Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds

Chiral sulfinyl compounds, sulfoxides, sulfoximines, sulfinamides, and other derivatives, play an important role in asymmetric synthesis as versatile auxiliaries, ligands, and catalysts. They are also recognized as pharmacophores found in already marketed and well-sold drugs (e.g., esomeprazole) and used in drug design. This review is devoted to the modern methods of preparation of sulfinyl derivatives in enantiopure or enantiomerically enriched form. Selected new approaches leading to racemic products for which the asymmetric variant can be developed in the future are mentioned as well.


INTRODUCTION
In this review, we would like to focus on the recent achievements in the synthesis of chiral sulfinyl compounds. Their common feature, a stereogenic sulfur atom is connected to electronegative oxygen atom by a polar, partially dative bond, although in all structures in this review it is consistently shown as SO moiety ( Figure 1). We limit our discussion to organosulfur derivatives, i.e., compounds with at least one S−C bond. Consequently, sulfilimines (lacking SO fragment), and sulfites or sulfates (no C−S bond present) will not be covered. Also sulfenyl compounds and sulfonyl derivatives will be only marginally mentioned as achiral starting materials or side products in the preparation of their sulfinyl counterparts. We dare to undertake this topic encouraged by the good reception of our review published in the year 2010 on the enantioselective preparation of chiral sulfoxides. 1 Since then, hundreds of articles have appeared devoted to this group of compounds. Although chiral, enantiopure, or enantioenriched sulfoxides have been mainly prepared using previously developed methods, also new approaches to them have been described. This situation calls for a review which would include novel protocols and new interesting examples. The present paper is, however, not a simple update of our previous article as we have decided to extend our interest to other important groups of chiral sulfinyl compounds, which are also prepared in a stereoselective manner, e.g., sulfinamides, sulfinimines, sulfinates and thiosulfinates, sulfoximines, sulfonimidamides, and sulfonimidates.
These derivatives deserve attention due to their importance in modern synthetic, medicinal, and agricultural chemistry. The sulfinyl group is considered as a valuable chiral auxiliary, used in the stereoselective preparation of variety of useful chiral compounds. It is relatively easy to introduce and remove, configurationally stable, and capable of high asymmetric induction. As an example, tert-butane sulfinamide introduced by Ellman and co-workers finds numerous applications in the synthesis of enantiomerically pure amines and their derivatives, in many cases exhibiting significant biological activity. 2 Recent reviews show the utility of various sulfur derivatives in organic synthesis. 3,4 Nonracemic sulfinyl compounds are also used in catalytic stereoselective reactions, both as ligands for transition metals and as chiral organocatalysts. Three important reviews published in the last five years deal with this emerging application of chiral sulfoxides and their analogues in asymmetric catalysis. 5−7 Chiral organosulfur derivatives are found in natural systems such as methionine sulfoxide, S-adenosyl methionine, allicin, or leinamycin 1 ( Figure 2). 8 Synthetic sulfinyl compounds often exhibit a significant biological activity. As a consequence, pharmaceutical and agrochemical industry manifest an increasing interest in these chemicals, part of which have been marketed as drugs, like esomeprazole 2 and its various derivatives used as antiulcer drugs or modafinil 3 ( Figure 2). Recently, the better synthetic availability of sulfoximines (as exemplified by roniciclib 4), sulfonimidamides, and sulfonimidates has led to the increased interest in their possible application in drug design. 9 These analogues of sulfones and sulfonamides, well recognized pharmacophores, offer additional possibilities of structural modifications which may affect their interactions within natural systems. In this context, the development of efficient methods of stereoselective preparation of sulfinyl compounds is of special importance.
Articles describing methods of preparation of sulfoxides, but also of other sulfinyl compounds, are collected in several books. Among the most recent, the first one, entitled "Chiral Sulf ur Reagents: Applications in Asymmetric and Stereoselective Synthesis", written by Marian Mikołajczyk, Joźef Drabowicz, and Piotr Kiełbasinśki, was printed in 1997 and contains chapters devoted to various types of sulfoxides, 10 sulfinic acid derivatives, 11 and sulfoximines. 12 Eleven years later, a book edited by Takeshi Toru and Carsten Bolm was issued. From the point of view of the present review, chapters on synthesis and application of chiral sulfinates, 13 sulfinamides, 14 and sulfoximines 15 are particularly important.
Important review articles and highlights underscoring the significance of particular groups of sulfinyl compounds will be introduced in respective sections. As we do not intend to repeat the material covered by them, only the most representative examples and the latest papers published up to the year 2019 will be discussed.

CHIRAL ORGANIC COMPOUNDS WITH A
TETRAHEDRAL SULFUR STEREOCENTER The study of stereochemistry of organic sulfur compounds has a long and rich history. 16 We shall limit our discussion to tetrahedral sulfur, which can become a stereogenic center when three (a lone pair of electrons takes the part of fourth substituent) or four different groups are attached to it. If we take into account only the chirality arising from the presence of the sulfinyl group, among trisubstituted derivatives sulfoxides are chiral if two carbon groups are different. A whole family of chiral compounds can be regarded as derivatives of sulfinic acids, which themselves are achiral due to proton exchange (however, chirality can result from isotopic substitution 17 ): sulfinic halides, sulfinamides and sulfinimines (N-sulfinylimines), sulfinates, and thiosulfinates (also thiosulfinic acids and their salts are chiral, although they are prone to slow decomposition and rarely prepared 17,18 ). Among their counterparts in which the place of lone electron pair is taken by a NR′ fragment, sulfoximines require two different carbon groups for chirality, while derivatives of sulfonimidic acids are chiral by definition ( Figure 3). Salts with three organic groups attached to sulfur should be also mentioned.
