on the development of several methods to incorporate fluorine into various substrates using flow microreactor devices. Flow chemical processes are becoming increasingly useful in the assembly of molecules because these methods readily accommodate automation and reaction optimization. They can provide many efficiency gains through the generation of less waste and lower solvent usage as compared with more conventional batch reactions.362 In that respect, they have studied the use of diethylaminosulfur trifluoride (DAST) in a continuous-flow reactor using inert plastic flow tubes to bring about the conversion of alcohols and carbonyl compounds to their corresponding fluoro derivatives. Treatment of (2S,3S)-3-phenylglycidol (433) with DAST at 50 °C in dichloromethane resulted in the preparation of the corresponding enantiopure 2-(fluoromethyl)oxirane (434) (Scheme 139).363 In another example, analogous chiral α,β-epoxy carbinol compounds 435 have been converted to the corresponding chiral

Scheme 132

alkyl group in the α-position with respect to the sulfoxide functionality, leading to the corresponding oxirane derivatives in high chemical yields and in synthetically useful levels of diastereoselectivity (de >70%).358 In a second example, Baklouti and co-workers have prepared substituted epifluorohydrin derivatives 429 by bromofluorination of the corresponding allylic alcohols 427 by means of Nbromosuccinimide (NBS) and triethylamine trishydrofluoride (Et3N·3HF), followed by intramolecular cyclization upon treatment with aqueous sodium hydroxide, inevitably leading to mixtures of oxetanes 428 and oxiranes 429 (Scheme 137).359 Later on, enantiomerically pure (S)-2-[(S)-fluoro(phenyl)methyl]oxirane (432) has been synthesized from (2S,3S)phenylglycidyl tosylate (430), which has been prepared from the Sharpless asymmetric epoxidation of cinnamyl alcohol with inexpensive natural tartrate ligands. Regioselective and stereospecific ring opening of the latter epoxide 430 with BF3·Et2O resulted in the formation of (2S,3S)-3-fluoro-2-hydroxy-3phenylpropyl p-toluenesulfonate (431), consistent with a reaction mechanism involving coordination of BF3·Et2O to the Scheme 133

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Scheme 134

Scheme 135

Scheme 136

Scheme 137

Scheme 139

monofluoromethylated α,β-epoxy derivatives 436 via fluorination with 2,2-difluoro-1,3-dimethylimidazolidine (DFI) in 1butyl-3-methyl-1H-imidazolium hexafluorophosphonate

([bmim][PF6]) for 4 h at room temperature (yield not reported) (Scheme 140).364 The determination of the conformational stability of epifluorohydrin has been the subject of several spectroscopic studies, including microwave, 365,366 infrared, and/or Raman367−370 and NMR studies.371−374 In all these studies,

Scheme 138

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6.3. Reactivity of Epifluorohydrin

Scheme 140

6.3.1. Ring-Opening Reactions of Epifluorohydrin. As mentioned before, Bravo and co-workers have studied the highly diastereoselective methylene transfer reaction from diazomethane to the carbonyl group of β-keto-γ-fluorosubstituted sulfoxides giving rise to the corresponding oxiranes.356,357 The synthetic opportunities associated with the epoxide ring and the sulfinyl group render these compounds highly promising, versatile building blocks for the synthesis of a variety of optically pure open-chain fluorine-containing compounds endowed with new functional groups. In that respect, the same authors have described several elaborations of (S)-2-fluoromethyl-2(sulfinylmethyl)oxirane (424), including ring opening by carbon, nitrogen, oxygen, halogen, and hydride-releasing nucleophiles (Scheme 141).357 Furthermore, the same research group has synthesized the corresponding enantiopure sulfur-free epoxy alcohol 448, epoxy acetal 446, and epoxy acid 447 by Pummerer rearrangement toward epoxy aldehyde 445 followed by treatment with sodium borohydride, methanol, and sodium chlorite, respectively (Scheme 142).375 Subsequent ring opening of epifluorohydrin 448 with benzylamine in THF at room temperature has led to the selective preparation of aminodiol 449 as the sulfur-free analogue of aminoalcohols 439.375

there is agreement that the most stable conformer in the solid, liquid, and gas phases is the conformer 1 (Figure 7), but there is

Figure 7. Conformational structures of epifluorohydrin.

