Isoxazolidine: A Privileged Scaffold for Organic and Medicinal

Review pubs.acs.org/CR

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry Mathéo Berthet,† Thomas Cheviet,† Gilles Dujardin,‡ Isabelle Parrot,*,† and Jean Martinez*,† †

Institut des Biomolécules Max Mousseron, IBMM UMR-5247 CNRS, Université de Montpellier, ENSCM, CC17-03, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France ‡ Institut des Molécules et Matériaux du Mans, IMMM UMR 6283 CNRS, Université du Maine, UFR Sciences et Techniques, Avenue Olivier Messiaen, 72085 Le Mans, France ABSTRACT: The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.

CONTENTS 1. Introduction 2. Occurrence of the Isoxazolidine Moiety in Natural Products 3. Synthetic Strategies To Prepare the Isoxazolidine Ring 3.1. 1,3-Dipolar Cycloaddition 3.2. Cyclizations of Unsaturated Hydroxylamines 3.2.1. Electrophilic Cyclizations 3.2.2. Palladium-Mediated Cyclizations 3.2.3. Radical Cyclizations 3.2.4. Michael Additions 3.3. Other Synthetic Strategies 3.3.1. From Isoxazolidinones 3.3.2. From Isoxazolines 3.3.3. From Isoxazolinium Salts 4. Isoxazolidines as Intermediates in Organic Chemistry 4.1. Reductive Ring Opening: Synthesis of 1,3Amino Alcohols 4.1.1. Ring Opening by Reduction under Catalytic Hydrogenolysis 4.2. Dismutative Ring Opening 4.2.1. Synthesis of 1,3-Aminocarbonyl Compounds 4.2.2. Synthesis of N-Oxide-1,3-amino Alcohols 4.2.3. Synthesis of 1,3-Hydroxylamino Alcohols 4.2.4. Synthesis of 1,3-Nitro Alcohols © 2016 American Chemical Society

4.3. From Ring Opening of Isoxazolidines to Novel Heterocycles 4.3.1. Synthesis of α-Amino Lactones 4.3.2. Synthesis of α-Hydroxy-lactams 4.3.3. Synthesis of Benzoazepines 4.3.4. Synthesis of Tetrahydro-1,3-oxazines 4.3.5. Synthesis of Tetrahydro-1,3-oxazin-2ones 4.3.6. Synthesis of β-Lactams 4.4. Thermic Rearrangement 4.4.1. Synthesis of β-Lactams 4.4.2. Synthesis of 1,4-Tetrahydropyridinones 4.4.3. Other Thermic Rearrangement of Isoxazolidines 5. Application in Organocatalysis 6. Natural Building Block Mimetics 6.1. Nucleoside Analogues 6.2. Carbohydrate Analogues 6.3. PNA Analogs 6.4. Peptidomimetics 6.4.1. Insertion into Peptides 6.4.2. Ligations 6.5. Steroid Analogues 7. Medicinal Chemistry 7.1. Cytotoxic Activities 7.1.1. Using DNA Intercalators 7.1.2. Using Transcriptional Activators

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Received: August 11, 2016 Published: December 16, 2016 15235

DOI: 10.1021/acs.chemrev.6b00543 Chem. Rev. 2016, 116, 15235−15283

Chemical Reviews 7.1.3. Using Other Strategies 7.2. Antiviral Activities 7.3. Antifungal/Antimicrobial Activities 7.4. Anti-Inflammatory Activities 7.5. Advanced Glycation End Inhibitor Activities 8. Other Applications 9. Conclusion Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations References

Review

group of Nishikawa developed the synthesis of the Nacylisoxazolidine part in the Zetekitoxin core by coupling an isoxazolidine and a tricyclic bis-guanidine carboxylic acid using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in N-methylmorpholine (NMM) (Scheme 1).2,3 Zetekitoxin AB was found to be a potent voltage-dependent sodium channel blocker, more potent than its analogue Saxitoxin for which no synthesis seems to have been developed (Figure 3). Isolated from the Chinese medicinal plant Dactylicapnos torulosa, dactylicapnosinine and dactylicapnosine were the first alkaloids with an isoxazolidine skeleton to be described. Since the structure of dactylicapnosine was elucidated by singlecrystal X-ray analysis by C. Steinbeck et al.,4 the structure of its less complex analogue, dactylicapnosinine, was ascertained by NMR experiments. To the best of our knowledge, neither their biological activity nor their total syntheses have been reported. However, we can mention the recent development of a visible light photoredox catalytic strategy to reach dactylicapnosinine analogues.5 Several others isoxazolidine-containing natural products were subsequently discovered, and their biological properties, biogenetic pathway, and/or synthetic accesses were usually more deeply investigated. Alsmaphorazine A, described as a modest inhibitor of NO production by lipopolysaccharidestimulated macrophages, and Alsmaphorazine B were isolated in 2010 by Morita et al. from the leaves of Alstonia pneumatophore. Their structure was elucidated by careful NMR analyses, MS, and CD. A probable biosynthetic route to Alsmaphorazines was proposed, involving intramolecular addition of the oxygen of an N-oxide intermediate to an epoxide moiety for creation of the isoxazolidine ring (Scheme 2).6 Another hypothetical biogenetic pathway suggesting an 1,3DC to obtain the isoxazolidine ring followed by oxidation steps was proposed by Vanderwal et al. Thus, inspired by these proposed biosynthetic pathways, they performed the first total synthesis of Alsmaphorazine B in 15 steps (Scheme 3).7 In the same way, all biogenetic pathways postulated for Pyrinodemins, Flueggines, Virosaines, Pyridomacrolidin, or Lycojaponicumins suggested a biosynthetic nitrone−alkene cycloaddition for construction of the five-membered heterocycle. The justification of such cycloadditions in the biosynthesis of the different isoxazolidine architectures has been recently investigated, essentially by density functional theory calculations, resulting in speculative discussions on the spontaneity of the reaction, with a possible role of an enzyme-catalyzed system.8 Dipolar cycloaddition in a biological environment was in fact widely used as a biomimetic transformation to synthesize isoxazolidine alkaloids. In particular, Pyrinodemin A total synthesis has undergone considerable interest. Isolated by Kobayashi et al. in 1999 from the Okinawan marine sponge Amphimedon sp, (±)-Pyrinodemin A displays a characteristic cis-cyclopent[c]isoxazolidine core.9 The structure originally proposed was afterward subjected to revision concerning the position of the double bond on the side chain. Kobayashi et al.10 finally corroborated in 2005 the Snider group proposal,11 validating that Pyrinodemin A naturally exists as a racemic mixture, the double bond being positioned at C15′−C16′. Among the various synthetic strategies initiated to reach the Pyrinodemin skeleton or Pyrinodemin A,12 the first enantio-

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1. INTRODUCTION The saturated five-membered isoxazolidine, containing adjacent nitrogen and oxygen atoms, part of several natural products, has shown increasing interest in the past decade. This heterocyle can be obtained through the well-known 1,3-dipolar cycloaddition, providing access to a large diversity of compounds. Other efficient strategies have been proposed to enlarge the variety of isoxazolidines that could not be obtained by this classical method. Since this moiety is rarely found in natural products, it represents an important synthetic intermediate, especially due to the labile nature of the N−O bond. Accordingly, several groups of investigators have developed mild conditions to improve the synthesis of a large variety of isoxazolidine derivatives and their use for the total syntheses of natural compounds. Alternately, isoxazolidines are important scaffolds in drug discovery mimicking a wide range of natural building blocks and being found to exhibit interesting diverse biological activities. The objective of the present review is to summarize and discuss the synthetic routes of the isoxazolidine ring, as well as the significance of this moiety in natural products, and the potential biological applications and physicochemical properties of the “isoxazolidine” structure. This review excluded isoxazolidine-3-one, isoxazolidine-5-one, isoxazolidine-3,5-diones, and isoxazolidinium salts. The numbering of the isoxazolidine ring is shown in Figure 1.

Figure 1. Isoxazolidine skeleton.

2. OCCURRENCE OF THE ISOXAZOLIDINE MOIETY IN NATURAL PRODUCTS The isoxazolidine moiety is a particularly useful intermediate for the synthesis of natural products being occasionally reported in natural products (Figure 2). This heterocycle always found as a fused bicyclic ring system has been highlighted in nine types of alkaloids extracted from marine sponges, plants, or fungal metabolites. Only Zetekitoxin AB, the first isolated isoxazolidine-containing alkaloid extracted from the skin of the Panamanian golden frog (Atelopus Zetecki), comes from an animal source. Discovered in 1969, its structure and relative stereochemistry was determined only in 2004 by Daly et al. through NMR and mass spectral analyses.1 The 15236


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Figure 2. Occurrence of the isoxazolidine moiety in natural products.

Scheme 1. Synthesis of a Structural Model of Zetekitoxin AB

Scheme 2. Biosynthetic Route for Alsmaphorazine A and B

Figure 3. Chemical structure of Saxitoxin.

4).13 The 14-step route relies on an asymmetric intramolecular dipolar cycloaddition to build the bicyclic fragment of the

selective and probably the most interesting access to the real structure was developed by Kouklovsky and co-workers (Figure 15237


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carcinoma cells as well as slight antimicrobial or antifungal activities.14 Biomimetic approaches have been also undertaken to develop a synthetic route to (−)-Flueggine A,15,16 (−)-Virosaine A, or (+)-Virosaine B,17 all three being isolated by Ye and co-workers from the same plant Flueggea virosa. About 1 year after the discovery of these novel Securinega alkaloids, the groups of Li 18 and Gademann 19 reported the total enantioselective synthesis of Flueggine A, Virosaine B, Virosaine A, and Bubbialidine, both inspired by primary biosynthetic proposals by involving a nitrone−alkene stereoselective intramolecular 1,3-dipolar cycloaddition as the last step of the synthesis. The syntheses of (−)-Flueggine A (Figure 5) and (+)-Virosaine B (Figure 6) have been achieved in 11 and 10 steps with good overall yields of 5.92% and 6.68%, respectively, whereas (−)-Virosaine A (Figure 6) was synthesized in 18 steps with an overall yield of 7.78%.18 While Virosaines do not inhibit the proliferation of several cancer cells, Flueggine A shows weak inhibitory activity against the growth of three different breast cancer lines. Pyridomacrolidin was isolated in 1998 from fungus Beauveria bassiana metabolites by Nakagawa et al.20 We can only mention a succinct biological study, the macrocyclic structure weakly inhibiting protein tyrosine kinase activity. The biogenetic pathway to Pyridomacrolidin has already been proposed, and various investigations to build the principal core of this natural compound by stereospecific 1,3-dipolar cycloaddition of a nitrone and a 2-cyclodecenone have already been published (Scheme 4).21−25 However, the total synthesis of the isoxazolidine metabolite still remains in progress. Concerning Lycojaponicumins A and B, a biogenic route involving an intramolecular cycloaddition between a nitrone and an alkene for the construction of the bicyclic isoxazolidine skeleton has been postulated.8,26 To the best of our knowledge no total synthesis has been reported so far. Finally, Setigerumine I, isolated from Papaver setigerum, containing an isoxazolidine moiety, was the most recent natural product discovered.27 However, only a few studies are currently available.

Scheme 3. Total Synthesis of Alsmaphorazine B

3. SYNTHETIC STRATEGIES TO PREPARE THE ISOXAZOLIDINE RING The 1,3-dipolar cycloaddition (1,3-DC) of nitrones and alkenes is one of the most developed reactions to prepare isoxazolidine compounds. Previous reviews covered the advances in the synthesis of isoxazolidines through 1,3-DC in solution28−35 and in solid phase.36 Although this section will give a brief survey of

Figure 4. Enantioselective strategy for (−)-Pyrinodemin A synthesis.

natural compound. Pyrinodemin A, such as other Pyrinodemins B, C, and D later discovered, exhibits potent cytotoxicity in vitro against murine leukemia L1210 and KB epidermoid

Figure 5. Enantioselective strategy for (−)-Flueggine A synthesis. 15238


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Figure 6. Enantioselective strategy for (−)-Virosaine A and (+)-Virosaine B syntheses.

Scheme 4. Access to the Principal Core of Pyridomacrolidin

the 1,3-DC principle and outline key synthetic advances, particularly in “green chemistry”, we will mainly focus on the synthesis of isoxazolidines through other synthetic pathways. Indeed, there are two logical disconnections in an isoxazolidine ring: the C3−C4 and O1−C5 bonds (Scheme 5, A) or/and the O1−C5 and N2−C3 bonds (Scheme 5, B). Scheme 5. Retrosynthetic Study of the Isoxazolidine Ring

Figure 7. Synthetic strategies to prepare the isoxazolidine ring.

cycloreactants, such as heterosubstituted dienophiles.34,35 Despite the numerous methodological improvements brought to this major class of cycloaddition, regio- and stereoselectivity of this reaction still represent a challenge for chemists. Considering that these selectivity features of 1,3-DC realized between nitrones and alkenes have been deeply reviewed,31,39−41 we will briefly remind here the principle of the reaction, we will draw the current scope of the isoxazolidines that can be reached in a selective manner, and we will highlight a few original syntheses, principally the works dealing with “green protocols”. The isoxazolidine synthesis through 1,3-DC involves a nitrone 1 as a 1,3-dipolar molecule and an alkene 2 as a dipolarophile by analogy with the dienophile of the Diels− Alder cycloaddition. Sterically demanding cycloreactants are well tolerated in a number of 1,3-DC reactions. From monosubstituted dipolarophiles, both regioisomers 3 and 4 (3−4 and 3−5) could be obtained, in which the regioselectivity principally depends on the R3 group (Scheme 6). In contrast with the Diels−Alder cycloaddition, in the case of 1,3-DC,

As previously mentioned, pathway A is routinely followed, while the use of disconnection B has only been recently reported thanks to the four different cyclizations of unsaturated hydroxylamines: (i) electrophilic cyclization, (ii) palladiumcatalyzed cyclization, (iii) radical cyclization, and (iv) Michael addition. Last, a third part will be devoted to others strategies briefly reported, such as the asymmetric reduction of isoxazolines or isoxazolidinones (Figure 7). 3.1. 1,3-Dipolar Cycloaddition

According to the literature, the principal synthetic route to access to isoxazolidines is the 1,3-dipolar cycloaddition of nitrones and ethylenic dipolarophiles, which was proposed by Morita et al. in 1967.37 This versatile pericyclic reaction, which can involve a range of electron-poor, neutral, and electron-rich dipolarophiles, offers the possibility of generating isoxazolidines with up to three new contiguous stereocenters. Such 1,3-DC reactions and relevant (3 + 2) processes have been reviewed in a general manner29,38 or more focused on some specific 15239


