Recent Advances in the Catalytic Asymmetric Reactions of Oxaziridines

Oxaziridines have emerged as powerful and elegant oxygen- and nitrogen-transfer agents for a broad array of nucleophiles, due to the remarkably high and tunable reactivities. However, the asymmetric catalysis involving oxaziridines is still in its infancy. Herein, this review aims to examine recent advances in the catalytic asymmetric transformations of oxaziridines, including oxidation, amination, cycloaddition and deracemization.


Introduction
Oxaziridines, discovered in the mid-fifties by Emmons, are electrophilic three-membered heterocycles containing oxygen, nitrogen and carbon atoms [1]. Due to their strained three-membered ring and the virtue of their relatively weak N-O bond, they exhibit unusually high and tunable reactivities and have received considerable attention from chemists. Since their discovery, oxaziridines have emerged as important and powerful oxygen-and nitrogen-transfer reagents for a broad array of nucleophiles, including organometallic compounds [2], enolates, silyl enol ethers, alkenes, arenes, thiols, thioethers and selenides, nitrogen nucleophiles and C-H bonds in organic synthesis [3][4][5][6][7][8][9][10]. The reactive site of the nucleophilic attack on the oxaziridine heterocyclic ring is attributed to the electronic nature and size of the substituent on the 2-nitrogen atom. The introduction of an electron-withdrawing group on the 2-nitrogen atom, such as N-phosphinoyl and N-sulfonyl oxaziridines commonly known as Davis reagents, would increase the leaving ability of the nitrogen atom and, thus, facilitate the oxygen atom transfer. Furthermore, the larger size of the oxaziridine N-substituent generally results in higher levels of oxidation versus amination [11]. On the contrary, oxaziridines could serve as the electrophilic nitrogen transfer reagents when the N-substituent is small, such as N-H, N-alkoxycabonyl and N-alkyl oxaziridines. Additionally, they could also undergo some attractive and intriguing [2,3]-sigmatropic rearrangements [12][13][14][15], ring expansion [16], ring-opening process [17], desulfurization [18], C-H ethoxycarbonylation [19] and cycloaddition reactions, involving the N-O, C-C or C-O bond cleavage.
Moreover, the optically active and synthetically accessible oxaziridines [20,21] have emerged as crucial chiral building blocks in natural products and versatile enantiopure organic substrates in several enantioselective transformations, such as oxidation and amination, as well as some intriguing cycloaddition reactions with a large number of alkenes or alkynes to generate a diverse range of five-membered ring heterocycles. High yields and enantioselectivities were successfully achieved Remarkably, oxaziridine 4 has served as an important family of organic active oxidizing agents due to its unique oxygen transfer capability. A series of nucleophiles that include sulfides [22], sulfoxides, alkenes [23], thiolates [24], phenols [25,26], naphthols, enolates, silyl enol ethers, selenides [27] and C-H bonds [28][29][30][31] could be oxidized via an asynchronous transition state in which N-O bond cleavage is faster than C-O bond cleavage ( Figure 2) [10]. Oxaziridinium salt 5, first discovered by Lusinchi and co-workers in 1976 [32,33], was generated by the oxidation of the corresponding iminium salt with peracid or monoperoxysulfate. It exhibits a special oxidizing power derived from the strongly electrophilic oxygen atom. Moreover, the positive charge on the nitrogen atom significantly enhances the oxygen-transfer ability. Hence, this section will reveal the synthetic utility of oxaziridine 4 and oxaziridium salt 5 in oxidation stereochemistry.

Olefin Epoxidation
Consistent with the electron-deficient oxaziridine 4, the positively charged oxaziridium salt 5 acts as the more powerful oxygen atom-transfer reagent rather than the nitrogen-transfer agent. Thus, the quaternized oxaziridinium salts could efficiently epoxidize alkenes at ambient temperature. They could be catalytically synthesized in situ from the corresponding iminium salts in the presence of a stoichiometric or excess oxidants. Page and co-workers employed iminium salt organocatalysts 11/12 in the asymmetric epoxidation of unfunctionalized alkenes 9 to generate optically active epoxides 10 (Scheme 1) [34]. Notably, the pseudoaxial substituent at a chiral center adjacent to the positively charged nitrogen atom in the binaphthyl-and biphenyl-derived salts significantly improved yields and enantioselectivities in many cases. Subsequently, they utilized the iminium salt 15-catalyzed asymmetric epoxidation as a tool in the kinetic resolution of racemic 2-substituted chromene substrates 13. Good enantioselectivities were achieved in all cases for the major epoxide diastereoisomers 14, and the corresponding minor diastereoisomers revealed generally higher enantioselectivity (Scheme 2) [35]. The diastereoselectivity and enantioselectivity were partially dependent on the size of the substituent at C2 of the chromene scaffold.