disagreement as to the second most stable conformer. In some of these studies, the conformer 2 has been reported as the second most abundant conformer,365,368,373,374 whereas others have reported the conformer 3 as the second most abundant conformer (Figure 7)366,367,370 or that it was impossible to determine the relative stability of the two high energy conformers.369,371,372 Scheme 141

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Scheme 142

Scheme 143

As mentioned before, Pericàs and co-workers have described a new procedure for the synthesis of optically pure (S)-2-[(S)fluoro(phenyl)methyl]oxirane (432) from (2S,3S)-phenylglycidyl tosylate (431).360 In addition, the same authors have tested the nucleophilic ring opening of the former epifluorohydrin 432 with α-chiral amines 450. They have found that upon either conventional heating or microwave irradiation the epoxide ring opening with racemic or optically pure primary or secondary amines 450 took place in good yields and with complete regioselectivity using lithium perchlorate as the promotor and THF as the solvent (Scheme 143). However, microwave irradiation consistently afforded higher yields, and few decomposition byproducts were observed compared to the use of conventional heating.360 In the next example, Olah and co-workers have demonstrated that epifluorohydrin 452, when heated to reflux temperature with trimethylsilyl cyanide and a catalytic amount of potassium cyanide/18-crown-6 complex in the absence of solvent, underwent regiospecific ring opening at the nonsubstituted epoxide carbon atom to yield the corresponding 3-(trimethylsilyloxy)nitrile 453 (Scheme 144).376 They have proposed a pentavalent dicyanotrimethylsiliconate as the de facto nucleophile, resulting from the interaction of potassium cyanide/18-crown-6 complex with trimethylsilyl cyanide.376

Scheme 144

6.3.2. Applications of Epifluorohydrin in the Synthesis of Cyclic Compounds. Bray and co-workers have demonstrated the reaction of racemic epifluorohydrin 452 with the anion of 2-substituted triethylphosphonoacetate 454 to yield the corresponding quaternary cyclopropyl ester 455 in 75% yield and with high diastereoisomeric excess (Scheme 145).377 According to the proposed reaction mechanism, the cyclopropane formation proceeded via an initial SN2 ring opening toward intermediate 456, followed by the transfer of diethylphosphonate Scheme 145

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Scheme 146

Scheme 147

Scheme 148

isolation of epiiodohydrins 461 and iodo enones 463 via intermediate alkoxy radicals 459 (Scheme 147).378 According to the proposed reaction mechanism, the intermediate alkoxy radical 459 cyclized onto the adjacent olefin moiety and the resulting terminal carbon radical 460 was trapped by iodine, affording the corresponding epiiodohydrins 461. An alternative pathway in this system is a β-scission to generate the corresponding enone derivatives 462, and subsequent trapping of the terminal carbon radicals generating the corresponding iodo enones 463.378 For smaller ring systems (n = 0, 1), relief of ring strain facilitated the β-scission pathway, resulting in relatively higher amounts of iodo enones 463 as compared to epiiodohydrins 461. As the strain energy decreased (n = 2, 3, 4, 8), the formation of epiiodohydrins 461 became energetically more favorable, leading to their occurrence as the major reaction products.378 Later on, the same authors have developed a more efficient preparation of epiiodohydrins 461 by means of iodobenzene diacetate and iodine under photochemical conditions, resulting in the exclusive formation of α-iodoepoxides 461 in 62−72% yield.379 On the basis of the same methodology, Rawal and co-workers have described the reaction of allylic alcohols 464 with

and formation of intermediate 457. Finally, the highly diastereoselective elimination of diethylphosphate during the subsequent ring closure of the latter intermediate 457 yielded the corresponding cyclopropyl ester 455 (Scheme 146). The observed diastereocontrol thus arises from an electronically governed diastereoselective ring closure.377 In conclusion, although the reactivity of epifluorohydrin derivatives is less studied as compared to epichlorohydrin and epibromohydrin derivatives, their ring opening with nitrogen-, carbon-, halogen-, and oxygen-centered nucleophiles can give rise to the selective synthesis of fluorinated synthons, which can serve as building blocks in the synthesis of medicinally important compounds. In the next section, this review will discuss the synthesis and synthetic applicability of epiiodohydrin derivatives in organic synthesis, with a special focus on their use in the synthesis of natural products.