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loss of the stereochemical integrity of the dipolarophile under the reaction conditions or to a catalyst-induced stepwise mechanism. Thus, it appears clearly that several conditions are necessary to ensure the regio- and stereocontrol that is required to optimize the cycloaddition result. In this aim, the broad use of chiral auxiliaries (typically used under simple thermal conditions) or of chiral catalysts (Lewis acid or organocatalysts) has been developed as mentioned in several reviews.29−31,38,39,41 As a representative example of the current state of the art, isoxazolidines produced by catalytic asymmetric 1,3-DC reactions of acyclic aldonitrones with different kinds of dipolarophiles are highlighted in Figure 8: compounds 5−8 from electron-rich dipolarophiles (vinyl ethers),43−47 compounds 9 and 10 from neutral ones (allylic alcohols),48,49 and compounds 11−25 from electron-poor ones (enals, enamides, enones, nitro olefins, methylene malonates).39,50−83 Only a limited number of examples concern nitrones bearing protecting groups at the nitrogen atom, mainly using a benzyl group. In other cases, N-substituents are an aryl or a methyl group. The cycloaddition of C-carboxy aldonitrones is of major synthetic importance because the corresponding isoxazolidines are direct precursors of α-amino acids and derivatives. To circumvent the negative stereochemical consequences of the Z/ E isomerism observed in this critical case, 5- and 6-membered ring cyclic C-carboxy aldonitrones, displaying a pure E geometry, have been used. This fruitful approach, leading to bicyclic adducts with high exo/endo and facial controls, has been essentially developed using chiral lactone and lactam nitrones under thermal conditions (Figure 9).84−102 Enantioselective access to such kind of adducts from achiral cyclic nitrones by catalytic asymmetric pathways has not yet been reported. Interestingly, acyclic carboxy ketonitrones are found to display a pure and stable E geometry. Accordingly, high levels of stereocontrol were reported by our group in chiral auxiliarycontrolled thermal 1,3-DC reactions involving aspartic nitrones and vinyl ethers,105,106 as well as in enantioselective cycloadditions involving alanine-containing nitrones and enals (Figure 10).103,104 Recently, original studies about 1,3-DC performed through a “green protocol” have been reported such as the efficient synthesis of N-benzyl-fluoro-isoxazolidines 38 in ionic liquids described by Chakraborty et al.107 (Scheme 8). Indeed, the corresponding endo isoxazolidines were exclusively synthesized in rather good yields (84−90%) by performing the reaction in [bmim]BF4 for ∼30 min, whereas under conventional conditions (DCM, rt for a few days), a 80/20 endo:exo mixture was recovered in moderate yields (57−62%). Moreover, ionic liquids present the advantage to be recycled several times without loss of activity and selectivity. With the aim to promote green chemistry conditions, Bhattacharya et al.108 performed in one pot the combination of the nitrone formation and the 1,3-DC in a water medium in the presence of cetyltrimethylammonium bromide (CTAB) as a surfactant catalyst. In this eco-friendly system, they obtained several substituted isoxazolidines with a high level of regio- and enantiocontrol. Under the same reaction conditions, the authors also reported an unprecedented stereoselective intramolecular nitrone cycloaddition.109 Often microwave-assisted synthesis was revealed to be a valuable alternative to conventional heating to accomplish a

Scheme 6. Formation of 3−4 and 3−5 Isoxazolidines through 1,3-DC

steric and electronic effects were both important to induce regioselectivity. With electron-rich dipolarophiles, both effects favor 3,5-regiocontrol; meanwhile, steric effects can counterbalance electronic effects in the case of some electron-poor dipolarophiles, which sometimes makes prediction difficult. As another difference to the Diels−Alder cycloaddition, steric effects are dominant to induce endo/exo control. Each of the 2 regioisomers can exist through 4 stereomers (4 diastereomers when one of the cycloreactants is chiral, 2 couples of enantiomers if not), depending on the endo/exo and facial approach. To illustrate that, the different stereomers of the (3− 5)-regioisomer are represented in Scheme 7. When the nitrone Scheme 7. 3,5-Stereomers Possibilities from 1,3-DC

exists through a Z/E equilibrium, like for some functional acyclic aldonitrones (R2 = ester),42 high levels of overall stereocontrol are even more difficult to reach, since each of the 4 stereomers can be produced by both an exo and an endo approach (Scheme 7). Indeed, the cis 2 isomer, for instance, can be produced by an exo approach of the dipolarophile to the bottom face of the Z nitrone, and also by an endo approach to the top face of the E nitrone. Last, when the dipolarophile is β-substituted, the number of possible stereoisomers is generally preserved, thanks to the stereospecificity of the concerted pericyclic process. However, this number can increase in some cases, due either to the in situ 15240


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Figure 8. Isoxazolidines produced by metal-based (A) and organo (B) catalytic asymmetric 1,3-DC of acyclic aldonitrones.

Figure 10. Isoxazolidines produced by asymmetric dipolar 1,3-DC reactions of carboxy ketonitrones (A) metal-based and (B) organocatalysis.

Scheme 8. Synthesis of Isoxazolidines Involving 1,3-DC in Ionic Liquids

more efficient reaction, due to its unique advantages, such as shorter reaction times, cleaner reactions, higher yields, and better selectivity. Since 1,3-DC was often realized under thermic conditions, chemists have naturally envisioned the reaction under microwave (MW) irradiation. Indeed, several 1,3-DC lead to the formation of isoxazolidine compounds when thermic heating did not produce any product.110,111 Furthermore, MW conditions can also lead to a different selectivity

Figure 9. Isoxazolidines produced by asymmetric dipolar 1,3-DC reactions of chiral cyclic nitrones.

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Scheme 9. Synthesis of Isoxazolidines by 1,3-DC under Microwave Irradiation

Scheme 10. Synthesis of N-Boc or N-Cbz Isoxazolidines through 1,3-DC

Depending on the N-protecting group (Boc or Cbz), 46 could produce the isoxazolidine 47 in the presence of TFA or the substituted δ-lactam 48 after hydrogenation. As previously discussed, the synthesis of isoxazolidine bearing a removable N-protecting group is highly desirable but difficult to obtain from 1,3-DC since the corresponding nitrone exhibits low stability. Access to N-acyl-protected isoxazolidines can proceed efficiently after selective N-deprotection, but this 2step method has been only described from C-carboxyketonitrone-derived adducts.83,93,106,118 Consequently, several groups developed new strategies to obtain this interesting intermediate for further synthetic applications. Among them is the cyclization of unsaturated hydroxylamines.

compared to thermic conditions. For example, Muthusubramanian et al.112 obtained only the desired bis-isoxazolidine diastereomers 41 and 42 by using MW irradiation, whereas under conventional heating, they principally observed formation of the monoisoxazolidines 43 (Scheme 9). Under conventional heating or MW irradiation, several groups also reported efficient isoxazolidine syntheses in free-solvent conditions.112,113,84,114−117 1,3-DC is a powerful reaction to prepare N-benzyl or N-aryl isoxazolidines, but these nitrogen-protecting groups are difficult to remove without a concomitant ring opening. As a valuable exception, the use of appropriate hydrogen transfer conditions proved its efficiency to achieve N-debenzylation with respect to the isoxazolidine ring of adducts produced from N-benzyl carboxy ketonitrones.93,106,118 Glycosylnitrones and tetrahydropyranosyl-substituted nitrones lead to N-protected isoxazolidines, which may be deprotected by acidic hydrolysis, and hydroxyaminolysis while leaving the N−O bond intact.105,119−122 N-Benzhydryl nitrones were also reported to yield cycloadducts, which could be removed by NBS oxidation,58 either in acidic conditions (HCl in MeOH)62 or via a reductive cleavage with Et3SiH.123 However, the synthesis of isoxazolidines bearing an easily removable electron-withdrawing group at nitrogen (crucial for performing further synthesis) was poorly exploited. Using phase-transfer catalysis (PTC), Ricci et al.124 reported an original asymmetric 1,3-DC from N-Boc or N-Cbz hydroxyl-α-amido sulfones 44 and gluconates 45 (Scheme 10) leading to isoxazolidines 46.

3.2. Cyclizations of Unsaturated Hydroxylamines

Unsaturated hydroxylamines, through intramolecular cyclization, offer an alternative method to efficiently form the 2,3bond and the 1,5-bond, affording original isoxazolidine derivatives. This strategy allowed access to novel isoxazolidines that could not be obtained by 1,3-DC. Depending on the intramolecular cyclization conditions that are applied, the reaction mechanism is different. Thus, we decided to divide this section in four subparts: (i) electrophilic cyclizations, (ii) palladium-catalyzed cyclizations, (iii) radical cyclizations, and (iv) Michael additions. 3.2.1. Electrophilic Cyclizations. Among the cyclization of unsaturated hydroxylamines, an interesting route to access the isoxazolidine skeleton concerned electrophilic cyclization, 15242


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Scheme 11. Possible Combinations for the Electrophilic Cyclization

which was highlighted by Lombardo et al.129 Initially described to build other heterocyclic ring systems such as oxazolines125 or pyrrolidines,126−128 this chemical strategy requires alkenes bearing N- or O-nucleophilic functionality. Such starting compounds are suitable for intramolecular cyclization by means of different electrophilic sources, halides or phenylselenides. Since all reported substrates were unsaturated hydroxylamine derivatives, various combinations for the intramolecular cyclization have been designed depending on the nucleophilic species involved and on the double bond position. Various synthetic strategies involving 5-exo cyclizations were reported leading to 5-halomethyl-, 3-halomethyl-, or 3-phenylselenyl-isoxazolidines, while synthetic strategies involving 5-endo cyclizations were described leading to 4-haloisoxazolidines and 4-phenylselenyl-isoxazolidine derivatives. To the best of our knowledge, no cyclization involving N-allylhydroxylamines has been yet investigated (Scheme 11). 3.2.1.1. Electrophilic 5-Exo Cyclizations. Starting from Nhomoallyl-hydroxylamine derivatives 49, electrophilic 5-exo cyclization to reach 5-iodomethyl isoxazolidines 50 has been investigated by Trombini et al.129,130 (Scheme 12). Formation

Scheme 13. Formation of Azetidine N-Oxide

Scheme 14. Unsuccessful Synthesis of Isoxazolidines by 1,3DC vs Successful Synthesis of Isoxazolidine through Electrophilic Cyclization

Scheme 12. 5-Exo Iodocyclization with Substituted Hydroxylamines

Similarly, Janza et al.131 investigated 5-exo cyclization of Ohomoallyl-hydroxylamine 54 in the presence of diverse electrophilic sources (E+ = NaOCl, PhSeBr, NBS, NIS, I2) to obtain various substituted isoxazolidines 55 (Scheme 15). of the heterocyclic moiety always takes place regioselectively after O-trialkylsilylation of the acyclic substrate. Despite the fact the O-tert-butyldimethylsilyl group increased selectivity in some examples, its use resulted in lower yields. Thus, the Otrimethylsilyl group was generally preferred. Among the electrophilic species tested, N-iodosuccinimide (NIS) was considered to be the most suitable electrophilic source. The configuration of the 3−4 position on the substrate (syn/ anti) was conserved in the reaction product. When R3 is an acetoxy group, in this particular case, 4−5-cis selectivity is induced since only the cis ring closure was obtained, independently of the substrate configuration. Moreover, in addition to the expected 5-exo cycloadduct 52 (yield 58%), a low yield of azetidine N-oxide 53 was observed (17%), arising from 4-exo cyclization (Scheme 13). Hence, Trombini et al. applied their methodology to the synthesis of isoxazolidine that could not be synthesized through 1,3-dipolar cycloaddition using alkenes, which contain either an enolether or an enolester functionality along with a nucleofuge as a substrate not suitable for 1,3-DC (Scheme 14).129

Scheme 15. 5-Exo Cyclization Using Substituted OHomoallyl-hydroxylamines

Subsequently, Moriyama et al.132 developed a green version forming bromonium species from KBr and oxone in situ. This strategy required the use of N-protected hydroxylamines (R1 = PhSO2, Ac, or Tos) to avoid a concomitant oxidation of the isoxazolidine into isoxazoline. Both research teams reported enantioselectivity and 3−5-cis selectivity in good to excellent yields (dr up to 11.3:1). Among the described electrophilic 5-exocyclizations, several were mediated by a Lewis acid, especially for the cyclization of allenic hydroxylamines 56 (Scheme 16).133 15243


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65 could be converted into the isoxazolidine 64 starting the reaction at −50 °C and leaving then the reaction mixture at room temperature (Scheme 19).

Scheme 16. Electrophilic 5-Exo Cyclizations of Allenic Hydroxylamines Mediated by a Lewis Acid

Scheme 19. Formation of Isoxazolidines and 1,2,4Dioxazines According to the studies of Bates et al.133−137 and Toste et al. the more suitable catalysts were based on silver and gold transition metals. Consequently, the synthesis of numerous natural products such as Porantheridine or (−)-Sedinine has been accomplished. Shi et al.139 also reported excellent yields of 5-exocyclizations using Yb(OTf)3. Last, Cossy et al.140 realized a unique Fe(III) complexcatalyzed intramolecular reaction from N-protected δ-hydroxylamino allylic acetates 58 (Scheme 17). Mechanistic studies 138

Scheme 17. Intramolecular Electrophilic 5-Exo Cyclization of O-Homoallyl-hydroxylamines

More recently, the research team of Tiecco et al. reported an extension of the methodology using optically active selenyl triflate 68 obtained from the diselenide 66, bromine, and silver triflate to increase the diastereoselectivity during the isoxazolidines synthesis.33 In contrast with previous works, hydroxylamine 67 was N-protected with an O-allyl oxime, which after reaction with the selenylating agent was converted by hydrolysis into the corresponding isoxazolidine 70 (Scheme 20). Various substituents were screened, leading to excellent yields (up to 93%) of an inseparable mixture of diastereomers (dr up to 93:7).

revealed that cyclization proceeded via an allylic carbocation intermediate. The cis product 59 was then favored by kinetic control when R2 = H (minimization of steric interactions) and by thermodynamic control when R2 = Ph (cis isomers were the more stable). However, starting from β-hydroxylamino allylic acetates, the trans product was preferentially formed, probably due to an SN2-type mechanism instead of a carbocationic pathway. 3.2.1.2. Electrophilic 5-Endo Cyclizations. To the best of our knowledge, 5-endo cyclizations could only be realized from O-allyl-hydroxylamines. Seleno cyclizations were reported by Tiecco et al.33,141,142 as well as Li et al.,143 whereas Egart et al.144 tested various halogeno cyclizations. As for the 5-exo cyclization of O-homoallyl-hydroxylamines, the 5-endo cyclization required use of N-protected hydroxylamines 60. However, contrary to 5-exo cyclization, the 5-endo cyclization leads preferentially or exclusively to a 3−4-trans selectivity, which was explained through a SN2 pathway (Scheme 18).