Sulfoxidation
Enantiopure sulfoxides have emerged as very important chiral synthons and auxiliaries in asymmetric synthesis. One of the most convenient and straightforward protocols to generate the chiral sulfoxides is the asymmetric oxidation of sulfides. To date, the most efficient and successful protocols for the asymmetric sulfoxidation include the modified Sharpless procedures and oxidation using the stoichiometric quantity of enantiomerically pure Davis reagents or oxaziridinium salts [4,[36][37][38]. However, asymmetric catalytic sulfoxidation, by comparison, has been less explored.
In 1995, Page and co-workers demonstrated the initial research work on the catalytic asymmetric sulfoxidation. The [(3,3-dimethoxycamphoryl)sulfonyl]imine 18, the precursor of the Davis reagent, was subjected to the terminal oxidant hydrogen peroxide to afford the chiral oxidant in situ, which promoted the asymmetric sulfoxidation of dialkyl sulfides 16 with excellent enantioselectivities (up to >98% ee) (Scheme 3) [39]. Five years later, the catalytic asymmetric oxidation of sulfides to sulfoxides was accomplished by the same group in the presence of the chiral nonracemic 3-substituted-1,2-benzisothiazole 1,1-dioxide 19 [40]. The stereochemical induction is determined largely by the absolute configuration of the carbon atom adjacent to the oxygen atom in the oxaziridine and α-hydroperoxyamine intermediates. In comparison with the Davis reagents, normal N-alkyloxaziridines are less reactive in the oxygen transfer process. Thus, the introduction of exogenous additives has also been investigated in the asymmetric oxidation of sulfides. Bohé et al. employed the exogenous methanesulfonic acid (MsOH) to promote the asymmetric oxidation of sulfides 20 with chiral N-alkyl oxaziridine 21, leading exclusively to the corresponding sulfoxides 22 (Scheme 4) [41]. Moreover, authors believed that the enhanced rate was attributed to the protonation of the basic nitrogen in the three-membered strained ring, affording the active oxaziridinium-like intermediates in situ. Therefore, a series of chiral oxaziridinium salts were developed to promote the asymmetric oxidation of sulfides to sulfoxides. In 2007, Bohé group synthesized a novel and effective oxaziridinium salt 23 for the highly enantioselective sulfoxidation in good yields and with up to >99% ee (Scheme 5) [42]. The synthetic utility of this protocol was demonstrated by the asymmetric synthesis of the biologically active proton pump inhibitor (R)-lansoprazole 25, a well-known sulfinyl-substituted benzimidazole, from the oxidation of sulfide 24 by oxaziridinium salt 23 (Scheme 6). The excellent enantioselectivity (97% ee) and good yield (60%) were obtained in this transformation.