Certainly, these derivatives differ in terms of chemical and configurational stability. Sulfinyl chlorides have been mainly prepared as reactive intermediates without bothering about enantiomeric purity, and their storage is problematic (a contact with moisture evolves gaseous HCl). 19−21 Sulfinic acids are prone to disproportionation, yielding diaryl thiosulfinates and sulfonic acids. 22 Stability of sulfinyl derivatives was extensively studied by Kice and co-workers. A mechanism of racemization  of thiosulfinates caused by nucleophiles or catalyzed by acids was analyzed as well as kinetics of alkaline hydrolysis of aryl thiosulfinates and thiosulfonates. 23−25 It was shown that the presence of a bulky substituent at sulfur increases the stability of thiosulfinates, and most work was done for tert-butyl derivative (see section 5). Various factors affecting racemization were summarized in a chapter written by Mikołajczyk and Drabowicz. 26 Several types of methods to prepare chiral sulfinyl compounds can be distinguished, taking into account which bond is formed in the course of reaction. Stereoselective oxidation of prochiral sulfur atom in sulfenyl compounds has been recognized as an efficient method of synthesis of nonracemic sulfoxides but is also of importance for other classes of organosulfur derivatives. Alternatively, one sulfinyl derivative can be converted into another, with concomitant formation of either sulfur−carbon or sulfur−heteroatom (N, O, S) bond.
In general, we can also consider possible transformations involving disubstituted (sulfides, disulfides, thiols, sulfenyl halides, sulfenic acid derivatives: sulfenates, sulfenamides), trisubstituted, and tetrasubstituted organosulfur compounds (Scheme 1). In conversions involving the first group to the members of the second and third one, chiral reactant or catalyst is necessary to yield optically active product (stereoselective formation of two new bonds constitutes a considerable challenge). Chirality transfer from another stereogenic center already present in the molecule is also possible in diastereoselective reactions.
Other transformations engaging chiral tri-or tetrasubstituted derivatives can be stereospecific, proceeding with either retention or inversion of configuration of sulfur atom. As proven by early experiments, substitution reactions, which typically make use of nucleophilic reagents, are in most cases associated with inversion, while conversions connected with change of coordination number keep the arrangement of substituents (the fourth one takes place of the lone pair or vice versa, see also section 9.1). 27−29 Kinetic resolution can be engaged in certain cases to increase the optical purity of desired products or to resolve racemic mixtures. Certain interconversions, like sulfonamide into sulfinylimine and vice versa, do not proceed at a stereogenic sulfur atom (this is also true for modifications within substituents, although certain reaction conditions may favor racemization). One should not forget about desymmetrization of achiral (e.g., meso) compounds, also resulting from modification of substituents.
Not all possible conversions can be treated as useful preparative methods. Yield and stereoselectivity are the main criteria, but economic and environmental aspects should be also taken into account. Procedures should be possibly general, operationally simple, and with the number of steps minimized. Last but not least, they should start from cheap and easily available materials. Therefore, deamidation of sulfoximines, which proceeds with retention of configuration, is not regarded as a practical synthetic route to enantiomerically pure sulfoxides. 30 Similarly, reduction of sulfones has never emerged as a convenient route to sulfoxides. 31,32 The subsequent sections will be devoted to the synthesis of particular groups of sulfinyl compounds, mainly in enantiomerically pure or enriched form. However, certain procedures leading to racemic mixtures will be also presented as at least part of them can be adapted to give single stereoisomeric products.

PREPARATION OF CHIRAL, NONRACEMIC SULFOXIDES
Our review on stereoselective preparation of chiral sulfoxides covered mainly literature from the years 2000−2008 (although referred also to classical papers). 1 In recent years, several other review articles devoted to this group of organosulfur compounds have been published, differing in their scope, size, and general message as well as topicality. Three important papers concerning application of chiral sulfoxides in asymmetric catalysis have already been mentioned in the Introduction. 5−7 A general review by Maguire and co-workers on the synthesis of enantioenriched sulfoxides, with a special attention paid to kinetic resolution, was published in 2011. 33 Several articles were devoted to asymmetric oxidations, including sulfoxidations, with a focus on environmentally benign methods. 34−36 A first part of a paper in which Franklin Davis described his "adventures in sulfur−nitrogen chemistry" (using his own words) described the preparation and use of chiral oxaziridine derivatives (known as Davis reagents) in enantioselective oxidation of sulfenyl compounds: sulfides, disulfides, and sulfenylimines. 37 In 2018, a review by Han et al. was published, presenting the developments in the preparation of optically active sulfoxides in the years 2011−2016. 38 An important issue of correct determination of stereochemical outcome of synthetic reactions has been discussed in detail. The problem is connected with self-disproportionation of enantiomers (SDE), the effect of change of enantiomeric composition during the purification process. We do not intend to present once more the details of all methods used for preparation of chiral, enantiomerically pure, or enantiomerically enriched sulfoxides. Their description can be found in previous reviews. In this section, we shall focus on the main tendencies that could be observed in field in the past decade.

Scheme 1. Possible Interconversions of Sulfinyl Derivatives
Chemical Reviews pubs.acs.org/CR Review catalytic oxidation systems are preferred, although Davis' oxaziridines are also used. 39 Attempts with new chiral stoichiometric oxidants (N-chloramine derivatives) were not very encouraging (up to 23% ee). 40 Consequently, transition metal catalysts (in particular, titanium-and vanadium-based) are commonly used. The long puzzling origin of the Kagan/Modena oxidation system based on Ti(IV) complexes of diethyl tartrate and tertbutyl hydroperoxide (TBHP) or cumene hydroperoxide (CHP) was studied by Corey's group. 41 DFT calculations were applied to compare geometries and energies of possible isomeric helical complexes formed in the course of reaction: the more stable P diastereomer was shown to preferentially yield one of the enantiomers of sulfoxide. This analysis led to design and synthesis of a chiral tetraol containing two tartrate moieties 5, which was found superior in the enantioselective oxidation of alkyl aryl sulfides in comparison with the original Kagan's system (Scheme 2).