Scheme 20. Synthesis of Isoxazolidines from Chiral Diselenide

Scheme 18. 5-Endo Electrophilic Cyclization of OHomoallyl-hydroxylamines

In 2013, Egart et al.144 reported the 5-endo bromocyclization from O-allyl-N-tosyl-hydroxylamine 71. After performing experimental studies, better conditions were attempted with N-bromoacetamide (NBA) in DCM at room temperature (Scheme 21). In these optimal conditions, they evaluated the substituent effect on the cyclization selectivity, their results being summarized in Table 1. The 3− 4 trans selectivity was observed by 1H NMR studies, which confirmed the formation of a bromonium bridge that was opened through a nucleophilic substitution with inversion of the configuration (SN2).

Tiecco et al. used phenyl-selenenyl sulfate produced in situ from diphenyl diselenide, ammonium persulfate, and trifluoromethanesulfonic acid in acetonitrile to perform seleno cyclization of O-allyl-hydroxylamines. In a preliminary study, they observed that formation of 1,4,2-dioxazines 65 depends both on reaction temperature and on R1 substituent. However, 15244


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cyclization/C-arylation of 77 in excellent yield and diastereoselectivity. After a methodological study on the catalyst structure and on the ligand, the best results were obtained with Pd2(dba)3/Xantphos and NaOtBu in toluene at 90 °C. Formation of the undesired N,N-bisarylation and the Hecktype side products was also totally suppressed. They extended the reaction on various substituted substrates 77 conserving a total diastereoselectivity for the cis product 78 (Scheme 23).

Scheme 21. 5-Endo Bromocyclization with NBA

Table 1. 5-Endo Bromocyclization with NBA

Scheme 23. Sequential N-Arylation/Cyclization/C-Arylation of O-Homoallyl-hydroxylamines

Even if the principal palladium-mediated carbo-etherification was realized from O-homoallyl-hydroxylamines, a few examples of efficient carbo-etherification of N-homoallyl-hydroxylamines 79 were described (Scheme 24).149 When R2 = H or Boc, the

3.2.2. Palladium-Mediated Cyclizations. Palladiumcatalyzed diastereoselective cascade reaction is a suitable method for the synthesis of heterocyclic compounds. Accordingly, several groups have naturally extended this method for carbo-etherification of unsaturated hydroxylamine substrates, providing a new stereoselective method for the construction of substituted isoxazolidines. In many cases the stereochemical outcome of these transformations is complementary to that of nitrone cycloadditions. The power of this cyclization was deeply studied to get suitable N-protected isoxazolidines. Thus, Dongol et al.145 synthesized isoxazolidine derivatives 75 from N-Boc-O-homoallyl-hydroxylamine 73 with a ratio cis/trans of up to 10:1. However, moderate to good yields were obtained, due to the isolation of a Heck coupling adduct 76. Changing either the catalyst loading or the ligand did not result in any improvement. This methodology was improved by Rosen et al.,146,147 who performed the efficient cyclization of the same hydroxylamine derivatives 73 using different experimental conditions, affording only the expected ring 74 in excellent yield and dr (Scheme 22). Using 2 equiv of aryl bromide, Dongol et al.,145 Peng et 147,148 al. accomplished an efficient sequential N-arylation/

Scheme 24. Palladium-Catalyzed Cyclization of NHomoallyl-hydroxylamine

formation of the Heck product was observed, whereas with R2 = Bn, Me, and tBu or with cyclic hydroxylamine, the desired Nprotected isoxazolidines 80 was obtained in 56−94% yield with a dr of up to 20:1. To target 5-vinyl-substituted isoxazolidines 82 not accessible through 1,3-DC, Merino et al.150 performed an original intramolecular cyclization of 81 (Scheme 25). By the action of Pd(0) or Pd(II) catalysts, the authors observed a different diastereoselectivity (cis or trans) that was explained by two alternative mechanisms.

Scheme 22. Palladium-Catalyzed Cyclization of N-Boc-O-homoallyl-hydroxylamine

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of 92 with TBAF implied removal of the silyl group and the intramolecular oxy-Michael addition, leading to the desired Boc-isoxazolidine 90 in 99% yield and dr 10:1 (Scheme 29). From this tandem reaction and inspired by the work of Edward and Davis,159 Yin et al.160 synthesized isoxazolidines 94 through a double-hetero-Michael addition of N-substituted hydroxylamines from quinone monoketals 93 (Scheme 30). Good to excellent yields of the corresponding isoxazolidines bearing a variety of substituents on the hydroxylamine function (R = Boc, Bn, Me, Ac) were obtained as well as several substituted or not quinone monoketals. However, 2-chloroquinone monoketals led to lower yields (17−32%). Isolation of the mono-Michael addition intermediate showed that the first conjugate addition was the N-addition. Furthermore, the first addition took place on the more electrophilic double bond when it was not substituted and on the sterically less hindered site when it was substituted. Depending on the electronic and steric effects governing the regiocontrol, the obtained products depended only on the steric hindrance induced by the substituent on the double bond. Last, starting from α,β-unsaturated carbonyl derivative 96, the synthesis of several 5-hydroxyisoxazolidines has been accomplished with a chemo- and stereo-selective control. Aza-Michael addition of an hydroxylamine either catalyzed by a chiral amine161 or by a Lewis acid (Yb(OTf)3),162 followed by an aldol condensation, yielded either N-Boc or N-Cbz cycloadducts 95 or N-unprotected isoxazolidines 97 (Scheme 31). Catalyzed by trimethylsilyl triflate, condensation of 2trimethylsilyloxyfuran 98 with an aldonitrone 99 led to the unsaturated hydroxylamine 100. After removal of the silyl group, an intramolecular oxy-Michael addition led to the bicyclic isoxazolidines 101. The first step displayed complete facial selectivity affording two diastereomers 100 in a 82/18 ratio. The desired cycle 101 was obtained in quantitative yield through a silica gel-induced ring closure (Scheme 32).163−165

Scheme 25. Palladium-Mediated Synthesis of 5-VinylSubstituted Isoxazolidines

Instead of Ar−X as the electrophilic source, Bates and SaEi,151 Dongol et al.,152 and Malkov et al.149 used carbon monoxide in methanol to directly afford the corresponding isoxazolidine methyl ester 84 (Scheme 26). Scheme 26. Palladium-Mediated Cyclization in the Presence of CO in Methanol

3.2.3. Radical Cyclizations. Among the cyclization of unsaturated hydroxylamines, there are only a few reports about radical cyclization. The first study was described by Janza and Studer153 in 2005. They described the generation of the alkoxy−amidyl radical under oxidative conditions using oiodoxybenzoic acid (IBX). By this method they mainly obtained the desired cycle 86 (54−71%) in a cis:trans 6:1 mixture with concomitant formation of two byproducts 87 and 88 (Scheme 27). Using either no or other N-protecting groups (N-PGs) such as Boc or sulfonyl, the reaction did not proceed, while using N-p-methoxybenzamide PG, the ester 87 was the major product formed (40%). Using copper complexes and (2,2,6,6-tetramethylpiperidin-1yl)oxyl radical (TEMPO) as mild oxidant on N-sulfonylhydroxylamines, Karyakarte et al.154 observed the selective formation of 3−5-cis-isoxazolidines with excellent yields and dr (up to 20:1), except with the β-phenyl substrate, which yielded the 3,4-trans product. They proposed a mechanism, which is described in Figure 11. 3.2.4. Michael Additions. The hetero-Michael addition reaction emerged as a powerful synthetic strategy to create C− N or C−O bonds. By means of bis-nucleophiles such as hydroxylamines, this method provided novel access to Nprotected isoxazolidines. After the first reports in 1978155 and then in the 1990s,156,157 the reaction was deeply developed in 2006 by Chen et al.158 After removal of the silyl group from NBoc-unsaturated hydroxylamines 89, an intramolecular oxyMichael addition was observed, leading to Boc-isoxazolidines 90 in excellent yields (99%) and dr (10:1) (Scheme 28). The isoxazolidine 90 could also be obtained from the α,βunsaturated aldehyde 91 thanks to a double-hetero-Michael addition. The one-pot amine-catalyzed aza-Michael addition of a hydroxylamine is followed by a Wittig homologation, affording the unsaturated hydroxylamines 92. Then treatment

3.3. Other Synthetic Strategies

3.3.1. From Isoxazolidinones. Also synthesized via an azaMichael addition followed by a cyclization step, isoxazolidine-3ones 104 have been efficiently converted into the corresponding 5-hydroxyisoxazolidines 105 in the presence of DIBAH thanks to a chemoselective reduction (Scheme 33).166 3.3.2. From Isoxazolines. Isoxazoline is an unsaturated five-member ring, which can be prepared by 1,3-DC of nitrile oxides and olefins. This substrate is easily transformed into the corresponding saturated cycle through various methods. For example, using different organometallics in the presence of etherate borane, Buhrlage et al.167 performed a nucleophilic addition on isoxazolines 106 to obtain original isoxazolidines 107 in 73−80% yield with a dr between 7:1 and 20:1 (Scheme 34, R = Bn, Ph, allyl, Me, thienyl, 2-methylallyl). Thus, they proposed an efficient method to prepare suitable Nunprotected isoxazolidines.

Scheme 27. Radical Cyclization of O-Homoallyl-hydroxylamines Using IBX

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Figure 11. Catalytic cycle with copper complexes.

Scheme 30. Double-Hetero-Michael Addition of NSubstituted Hydroxylamines Using Quinone Monoketals

Scheme 28. Synthesis of N-Boc Isoxazolidine via an Intramolecular Oxy-Michael Addition

Thanks to the use of borane/1,2-amino alcohol complex as chiral source, a racemic mixture of isoxazolines could be efficiently reduced into diastereomerically pure isoxazolidines. By changing the chiral source and the substrate, Tokizane et al.168 succeeded to orientate the reaction to the privileged formation of one product. Using (−)-norephedrine as the chiral source and 2,4-diphenyl-isoxazoline as the substrate, only isoxazolidines 109 in 84% with a 6:4 cis/trans ratio were obtained. In contrast, using (−)-ephedrine as the chiral source, only the starting isoxazoline 108 was recovered (Scheme 35). By applying a similar method, cis-3−5-substituted isoxazolidines 112 were obtained in 8:2 dr by reduction with NaBH4 in acetic acid without using any chiral source. A second step of reduction with Zn/AcOH led to formation of the corresponding cis-1,3-amino alcohol 113 (see section 4.1.1.1). However, when the isoxazoline was directly submitted to the Zn/AcOH reduction, formation of the trans-1,3-amino alcohol 110 was observed (Scheme 36).169 Last, 3-substituted 2,3-dihydroisoxazoles 115 were efficiently converted into 2,3,4-trisubstituted isoxazolidines by an oxidative process. The 2,3-dihydroxy cycle 116 was obtained in the presence of K2OsO4·2H2O and NMO in acetone−water, whereas 2-hydroxy-3-bromo isoxazolidines 114 were synthesized thanks to NBS in H2O/THF (Scheme 37).170 3.3.3. From Isoxazolinium Salts. Hydrogenation of isoxazolinium salts 117 in the presence of iridium catalyst

lead to a fully saturated cis-isoxazolidine 118 in excellent yield and er (up to 89:11), Scheme 38.171 Interestingly, when the reaction was performed in the presence of a double amount of catalysts in THF at 70 °C for 4 h, a mixture of saturated and unsaturated rings 120, 121, and 122 was obtained, Scheme 39.

4. ISOXAZOLIDINES AS INTERMEDIATES IN ORGANIC CHEMISTRY The interesting reactivity of the N−O bond in the isoxazolidine ring has given rise to a vast variety of complex and novel heterocycles or open-chain products. The widespread occurrence of these various functionalized frameworks in many drugs has encouraged the development of several methods for the selective transformation of readily available isoxazolidine precursors. In this section, we will mainly focus on the studies concerning chemical reactivity of isoxazolidines since 2000 (Figure 12). 4.1. Reductive Ring Opening: Synthesis of 1,3-Amino Alcohols

Isoxazolidines provided easy access to a variety of 1,3-amino alcohols, compounds that have significantly contributed to the advancement in asymmetric synthesis.172 Due to the labile nature of the N−O bond under mild conditions, the reductive

Scheme 29. Synthesis of N-Boc Isoxazolidine via a Double Michael Addition

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Scheme 31. Aza-Michael Addition and Aldol Condensation-Mediated Synthesis of 5-Hydroxyisoxazolidines

Scheme 32. Synthesis of Bicyclic Isoxazolidines by an Intramolecular Oxa-Michael Addition

Scheme 36. Synthesis of isoxazolidines by reduction of isoxazolines with NaBH4

Scheme 33. Synthesis of Isoxazolidines by Reduction of Isoxazolidin-3-one in the Presence of DIBAH

Scheme 37. Synthesis of Isoxazolidines by Isoxazoline’s Oxidation

Scheme 38. Synthesis of Isoxazolidines by Reduction of Isoxazolinium Salts

Scheme 34. Synthesis of Isoxazolidines by Nucleophilic Addition on Isoxazolines

4.1.1. Ring Opening by Reduction under Catalytic Hydrogenolysis. 4.1.1.1. Using Pd Catalysts. Preparation of 1,3-amino alcohols by catalytic hydrogenolysis is one of the principal routes developed from isoxazolidines. First described by Itoh et al.173 and by Grashey et al.174 in 1960, the protocol consisted on the oxazolidine reduction under H2 atmosphere in the presence of Adam’s Pt catalyst or Pd/C, respectively. This method was further extended, and nowadays the reductive cleavage occurs upon stirring under H2 (1 atm) in methanol or

cleavage of isoxazolidines has been performed using various methods such as catalytic hydrogenation, metal complexes, hydrides, etc. Then a large range of choice to obtain selectivity versus the other functional groups present on the substrate has been created.