Enolate Oxidation
The hydroxylation of an enolate is one of the most practical and efficient protocols for the introduction of a hydroxyl group adjacent to a carbonyl group [3]. Since the pioneering work by the Davis group in the 1980s [43][44][45], N-sulfonyloxaziridines have served as the preferred oxidizing reagents in this transformation, due to the high efficiency, commercial availability, lack of byproducts and ease of work-up. Nevertheless, the asymmetric oxidation reaction of enolates [46][47][48][49][50], aza-enolates [51] and phosphonate anions [52] generally require a stoichiometric amount of chiral oxaziridine or auxiliary.
Togni and co-workers reported an initial research concerning the catalytic enantioselective α-hydroxylation of various β-keto esters 26 catalyzed by a chiral titanium complex [TiCl 2 ((R,R)-1-Np-TADDOLato)(MeCN) 2 ] 29 (Scheme 7) [53]. A variety of α-hydroxylated products 28 were obtained in high yields and enantioselectivities (up to 94% ee) with racemic N-sulfonyloxaziridine 27 as the terminal oxidizing agent. However, the enantioselectivity relied on the size of the ester substituent. An ester substituent smaller than the tert-butyl group enabled the modest enantioinduction in this transformation. Moreover, the authors proposed a possible mechanism involving the formation of chiral titanium-bound enolate via the coordination of the Lewis acid complex 29 to the β-keto ester substrate 26, epoxidation of the enolate and subsequent ring-opening process to the final 2-hydroxylated 1,3-dicarbonyl compound 28. A few years later, an asymmetric Cu(I)-, Pd(II), Zn(II) or Fe(III)-catalyzed α-hydroxylation of β-keto esters has also been reported by Shi [54,55], Hii [56], Ding [57] and Che [58] group, respectively. Scheme 7. Titanium-catalyzed asymmetric hydroxylations.
In 2009, the first dynamic kinetic enantioselective α-hydroxylation of racemic malonates 30 and oxaziridine 31 was achieved by the Shibata group [59]. The (R,R)-DBFOX-Ph 33/Ni II complex was employed to promote this transformation to generate the chiral α-hydroxy malonate 32 with a quaternary stereocenter in high yield and enantioselectivity (up to 98% ee) (Scheme 8). Furthermore, the less active pronucleophile N-nonsubstituted α-alkoxycarbonyl amide 34 with the higher pKa of α-hydrogen than the related 1,3-dicarbonyl compound was oxidized via a catalytic asymmetric hydroxylation (Scheme 9) [60]. Shibasaki et al. established the prasedymium isopropoxide [Pr(OiPr) 3 ] and a fluoro-substituted amide-based-ligand (S)-37 as the optimal and effective catalytic system and N-sulfonyl oxaziridine 35 as the oxidizing reagent. The authors believed the praseodymium salt formed a complex with N-nonsubstituted α-alkoxycarbonyl amide 34, whereas, the amide-based ligand (S)-37 and oxaziridine 35 assembled together through the coordination and hydrogen bonding resulting in the associated transition state. Thus, the trans amide N-H proton is particularly crucial to the assembled transition state. Scheme 9. Catalytic asymmetric hydroxylation of N-nonsubstituted α-alkoxycarbonyl amide.
The Shibata group reported the pioneering work on the zinc (II)-catalyzed asymmetric catalytic hydroxylation reaction of both 3-alkyl and 3-aryl-2-oxindoles 38 (Scheme 10) [61]. This protocol utilized the chiral DBFOX-Zn(II) complex as the catalyst and racemic saccharin-derived oxaziridine 31 as the terminal oxidant, leading to the enantioselective synthesis of the pharmaceutically important chiral 3-hydroxy-2-oxindoles 39 with up to 97% ee. Moreover, this methodology has been successfully applied to the enantioselective hydroxylation of β-keto esters. Subsequently, Naganawa and co-workers discovered an unprecedented Cu(II)-catalyzed enantioselective oxygen transfer reaction of 3-aryl-2-oxindoles with racemic Davis oxaziridine using the original phenanthroline as N,N,O-tridentate ligand [62]. More recently, a chiral iminophosphorane organocatalyzed enantioselective hydroxylation of 3-substituted oxindoles was developed with racemic oxaziridine, leading to the construction of optically active 3-substituted-3-hydroxy-2-oxindoles in excellent yields and moderate to excellent enantioselectivities [63]. Recently, a highly chemo-and enantioselective hydroxylative dearomatization of 2-naphthols 40 with racemic oxaziridines 41 was accomplished by the Feng group using a N,N -dioxide-scandium(III) complex catalyst (Scheme 11) [64]. This approach afforded a number of substituted ortho-quinols 42 in high yields and enantioselectivities. Notably, the choice of the scandium salt's counterion efficiently suppressed the α-ketol rearrangement. The desired R-configured product 42 was generated by the Si-face attack of the oxaziridine on the α-position of 2-naphthol. Scheme 11. Catalytic asymmetric hydroxylative dearomatization of 2-naphthols.
In addition to the above-mentioned Lewis acid-mediated catalytic asymmetric α-hydroxylation, there have been some highly enantioselective organocatalytic protocols to α-hydroxy carbonyl compounds with oxaziridines as oxidants. Zou et al. disclosed the construction of a novel library of guanidines 46 derived from ethyl L-tartrate as the chiral source and their application to catalytic asymmetric α-hydroxylation of β-keto ester and β-dicarbonyl substrates 44 with remarkable efficiency and excellent enantioselectivity (Scheme 12) [65].
In 2015, the Jacobsen group described a novel and simple aminobenzamide catalyst 54 for the asymmetric α-hydroxylation of α,α-disubstituted aldehydes 51 with oxaziridine 52 developed by the Yoon group (Scheme 14) [67]. The α-hydroxy aldehydes bearing tetrasubstituted, stereogenic centers 53 were generated in excellent yields with high enantioselectivities. The stereoselectivities of these transformations mainly depended on the E/Z ratio of the key enamine intermediates.