In a series of publications, Cardelliccio and co-workers thoroughly studied oxidation of sulfides by titanium/(S,S)-or (R,R)-hydrobenzoin (HB, 6) catalytic system. 42−47 Through a combination of experimental and theoretical work, they found that benzyl aryl sulfides were particularly efficiently oxidized by TBHP (yields up to 92%, ee 84 to >98%), which was rationalized by different interactions in diastereomeric octahedral adducts formed by [Ti(HB) 2 ] 4+ with substrate and TBHP. 42−44 However, they found that for aryl benzyl or aryl phenacyl sulfides containing fluorinated substituents, tertbutyl hydroperoxide was relatively inefficient but could be replaced with CHP, which resulted in satisfactory yields and much improved enantioselectivity (Scheme 3). 45−48 Again, this observation was explained by the calculated degeneracy of the octahedral diastereomers formed when TBHP was applied, while in the case of CHP, additional interactions stabilized mainly one of complexes leading preferentially to one enantiomer.
Talsi and Bryliakov explored titanium complexes with salan derivatives; oxidation of pyridylmethylthiobenzimidazoles led to enantiopure proton pump inhibitors. 49−52 Also, other groups prepared various enantiomerically enriched sulfoxides using chiral tetradendate and tridendate Ti(IV) complexes as catalysts. 53−56 An interesting dinuclear system based on 8quinolinol-derived ligand 7, which was found efficient in epoxidation of a variety of homoallylic alcohols, was checked in sulfoxidation by Bhadra et al. (Scheme 4). 57 γ-Hydroxypropyl sulfides were converted to the corresponding sulfoxides (difficult to prepare by other routes) in high yield and with ee values up to 95%; the presence and placement of hydroxyl group was found crucial for the observed stereochemical outcome.
Modified Schiff bases were introduced by several research groups as chiral tridendate ligands for vanadium(IV), typically applied as VO(acac) 2 in a two-phase system with hydrogen peroxide as oxidant. 58−64 Manganese was used in combination of salen 65,66 or another tetradendate, N4 ligand 8; the latter, with carboxylic acid 9 as additive and H 2 O 2 as oxidant, allowed highly enantioselective, gram-scale preparation of various sulfoxides also in the flow system (Scheme 5). 67−69 Chiral salen-type Fe(III) complexes were also used in successful sulfoxidations with peroxides. 70,71 Nishiguchi et al. applied iron(III) complex with a Schiff base 11 in preparation of proton pump inhibitors and received esomeprazole 2 in 87% yield (12% of sulfone was formed) and >99% ee (Scheme 6). 72 Optimized reaction conditions included slow addition of aqueous hydrogen peroxide and the use of lithium 4dimethylaminobenzoate additive 12 and ethyl acetate as a solvent. Both ligand and carboxylate could be prepared in situ, and the reaction was conducted on a kilogram scale (up to 4.66 kg of sulfide 10). Other derivatives (lansoprazole, pantoprazole, rabeprazole) were obtained in 75−87% yield and 83− 98% ee.
A new concept of asymmetric counteranion-directed catalysis (ACDC) 73 was tested by Liao and List; the catalyst 13 consisted of an achiral iron(III) cationic complex and an enantiopure phosphate counteranion. 74 High yields and enantioselectivities were noted, setting the new record for salen-Fe systems (Scheme 7).
The best effects of asymmetric induction (up to 97% ee) were also achieved in the category of copper-Schiff base catalysts described by Maguire and co-workers. 75 The first use of nucleic acid-bound copper(II) complex with bipyridine in sulfoxidation of thioanisole by aqueous hydrogen peroxide was reported by Cheng et al. 76,77 A transfer of chirality for Gquadruplex DNA to the product was observed with the enantiomeric excess up to 56% (99% conversion). CD and fluorescence quenching measurements showed that the limited stereoselectivity may result from relatively weak, nonspecific interactions of both thioanisole and Cu complexes with the quadruplex.