7. EPIIODOHYDRIN IN ORGANIC SYNTHESIS 7.1. Synthesis and Reactivity of Epiiodohydrin

In a first example, Galatsis and co-workers have exploited the reactivity of tertiary allylic alcohols 458 toward mercuric oxide and iodine in carbon tetrachloride at reflux, resulting in the AV


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PhI(OAc)2 and I2 in cyclohexane, leading to the corresponding substituted epiiodohydrin derivatives 467 as a mixture of two diastereoisomers (Scheme 148).380 Subsequently, a solution of α-iodo epoxides 467 and (nBu3Sn)2 in dry benzene has been irradiated with a sunlamp for 45 min, resulting in the formation of iodohydrindanes 470 by γ-hydrogen abstraction of the intermediate allyloxy radicals 468 followed by cyclization (Scheme 149).380

Scheme 151

Scheme 149

considered to be energetically more favorable, resulting in the selective formation of trans-epoxides 475 (Scheme 152).381 7.2. Epiiodohydrin in the Synthesis of Natural Products

In recent years a great deal of interest has been devoted toward the synthesis of acyclic, long chain, terminal allylic alcohols owing to their various applications in diverse areas such as synthetic, medicinal and pharmaceutical chemistry.382 In addition, from a retrosynthetic point of view, terminal allylic alcohols are useful intermediates in the total synthesis of many natural and bioactive compounds.383 Among others, the synthesis and reductive ring opening of substituted 2,3-epoxy-1-iodides has been demonstrated to be a valuable synthetic strategy for the preparation of terminal allylic alcohols. In that respect, Shaw and co-workers have studied the iodination of 2,3-epoxy alcohols 481 in dry toluene upon treatment with molecular iodine in the presence of imidazole and triphenylphosphine (PPh3 ) to yield the corresponding 2,3-epoxy-1-iodides 482 in 45−70% yield (Scheme 153).384 In order to achieve a selective reductive ring opening of the latter epoxides 482, various reagents, including NaBH4/InCl3, triethylsilane and activated magnesium metal under different reaction conditions were tested out, and finally the use of commercially available zinc dust in ethanol under reflux furnished the desired terminal allylic alcohols 483 in high yields (Scheme 153).384 According to the proposed reaction mechanism, the observed zinc-induced reductive ring opening proceeded through the formation of organometallic intermediates 484, followed by opening of the three-membered epoxide ring to form alkoxides 485. Finally, abstraction of a proton from the solvent gave the premised terminal allylic alcohols 483 (Scheme 154).384 This synthetic methodology, that is, iodination of appropriate epoxy alcohols by means of molecular iodine, imidazole, and triphenylphosphine followed by zinc-mediated reductive ring opening toward the corresponding terminal allylic alcohols, has been used in the total synthesis of a variety of natural products, including mueggelone,385 azaspiracids,386 guggultetrol,387 nonenolide and desmethyl nonenolide,388 salicylihalamides A and B,389 B ring labdane diterpenes,390 sordidin,391 putaminoxin,392

Another illustration comprises the ethoxide-induced coupling reaction of ethyl acetoacetate 141 and epiiodohydrin 471, resulting in the formation of a mixture of dihydrofuran 142 and tetrahydropyran 143 in 43% yield (Scheme 150), following the same reaction mechanism as described for epichlorohydrin 5 and epibromohydrin 6.222 An interesting method for the diastereoselective synthesis of trans-iodovinyl epoxides 475 by modification of α-allenic alcohols 472 has been developed by Friesen and co-workers.381 Treatment of an ethereal solution of the latter unsaturated alcohols 472 with iodine resulted in the selective addition of iodine across the terminal double bond of the allene moiety, affording unstable but isolable Z- and E-diiodides 473 and 474, respectively (Scheme 151). Subsequently, different basic reaction conditions have been tested in order to effect an intramolecular SN2′ displacement (NaOH/MeOH, NaH, LDA, NaHMDS, KHMDS, K2CO3, Ag2CO3; each in a variety of solvents), and optimal results were obtained using NaHMDS in diethyl ether, yielding a diastereoisomeric mixture of trans- and cis-iodovinyl epoxides 475 and 476 with a high diastereoselectivity (>100:1) toward the trans-derivatives 475 (Scheme 151).381 The high diastereoselectivity is explained as follows. In the reaction transition states arising from conformers 478 and 480, there is a severe steric interaction between the R group and either the iodine atom or the iodomethylene fragment, respectively. These steric interactions are absent in the transition states arising from conformers 477 and 479. Thus, the latter SN2′ pathway is Scheme 150