Scheme 35. Synthesis of Isoxazolidines by Reduction of Isoxazolines with Borane/1,2-Amino Alcohol Complexes

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Scheme 39. Synthesis of Isoxazolidines and Isoxazolines by Isoxazolinium Salts Reduction

Scheme 41. Synthesis of Validamine Analogs

By contrast, Yadav and Taylor178 synthesized quantitatively 1,3-syn amino alcohols from cis-isoxazolidines 130, allowing efficient synthesis of (2S,4R)-2-amino-4-hydroxyadipic acid (Ahad) 131, a constituent amino acid of theonellamides A−F that have been shown to inhibit growth of prototypical fungi and cancer cell lines (Scheme 43). For the synthesis of the amino alcohol 133, Evans et al.179 started from the isoxazolidine 132. In addition, to perform the concomitant hydrogenation of both N−Bn and N−O bond cleavage, they realized in a one-pot reaction a concurrent N-Boc reprotection by the addition of Boc2O into the reaction mixture (Scheme 44). Similarly, Piotrowska et al.180 reported a concomitant N(Me)Phenyl deprotection with both the N−O bond reduction and the N-Boc reprotection to obtain 135 (Scheme 45). Interestingly, Argyropoulos et al.181 succeeded to conserve the N−Bn part during the N−O bond hydrogenolysis of an isoxazolidine ring forming the mesylate salt of the amino alcohol intermediate137. They prepared the corresponding N− Bn amino alcohol 138 in moderate yield (65%) (Scheme 46). Similarly, Vasella et al. preserved a Cbz protecting group during the reductive ring opening using H2/Rh−C or H2/Pt.182,183 4.1.1.2. Using Raney-Ni Catalyst. Catalytic hydrogenation of the N−O bond could also be achieved using Raney-Ni.184 Then Budzińska and Sas185 realized the efficient ring opening of the isoxazolidine 139 to afford the 4-hydroxypiperidine derivative 140 (Scheme 47). Hashimoto et al.61 also realized a N−O bond cleavage of various isoxazolidines in the presence of Raney-Ni in methanol (93% yield). Like for the catalytic hydrogenation in the presence of palladium, the use of Raney-Ni also allowed the concomitant N-benzyl group removal and the N-Boc protection during the isoxazolidine ring opening. As an example, Selim et al.104 converted the bicyclic isoxazolidine 141 into the N-Boc amino alcohol 142 in 94% yield, preserving the stereochemistry of both quaternary centers (Scheme 48). 4.1.1.3. Reduction with Zn/H+. An improved method for the reductive cleavage of isoxazolidines is the use of zinc powder in glacial acetic acid and methanol.186 The reaction is typically completed within a few hours and yields the desired 1,3-amino alcohol after basic workup to remove the excess of acetic acid and column chromatographic purification. This reductive cleavage avoids undesired removal of other protecting groups

Figure 12. Isoxazolidines as intermediates in organic chemistry.

ethanol in the presence of Pearlman’s catalyst Pd(OH)2/C (10−20%) for a few days. Applying these experimental conditions, Aouadi et al.97,98,175 efficiently converted compounds 123 into the expected 1,3-amino alcohols 124 in 74− 99% yield (Scheme 40). Scheme 40. Synthesis of 1,3-Amino Alcohols

When a compound with another hydrogeno-sensitive functional group such as R2 = CH(Me)CH2OBn was used, removal of the benzyl alcohol was concomitant with the N−O bond reduction. The one-pot reductive cleavage and removal of the N- or O-benzyl protection was also developed by Chakraborty et al.176 during the synthesis of unnatural glycosidase inhibitor Validamine analogs. Three new aminocyclohexitols such as 126 were then obtained in 80−85% yield (Scheme 41). By anticipating a global hydrogenation at the final step, Bates et al.177 efficiently removed both the benzyl ester and the Cbz carbamate and generated the amine from the azide group during the N−O bond cleavage. The natural antibacterial (+)-Negamycin 129 was obtained with a 1,3-anti orientation between the hydroxyl and the amino groups, a geometry totally preserved from the trans-isoxazolidine precursor 128, Scheme 42. 15249


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Scheme 42. Synthesis of Negamycin

Scheme 43. Synthesis of (2S,4R)-2-Amino-4-hydroxyadipic Acid Derivatives

Scheme 47. Synthesis of a 4-Hydroxypiperidine Derivative

Scheme 44. Synthesis of Amino Alcohols through Isoxazolidine Ring Opening

Scheme 48. Conversion of a Bicyclic Isoxazolidine Ring into the Boc Amino Alcohol Derivative

Scheme 45. Synthesis of Amino Alcohols through Isoxazolidine Ring Opening

the protected tricyclic isoxazolidine 143 with Zn/AcOH (Scheme 49). Similarly, during the preparation of the azabicyclic core of the Stemona alkaloids, Cid et al.188 realized a methodological study on an isoxazolidine-containing tricyclic compound 146 to find the more appropriate conditions for the reduction of their azabicyclic target. The best results were obtained with 10 equiv of zinc powder in 10% aqueous HCl, under sonication, at room temperature (Scheme 50, part a). Even though they reached 80% yield when X = phenylthio substituent, lower yields were obtained with other substituents. To increase the yield and to directly obtain the more stable N-protected amino alcohols, they first synthesized the isoxazolidinium salt 148 in the presence of benzyl bromide. Then treatment of 148 with activated zinc powder in AcOH and 10% aqueous HCl gave the expected protected amino alcohol 147 in quantitative yield (Scheme 50, part b). The authors concluded that in most cases formation of the N-benzylisoxazolidinium salt prior to reduction leads directly to the more suitable N-protected amino alcohol with a significant improved yield. In light of these results, the azepine ring 150 was efficiently synthesized by intramolecular N-alkylation followed by N−O bond cleavage of the intermediate 149 (83% yield) (Scheme 51). With the aim to access to the analogue 153 of both polyalcohol azabicyclic (−)-steviamine and (+)-hyacinthacine C5, Lahiri et al.189 accomplished selective ring opening by zincmediated N−O reduction of the bicyclic isoxazolidine 151 (Scheme 52). Molander and Cavalcanti190 developed the Zn/AcOH ringopening reduction of isoxazolidines. Interestingly, when 155 reacted with Zn/AcOH for only 10 min at room temperature, the corresponding 1,3-amino alcohol 156 was obtained in 85% yield (Scheme 53). However, the lactam 154 was directly obtained by heating compound 155 at 40 °C for 2 h, probably by cyclization between the amino function of the intermediate amino alcohol and the carbonyl of the α-methyl ester.

Scheme 46. Synthesis of Protected Aza-C-Disaccharide Derivative

(i.e., benzyl protecting groups, for instance). In this way, Aschwanden et al.169 realized a chemoselective ring opening of isoxazolidines in 72−96% yield, without affecting the N-Bn initial protection. This chemoselectivity was further illustrated by Höck et al.187 during the synthesis of the isoquinuclidine core of the Iboga alkaloid family 145. Indeed, they obtained the target key intermediate 144 in excellent yield after reduction of 15250


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Scheme 49. Reduction of an Isoxazolidine Compound by Zn/AcOH

4.1.1.4. Reduction with Molybdenum Hexacarbonyl. First described in 1990 by Cicchi et al.192 the reduction of isoxazolidines in the presence of Mo(CO)6 allowed the selective cleavage of highly functionalized compounds since the reaction happened in neutral conditions. Indeed, it required only heating in acetonitrile and by the presence of some water during the work up. By this procedure, various functionalized isoxazolidines 157 were efficiently reduced in high yield and a mechanism for the reaction was proposed (Scheme 54). Intermediates 158 and then 159 would form rapidly via coordination between isoxazolidine’s-containing heteroatoms and molybdenum ion. The preceding equilibrium moved to the expected compound 160 through decomposition of the complex 159 by water. The coordination with Mo is strongly dependent on steric factors. Then the reduction fails or gives poor yields when R1 or R2 are hindered substituents (R1 = tBu, Bn ; R2 = CO2Bn, CO2Me, Ph). Although disappearance of the starting material was always observed on TLC, formation of the intermediate 159 was totally prevented by the steric hindrance close to the nitrogen atom that released the total starting isoxazolidine (Scheme 54). Shibue et al.193 performed a reductive cleavage of 161 in high yield despite the presence of the somewhat hindered Fmoc protecting group. After Fmoc removal, the methyl ester of the amino acid Tubuvaline 162 was obtained, being a part of the cytotoxic natural tetrapeptide Tubulysins (Scheme 55). Kaliappan et al.194 applied this simple and mild method for the reduction of an acid-sensitive oxa-bridged isoxazolidine into the corresponding 1,3-amino alcohol that was recovered in excellent yield (85−93%). In several cases, addition of NaBH4 was needed to complete the reaction. During the synthesis of 8-epihalosaline, Sancibrao et al.195 first applied catalytic hydrogenation (Rh−C) on compound 163. In this condition the double bonds were

Scheme 50. Synthesis of Amino Alcohols by Zn/AcOH Reduction of Isoxazolidine-Containing Tricyclic Compounds

a Treatment of 146 with Zn/AcOH. bTreatment of 146 with BnBr in THF and then with Zn/AcOH.

Scheme 51. Synthesis of the Azepine Derivative by Zn/ AcOH Reduction of Isoxazolidine

In 2000, Boruah and Konwar191 described few examples in which a mixture of Zn−AlCl3·6H2O−THF was used to efficiently reduce in mild experimental conditions isoxazolidines to yield 1,3-amino alcohols in 80−90% yields. Although excellent yields were recovered, this protocol was not described further. Scheme 52. Synthesis of Polyalcohol Azabicyclic Analogues

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Scheme 53. Zinc-Mediated N−O Reduction of an Isoxazolidine Compound

Scheme 54. Reduction of Isoxazolidines in the Presence of Mo(CO)6

Scheme 55. Synthesis of Tubuvaline

Scheme 56. Synthesis of the Amino Alcohol 126 Using Mo(CO)6/NaBH4 Reduction

Scheme 57. Isoxazolidine Ring Opening Using Trimethylsilyl Iodide

4.1.1.5. Reduction with Trimethylsilyl Chloride/KI/H2O. In 2002, Boruah and Konwar197 developed a different stereoselective route to reduce the isoxazolidine ring using trimethylsilyl iodide (TMS-I) in water at room temperature. The mechanism proposed shows that TMS-I (generated in situ from TMS-Cl and KI) first chelated the oxygen atom forming the complex 168, which was opened into 169 through the attack of the iodide anion on the nitrogen atom. Then I2 was liberated thanks to HI generated from KI and water. After treatment of 170 with water, the expected amino alcohol 171 was produced after TMS-OH elimination (Scheme 57).

reduced, yielding a major compound 164, containing the isoxazolidine ring intact, along with the cyclic amide 165 and the desired amino alcohol 166 with a 10/1.5/1 ratio. When the previous mixture was subjected to Mo(CO)6 reduction in the presence of NaBH4 in CH3CN−H2O, the amino alcohol 166 was obtained in 57% yield over two steps (Scheme 56). Upon treatment with Mo(CO)6 and NaBH4, Bates et al.136,137 selectively opened a N-Boc isoxazolidine ring in good yield preserving the N-protecting group and without affecting the double bond. Last, Chatterjee et al.196 also achieved N−O bond cleavage by applying the same protocol. 15252


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The authors observed that the reaction proceeded in short reaction times in the presence of water, producing an excellent yield of the corresponding amino alcohols (80−95%). The same protocol was applied by Peng et al.148 and Bădoiu et al.63 for the synthesis of cis-N-aryl-1,3-amino alcohols. Indeed, reductions using catalytic hydrogenation Zn/AcOH or with LiAlH4 failed, while excellent conversions (90−98%) in the presence of TMS-I in water were observed. 4.1.1.6. Reduction with Samarium Iodide. During their ongoing research for the transformation of 5-spirocyclopropane isoxazolidines 172 to the corresponding β-amino-cyclopropanols 175, Revuelta et al.198 developed a new N−O bond reduction procedure. After testing various classical methods, i.e., H2/Pd/C, Zn/H+, or Mo(CO)6, they failed to produce the desired amino alcohol probably because of the known instability of the cyclopropane ring under acidic, basic, thermic, or hydrogen conditions. Since samarium iodide has been intensively used as a reducing agent of isoxazole,199 nitro compounds, or hydroxylamines, Revuelta et al.200 decided to apply this reagent to isoxazolidine rings. They isolated 10 amino alcohols in 70−98% yields using 3.5 equiv of SmI2 in THF at room temperature. The reaction mechanism suggested the formation of Sm(III) alcoholate 173 followed by the reduction of the nitrogen central radical by a second equivalent of SmI2. Last, hydrolysis of complex 174 with NH3/H2O afforded the expected amino alcohol 175 (Scheme 58).

Scheme 60. Ring Opening of Isoxazolidines by Mo(CO)6 or SmI2

Protecting the nitrogen atom by several other electronwithdrawing groups (Boc, Cbz, C(O)Cy, ...), Zhao et al.202 also converted 5-hydroxy-isoxazolidines into the corresponding 1,3aminoaldehydes thanks to the use of Mo(CO)6 (56−83% yields). 4.1.1.7. Miscellaneous. Several others procedures were employed to reduce isoxazolidines. Tufariello et al.203 observed cleavage of the N−O bond during reduction of a mesylate using a mixture of NiCl2−LiAlH4 (1:1 molar). This protocol was not further extended. However, LiAlH4 in THF efficiently opened the isoxazolidine ring. Indeed, Garciá Ruano et al.204 performed the ring opening of isoxazolidine 180 at the same time as other transformations (lactone opening, alcohol deprotection, ester reduction) (Scheme 61). However, LiAlH4 being a potent reducing reagent that can affect several functional groups should be used with caution.

Scheme 58. Reduction of 5-Spirocyclopropane Isoxazolidines with Samarium Iodide

Scheme 61. Reduction of an Isoxazolidine by LiAlH4

This selective and mild procedure offered an alternative to solve synthetic problems.201 Westermann et al.100 noticed that common reducing reagents such as H2/Pd or Zn/AcOH interfered with the O-benzyl protecting groups, whereas SmI2 allowed selective cleavage of the N−O bond preserving the protecting groups. Chen et al.158 also performed reduction of isoxazolidine 176 with SmI2 (99% yield), keeping intact a methyl ester and a N-Boc protecting groups (Scheme 59).

Walts and Roush205 showed that Zn/AcOH was more efficient than LiAlH4 in THF (95% yield in 3.5 h vs 70% yield in 22 h, respectively) or exotic mixtures such as Na−Hg in EtOH (nd) and Al−Hg in THF/H2O (91% in 2−3 days) for the reduction of N-benzyl-unfunctionnalized polycyclic isoxazolidines. Cicchi et al.206 developed an original method to reduce the N−O bond of hydroxylamines and isoxazolidines in the presence of indium metal. Although they succeeded to reduce several hydroxylamines in good to excellent yields, they reported only one case of isoxazolidine ring opening giving the corresponding 1,3-amino alcohol (63% yield).

Scheme 59. SmI2 Reduction of an Isoxazolidine

4.2. Dismutative Ring Opening

Dujardin and Py93,105,106,118 have shown that in the presence of SmI2 or Mo(CO)6 the ring opening of 5-ethoxyisoxazolidines can afford β-amino aldehydes. However, these compounds were unstable due to the reaction between the amino group and the aldehyde function, resulting in the ring opening. Thus, the amino group needs to be protected by an electron-withdrawing protecting group to decrease its nucleophilic character. Choosing the acetamide protecting group, the authors succeeded to efficiently prepare the stable 1,3acetamidoaldehyde 179 by ring opening of 178 in the presence of Mo(CO)6 or SmI2 (Scheme 60).