Rubottom Oxidation
More recently, the Ooi group synthesized a novel class of chiral N-sulfonyl oxaziridines as uniquely reactive chiral organic oxidants [68]. Notably, they developed an asymmetric catalytic Rubottom oxidation of silyl enol ether 55 catalyzed by the requisite chiral N-sulfonyl oxaziridine, in situ generated by the oxidation of a catalytic amount of the parent α-imino ester 58, with L-isoleucine-derived triaminoiminophosphorane 57 as an organocatalyst and H 2 O 2 as a stoichiometric terminal oxidant (Scheme 15).

Asymmetric Amination of Oxaziridines
Electrophilic amination is an important Nu-N bond formation reaction in which an electron-poor nitrogen is transferred to an electron-rich carbon [69][70][71][72], nitrogen [73][74][75], sulfur [76] or phosphorus nucleophile. Collet and co-workers completed a pioneering work in which aldehyde-derived N-Boc-oxaziridines could promote the electrophilic amination of various nucleophiles [11,77]. Notably, the N-substituent on the nitrogen plays a significant role in the oxaziridine reactivities. In fact, N-H, N-alkoxycabonyl and N-alkyl oxaziridines are usually utilized as electrophilic aminating agents, presumably due to the small substituent on the nitrogen atom.
However, the amination process is always hampered by the competitive oxidation and aldol reaction. Furthermore, oxaziridines could also be converted to amides via the transition metal-catalyzed radical rearrangement [78]. Thus, the combination of this rearrangement with the previous oxaziridine synthesis is a synthetically valuable process to generate amides from carbonyl compounds.
Additionally, asymmetric versions of electrophilic amination of oxaziridines generally require stoichiometric amounts of chiral reagents or the presence of enantiomeric induction of the substrates. In 1998, Enders et al. disclosed the nitrogen atom transfer reactivity of N-Boc oxaziridines in the asymmetric electrophilic amination [79]. The stereochemistry of chiral α'-silyl ketones substrates was transferred to the final desired α-amino ketones.
Recently, the Banerjee group demonstrated the unique N-substituent directed dual reactivity of oxaziridine 59 toward donor-acceptor cyclopropane 60 (DAC) (Scheme 16) [80]. The ring expansion of DAC was accomplished via the N-substituent controlled selective N-transfer of oxaziridines, directly leading to the azetidine derivatives 61 in moderate to good yields. Interestingly, the N-alkyl substituted oxaziridines with α-hydrogen like N-methyl, N-isopropyl led to the pyrrolidine derivatives through a [3+2] cycloaddition reaction between DACs and in situ generated imine.
Additionally, Yoon and co-workers reported the initial works toward the asymmetric aminohydroxylation catalyzed by a chiral copper(II) bis(oxazoline) complex (Scheme 17) [85]. Good yields and modest to good enantioselectivities were achieved in the aminohydroxylation of a variety of styrenes 62 with racemic N-sulfonyl oxaziridine 35 (Davis oxaziridine) in the presence of commercially available copper(II) hexafluoroacetylacetonate [Cu(F 6 acac) 2 )] and chiral ligand (R,R)-Ph-Box 64. Besides, the enantiopurities of the resulting amino alcohols upon acid-catalyzed hydrolysis of 63 could be improved to very high levels (>99% ee) through recrystallization. This protocol is a crucial complement to the enantioselective Sharpless aminohydroxylation reaction [86] and the regioselectivity is much higher. They quickly discovered, however, that anionic halocuprate(II) complexes CuCl 2 /Bu 4 N + Cl − could serve as remarkably more active catalysts for aminohydroxylation of less reactive oxaziridines (3,3-dimethyl oxaziridines) than neutral copper(II) salts [87]. In addition, these halocuprate catalyst systems have been applied to the aminohydroxylation of N-acyl indole derivatives 65 with racemic N-sulfonyl oxaziridines 35. When a chiral N-acyl group was applied, the resulting aminal products 66 could be converted in a single step into the enantiomerically enriched 3-aminopyrroloindoline 67, a common structural core present in numerous biologically active indole alkaloids (Scheme 18) [88].