Molybdenum(VI) complexes of chiral Schiff bases 78,79 or imidazolium-based zwitterionic dicarboxylic acid derived from L-valine 80,81 were also used in asymmetric oxidation of sulfides, albeit with moderate or low enantioselectivity, which could be improved by kinetic resolution. 80 Chirality of coordination compounds can result not only from the presence of appropriate ligands but also from a stereogenic center located on the central ion. In possible catalytic conversions, this core is usually directly engaged in the catalytic action, and it is not surprising that chiral-at-metal complexes have already found application in various asymmetric transformations. 82,83 Ye and co-workers explored the strategy based on the use of such octahedral ruthenium(II) or iridium(III) complexes with 2,2′-bipyridyl or 2-phenylpyridyl ligands, capable of catalyzing enantioselective oxidation of sulfides by m-CPBA but also of preferential coordination of one enantiomer of sulfoxide (dynamic thermodynamic resolution). 84−87 Enantiomeric excess of up to 99% was reached for various derivatives, including modafinil acid and its analogues. Photooxidation of hydroxysulfides catalyzed by iridium complex of 2-phenylquinoline connected with coordination-based resolution of enantiomers was reported by Li and Ye in 2019 (Scheme 8). 88 Construction of supramolecular assemblies and metal− organic frameworks capable of selective oxidation of sulfides to sulfoxides was reported by several groups. 89−93 Certain systems containing chiral subunits led to high enantioselectivities. 91 In our previous review on stereoselective synthesis of sulfoxides, we expressed our expectation that organocatalytic sulfoxidation would attract growing attention. 1 88 actual development has been not so impressive. 94−96 However, promising results were obtained with flavin-derived catalysts 97,98 and BINOL-based phosphoric acid derivatives. 99−101 The latter allowed an enantioselective preparation of (R)sulindac 20 (95% yield, 98% ee, Scheme 9). However, (R)modafinil was identified as a more difficult goal, and organocatalyzed oxidation of its parent sulfide with hydrogen peroxide solution was performed with up to 26% ee. 102 3.1.2. S−C Bond Formation. Preparation of sulfoxides in Friedel−Crafts-type reactions dates back to the 1974 paper of Olah and Nishimura. 103 Among recent applications, sulfinylation of indoles through electrophilic substitution with arylsulfinic acids described by Miao et al. is worth mentioning, as it was performed in water at room temperature without any additives. 104 Another green Friedel−Crafts sulfinylation of aromatic compounds with sulfinic esters was carried out in ionic liquid and accelerated by ultrasound irradiation. 105 Sulfinamides were applied in a similar, visible light-accelerated transformation of heteroaromatic substrates. 106 A lack of source of chiral induction in all above reactions resulted in formation of racemic products.
In recent years, a considerable progress in the enantioselective synthesis of sulfoxides has been connected mainly with the development of methods based on the reactions of sulfenate anions with electrophiles. In 2004, structure, methods of generation, and reactions of sulfenic acid anions were reviewed by O'Donnell and Schwan. 107 In the following years, efficient routes to these underexplored intermediates were introduced and their subsequent arylations catalyzed by transition metal complexes were described. Perrio and coworkers identified β-sulfinyl esters as versatile precursors of a sulfenate anion. 108 Various bases (NaHMDS, KHMDS, NaH, LDA, n-BuLi, t-BuOK) were efficient in its generation, and reaction with benzyl or alkyl halides led to expected sulfoxides in up to 95% yield. To obtain enantioenriched products, the authors added enantiopure sparteine to the system and observed a weak asymmetric induction (ee up to 29%). The same method of generation of sulfenate anion from β-sulfinyl esters was used by Madec, Poli, and co-workers, who connected it with palladium-catalyzed allylic alkylation 109 and arylation. 110 Enantioenriched aryl−aryl and aryl−benzyl sulfoxides were prepared by this group by applying palladium catalyst with a chiral ligand. 111 Josiphos-type derivatives appeared most efficient in this role (Scheme 10). A pseudodomino process of palladium-catalyzed arylation of anions obtained from allylic sulfoxides was also described. 112 The achievements by Poli, Madec, and co-workers in the field were summarized in a short review published in 2010. 113 Perrio's group focused their attention on a diverse approach involving the use of phase-transfer reagents serving both as catalysts and chirality source. 114,115 Cinchona alkaloid-based ammonium salt was found optimal for this task; it was applied in a two-phase system (aqueous NaOH/toluene−dichloromethane mixture), sulfinyl sulfone served as a starting material, and methyl iodide as an electrophile. The yields were high (up to 96%), but the enantioselectivity was moderate (up to 58% ee, Scheme 11).
An improvement of methodology based on chiral phasetransfer catalyst was introduced by Zong et al., who described a highly enantioselective alkylation of sulfenate anions bearing heteroaryl substituents in the presence of novel halogenated chiral pentanidium salts (Scheme 12). 116 The reaction was performed in cyclopentyl methyl ether or diethyl ether and concentrated aqueous cesium hydroxide; yields and enantioselectivities, particularly for benzyl derivatives, were high (up to 99% ee).
Another report from Perrio's group explored a possibility of sulfenate anion generation by pyrolysis of tert-butyl sulfoxides followed by the action of K 3 PO 4 as a base and palladiumcatalyzed coupling with aryl halides or triflates. 117 Induction of chirality in this process was only studied with a planar-chiral racemic substrate, for which 50% de was observed.
Also other research teams contributed to the development of chiral sulfinate methodology. Schwan and co-workers investigated mainly diastereoselective alkylations. 118,119 Nolan and co-workers published their improvement to the existing methodology, which suffered from the limited availability of activated sulfoxides required for anion generation and the need of using aryl iodides. 120 To overcome these drawbacks, they applied palladium complexed with N-heterocyclic carbene (NHC) as a precatalyst and observed a direct S-arylation of nonactivated aryl sulfoxides by aryl chlorides and bromides. The reaction was not performed in the asymmetric variant.
Walsh and co-workers studied palladium-catalyzed arylations of benzylic sulfoxides. 121,122 Later on, they concentrated their efforts on finding mild conditions for generation of sulfenate. 123,124 In their preparation of enantioenriched aryl− aryl sulfoxides, sodium tert-butoxide was chosen as a base, and the chiral catalyst was formed in situ from Pd(dba) 2 and enantiopure ferrocene-based bis-phosphine 21. 125 Nineteen sulfoxides were prepared, including these bearing heteroaryl groups, in 73−98% yield and 70−95% ee. An elegant route to two enantiomers of 3-quinolino 6-quinolino sulfoxide was proposed using the same catalytic system and regioisomeric starting materials. As an extension of their studies, Walsh and co-workers described the use of CsF to generate sulfenate anions and their Pd-catalyzed reaction with alkenyl and aryl bromides (Scheme 13). 126 Ferrocene-based chiral phosphine ligand 21 and [Pd(allyl)Cl] 2 as a palladium source were efficient in the process affording various enantioenriched (49− 92% ee) sulfoxides in 44−94% yield.