4.2.1. Synthesis of 1,3-Aminocarbonyl Compounds. De Shong et al.207 and then Murahashi et al.208 developed a redox ring opening of 5-alkoxy isoxazolidines, induced by Nquaternarization under basic and/or thermal conditions, which was further used by several other authors.209−214 Dugovič et al.210 succeeded to obtain valuable α-methylene-β-amino esters 183 in a two-step sequence. First, the isoxazolidine ring 182 was treated with reactive alkylating agents such as methyl (or allyl) triflate to afford the N-benzyl-N-methylisoxazolidinium salts. The second step was the N−O bond cleavage in the 15253


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afford the corresponding oximes 195 along with carbonyl derivatives 196 in good to excellent yields (Scheme 66).222 More recently, Morozov et al.223 based their synthetic strategy on a repetitive sequential 1,3-dipolar cycloaddition/ oxidative isoxazolidine ring opening to obtain a chiral C2symmetric sterically hindered pyrrolidine nitrone 201 (Scheme 67). 4.2.3. Synthesis of 1,3-Hydroxylamino Alcohols. Mulvihill et al.224 investigated the ring opening of N-acyl isoxazolidines to obtain functional N-hydroxylamides. Depending on the reagents that were employed, the reaction evolved to 1,3-hydroxylamido alcohols (in aqueous media) or to 1,3hydroxylamido ethers (in alcohol media). Furthermore, using Pd(0) complex, they only obtained syn products 205 (85− 86%), whereas in the presence of Fe(III) species, they principally obtained anti-hydroxylamines 206 (65−75%). The authors explained this stereoselectivity by formation of both intermediates 202 and 204 as shown in Scheme 68. Miller’s research team showed that In(OTf)3 in various alcoholic media also induced an efficient isoxazolidine ring opening to afford anti-hydroxylamides 206 (R1 = Bn, OtBu and R2 = Me, iPr, tBu) with good to excellent regio- and stereoselectivity.225,226 More recently, Flores et al.227 proposed an original synthesis of hydroxylamines 210 by the addition of an organometallic reagent to isoxazolidines 207 bearing a sulfone function on C4 (Scheme 69). They attempted moderate to good yields (35− 78%) with various organo-Li reagents (n-BuLi, MeLi, ...) and organometallics (PhMgBr, BnMgCl, ...), the best result being obtained with MeMgBr (74−78%). In contrast, the corresponding pyrrolidines 214 were obtained in good to excellent yields (45−94%) by applying the same experimental conditions, starting from the corresponding isoxazolidines 211 bearing a sulfone function on C5 (Scheme 70). 4.2.4. Synthesis of 1,3-Nitro Alcohols. By an unprecedented procedure, Roger et al.228 synthesized 1,3-nitro alcohols by 1,3-dipolar cycloaddition on nitronic acid precursors, followed by oxidative ring cleavage. They first isolated several isoxazolidines 216 N-protected by an O-silyl that were stable enough to provide satisfactory spectroscopic data. Removal of the silyl PG gave a spontaneous noncatalyzed aerobic oxidation to furnish the expected hydroxymethyl nitro compounds 217 in moderate to good yields (Scheme 71). Although the yield needed to be improved, the authors applied this method to prepare highly functionalized furan and pyrrolidine compounds.

presence of triethylamine, yielding the expected compound 183 with moderate to good conversion (Scheme 62). Scheme 62. Synthesis of α-Methylene-β-amino Esters 183 from Isoxazolidines

Such strategies were also fruitfully applied to 5-oxazolidinyl isoxazolidines, leading to 1,3-amino imides.84,215 In the case of 5-alkoxy-isoxazolidines, the ring opening can also lead to Nprotected 1,3-aminoesters without prior quaternarization of the nitrogen atom but thanks to the influence of a strong electronwithdrawing N-acyl substituent, as demonstrated by the group of Dujardin.105,106,118 Indeed, by a typical SmI2 treatment that led to amidoaldehydes from N-acetyl isoxazolidines, the authors synthesized 1,3-aminoesters 185 (60−75% yields) from Ntrifluoroacetyl isoxazolidines 150, while use of the Mo(CO)6 protocol was unsuccessful to open the isoxazolidine ring (Scheme 63). A simple catalytic hydrogenation of 5-thioacetal isoxazolidine 186 also induced the creation of the ring into the corresponding 1,3-aminocarbonyl compound 187. Aggarwal et al.216 applied these experimental conditions to efficiently synthesize the naturally occurring antibiotic (−)-Cispentacin 188. Despite various assays, in order to be removed, the benzyl deprotection required a second hydrogenation in the presence of Pearlman’s catalyst in ethanol. The synthesis of L-(4S)amino-β-proline 189 was then achieved in good yield using these experimental conditions (Scheme 64). For the preparation of β-aminoketones 192, Kumar and Ramana217 proposed an unprecedented catalytic redox-neutral cleavage of the N−O bond in oxazolidines. Indeed, a one-pot [3 + 2]-cycloaddition of nitrones 190 with olefins 191 followed by the Ru-catalyzed redox-neutral N−O bond cleavage of the isoxazolidine intermediate yielded 2,2-disubstituted pseudoindoxyls 192 (Scheme 65). 4.2.2. Synthesis of N-Oxide-1,3-amino Alcohols. First investigated by Lebel and Spurlock218 in 1964, the oxidative ring opening of isoxazolidines to yield N-oxide-1,3-amino alcohols was then particularly studied by Ali et al.219,220 Previously accomplished by peracetic acid, peroxides, or mCPBA, this procedure (the oxidative ring opening of isoxazolidines) is now largely preferred for the synthesis of N-oxide-1,3-amino alcohols. Indeed, Berranger and Langlois221 obtained hydroxyl-nitrones 194, which were hydrolyzed to

4.3. From Ring Opening of Isoxazolidines to Novel Heterocycles

The reactivity of both functions generated during the ring opening of isoxazolidines allowed access to new heterocycles such as lactones, lactams, oxazinanes, etc. 4.3.1. Synthesis of α-Amino Lactones. Inouye et al.229 first described a spontaneous cyclization during the isoxazoli-

Scheme 63. Ring Opening of Isoxazolidines by SmI2

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Scheme 64. Catalytic Hydrogenation of a 5-Thioacetal Isoxazolidine

(Scheme 76). After testing various catalysts, they finally selected [IPrAuCl]/AgSbF6 (5 mol %) that allowed access to excellent chemoselectivity with a yield up to 94%. Furthermore, the same catalyst was also used to efficiently promote the synthesis of isoxazolidines 230 by 1,3-DC. Naturally, the onepot synthesis of the expected benzoazepines was performed but with lower yield than that obtained following the two-step sequence. 4.3.4. Synthesis of Tetrahydro-1,3-oxazines. Conversion of N-alkyl-isoxazolidines into tetrahydro-1,3-oxazines was first discussed by Lebel et al.236 in 1967. Working on bicyclic isoxazolidines, they obtained good yields of the expanded ring either following ultraviolet light irradiation in hexane or by heating in the presence of a strong base such as t-BuOK in DMSO. The rearrangement of isoxazolidines to 1,3-oxazinanes could also be achieved in the presence of metal catalysts, as it was initially shown by Khumtaveeporn and Alper237on 3arylisoxazolidines (R2 = Aryl). Indeed, they observed that iridium complexes could act as catalysts for this conversion by an intermolecular hydrogen transfer reaction. Actually, the reaction occurred only under carbon monoxide atmosphere; thus, 1,3-oxazines 237 were obtained as side products resulting from in situ reduction of the corresponding tetrahydro-1,3oxazin-2-ones 236. However, they obtained moderate yields, the starting isoxazolidines being the hydrogen source for the carbonylation reduction reaction. By adding 1 equiv of cyclohexene, the authors succeeded to increase the yield from 37% to 61%. In contrast, when R2 = alkyl (iPr or CH2CH2Ph), a different rearrangement involving migration of the substituent to the ring nitrogen was described, yielding the 1,3-oxazines 234 (53−66%). To prove the reaction mechanism was different, a rearrangement on N-Bn-isoxazolidines was performed, and they effectively obtained the expected 1,3oxazines 233 (Scheme 77). An improvement of this rearrangement has been more recently reported by the team of Kang238,239 via a Ru-catalyzed N-demethylation rearrangement of isoxazolidines 238. Thanks to activation by the catalyst, the N-methyl could be inserted into the N−O bond, yielding the ring expansion (1,3oxazinanes 239). After further investigations to find the best conditions, this strategy of self-hydride transferring cleavage of N−O bonds demonstrated good tolerance to a range of functional groups with good to excellent yields, even when the N-substitution was limited to the methyl group (Scheme 78).

Scheme 65. Synthesis of Pseudoindoxyls

dine N−O bond reduction. Indeed, they observed the transformation of 2-Bn-3-(ethylester)-isoxazolidines into αamino lactones. The reaction, leading to the 1,3-amino alcohol 219 intermediate, proceeded through the N−O bond reduction concomitant with the benzyl removal in the presence of Pd(OH)2 under H2 atmosphere (see section 4.1.1.1). The presence of an ester function in the C3 position implied a spontaneous cyclization governed by the hydroxyl group yielding the α-amino-lactone 220 (Scheme 72). This reaction was extended to various isoxazolidines bearing an ester function in the C3 position. Several reduction reagents were used depending on the substrate. Tran et al.230 and Chakrabarty et al.231 choose Zn/AcOH, while Morita et al.232 preferred Mo(CO)6. 4.3.2. Synthesis of α-Hydroxy-lactams. Like for the access to α-amino lactone, the synthesis of α-hydroxy-lactams 223 was achieved using reductive conditions on 5-(COX)isoxazolidines 221. In this case, the spontaneous cyclization was governed by the amino group reactivity (Scheme 73). For example, Cardona et al.233 reported the total synthesis of 7-deoxycasuarine 226 and hyacinthacine A2 227 via an “isoxazolidine to α-hydroxy-lactam” rearrangement. The N−O bond reduction was performed by Zn/AcOH reduction that directly led to the cyclic compound 225 in 80% yield. Further modifications afforded both bioactive alkaloids 226 and 227 (Scheme 74). To provide the core-bridged ring system of the Yuzurimine, Daphnilactone B, and Bukittinggine belonging to the Daphniphyllum alkaloid’s family, Coldham et al.234 used catalytic hydrogenation over Raney-Nickel to reduce the N− O bond of 228 that directly promoted lactamization between the nitrogen and the ester part (75% yield) (Scheme 75). 4.3.3. Synthesis of Benzoazepines. Pagar and Liu235 recently reported an original diazo-containing isoxazolidine ring expansion through a novel 1,2-H-shift/[3,3] rearrangement to create the seven-membered benzoazepines 231 or 232 Scheme 66. Synthesis of N-Oxide-1,3-amino Alcohols

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Scheme 67. Synthesis of a Chiral C2-Symmetric Pyrrolidine Nitrone

Scheme 68. Synthesis of Hydroxylamines from Isoxazolidines

Scheme 70. Synthesis of Pyrrolidine Derivatives from Isoxazolidines

Scheme 71. Synthesis of 1,3-Nitro Alcohols by 1,3-Dipolar Cycloaddition on Nitronic Acid Precursors

Tetrahydro-1,3-oxazinanes can also be synthesized through a spontaneous evolution of 241, which resulted in a N-alkylisoxazolidine ring opening induced by a peracid. In four examples, Hashmi et al.240 observed only formation of the 1,3oxazinanes ring 242 from N-methyl-isoxazolidines 240 with yields up to 90% (Scheme 79). However, depending on the substituents, a mixture of compounds 241 and 242 was obtained in a ratio evolving with time. Indeed, a 1H NMR study in CDCl3 revealed the presence of isomers 241 and 242 in an approximate ratio of 70:30, 84:16, 93:07, and 100:0 after 3, 6, 9, and 12 h, respectively, probably due to tautomerization between the two compounds. 4.3.5. Synthesis of Tetrahydro-1,3-oxazin-2-ones. The carbonylation of N-methyl-isoxazolidines 244 was accomplished by Khumtaveeporn and Alper237 by reaction with carbon monoxide in benzene and in the presence of 1 mol % of

Scheme 72. Synthesis of α-Amino Lactones

rhodium catalyst [Rh(CycloOctaDiene)Cl]2. Thus, with rhodium metal, the authors only or mainly obtained the cyclic

Scheme 69. Synthesis of Hydroxylamine Derivative in the Presence of an Organometallic Reagent

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Scheme 73. Synthesis of α-Hydroxy-lactams

contraction involving a thermic rearrangement of isoxazolidines in alcoholic media. This transformation was first reported by Padwa et al.245 on the 5-nitroisoxazolidine 259 to obtain the trans-β-lactam 262 by heating the reaction mixture in methanol. In contrast, using UV light irradiation afforded the cis-β-lactam 261 that was easily converted into the thermodynamically more stable trans isomer 262 (Scheme 84). The reaction was then further extended on 5-spirocyclopropane-isoxazolidines 263. In this case, the reaction occurred in the presence of protic acids (i.e., trifluoroacetic acid) at 70−110 °C through the formation of biradical cationic intermediates 264 and 265 followed by ethylene release (Scheme 85). For the past decade, this rearrangement was principally developed by Zanobini et al.,246 Marradi et al.,247 and Cordero et al.248 on a wide variety of products differently substituted. The synthesis of more complex β-lactams of biological interest was efficiently accomplished thanks to the total preservation of the isoxazolidine precursor stereogenic centers. For example, Diethelm and Carreira249 realized the total synthesis of (±)-Gelsemoxonine 270 in 21 steps, one of them including the ring contraction of isoxazolidine 268 to yield the β-lactam 269 (Scheme 86). 4.4.2. Synthesis of 1,4-Tetrahydropyridinones. The same spirocyclopropane-isoxazolidines 266, in nonprotic acid media, gave the tetrahydropyridin-4-ones 273 via a thermic ring expansion that occurred through biradical intermediates 271 and 272. This rearrangement, called the “Brandi reaction”, was described in 1992.250 The mechanism first proposed (Scheme 87) was then confirmed by Ochoa et al.251 with the help of mixed RDFT/UDFT calculations. This process has been successfully applied to the synthesis of several substituted 1,4-tetrahydropyridinone252 including indolizidinone 275 and 276253,254 and isoquinoline 277254 alkaloids (Scheme 88). With the aim to avoid the thermic conditions, Revuelta et al.117,200 also performed the following two-step procedure at lower temperature. The first transformation was the selective SmI2-mediated cleavage of the N−O bond of isoxazolidine 278 preserving the sensitive cyclopropanol moiety (see section 4.1.1.5), while the second step was the Pd(II) or Pd(0) cyclization of aminocyclopropanols 279. They principally obtained the 1,2-dihydropyridinones 284 and as side products the 1,4-tetrahydropyridinones 280 up to a 1:1 mixture. Thus,

carbamate 245 with variable yields (20−82%), whereas with iridium catalyst, a spontaneous carbonylation reduction was observed, leading to compound 243 (Scheme 80). 4.3.6. Synthesis of β-Lactams. Van Berkom et al.241 developed the base-induced ring contraction of the nitroso acetal 246 to obtain the N-organyloxy-β-lactam 248. Since the acyl nitro intermediate 247 could be isolated, the reaction mechanism described in Scheme 81 for the lactamization step was confirmed. Furthermore, upon stronger basic conditions, the N-organyloxy-β-lactam 248 evolved to a mixture of the enantiomer 249 and the rearranged β-lactams 250. The mechanism proposed by the authors to explain the second product formation involved a base-induced lactam deprotonation followed by N−O bond cleavage (Scheme 81). Taking up the finding of Diev et al.,242 several groups demonstrated that the “isoxazolidine to β-lactam transformation” could be achieved with other groups than nitro in the 5 position of the heterocyclic ring. For example, Aurich and Quintero243 showed that the cyano function could eventually serve as a leaving group during the cyclization, since they succeeded to efficiently convert the bicyclic isoxazolidine 251 into the expected β-lactam 253. After testing various basic conditions, LDA gave the best results (Scheme 82). Originally, during an investigation on the catalytic hydrogenation of 4,5,5-trifluoro-4-trifluoromethyl-isoxazolidines 254, Jakowiecki et al.244 reported that 1,3-amino alcohol intermediates 255 (see section 4.1.1.1) spontaneously evolved into 1,3-aminoacyl fluorides 256 and then to α-trifluoromethyl-βlactams 257 (Scheme 83). However, under treatment with various bases (pyridine, DBU, LDA, or n-BuLi) at various temperatures, compound 254 remained unchanged or underwent decomposition. 4.4. Thermic Rearrangement