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Scheme 152

Scheme 153

hypocholesterolemic activity,401 and pestalotiopsin A, an immunosuppressant agent,402 respectively. Reductive dehalogenation of intermediate 2,3-epoxy-1-iodides toward the corresponding 2-methyloxirane derivatives using different reagents including NaBH3CN, NaBH4, and LiBHEt3 in different solvents (THF, HMPA, MeCN, THF/HMPA) has been performed as a key step in the total synthesis of sphingofungin F,403 azadirachtin,404 epothilone B,405 and anisatin.406 In the next example, Nakata and co-workers have developed the stereoselective synthesis of both (Z)- and (E)-3-hydroxy-1alkenyl iodides (487 and 488) from the same epiiodohydrins (486) by using NaHMDS in DMF and LDA in THF, respectively (Scheme 155).407 However, next to the desired vinyl iodides 487 and 488, small amounts of the corresponding deiodinated allylic alcohols 489, alkynes 490, and bis(trimethylsilyl)aminosubstituted epoxides 491 have been observed as well in the crude reaction mixtures as a result of the base-promoted dehalogenative ring opening of the starting epoxides 486, deprotonation followed by alkylidenecarbene formation and a

Scheme 154

synargentolide A,393 anamarine,394 stagonolide,395 1α,25-dihydroxy-22-oxavitamin D3,396 isofregenedol,397 cortistatin A,398 eremantholide A,399 and panaxytriol.400 In addition, transformation of substituted epiiodohydrin derivatives toward the corresponding allylic alcohols by means of tert-butyllithium in diethyl ether or n-butyllithium in tetrahydrofuran has also been described in the synthesis of breynolide, a natural product with Scheme 155

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1,2-alkyl shift of vinyl iodides 487 and 488, and nucleophilic substitution of the starting epoxides 486 by hexamethyldisilazane (in the case of NaHMDS as the base), respectively.407 Later on, this NaHMDS-mediated ring opening of 1-iodo-2,3epoxides toward the corresponding vinyl iodides has been used in the total synthesis of resolvin D6, an anti-inflammatory compound produced by the human body from the ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.408 From the above-described paragraphs it is clear that epiiodohydrin derivatives are used widely as intermediates in natural product synthesis, as demonstrated by their use in the synthesis of, for example, putaminoxin, anamarine, panaxytriol, sphingofungin F, and resolvin D6. Hereby, zinc-induced reductive ring opening and reductive dehalogenation by means of NaBH3CN, NaBH4, and LiBHEt3 comprise the main synthetic tools in the stereoselective synthesis of the natural products.

recent years, which indicate a continued interest in the chemistry of epihalohydrins.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; matthias.dhooghe@UGent. be; [email protected]. Notes

The authors declare no competing financial interest. § Ph.D. fellow of the Research FoundationFlanders (FWO Vlaanderen). Biographies