Aryl−aryl, but also alkyl− and benzyl−aryl sulfoxides were enantioselectively prepared by Zhang and co-workers via arylation of sulfenate anions catalyzed by palladium complexes. 127 Among various chiral phosphine ligands tested, optimum results were obtained for a new xanthene-based phosphine derivative (R,R S )-24 bearing 1-adamantyl and sulfinamide moieties. Cs 2 CO 3 was used as a base, Pd 2 (dba) 3 · CHCl 3 as a palladium source, and mesitylene as a solvent (Scheme 14). The versatility of the system was demonstrated by the synthesis of over 100 different sulfoxides, including sulindac, in most cases with enantiomeric excess higher than 90%. A possibility of scaling-up of the protocol was also shown.
Although palladium-catalyzed reactions of sulfenate anions were commonly performed, protocols in which this noble metal was not used were described as well. A CuBr 2 -catalyzed reaction of sulfenate anions generated from sulfoxide ester by cesium carbonate with benzyl radicals formed from arenes by tert-butyl perbenzoate was developed by Bolm and coworkers. 128 Transition metal-free arylations were also reported by this group; they obtained racemic aryl−aryl and alkyl−aryl sulfoxides from β-sulfinyl ester and diphenyliodonium triflate with KOH as a base in a water−toluene biphasic system at room temperature. 129 In a search for the cheaper methodology for sulfoxide synthesis under milder conditions, Zhang's group developed a transition metal-free protocol of arylation of sulfenate anions. 130 Aryl or alkyl sulfenate anions were generated at room temperature and reacted with diaryliodonium salts. A variety of aryl−aryl and alkyl−aryl sulfoxides were prepared in 62−91% yield. A possibility of scaling-up the reaction was demonstrated; however, it was not applied in the enantioselective preparation of sulfoxides. Racemic alkynyl sulfoxides were prepared by Waser and co-workers in an efficient metalfree method using ethynyl benziodoxolone (EBX) reagents to trap sulfenate anions. 131 Synthetic methods based on reactions of sulfenate anions allow for the preparation of a variety of chiral sulfoxides, and in many cases yields and enantioselectivities are excellent. Despite of certain drawbacks (alkyl−alkyl sulfoxides cannot be prepared directly), these routes should be treated as an important alternative way of C−S bond formation for Andersen's method based on nucleophilic substitution.

Biological Preparations
Biotechnological methods of preparation of chiral sulfoxides provide an interesting alternative to purely chemical systems. In most cases, oxidation with enzymes results in high enantioselectivity and turnover number. Possible drawbacks are connected mainly with sensitivity of biocatalysts and, sometimes, their wide substrate scope. A longer discussion can be found in our previous review; 1 in 2018, sulfoxidations with biological systems were also summarized. 132 Two main approaches to enzymatic synthesis of optically active sulfoxides can be distinguished. Whole-cell preparations are operationally simpler and do not require addition of cofactors, although the nature of active catalytic species is not certain. Not surprisingly, the majority of recent reports in this area concern the use of bacteria or fungi for sulfoxidation. 133 Several research groups reported on the enantioselective oxidation of sulfides catalyzed by appropriately modified enzymes into which metal cofactors were introduced. Such artificial metalloenzymes were based on normally redoxinnocent transport protein 145 or bovine serum albumin. 146,147 In another approach, appropriately designed mutations in the heme pocket of dye-decolorizing peroxidase resulted in introduction of its ability to catalyze oxidation of sulfides with high conversion and enantioselectivity (both up to 99%). 148 Among the latest biocatalytic stereoselective preparations of sulfoxides, asymmetric sulfoxidation of 1-thiochroman-4-one derivatives by cytochrome P450-BM3 monooxygenase was described by Reetz and co-workers (Scheme 15). 149 Directed evolution allowed increasing of the stereoselectivity (ee increased from 50% for the wild-type enzyme to 86−93%) and even to reversing of the stereochemical preference.
Enzymes can be used also for the reductive resolution of racemic sulfoxides. Electrochemical regeneration of DMSO reductase applied in such a process was described by Chen et al. 150 Methionine reductase was also exploited by Chen and co-workers; newly identified homologues tolerated various substrates at high concentration and led to ca. 50% yield (maximum value for resolution) and >99% ee (Scheme 16). 151−153

STEREOSELECTIVE SYNTHESIS OF SULFINATES
Esters of sulfinic acid RS(O)OR′ have been treated mainly as valuable synthetic intermediates for other sulfinyl derivatives. A relatively easy preparation of these configurationally stable derivatives bearing a chiral R′ fragment followed by separation of diastereomers allows their transformation into enantiomerically pure sulfoxides and other derivatives. Methods of preparation and major applications of sulfinates were reviewed in book chapters. 11,13 Consequently, in this section, only a short overview of older contributions will be presented, with the stress on the possible diverse synthetic routes.

SO Bond Formation
Stereoselective sulfoxidation as the method of preparation of optically active sulfinates has not gained popularity in comparison to other approaches, which make use of more available starting materials, are operationally simpler and more efficient. The attempts of enantioselective reactions of sulfenates with chiral oxidants (e.g., peroxocamphoric acid 154 ) or catalytic oxidation systems (Kagan's method 155 ) were not particularly encouraging (maximum ee of 36% was reached).
Diastereoselective oxidation of benzenesulfenates bearing a phosphonate group at the ortho-position leading to the corresponding sulfinates was investigated by Vazeaux, Drabowicz, and their co-workers. 156 Starting sulfenates 27 were obtained in the reaction of chiral alcohols with sulfenyl chloride 26 (in turn prepared from thiol 25, Scheme 17).