4.4.1. Synthesis of β-Lactams. The synthesis of β-lactams could also be achieved in one step from the efficient ring Scheme 74. Synthesis of 7-Deoxycasuarine and Hyacinthacine

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Scheme 75. Synthesis of the Core-Bridged Ring System of Daphniphyllum Alkaloid Compounds

Scheme 76. Synthesis of Benzoazepines

Scheme 77. Synthesis of 1,3-Oxazines

with 5% Na/Hg in THF/EtOH, they directly obtained the corresponding 1,4-tetrahydropyridinone 286 in 69%. Thanks to this key step, they accomplished a total synthesis of the alkaloid (±)-2,7,8-epi-perhydrohistrionicotoxin 287 (Scheme 90). 4.4.3. Other Thermic Rearrangement of Isoxazolidines. In 2012, Tran et al.256 reported that the same spirocyclopropane-isoxazolidines 290 obtained from the reaction between a nitrone 288 and an acceptor ringsubstituted methylene cyclopropane 289 could be postulated as an intermediate during the synthesis of the quinolone 291 (Scheme 91). Diev et al.242 also described the unusual transformation of bicyclic isoxazolidines 292 into the sterically hindered polyarylsubstituted aziridines 293 and pyrroles 294 that could be separated (Scheme 92). A simple heating of the isolated aziridines 293 allowed the recovery of pyrroles 294 in good yields. In 2003, Liard et al.257 showed that arylbenzyl-nitrenium ions could be generated through an unprecedented thermic rearrangement of isoxazolidines. Indeed, the cycloaddition between C,N-diaryl-nitrones 295 and 2-morpholin-4-yl-acryl-

Scheme 78. Synthesis of 1,3-Oxazinanes by Ring Expansion of Isoxazolidines

Scheme 79. Synthesis of 1,3-Oxazinanes from N-Methylisoxazolidines

the two-step method did not represent a valuable alternative to the thermic ring expansion (Scheme 89). Wilson and Padwa255 succeeded in proposing an efficient ring contraction without heating. Indeed, by reduction of 285 Scheme 80. Carbonylation of N-Methyl-isoxazolidines

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Scheme 81. Synthesis of β-Lactams by Base-Induced Ring Contraction of a Nitroso Acetal

Scheme 82. Synthesis of β-Lactams from Isoxazolidines

Scheme 84. Thermic Rearrangement of Isoxazolidine

onitrile 296 gave a mixture of five products in variable amounts depending on the experimental conditions that were used. To explain this result they first proposed the formation of the unstable isoxazolidine 298, which could produce a variety of different compounds (300, 301, 302, 303, and 304) (Scheme 93). In pathway A the hydrogen cyanide elimination was the starting point of the reaction, while in pathway B formation of the nitrenium ion 299 was involved through an initial heterolytic cleavage.

(Scheme 95). The experimental conditions needed an acidic cocatalyst, the more appropriate being (+)-10-camphor sulfonic acid (CSA). By reaction between cinnamaldehyde 315 and 5,5-bicyclic isoxazolidines 316 for a few minutes, a single geometrical isomer of the iminium ion 317 has been observed by 1H NMR in CD3OD/D2O (19:1), indicating its involvement in the catalysis (Scheme 96). Originally, Miyoshi et al.261 developed umpolung reactions (unconventional methods for the synthesis of molecules) to promote nucleophilic α-arylation and α-alkylation of ketones 318 via enamine intermediates. Instead of reacting with an electrophile, the enamine 320, bearing a second α-heteroatom, after chelation with a Lewis acid, will be attacked by a nucleophile. In this case, the nucleophile employed was directly linked to the Lewis acid [(R)3−Al] (Scheme 97). Thus, using mild and simple experimental conditions, they reported several examples in which the resulting compounds 323 were obtained in good to excellent yields, proposing an interesting alternative to conventional chemistry.

5. APPLICATION IN ORGANOCATALYSIS Since 2000, use of a secondary amine to catalyze various organic reactions (cycloaddition, aldolization, ...) has been developed by several groups, starting from the reports of Ahrendt et al.258 To increase the stereoselectivity, many groups focused on the use of the cyclic secondary amine, piperidine, pyrrolidine, and (L)-proline being probably the most popular. This was the start of elaborate novel aza-heterocycles and using them as organocatalysts. In this context, Brazier et al.259 compared the isoxazolidine ring with the pyrrazolidine and hydrazine rings in the iminium ion-catalyzed Diels−Alder reaction between cyclopentadiene 305 and cinnamaldehyde 306. Disappointingly, the isoxazolidine 309 was substantially less active than the pyrrazolidine 310, itself being less active than the acyclic hydrazide 311 (Scheme 94). Doyle and Heaney et al.260 described the significant organocatalytic activity of 5,5-bicyclic isoxazolidines 312, 313, and 314 in the same iminium ion-catalyzed Diels−Alder reaction. Indeed, by using catalysts bearing a second oxygen αheteroatom, they succeeded in obtaining good to excellent yields (up to 96%) with an endo/exo ratio up to 38:62

6. NATURAL BUILDING BLOCK MIMETICS 6.1. Nucleoside Analogues

In the research of effective, selective, and less-toxic antiviral and anticancer drugs, nucleoside analogues have always been of

Scheme 83. Catalytic Hydrogenation of 4,5,5-Trifluoro-4-trifluoromethyl-isoxazolidines

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Scheme 85. Synthesis of β-Lactams from 5-Spirocyclopropane-isoxazolidines

Scheme 86. Ring Contraction of Isoxazolidine in the Synthesis of (±)-Gelsemoxonine

Scheme 87. Thermic Ring Expansion of Spirocyclopropane-isoxazolidines

Scheme 88. Synthesis of Indolizidinone and Isoquinoline Alkaloids through Thermic Ring Expansion of Spirocyclopropaneisoxazolidines

physiologically present (i.e., pseudo uridine, for example). Their syntheses have been reported by Chiacchio et al.266 and Coutouli-Argyropoulou et al.267 The diastereoselective and enantioselective syntheses of psico-derived isoxazolidinyl nucleosides were also reviewed by Richardson et al.268 Some other less investigated families of isoxazolidinecontaining nucleosides can be mentioned, including the locked bicyclic derivatives, in which the isoxazolidine ring is constrained by a pentacarbon cycle linking the nitrogen and its neighboring carbon. These isoxazolidinyl nucleosides were synthesized and studied in particular by Coutouli-Argyropoulou et al.269 (Figure 14). Most of the syntheses of the bicyclic isoxazolidinyl nucleoside analogues were performed through 1,3-dipolar cycloaddition of a nitrone on an olefin. Another way to design nucleoside analogues was recently described by Versteeg et al.,270 who synthesized 2′-spiroisoxazolidine thymidine analogues, which correspond to a normal ribose ring linked to a nucleobase but also linked by a common carbon at the isoxazolidine ring (Figure 14). Several studies reported in vitro and in vivo assays to evaluate the potency of isoxazolidinyl nucleosides against viruses, bacteria, and cancers. Indeed, isoxazolidine moieties are proved to be efficient against virus infection with several different activities. The most common family of compounds containing

great interest. In this context, isoxazolidines were largely used to mimic the sugar part of nucleosides. The replacement of the furanose ring by an isoxazolidine moiety has been widely investigated. Pan et al.262 and Romeo et al.263 extensively reviewed the synthesis of isoxazolidinyl nucleosides and their applications as antiviral, antibacterial, antifungal, and antitumor drugs. More recently, a significant review of the different classes of isoxazolidine-containing nucleosides was reported by Kokosza and Piotrowska,264 in which they describe all different types of these derivatives and their most remarkable synthetic pathways. They described five families of isoxazolidine-containing nucleosides, composed of isoxazolidinyl nucleosides, homonucleosides, C-nucleosides, N′O-psico-nucleosides (containing psicose), and phosphonated derivatives (including all previous nucleoside rings bearing a phosphonate group) (Figure 13). Nucleosides bearing a hydroxymethyl group had to be activated by intracellular phosphorylases. The phosphonated derivatives had to be activated by intracellular phosphorylases and are also more resistant to enzymatic degradation because of the insensitive P−C bond. Their synthesis and biological evaluations were reviewed by Giofre et al.265 Homonucleosides, having a methyl group between the ring and the nucleobase, were also designed with the same goal. C-Nucleosides are 15260


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Scheme 89. SmI2-Mediated Cleavage of the N−O Bond of Isoxazolidines for the Synthesis of Dihydropyridinones

Scheme 92. Synthesis of Pyrroles

Leggio et al., in 1996, apparently first had the idea to include a nitrogen nucleus in the usual ribose ring of nucleosides and tested it as an antiviral drug on HIV.271 The same group of investigators developed the 4′-aza-2′,3′-dideoxythymidine (ADT) 325 that inhibits HIV replication at lower doses than AZT 324.272 Chiacchio et al.273 reported that AdFU 326 (or ADF), a 5-FU isoxazolidinyl nucleoside derivative, induced apoptosis of lymphoid and monocytoid cells, acting on the Fasinduced cell-death signal. The same authors studied the phosphonated derivatives of isoxazolidine nucleoside 329 with different nucleobases that were tested on HTLV-1 (human retrovirus).274 These compounds inhibited the enzymatic activity of the reverse transcriptase, protecting human cells from the virus. Romeo et al.275,276 designed and synthesized a new class of antiviral agents, truncated phosphonated derivatives 327, as well as truncated reverse isoxazolidinyl nucleosides (TRINs) 328 as inhibitors of the HIV-1 reverse transcriptase (Figure 15). Procopio et al.277 developed conformational locked nucleoside analogues 333 bearing a bicyclic isoxazolidine moiety in a S-type conformation (molecular modeling and NOE analysis), opening a new area of research on this type of compounds. On the basis of studies showing that reverse transcriptase recognized separately two nucleoside analogues with locked conformations, they proposed locking the furanose ring onto one rotamer. Singh et al.278 reported a series of nucleoside analogues 330, 331, and 332 with cytotoxic activity higher than Mitomycin C against the growth of HT-29 colon cancer lines. Nevertheless, against lung, liver, prostate, and breast cancer, they presented lower results than Mitomycin and Paclitaxel (Figure 15). Recently, Bortoloni et al.279 designed, synthesized, and evaluated the biological activity of the new analogues 334 and 335, which presented a significant antiproliferative activity on lymphoblastoid cell lines (Figure 16). Recently, a new series of isoxazolidinyl nucleosides having a linker separating the nucleobase/aryl substituents from the isoxazolidine ring was developed (Figure 17). Kokosza et al.280 used a carbamoyl linker (i.e., compound 336), while Piotrowska et al.281 investigated a 1,2,3-triazole linker (i.e., compound 337). Both classes of compounds have been tested on viruses and cancer lines, but the results that were obtained were modest.

Scheme 90. Ring Contraction of an Isoxazolidine in Nonthermic Conditions

an isoxazolidine ring are the nucleoside analogues, through the mimetic of the isoxazolidine with the furanose ring. Many works reported this way mimic nucleosides. Synthesis and cytotoxicity evaluation of some compounds appeared to be very interesting. Scheme 91. Synthesis of Quinolones

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Scheme 93. Cycloaddition of 2-Morpholin-4-yl-acrylonitrile on C,N-Diaryl-nitrones and Thermic Rearrangement of Isoxazolidines

Scheme 94. Iminium Ion-Catalyzed Diels−Alder Reaction

Scheme 95. Bicyclic Isoxazolidine-Derived Organocatalysts

Scheme 96. Formation of an Imminium Ion by Reaction between the Cinnamaldehyde and a 5,5-Bicyclic Isoxazolidine

6.2. Carbohydrate Analogues

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Scheme 97. Nucleophilic α-Arylation and α-Alkylation of Ketones

Figure 13. Different classes of isoxazolidine-containing nucleosides.

Figure 14. Example of bicyclic isoxazolidinyl nucleoside analogues and spiro sugar-isoxazolidines. Figure 16. Potential antiproliferative isoxazolidine nucleosides.

al.282 synthesized a C-linked isoxazolidine new sugar, but no biological activity was reported. Fišera283 reviewed in 2007 the formation of isoxazolidine moieties from sugar-derived nitrones.

Actually, isoxazolidines are often described in a key step for total syntheses of carbohydrates analogues (often to form 1,3amino alcohol moieties).181,284,175,285 Similarly, Sharma et al.286

Figure 15. Structure of different antiviral/antitumor isoxazolidinyl nucleoside analogues. 15263


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functional groups. Panfil et al.291 synthesized fused bicyclic isoxazolidine-sugars to obtain sugar enlactones, Figure 21.

Figure 17. Isoxazolidine nucleosides with carbamoyl and triazole linker (R = nucleobase, Ar = aryl group).

performed in 2001 the syntheses of tricyclic isoxazolidine furano-pyran sugar derivatives using 1,3-dipolar cycloaddition either of an oxime or of a nitrone on an olefin, Figure 18.

Figure 21. Skeleton of fused bicyclic isoxazolidine-sugar of Panfil et al.

Das et al.292 experimented on 1,3-dipolar cycloaddition to build furanose-fused oxepane 339, thiepane 340, azepane 341, and other derivatives. Similarly, Shing et al.293 used the same strategy for the synthesis of hept-6-enose rings, Figure 22.

Figure 18. Sugar analogues tricyclic isoxazolidine furano-pyrans.

Therefore, some studies describe compounds composed of a sugar and of an isoxazolidine moiety with no reported biological activity. One can mention spiro sugar-isoxazolidines synthesized by Yokoyama et al.287 Richard et al. used these patterns as building blocks for the synthesis of peptidomimetics, and they also prepared these compounds by 1,3-DC of exo-glycals on nitrones (Figure 19).288 On endothelial human

Figure 22. Furanose-fused oxepane, thiepane, and azepane.