8. CONCLUDING REMARKS Epihalohydrins have a long-standing tradition in polymer and resin synthesis. In addition, they are versatile synthons used in organic synthesis and medicinal chemistry. Enantiopure epihalohydrins are easily accessible by hydrolytic kinetic resolution, and substituted enantiopure epihalohydrins can be synthesized by Sharpless asymmetric epoxidation of allylic alcohols followed by transformation of the alcoholic group to a halogen atom. The high synthetic flexibility of epihalohydrins (especially epichlorohydrins and epibromohydrins) is due to their intrinsic reactivity. The ring opening of epihalohydrins takes place by nucleophilic attack, mainly at the less-hindered site of the ring. In substituted epihalohydrins, however, steric and electronic factors can have profound implications on the reaction route. Also, some specific reagents lead to the formation of rearranged products. Amines, azides, carboxylic acids, anhydrides, alcohols, phenols, thiols, phosphites, and carbanions lead to ring opening of epihalohydrins mediated by various types of catalysts. The products obtained by ring opening of epihalohydrins are also valuable building blocks in organic synthesis. The nucleophilic substitution of the halogen atom in epihalohydrins leads to the formation of functionalized oxiranes. Epihalohydrins have been employed in the direct synthesis of many heterocyclic compounds containing one or more heteroatoms in three- to nine-membered rings and in macrocycles. These heterocycles include oxiranes, thiiranes, selenetanes, azetidines, alkylidene− tetrahydrofurans, pyrrolidines, cyclic carbonates/thiocarbonates, imidazoles, triazoles, pyrroles, oxazolidines, thiazolidines, morpholines, etc. Cyclizations involving dilithiated anions and different cycloadditions constitute principal methodologies for the direct synthesis of heterocylic compounds from epihalohydrins. The nucleophilic substitution reactions of epihalohydrins have been widely used in medicinal chemistry for the synthesis of bioactive compounds such as antimicrobials, antituberculars, antimalarials, antivirals, antioxidants, antihyperglycemics, uterine-relaxants, spermicidals, β-adrenergic receptor antagonists, calcium entry blockers, etc. The reactions of enantiopure epihalohydrins, especially epichlorohydrin and epibromohydrin, leading to ring-opened products or alkylated oxiranes, have been employed as key reactions in the synthesis of many natural products with complex molecular structure. Recent years have witnessed a resurgence of interest in developing new, efficient, recyclable, and environmentally friendly catalysts for kinetic resolution and enantioselective ring opening of epihalohydrins. Many new applications in heterocycle synthesis have emerged in

Girija S. Singh was born in Sasaram (Bihar), India. He received his BSc and MSc degrees from the U. P. College (then Gorakhpur University), Varanasi, India, in 1977 and 1979, respectively. He received his PhD degree from Banaras Hindu University (BHU), India, completing his doctoral thesis on the reactions of diazoalkanes and diazoketones with imines, amines, and hydrazones in October, 1984. During this research, he was recipient of the junior and senior research fellowships of the CSIR, New Delhi. Since then, he has occupied teaching and research positions at various universities, such as Banaras Hindu University, India (PDF, Research Associate, Pool-Officer, Reader), Osaka University, Japan (PDF), University of Zambia (Lecturer), and University of Botswana (Lecturer, Senior Lecturer, Associate Professor). He is currently working as a Professor of Chemistry at University of Botswana. He has authored 78 publications in books and in peer-reviewed journals. He is a member of many professional societies, including the American Chemical Society and the Chemical Research Society of India. He is also on the editorial boards of some chemistry journals. His research interests include the study of synthesis and reactivity of biologically important heterocycles, reactions of carbenoids and ketenes, metal-catalyzed oxidations, and organic chemistry education.

AY


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career at the Belgian National Fund for Scientific Research, where he went through all stages up to the position of Research Director. During this career, he was affiliated with the Department of Organic Chemistry, Faculty of Bioscience Engineering at Ghent University, where he took up teaching positions since 1987. He is now Full Professor in organic chemistry at the latter institution. He was a guest professor at the Centre Universitaire de Recherche sur la Pharmacopée et la Médecine Traditionelle in Butare (Rwanda, Central Africa) and at the Universities of Perpignan (France), Helsinki (Finland), Leuven (Belgium), Siena (Italy), Barcelona (Spain), Sofia (Bulgaria), Buenos Aires (Argentina), and Pretoria (South Africa). He was awarded the degree of Doctor honoris causa from the Russian Academy of Sciences in Novosibirsk (Russia) in 1998 and from the University of Szeged (Szeged, Hungary) in 2007. He obtained the Medal of Honour of Sofia University (Bulgaria) in 2006 and was awarded the A. N. Kost medal of the Mendeleev Russian Chemical Society in 2010. He is a Member of the Royal Flemish Academy of Belgium, Section Natural Sciences and the Academia Scientiarum et Artium Europea (European Academy of Sciences and Arts), Salzburg (Austria). He is a Fellow of the Royal Society of Chemistry (U.K.) and an IUPAC Fellow. He is the author of 590 articles in international peer-reviewed journals. His research interests include (1) the synthesis of heterocyclic compounds, with focus on agrochemicals, pharmaceuticals, and natural products; (2) flavor chemistry; and (3) the bioassay-guided isolation of bioactive natural products from medicinal plants.