Menthyl derivatives were oxidized with tested oxidants with high yield and variable diastereoselectivity (up to 76% de for NBS), and the direction of asymmetric induction could be changed if the appropriate enantiomer of chiral oxaziridine was applied. Among other chiral alcohols, 8-phenylmenthol 30 and trans-2-phenylcyclohexanol 31 led to reasonable results (also for (R)-Greene's alcohol 34, and one of enantiomers of Davis' oxaziridine 35 86% de was noted, while for the other enantiomer ent-35 de = 9% and a reversed stereochemical preference was found).

S−O Bond Formation
The first successful preparation of optically active sulfinates was achieved by Phillips in 1925, who obtained alkyl ptolylsulfinates by transesterification. 157 Since that time, numerous protocols have been described with chirality transfer from reactants (diastereoselective preparations) or auxiliaries used (enantioselective synthesis). The latter methods often utilized chiral tertiary amines, which were used in the reaction of racemic sulfinyl chlorides and achiral alcohols. As an example, preparation of sulfinates through enantioselective dynamic kinetic resolution of racemic tert-butanesulfinyl chloride was achieved by Ellman and co-workers. 158 This compound was subjected to the reaction with benzyl alcohol in the presence of proton sponge and a chiral base (N-methyl imidazole-containing octapeptide) led to the best results (99% yield, 80% ee, for only 0.5% of the catalyst). This catalyst was later replaced by relatively cheap and available Cinchona alkaloids, and the method extended over other (mainly benzyl) alcohols (Scheme 18). 159 Simultaneously, highly enantioselective preparation of arenesulfinates from racemic sulfinyl chlorides and achiral alcohols assisted by Cinchona alkaloids was reported by Shibata, Toru, and co-workers (up to 99% ee). 160,161 A variety of chiral alcohols have already found use in diastereoselective preparation of sulfinates. Menthol 29 has often been applied; 162 Andersen's method of stereoselective synthesis of sulfoxides is based on the crystalline (1R,2S,5R,S S )-(−) menthyl p-toluenesulfinate. 163 Diacetone-D-glucose (DAG), a sugar-derived alcohol 33, was also identified as a particularly useful auxiliary (both are commercially available). 164 Cholesterol, ephedrine, and various sugar alcohols including cyclodextrin should be also mentioned.
Mikołajczyk, Drabowicz, and co-workers thoroughly analyzed the stereospecifity of substitution at a stereogenic sulfur atom. Conversion of enantiomerically enriched sulfinamides to Chemical Reviews pubs.acs.org/CR Review sulfinates in the presence of strong acids was shown to proceed with a predominant inversion of configuration. 165 (S)-N,N-Diethyl p-toluene sulfinamide was first prepared from the corresponding menthyl sulfinate and Et 2 NMgBr. Its reactions with alcohols were found to proceed with medium to excellent stereospecifity, dependent mainly on the structure of alcohols; a complete inversion was observed for primary ones, and the steric hindrance exerted by secondary and tertiary alcohols resulted in partial racemization. Also, transesterification of sulfinates with 2-propanol in the presence of strong acids was primarily shown to proceed with a predominant inversion of configuration, with stereochemical outcome dependent on both sulfinate and acid used (up to 40% ee). 166,167 The stereochemistry of conversion of sulfinamides to sulfinate esters was later found to be more complex. 168 Bujnicki et al. investigated the effect of substituents of sulfinamide and the structure of alcohol and found that in certain cases a predominant retention of configuration was observed. 169 It was associated with a combination of sterically hindered alcohol and a bulky leaving amine fragment. Moreover, the stereochemical preference could be changed by addition of inorganic salt to the system while solvent change did not affect much the stereoselectivity. Analysis of reaction kinetics allowed the authors to propose a mechanism of the reaction involving addition, leading to sulfurane intermediates capable of pseudorotation (forced by steric factors).
A novel approach to the preparation of sulfinate esters was introduced by Jacobsen et al. 170 A mixed anhydride was prepared from sodium sulfinate and trimethylacetyl chloride, and reacted with various primary and secondary alcohols in the presence of trimethylamine. Esters were formed in 57−82% yield. Sulfination of nonactivated alcohols with the use of sulfonyl isocyanides was achieved by Ji et al. 171 A double activation was provided by Lewis acid (bismuth(III) triflate) and Brønsted acid (CCl 3 COOH). Asymmetric variant of these two protocols was not proposed.

S−C Bond Formation
Reactions of sulfites and chlorosulfites with organometallic reagents also provided sulfinates with a variable yield and stereoselectivity. Optically active tert-butyl sulfinates were prepared from symmetrical dialkyl sulfites and tert-butylmagnesium chloride in the presence of chiral amines (the optimal results, ee up to 74%, were obtained for Cinchona alkaloids, bearing also a hydroxyl group; Scheme 19). 172 An appropriate choice of the auxiliary allowed to prepare both optical antipodes of the product. An alternative method based on a kinetic resolution upon reaction of racemic thiosulfinates with Grignard reagents and quinine was also developed; it allowed preparation of nonracemic sulfinates with nonbulky alkyl or aryl substituents with ee up to 33%.
The use of chiral sulfites leading to diastereomeric mixtures of sulfinate products was also described. 173,174 Kagan's group converted the obtained, purified esters into enantiopure sulfoxides. 173 An interesting homolytic substitution process in which certain sulfinates under radical conditions (Bu 3 SnH, AIBN, heating in benzene) underwent an intramolecular cyclization to give cyclic esters (sultines) was reported by Coulomb et al. 175 An optically enriched starting compound led to the product with a complete inversion of configuration (Scheme 20); the similar conclusion was drawn for the cyclization of chiral sulfinamides. When a new stereogenic center was created, a preference for trans configuration was observed Chemical Reviews pubs.acs.org/CR Review and two sultines were formed with a complete diastereoselectivity.