6.3. PNA Analogs

Peptide nucleic acids (PNAs) are oligomers in which the monomer, a mix between a peptide and a nucleic acid, is constituted of a N-disubstituted glycine by a purine or pyrimidine nucleobase through an amide bond and by an aminoethyl moiety (Figure 23). PNAs can be considered either as nucleobases linked to oligo-peptidomimetics or as nucleic acid mimetics. In PNAs, the backbone is composed of repeating N-(2-aminoethyl) glycine units linked through amide bonds that correctly spatially orient the nucleobases in order to strongly and specifically bind to natural complementary DNAs or RNAs. To increase the water solubility of PNAs and to improve their biological activity, several conformationally constrained analogues have been designed. Indeed, PNAs containing double bonds or carbocyclic or heterocyclic rings were deeply studied.294 Unexpectedly, only one report focuses on the introduction of the isoxazolidine skeleton, which constrains the structure. Obtained through 1,3-DC, the PNA analogue 344 was designed by Merino et al.114 thanks to the Vörbruggen protocol (incorporation of the thymidine nucleobase).295 However, further investigations are still in progress.

Figure 19. Peptidomimetic spiro sugar-isoxazolidines.

cells, they weakly inhibited the VEGF-A 165 (Vascular Endothelial Growth Factor)/NRP-1 (Neuropilin 1, coreceptor for VEGF) binding and could be considered as lead compounds for future investigations. Oukani et al.289 developed spiro sugar-isoxazolidines to build long-chain sugars in order to mimic disaccharides. Starting from the structure of some complex antibiotic nucleosides (tunicamycins for example) as models, the 1,3-dipolar cycloaddition between two sugar moieties was used to increase the chain length and to obtain chiral undecose sugars from two hexose sugars (Figure 20). Similarly, Singh and Panda290 used these carbohydrate analogues as a chiral pool and as scaffolds to attach several

6.4. Peptidomimetics

6.4.1. Insertion into Peptides. Vasella and Voeffray296 first reported that isoxazolidines bearing an ester function in position 5, named 5-oxaproline (5-Opr), could be used as proline analogues. The same group of investigators also demonstrated that 5-Opr could be inserted into peptides, realizing efficient coupling reactions, either on the amino or on the carboxylic acid function.297 Indeed, they synthesized two dipeptides 347 and 350 containing 5-oxaproline by the mixed anhydride method in 90% and 87% yields, respectively (Scheme 98). The synthesis of the 5-oxaproline-containing captopril analogue 351 was also described, this compound being however 5 times less potent than the captopril analogue, the well-known angiotensin-converting enzyme (ACE) inhibitor 352 (Figure 24).

Figure 20. Example of undecose sugar synthesized by Oukani et al. 15264


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Figure 23. Structure of PNA and PNA analogues.

observed that 25% of the conjugate was intact in the bile after 40 min, whereas when the peptide was injected alone only 4% could be detected. Last, longer 5-Opr-containing peptides (7−9 residues) were described in a patent by Molling et al.302 as HIV protease inhibitors. In this patent, solid-phase peptide synthesis (SPPS) was applied using a Fmoc strategy. To prepare hepta- to nonapeptides bearing a 5-oxaproline residue, the heptapeptide H-Ser-Phe-Asn-Phe-(5-Opr)-Gln-Ile-OH was obtained in an overall yield of 18% and exhibited an IC50 ≈ 10−6 M as a HIV protease inhibitor. Shireman and Miller303 developed a procedure in which the dipeptide Cbz-Ala-(5-Opr)-OMe 359 was cyclized into the corresponding DKP 360. The cyclization is followed by a transpeptidation in the presence of MeOH/SOCl2 to afford the new dipeptide H-(5-Opr)-Ala-OMe 361 with complete control of stereochemistry. The novel dipeptide was then coupled with Cbz-Gly-OH by an acid preactivation as HOAt ester to give the tripeptide 362 in 68% yield (Scheme 100). The coupling of Cbz-Gly-OH was also efficiently accomplished with 5-oxaproline acid under PyBOP/Et3N activation. 6.4.2. Ligations. Insertion of 5-oxaproline at the N-terminal of a peptide has afforded a novel ligation approach. It was reported that decarboxylative condensation of α-keto carboxylic acids 363 and isoxazolidines 364 resulted into the amide 365 (Bode et al.304). This powerful coupling method, named “αketoacid-hydroxylamine (KAHA) ligation”, is performed in aqueous media under mild conditions. It requires no reagent or catalyst and produces the expected amide bond formation in excellent yields with water and CO2 as byproducts (Scheme 101). Furthermore, the ligation is totally chemoselective and compatible with the presence of unprotected functional groups. Examples including R2 = CH2CH2COOH (91% yield) or R2 = (CH2)4−NH3+TFA− (>90% yields by NMR) have been reported.305 Pattabiraman et al.306 performed unprecedented native ligations from a N-terminal isoxazolidine peptide and a Cterminal α-ketoacid fragment. Both peptide fragments 366 and 367 were prepared by Fmoc solid-phase peptide synthesis (SPPS) (insertion of 5-Opr pattern was performed in solution) followed by the KAHA ligation in solution. The T33T Pup protein 368 was recovered in 43−51% yield (Scheme 102). The mechanism of the ligation reaction has been investigated by HMBC NMR and indicated the formation of esters 370, which were easily rearranged into the expected amides 371 in basic buffers (Scheme 103).307

Scheme 98. Synthesis of 5-Oxaproline-Containing Dipeptides

Figure 24. Chemical structure of captopril and of the 5-oxaprolinecontaining captopril analogue.

From this piece of work, several 5-Opr-containing bioactive peptides were synthesized. Gunzler et al.298 inserted 5-Opr into the tripeptide Cbz-Phe-(5-Opr)-Gly-OBn, which was able to inhibit the prolyl-4-hydroxylase enzyme activity (IC50 0.8 μM). To determine the mechanism of the prolyl-4-hydroxylase inactivation, Wu et al.299 reported the synthesis of a highly fluorescent 5-oxaproline containing peptide 358. For each coupling step, they described a preactivation using dicyclohexylcarbodiimide (DCC) as coupling reagent in the presence of hydroxybenzotriazole (HOBt) and of N-methylmorpholine (NMM) in THF (Scheme 99). The same group of investigators showed that the more efficient peptide to inhibit the enzyme was in fact the tetrapeptide Ac-Pro-(5-Opr)-Phe-Gly-OBn (ID50 = 0.2 μM).300 On the other hand, Kramer et al.301 covalently linked the fluorescent inhibitor NBD-βAla-Phe-(5-Opr)-Gly-OH to the biliary acid taurocholic acid to deliver the bioactive peptide to the liver using a specific transporter system (Figure 25). Indeed, after injection of the conjugated peptide−biliary acid, they 15265


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Scheme 99. Synthesis of the Fluorescent 5-Oxaproline-Containing Peptide

Figure 25. NBD-βAla-Phe-5-Opr-Gly-taurocholic acid chemical structure.

Scheme 100. Synthesis of a Tripeptide-Containing Opr

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Frank et al. 315 also described D-ring fused steroid isoxazolidine 380 obtained by Lewis-acid-catalyzed 1,3-DC of 379 (Scheme 106). Its antiproliferative activity was evaluated on rat testicular C17,20-lyase by means of a radiosubstrate incubation technique. Compound 336 exhibited lower activity than the arylpyrazoline 337 and the reference ketoconazole (IC50 = 26, 5.8, and 0.75 μM, respectively). Tinant et al.316 described bridge ring derivatives 383 that came from a transannular reaction between the hydroxylamine hydrochloride and the trans-ketone 382 (Scheme 107). They especially studied the UV irradiation of 383, which led to an oxidative isoxazolidine ring opening forming several products including the nitro compounds 384.317,318 The same group of investigators developed the acid-catalyzed rearrangement of bridged N-Me-isoxazolidines 386 into the perhydro-3,1-oxazine derivative 387.319,320 This reaction involved the insertion of the N-methylene group in the N−O bond. On the other hand, treatment of the same steroid derivative 386 by hydroxylamine hydrochloride in boiling ethanol−pyridine led to formation of the aromatic compound 385 (Scheme 108).319 Colombi et al.321 realized, to the best of our knowledge, the synthesis of the only spiro-isoxazolidine steroid derivative by reaction between benzonitrile oxide and the terminal unsaturated steroid scaffold. The reaction afforded several stereoisomers having an isoxazolidine-oxadiazoline structure 388 (Figure 27). Thanks to circular dichroism and X-ray analysis, the structure of each isomer was ascertained. Since isosteviol derivatives with D-ring modification were shown to exhibit high cytotoxic activity, Zhu et al.322 proposed the synthesis of novel isosteviol derivatives 391 containing the carbothioamide-substituted isoxazolidine heterocyclic fragment. The isoxazolidine ring was obtained by intramolecular 1,3-DC of the oxime 389, and the thioamide bond was then formed by reaction between 390 and suitable substituted phenyl isothiocyanides (Scheme 109). However, all isoxazolidine derivatives 391 were less potent against four cancer cell lines than their pyrazole analogues and the reference compound Cisplatin.

Scheme 101. Amide Bond Formation

6.5. Steroid Analogues

Steroids are a valuable class of polycyclic natural products that exhibit an interesting potential for a wide range of pathologies such as prostatic diseases308 or cancers.309,310 The first isoxazolidinyl steroid described was the 16α,17α-fused isoxazolidine 372, reported in 1964 by Culbertson et al.311 (Figure 26). Using the 1,3-DC methodology (see section 3.1), a complex mixture of isomers was obtained from which only two of them were isolated in 6% and 15−28% yields. Until 1998 most of the isoxazolidines-containing steroids reported in the literature included the steroid D-ring fused with the isoxazolidine part. 312 For example, Monahan et al.313 synthesized steroid analogues 373 that exhibited interesting activity as anti-inflammatory agents, especially when X = F and R = Me. The authors observed a more important antiinflammatory topic activity compared to β-methasone 17valerate (Figure 26). Thanks to an intramolecular cyclization of steroid unsaturated aldehyde 375, Merniak et al.314 obtained 16α,17α-cisfused isoxazolidines. The one-step procedure involved the Nmethylhydroxylamine hydrochloride that led to the formation of compound 374, whereas the two-step reaction with the hydroxylamine hydrochloride followed by the Lewis-acidmediated 1,3-DC afforded both cis enantiomers 376 (Scheme 104). The same group also developed the 1,3-DC methodology in the α- and β-estrone series. By reaction between the nitrone 377 and N-phenylmaleimide (NPM), the isoxazolidine derivative 378 was obtained in high stereoselectivity (determined by X-ray diffraction analysis) and yield (78% in the α series, represented in Scheme 105 and 75% in the β series).

Scheme 102. Synthesis of the T33T Pup Protein by Chemical Ligation Involving a N-Terminal Isoxazolidine-Containing Fragment

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Scheme 103. Reaction Mechanism of the Ligation Reaction

Minter et al.330 They reported the synthesis and design of isoxazolidine 398 that exhibited transcription activation as potently as the peptide control ATF-4 (Figure 31). Key functional elements present in ATF-4 such as isobutyl, carboxylic acid, hydroxyl, and phenyl were incorporated on the isoxazolidine ring to afford an adequate equilibrium between hydrophobicity and polarity that is crucial for overall potency. The authors developed other transcriptional activator domains (TAD), such as compound 399 (EC50 = 33 ± 6 nM), which was more potent than the peptoid-based TADs (EC50 ≈ 10 μM).331−333 7.1.3. Using Other Strategies. The cytotoxicity of isoxazolidine compounds was evaluated toward cancer cell lines by several groups of investigators (Figure 32). Khazir et al.334 reported the spiro derivative of the sesquiterpenoid lactone (−)-α-santonin 400 that showed high potency against PC-3, MCF-7, and THP-1 cancer cell lines (IC50 10, 300, and 500 nM, respectively). The in vitro inhibitory potential of the isoxazolidines 401 revealed a percentage of growth inhibition of cancer cell lines similar to the reference compounds Paclitaxel and Mitomycin C. Similarly, the enediyne 402 exhibited a cytotoxic effect, the stronger being obtained with HT-29 colorectal adenocarcinoma cells. Last, Singh et al.335 described chromano-piperidine fused isoxazolidines that showed a higher cytotoxic activity against COLO-05 than 5-fluorouracil. However, the results obtained on PC-3 cell lines were clearly more relevant with the spiro isoxazolidines 400 (IC50 = 10 nM) than with 403 (IC50 = 64 μM).

Figure 26. Examples of 16α,17α-fused steroid isoxazolidine analogues.

7. MEDICINAL CHEMISTRY 7.1. Cytotoxic Activities

Since the natural alkaloids Pyrinodemin-A9 and the isoxazolidinium salts323 displayed interesting cytotoxicity, the isoxazolidine scaffold has naturally emerged as a potential candidate in the field of anticancer drug discovery. A promising approach has been found by elaboration of isoxazolidinyl DNA intercalators or transcriptional activators. 7.1.1. Using DNA Intercalators. In the area of developing novel cancer drugs and therapies, the design of DNA intercalators and alkylating agent is one of the most promising strategies.324 First proposed by Lerman,325 DNA intercalation consists in inserting a planar polycyclic molecule between two base pairs without affecting the hydrogen DNA helix bonds (Figure 28). Since 2006, Rescifina et al.326−329 has reported the generation of isoxazolidinyl polycyclic aromatic hydrocarbons (PAH), which exhibited moderate to good cytotoxicity toward various cell lines; molecular docking analyses revealed that the presence of 9-phenanthryl (compounds 393 and 394) or 1pyrenyl (compounds 392, 395, and 396) substituents induced the desired DNA-intercalator property, Figure 29. The same group of investigators also developed isoxazolidinyl PAH-calix[4]arene conjugates 397, which exhibited higher cytotoxicity toward three human tumor cell lines (IC50 95 nM) (Figure 30). In this case, molecular modeling studies along with circular dichroism analysis clearly confirmed intercalation of the compounds within the DNA double helix with a slight preference for the GC bases. 7.1.2. Using Transcriptional Activators. Transcriptional activators are another promising family of DNA binding molecules. Generally reported for large size compounds, the activator property with a small molecule was highlighted by

7.2. Antiviral Activities

Quite a few medicinal compounds used against viruses are nucleoside analogues. However, some isoxazolidines are known to inhibit the HIV-1 replication. As described by Loh et al.,336 isoxazolidine sulfonamides 404 and 405 blocked the transcriptional activation of HIV-1. The size of the halogen and the presence of aromatic rings seemed to be important for the antiretroviral activity when the two compounds were tested on the HIV-1 vector and on the wild-type NL4.3 HIV-1 (Figure 33). Lynch et al. 337 also evaluated the ability of some isoxazolidines against HIV infection. They designed and tested the bicyclic isoxazolidine 406 as a CCR5 receptor antagonist. This compound blocked the MIP-α (chemokine CCL3) binding to the receptor, thus inhibiting the immune response. The isoxazolidine framework was used in this study to constrain

Scheme 104. Intramolecular Cyclization of Steroid Unsaturated Aldehydes

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Scheme 105. Fused-Isoxazolidine Derivatives in α-Oestrone Series

Scheme 106. Synthesis of the Isoxazolidine-Containing Steroid

Scheme 107. Synthesis of Bridged Steroid Isoxazolidines

Scheme 108. Oxidative Hydrolysis and Acid-Catalysed Rearrangement of the Steroid Isoxazolidine 386

Figure 27. Steroidal 3-spiro-isoxazolidine-[2,3-d]-oxadiazoline. Figure 28. Example of DNA intercalators.