Karen Mollet was born in Ghent, Belgium, in 1986. She graduated as Bioengineer in Chemistry at Ghent University in 2009. For her Master Thesis, she worked on the synthesis of aza(heterocyclic) compounds using functionalized azetidin-2-ones. Currently, she is working as a Fellow Researcher of the Research FoundationFlanders (FWO Vlaanderen) in the PhD program at Ghent University under the guidance of Prof. N. De Kimpe and Prof. M. D’hooghe. Her research interests are focused on the application of β-lactams for the stereoselective synthesis of novel mono-, bi-, and tricyclic nitrogen compounds.

Matthias D’hooghe was born in Kortrijk, Belgium, in 1978. He received his Master’s diploma in Bioscience Engineering in 2001 and his PhD degree in 2006, both from Ghent University (Belgium). In 2007, he became Assistant Professor in the group of Prof. N. De Kimpe, and in 2009 he performed a short postdoctoral stay with Prof. D. Vogt at Eindhoven University of Technology (The Netherlands) in the field of homogeneous catalysis. In October 2010, he was promoted to Associate Professor at the Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University. His main research interests include the chemistry of small-ring azaheterocycles, with a special focus on aziridines, azetidines, and β-lactams, and the synthesis of bioactive compounds. He is the author of 83 publications in international peer-reviewed journals. Prof. D’hooghe has been elected as a laureate of the DSM Science & Technology Awards 2007 and as a finalist of the European Young Chemist Award 2012.

ACKNOWLEDGMENTS We thank the Chemistry Department at the University of Botswana, the Research Council of Ghent University, and the Research FoundationFlanders (FWOVlaanderen) for providing the facilities and financial support. REFERENCES (1) (a) Berthlot, L. Ann. Chim. 1856, 48, 306. (b) Dittmer, D. C.; Sedergran, T. C. In Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York, 1985; p 670. (2) U.S. Department of Health and Human Services, Secretary Kathleen Sebelius, 12th Report on Carcinogens, June 10, 2011. (3) Sienel, G.; Reith, R.; Rowbottom, K. T. Epoxides; Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2005. (4) (a) Braun, G. J. Am. Chem. Soc. 1932, 54, 1248. (b) Hartman, W. W.; Boomer, G. L. Org. Synth. Collect. 1943, 2, 256. (5) Conant, J. B.; Quayle, O. R. Org. Synth. Collect. 1941, 1, 292. (6) (a) Georgy, D. S.; Leonid, Z. N. Chem. Eng. Trans. 2011, 24, 43. (b) Ma, L.; Zhu, J. W. Chem. Eng. Res. Des. 2007, 85, 1580. (7) Kamata, K.; Sugahara, K.; Yonehara, K.; Ishimoto, R.; Mizuno, N. Chem.Eur. J. 2011, 17, 7549. (8) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. F. Science 1997, 277, 936. (9) Jacobsen, E. Acc. Chem. Res. 2000, 33, 421. (10) Abderhalden, E.; Eichwald, E. Chem. Ber. 1915, 48, 1847. (11) Kasai, N.; Tsujimura, K.; Unoura, K.; Suzuki, T. J. Ind. Microbiol. Biotechnol. 1992, 9, 97. (12) Weijers, C. A. G. M.; van Ginkel, C. G.; de Bont, J. A. M. Enzyme Microbiol. Technol. 1988, 10, 214. (13) Ellis, M. K.; Golding, B. T.; Watson, P. J. Chem. Soc., Chem. Commun. 1984, 1600. (14) Baldwin, J. J.; Raab, A. W.; Menslor, K.; Arison, B. H.; McClure, D. E. J. Org. Chem. 1978, 43, 4876. (15) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776. (16) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307. (b) Thakur, S. S.; Li, W.; Kim., S.-J.; Kim, G.-J.

Norbert De Kimpe obtained the diploma of chemical agricultural engineer in 1971, his PhD degree in 1975, and his habilitation degree in 1985, all from Ghent University, Ghent (Belgium). He performed postdoctoral research work at the University of Massachusetts, Harbor Campus, in Boston (USA) (1979), and at the Centre National de Recherche Scientifique (CNRS) in Thiais, Paris (France) (1983), where he worked on unstable nitrogen-substituted sulfenyl derivatives and electron-deficient carbenium ions, respectively. He made his scientific AZ


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