Other Methods
Formation of two bonds in one process was also reported. Sulfinates (but only racemic) were prepared using aerobic, copper-catalyzed reaction of thiols and alcohols. 176 Shyam et al. showed that also disulfides and thiosulfinates could be reacted with benzyl alcohol to give the desired ester, although in lower yield. The racemic O-alkyl alkylsulfinates were resolved using formation of inclusion complexes with β-cyclodextrin. 177 The highest optical purity of 70% was achieved for complexed Oisopropyl methylsulfinate.

SYNTHESIS OF OPTICALLY ACTIVE
THIOSULFINATES Thioesters of thiosulfinic acid (or disulfide S-oxides) belong to chiral sulfinyl compounds exhibiting limited chemical and configurational stability (see section 2). As the increase of steric hindrance exerted by groups connected to sulfur atoms results in the stabilization, majority of studies focused on tertbutyl tert-butane thiosulfinate 42 (Scheme 21). High-yielding and enantioselective methods have been developed for its preparation from a cheap and easily available tert-butyl disulfide 39, and thus this thiosulfinate is regarded as a valuable starting material for the synthesis of other enantiopure sulfinyl compounds: sulfinamides, sulfoxides, sulfinates, and others. 27,178 Asymmetric sulfoxidation procedures are of particular importance, and they include chemical and enzymatic procedures. Other methods, although less significant and with limited practical use, should not be completely neglected.  154,179,180 In 1965, Kice and coworkers described an asymmetric oxidation of aryl disulfides to thiosulfinates. 181 The use of chiral peroxycamphoric acid led to the optically active product in ca. 60% yield and very low enantioselectivity (ca. 3% ee based on the given specific rotation). Davis' 2-sulfonyloxaziridines were slightly more efficient (14% ee for oxidation of tert-butyl disulfide, but only 2% ee for p-tolyl derivative), 182 and Kagan's system (t-BuOOH/Ti(O-iPr) 4 /DET) allowed to increase the enantiomeric excess to 52%. 155 Further improvement was possible after introduction of vanadium Schiff base catalysts. In 1997, Ellman and co-workers developed an enantioselective method of preparation of tertbutane tert-butyl thiosulfinate 42 by oxidation of the corresponding disulfide 39 with hydrogen peroxide in a biphasic system in the presence of chiral vanadium complex (Schiff base 40 introduced by Bolm and Bienewald 183 was used, Scheme 21). 178,184 In subsequent studies, it was proven that slow addition of 30% aqueous H 2 O 2 and the use of cosolvent with low miscibility with water (CHCl 3 was found optimal) were of importance for the observed stereoselectivity (up to 91% ee was reached), which is otherwise limited by a nonenantioselective oxidation. 185 Later, change of chiral ligand to the one derived from cis-1-aminoindan-2-ol and 3,5-di-tertbutylsalicylaldehyde (41) allowed to exchange the two-phase solvent system to acetone, and to apply the protocol on a kilogram scale (99% conversion, 85−86% ee). 186,187 The product could be purified by a simple crystallization and obtained in both enantiomeric forms, depending on configuration of the Schiff base. 187 An enantiopure analogue of tert-butylsulfinamide attached to a polystyrene support was also prepared in Ellman's group using a dynamic resolution methodology. 188 Its utility in the enantioselective synthesis of chiral amines and alkaloids was demonstrated.
Other chiral Schiff bases were tested by Ma et al. in vanadium-catalyzed enantioselective oxidation of disulfides by hydrogen peroxide. 189 tert-Butane tert-butyl thiosulfinate was obtained in 30−93% yield and 4−88% ee when ligands derived form 3,5-di-tert-butylsalicylaldehyde and aminoalcohols were applied. Also para-tolyl disulfide was oxidized by H 2 O 2 under these conditions, albeit in lower yield and enantioselectivity (ee < 40%). Both esterified and reduced derivatives of Schiff bases were found to be inefficient chiral inducers.
5.1.2. Enzymatic Methods. Cyclohexanone monooxygenase was applied by Colonna and co-workers in the asymmetric oxidation of disulfides. 190 An excellent enantioselectivity (97% ee and 90% conversion) was observed only for tert-butyl disulfide 37 (Scheme 22), while three other thiosulfinates were obtained in low yield and ee up to 70%, which was attributed to their lower stability and ease of racemization. A regioselective oxidation of sulfur atom Chemical Reviews pubs.acs.org/CR Review connected to tert-butyl substituent was noted for the unsymmetrical substrate, p-tolyl tert-butyl disulfide. Bovine serum albumin was tested as a chiral auxiliary in oxidation of disulfides; desired products were formed, but stereoselectivity was unsatisfactory. 191 Instead, an oxidation system based on chiral fructose-derived dioxirane was applied, which led to high conversion and ee up to 75%. Also, Boyd et al. described oxidation of 1,2-disulfides using enzymatic methods. 192−194 While acyclic substrates failed to give expected thiosulfinates under conditions used, 1,2dithiane was converted into S-oxide quantitatively and with 96% ee by chloroperoxidase (CPO) and H 2 O 2 (Scheme 23).