Scheme 18. Synthesis of enantioenriched 3-aminopyrroloindolines 67.
As a complement of the analogous copper(II)-catalyzed reaction, the Yoon group reported a highly enantioselective and regioselective aminohydroxylation catalyzed by a combination of a highly electron-deficient iron(II) triflimide and bis(oxazoline) ligand 71 (Scheme 19) [89]. The reaction of alkenes 68 and N-sulfonyl oxaziridine 69 afforded a variety of oxazolidine products 70, which could be easily manipulated to construct highly enantioenriched free amino alcohols under the standard acid-catalyzed hydrolysis conditions. Thus, these oxaziridine-mediated asymmetric aminohydroxylations of olefins 68 could yield both regioisomers of optically active 1,2-aminoalcohols. Moreover, the regiochemistry was mainly dependent on the choice of transition metal catalyst. Recently, an asymmetric chiral N-heterocyclic carbene catalyzed formal [3+2] cycloaddition of α-aroylxoxyaldehydes and enantiopure oxaziridines was developed by the Smith group for the generation of oxazolidin-4-one products [91]. Excellent diastereo-and enantioselectivities were achieved. Acyl azolium enolate, in situ generated from the α-aroylxoxyaldehyde and NHC catalyst, attacked the electrophilic oxygen of chiral oxaziridine resulting in α-oxidation and N-O bond cleavage of the oxaziridine.
Besides, the commercially available isothiourea catalyst (2S,3R)-HyperBTM 85 was utilized to promote the formal [3+2] cycloaddition of homoanhydrides 82 and oxaziridines 83 by the Smith group (Scheme 22) [92]. This process allowed the assembly of stereodefined oxazolidin-4-ones 84, which could be subjected to the deprotection and reduction for the generation of enantioenriched α-hydroxy carboxylic acid. In addition to the above-mentioned alkenes and ketenes, azlactones 86 also served as the nucleophiles in the aminohydroxylations of oxaziridines 87 in the presence of a chiral bis-guanidinium salt 90 (Scheme 23) [93]. This protocol allowed the construction of a variety of optically active oxazolidin-4-ones 88 with up to 92% ee and the recovery of a series of enantioenriched oxaziridines 89 with good S factors.  [94,95]. Moreover, arynes have also been subjected to the oxaziridine to afford a set of dihydrobenzisoxazoles via the [3+2] cycloaddition [96]. Recently, the Woo group reported a visible-light photoredox-catalyzed [3+2] cycloaddition of oxaziridines via the C-O bond cleavage [97]. This methodology was a greener, atom-economical reaction of a set of oxaziridines and alkynes and afforded various 4-isoxazolines in good to excellent yield. It was noteworthy that the photoredox-catalyzed in situ generation of nitrone from the oxaziridine by single-electron transfer (SET) was involved in the reaction mechanism.

Deracemization
In addition to kinetic resolution and synthesis of a chiral compound from an achiral precursor, deracemization is also an attractive and important asymmetric catalytic strategy of preparing chiral compounds. Recently, the Míšek group demonstrated the first one-pot biocatalytic deracemization of chiral sulfoxide 91 (Scheme 24) [98]. The combination of the highly enantioselective enzyme methionine sulfoxide reductase A (MsrA) and an oxaziridine-type oxidant 92 rendered high ee values of various aryl-alkyl and alkyl-alkyl sulfoxides. In this transformation, the lipophilic oxaziridine was utilized to oxidize the sulfide back into the racemic sulfoxide. Scheme 24. Deracemization of chiral sulfoxides.

Conclusions
On the basis of the unusually high and tunable reactivity, the wide applications of oxaziridines have been investigated in a set of catalytic asymmetric transformations, including classic oxidation, amination and aminohydroxylation, as well as some intriguing deracemization. These protocols could efficiently and expeditiously furnish versatile and intriguing enantiopure auxiliaries and scaffolds with diverse pharmacological activities, such as optically active epoxides, sulfoxides, α-hydroxyl carbonyl compounds, α-amino carbonyl compounds, 1,3-oxazolidines and oxazolidin-4-ones. However, the catalytic asymmetric amination is still less reported. In the future, the potential synthetic utility of oxaziridines in some novel and fascinating transformations need to be further explored to achieve some important enantiopure building blocks.

Conflicts of Interest:
The authors declare no conflict of interest.