N-substituted pyrrolidines to enhance the receptor recognition (Figure 34).

Scheme 109. Synthesis of Isosteviol Derivatives Containing a Carbothioamide-Substituted Isoxazolidine Heterocyclic Fragment

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Figure 29. Isoxazolidine compounds as DNA intercalator. Cell lines: Molt-3, THP-1, U-937, and Vero.

fungicide has a systemic action with both protective and curative activity against brown rot disease.339,340 To evaluate the toxicity of SYP-Z048 toward nontarget organisms, Liu et al.341 studied its degradation in aqueous solution and in response to sun exposition. They isolated and identified 11 photo side products that allowed suggesting a mechanism for photodegradation. They proposed an isoxazolidine ring opening and dechlorination of the benzene part. Further studies are still in progress to determine the toxicity of these resulting side products. The group of Rangappa reported N-aryl-3−5-disubstituted rings, which exhibited antifungal or antimicrobial activity against three fungus and three microorganisms. The activity of these compounds was similar to or even better than the reference Nystatin (for fungi) and Streptomycin (for bacteria) (Figure 36).342−344 Zelechowski et al. also described disubstituted isoxazolidines 410 that exhibited high fungicidal activity. The best activity was obtained against Rhizoctonia solani and Botrytis cinerea with higher or similar potency than the reference Propiconazole on mycelial growth.345 Although they were less active against E. coli X580 than the reference penicillin, 3,5-disubstituted isoxazolidines 411 were reported by Nora et al.346 as novel potential antibiotics (Figure 37). Raunak et al.347 tested the antitubercular activity of the spiroisoxazolidines 412 and 413 against the Myco-bacterium tuberculosis H37Rv (ATCC 27294) (Figure 38). The best inhibition (15−29%) was obtained with the series 412, especially when R1 = H and R2 = Cl (29% of inhibition).

Figure 30. Isoxazolidinyl PAH-calix[4]arene conjugates as DNA intercalators. Cell lines: FTC133, 8305C, and U87MG.

7.3. Antifungal/Antimicrobial Activities

Fungal and microbial infections imply a considerable risk to human health and life. The development of novel drugs is still a challenge to enlarge the panel of resources of antifungal and antimicrobial available drugs.338 Discovered in 1997 by the China Shenyang Research Institute of Chemical Industry, SYP-Z048, a mixture of two diasteromers 3-[5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl] pyridine 407, is an important example of fungicide developed to control plant-pathogenic fungi (Figure 35). Compound SYP-Z048 showed high potency against a wide range of plant pathogens (EC50 in the 0.008−1.14 μg/mL range). The studies performed by Chen et al. revealed that the

Figure 31. Isoxazolidinyl TAD. 15270


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Figure 32. Example of cytotoxic isoxazolidines.

Figure 33. Isoxazolidine sulfonamides HIV-1 replication inhibitors.

Figure 36. N-Aryl-3−5-disubstituted isoxazolidines as antifungal and antimicrobial agents. aMIC (mM) of the reference Nystatin for fungi and Streptomycin for bacteria.

Figure 34. Bicyclic isoxazolidine CCR5 receptor antagonist.

formation. The accumulation of these products, unusually increased in patients suffering diabetes mellitus, is responsible for many diseases such as Alzheimer’s or cardiovascular diseases. The three isoxazolidine-containing compounds 415 (Figure 40) exhibited a 6-fold better activity than the reference aminoguanidine (IC50 = 40.5 μM). Interestingly, the stereochemistry of the substrate mainly influenced the potency. Indeed, enantiomers of 415 showed lower activities with IC50 = 63.90−126.67 μM.

Figure 35. SYP-Z048, an isoxazolidine fungicide.

Interestingly, the 413 isomer series showed lower inhibition, while they exhibited higher anti-invasive property against MCF7/6 mammary carcinoma cells (activity at 10 μM).

8. OTHER APPLICATIONS An unusual application of isoxazolidine moieties is to inhibit corrosion of steel, as demonstrated by Ali et al.350,351 in several publications. Compounds 416, 417, and 418 showed more than 80% of protection of steel against corrosion in acidic conditions at a 50 ppm concentration. According to their investigations, this activity was due to the presence of the neighbor N−O heteroatoms. Indeed, the mechanism of corrosion is essentially due to the presence of three lone electron pairs that can interact with the metal d orbitals. Furthermore, the lipophilic long alkyl chain of 416 and 384 forms a protective film on the steel surface, preventing contact with the aqueous environment (Figure 41).

7.4. Anti-Inflammatory Activities

Setoguchi et al.348 proposed the derivative 414 bearing an isoxazolidine part that exhibited VLA-4 antagonist activity (VLA-4 is an antigen-4, which plays an important role in the mechanism of cell inflammation). Although compound 414 was not chosen as a lead compound, it exhibited an excellent IC50 and was orally efficacious (Figure 39). 7.5. Advanced Glycation End Inhibitor Activities

Kaur et al.349 reported pyrrolo-isoxazolidine derivatives 415, which inhibited advanced glycation end (AGE) product 15271


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Figure 37. Example of disubstituted isoxazolidines with fungicidal or antibacterial activity. aPercent of inhibition of mycelial growth. bPercent of inhibition of mycelial growth of the reference Propiconazole. cGrowth inhibition zones in millimeters. dGrowth inhibition zones of the reference Penicillin G in millimeters.

Figure 38. Two spiro-isoxazolidines isomers with different biological activities. Figure 40. Isoxazolidine compounds with AGE inhibitor activity.

Figure 39. Isoxazolidine compound with anti-inflammatory activity.

In addition, other rare applications of isoxazolidines, such as insecticides and fungicides, are described in several patents. A U.S. patent352 reports on the activity of isoxazolidine derivatives on various pests, such as Arachnida and nematodes, and on a wide range of fungal plant diseases without any damage on the vegetation.

Figure 41. Example of potent corrosion protectors.

various desirable derivatives has been deeply investigated, allowing the accomplishment of successful total syntheses. On the other hand, the unique isoxazolidine skeleton makes this structure a scaffold of choice to mimic natural building blocks with remarkable bioactivities. The number of reports describing isoxazolidine-containing highly active compounds leads to the expectation that this scaffold will further emerge as a potential candidate in the field of drug discovery.

9. CONCLUSION Undoubtedly the importance of the isoxazolidine ring has significantly increased since optimization of the 1,3-DC and rationalization of the process. Several more original methods were proposed to access isoxazolidines that could not be obtained through 1,3-DC, enlarging the diversity of structures. The synthetic transformation of the isoxazolidine ring into 15272


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AUTHOR INFORMATION

design and production of original biomaterials, green chemistry, and pharmacology of neuropeptides of the gastrointestinal tract.

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

ACKNOWLEDGMENTS We thank the ANR (ANR-11-BS07-005), the LABEX ChemiSyst, and the INCa (INCA PLBIO INCA 5959) for financial support.

Notes

The authors declare no competing financial interest. Biographies

ABBREVIATIONS 1,3-DC: 1,3-dipolar cycloaddition 5-FU: 5-fluorouracil 5-Opr: 5-oxaproline Ac: acetyl ACE: angiotensin converting enzyme ACN: acetonitrile AcOH: acetic acid ADT: 4-aza-2,3-dideoxythymidine ADF: 5-fluorouracil isoxazolidinyl nucleoside derivative AGE: advanced glycation end products AgOTf: silver trifluoromethanesulfonate Ar: aryl group Arg: arginine Asn: asparagine Asp: aspartic acid AZT: azidothymidine Bn: benzyl BnBr: benzyl bromide Boc: tert-butyloxycarbonyl Boc2O: di-tert-butyldicarbonate Cbz: carboxybenzyl CCR5: C−C chemokine receptor cHx: cyclohexyl cod: 1,5-cyclooctadiene COMU: (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate CTAB: cetyltrimethylammonium bromide CSA: camphor sulfonic acid Dba: dibenzylideneacetone DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene DCC: dicyclohexylcarbodiimide DCE: dichloroethane DCM: dichloromethane DIBAH: diisobutylaluminum hydride DIEA: diisopropylethylamine DKP: diketopiperazine DMSO: dimethyl sulfoxide DNA: desoxyribonucleic acid Dpe phos: oxidi-2,1-phenylene-bis-diphenylphosphine E: electrophilic group EC50: half-maximal effective concentration Et: ethyl EtOH: ethanol Fmoc: 9-fluorenylmethyl-oxycarbonyl Gln: glutamine Glu: glutamic acid Gly: glycine HCTU: 2-(6-chlor-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate HIV: human immunodeficiency virus HOAt: 1-hydroxy-7-azabenzotriazole HOBt: hydroxybenzotriazole HR37Rv: Mycobacterium tuberculosis

Mathéo Berthet was born in Roussillon (France) in 1989. After receiving his Master’s degree in Organic and Medicinal Chemistry at the University of Montpellier (France), he started his Ph.D. studies under the supervision of Prof. Jean Martinez and Dr. Isabelle Parrot at the Institute of Biomolecules Max Mousseron (IBMM) in Montpellier. He is currently completing his Ph.D. degree, which is essentially focused on the synthesis and biological valorization of oxaproline and oxadiazine-3,6-diones moieties. Thomas Cheviet was born in Besançon (France) in 1993. He performed, during his Master’s degree at the University of Montpellier, an internship at the Institute of Biomolecules Max Mousseron (IBMM) under the supervision of Mathéo Berthet and Dr. Isabelle Parrot for 5 months. In 2016 he started Ph.D. studies under the supervision of Dr. Suzanne Peyrottes, in IBMM, focused on the synthesis and study of bioactive molecules on Plasmodium falciparum metabolism of purines. Gilles Dujardin was born in France in 1957. He studied chemistry at the University of Rouen (France), where he earned his Ph.D. degree in Chemistry in 1990 under the supervision of Prof. P. Duhamel and J.M. Poirier. After postdoctoral research with Prof. J.-P. Genet (ENSCP Paris), he was appointed a CNRS researcher at the Université du Maine (Le Mans, France) in 1991 and became Director of Research in 2002. His current research interests concern new methodologies in organic synthesis (cycloaddition reactions, quaternary amino acids, and diazoketone chemistry) and total synthesis of natural products and bioactive molecules. Isabelle Parrot was born in France in 1973. She achieved her Pharm.D. and Ph.D. degrees under the supervision of Prof. C-G. Wermuth (1998−2001) at the Faculty of Pharmacy in Strasbourg (France) for work on the pallado synthesis and chlolinergic activities of various pyridazines and the development of new fluorescent ligands. She joined in 2001 Prof. C. Khosla’s group at Stanford University as a postdoctoral fellow and was appointed Assistant Professor in Organic and Medicinal Chemistry at the University of Montpellier (France) in 2002. Her research interests in the Max Mousseron Institute include the synthesis of peptidomimics and the development of original heterocycles and biologically active ligands. Jean Martinez received his Ph.D. degree in Organic Chemistry from the University of Montpellier at the Ecole Nationale Supérieure de Chimie de Montpellier under the direction of Prof. F. Winternitz. He completed his chemical education as a postdoctoral fellow with Dr. E. Bricas, Orsay, University of Paris Sud, and then with Prof. M. Bodanszky, Case Western Reserve University, Cleveland, OH. Back in France he was recruited as a CNRS Research Associate and then as a Research Director at the University of Montpellier. Pursuing his investigation at the interface of chemistry and biology, he was appointed as Full Professor in both Organic Chemistry and Medicinal Chemistry at the University of Montpellier. He founded the Institute of Biomolecules Max Mousseron in 2007; he was the Director until December 2014. In 2015, he became the Head of the Department of Amino Acids, Peptides and Proteins. His current research interests focus on peptide chemistry, stereoselective syntheses of biomolecules, 15273


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tBu: tert-butyl TBS: tert-butyldimethyl silyl TEMPO: 2,2,6,6-(tetramethylpiperidin-1-yl)oxyl radical Tf: triflate TFA: trifluoroacetic acid THF: tetrahydrofuran Thy: thymine TLC: thin layer chromatography TMS-I: trimethylsilyl iodide TMS-OH: trimethylsilyl hydroxide TMSOTf: trimethylsilyl trifluoromethanesulfonate Tol: toluene TRINS: truncated reverse isoxazolidinyl nucleoside Ts: tosyl Tyr: tyrosine UDFT: unrestricted density functional theory VEGF-A: vascular endothelial growth factor A Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Yb(OTf)3: ytterbium(III) trifluoromethanesulfonate

HSV-1: herpes simplex virus type 1 HTLV-1: human T-cell leukemia virus type 1 IC50: half-maximal inhibitory concentration i-Bu: isobutyl IBX: o-iodoxybenzoic acid ID50: half-maximal dose infection Ile: isoleucine i-Pr: isopropyl i-PrOH: isopropanol IUPAC: International Union of Pure and Applied Chemistry KAHA: α-keto-acidhydroxylamine LDA: lithium diisopropylamide Ln: ligand L m-CPBA: m-chloroperbenzoic acid Me: methyl MeOH: methanol MIC: minimal inhibitory concentration MsCl: methanesulfonyl chloride MW: microwave MOM: methoxymethyl ether Morph: morpholine m,p-OBn-Ph: 3,5-dibenzyloxyphenyl MRTIC: minimal reverse transcription inhibition concentration NBA: N-bromoacetamide NBD: 7-nitro-1,2,3-benzoxadiazole NBS: N-bromo succinimide n-Bu: n-butyl n-BuLi: n-butyllithium NCS: N-chloro-succinimide n-hex: n-hexyl NIS: N-iodosuccinimide NMM: N-methylmorpholine NMO: N-methylmorpholine N-oxide NPM: N-phenylmaleimide NRP-1: neuropilin 1 PAH: polycyclic aromatic hydrocarbons p-CF3-phenyl: p-(trifluoromethyl)phenyl p-Cl-Ph: p-chlorophenyl PG: protecting group Ph: phenyl Phe: phenylanaline p-MeO-Ph: p-methoxyphenyl PNA: peptide nucleic acid Pro: proline PTC: phase-transfer catalysis p-TSA or p-TsOH: p-toluenesulfonic acid PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate R: undefined chemical group RCM: ring-closing metathesis RDFT: reference state density RM: organometallic reagent RNA: ribonucleic acid Rt: room temperature Ser: serine S-Phos: 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl SPPS: solid-phase peptide synthesis T33T Pup protein: prokaryotic ubiquitin-like protein TAD: transcriptional activator domain t-AmOH: tert-amyl alchohol TBAF: tetrabutylammonium fluoride TBME: methyl tert-butyl ether

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