Other tested systems: cyclohexanone monooxygenase and whole cells expressing arene dioxygenases were inefficient in this transformation. CPO catalyzed oxidation of a bicyclic substrate in 59% yield and 47% ee (Scheme 23); in both cases, configuration of the main isomer was established as S. A possibility of stereoselective deoxygenation of racemic dithiane-derived thiosulfinate by dimethyl sulfoxide reductase (DMSOR) to yield enantioenriched residual substrate (95% ee, S isomer) was demonstrated as well. 192,193

S−S Bond Formation and Other Preparations
Drabowicz and Mikołajczyk explored various possibilities for preparation of nonracemic thiosulfinates from other sulfinyl derivatives. Thermal decomposition of di-tert-butyl sulfoxide in the presence of equimolar amount of enantiopure chiral amines led to the formation of nonracemic t-butyl tbutanethiosulfinate (Scheme 24). 195 Although enantiomeric excess was low (1−26%, the latter value for quinine as inducer of chirality), both enantiomers of thiosulfinate could be prepared, and amines could be recovered after the reaction. Other thiosulfinates could not be prepared with this method, which was attributed to their instability under the conditions used.
Chiral amines were also applied as chiral inducers in the condensation of sulfinyl chlorides with thiols. 27 196 Nonracemic thiosulfinates were also prepared by Drabowicz and Mikołajczyk by treatment of enantiomerically enriched sulfinamides with thiols in the presence of trifluoroacetic acid. 197 The reaction took place with predominant inversion of configuration, with stereospecifity in the range of 30 to >80%, dependent mainly on the structure of thiols.
tert-Butane tert-butyl thiosulfinate was obtained by Liao et al. by resolution of racemate using inclusion crystallization with (R)-binol, yielding both enantiomers with high enantiomeric purity (ee > 99%). 198 6. STEREOSELECTIVE PREPARATION OF SULFINAMIDES AND SULFINIMINES Trisubstituted sulfinyl compounds of the general formula R 1 S(O)NR 2 R 3 (sulfinamides) or R 1 S(O)NCR 2 R 3 (sulfinimines/N-sulfinylimines) belong to most important chiral auxiliaries in asymmetric synthesis, used in preparation of a great variety of optically active heteroorganic compounds containing a nitrogen atom. Primary (R 2 = R 3 = H), secondary (R 2 = alkyl, aryl, R 3 = H), and tertiary amides can be prepared; the appropriate choice of R 1 −R 3 groups results in modification of their properties, e.g., basicity and nucleophilicity of the nitrogen atom, which may influence the course of asymmetric reactions.
A chapter of "Chiral Sulf ur Reagents" by Mikołajczyk, Drabowicz, and Kiełbasinśki presents methods of stereoselective preparation of sulfinamides and N-sulfinylimines (named N-alkylidenesulfinamides throughout the chapter) and their synthetic applications published up to 1996. 11 In their chapter from the book, edited by Toru and Bolm, Senanayake and co-workers covered the literature up to 2007, with a special focus of a general preparative route introduced in their laboratory. 15 Ellman and co-workers published two review papers in which tert-butanesulfinamide was presented as a useful synthetic intermediate in asymmetric reactions. 199,200 N-Sulfinylimines, the family of compounds of great synthetic importance, were the subject of the second part of article by Davis, who briefly described the synthesis of enantiomerically pure compounds from his group, more widely showing their great potential as chiral auxiliaries and reactants. 37 In their papers published in 2002 and 2009, respectively, Ellman's group and Ferreira and co-workers narrowed their topic to tert-butanesulfinimines: their enantioselective preparation, postsynthetic modification, and use in asymmetric transformations, mainly in the synthesis of chiral amines. 201,202 Typically, optically active sulfinamides are prepared from enantiomerically pure sulfinates, thiosulfinates, or sulfinyl chlorides (the latter generated in situ) by a nucleophilic Only a few examples of preparation of sulfinamides by oxidation of corresponding sulfenamides were reported. This approach is hindered by a limited scope of available substrates, although they can be prepared, e.g., from thiols, disulfides or sulfenyl halides. 203 Among recent examples, a nonstereoselective oxidation of various sulfenamides by KF/m-CPBA system in acetonitrile−water at 0°C in 82−94% yield was performed by Datta et al. 204 The reaction was fast (5−20 min), and overoxidation products were not formed. A recent report by Tang and co-workers on enantioselective oxidation of sulfenamides with hydrogen peroxide mediated by a chiral binaphthyl-based phosphoric acid derivative showed the possibility of preparation of nonracemic sulfinamides via S O bond formation (Scheme 26). 205 Under optimized reaction conditions (dichloromethane/35% aqueous H 2 O 2 /5% of catalyst/MgSO 4 additive/0°C), overoxidation to sulfonamide was not observed, and various derivatives were isolated in 65− 96% yield and with high enantioselectivity (in most cases 90− 99% ee). A proposed mechanism involved activation of reactants by a catalyst through hydrogen bond formation, and the observed stereochemical outcome was substantiated with DFT calculations of transition states. The prepared sulfinamides were further converted into other compounds from this class (vide infra) and sulfoxides. 205 Other attempts involving oxidation of sulfenyl derivatives formed from thiols or disulfides are worth mentioning. N-tert-Butanesulfinylphthalimide was prepared by treatment of the corresponding sulfenyl derivative (obtained from N-bromophthalimide and tert-butyl disulfide) with peroxyacetic acid. 206 Ring opening under Lewis acid catalysis (samarium triflate was used) followed by the addition of ammonia yielded tert-butane sulfinamide. Unfortunately, all attempts to perform the process in a stereoselective manner were unsuccessful. Coppercatalyzed oxidative coupling of thiols or disulfides with amines was reported by Taniguchi. 207 Reactions were carried out under air, and the presence of dioxygen was found necessary for the reasonable yield. Only achiral reactants and catalysts were tested.
N-Sulfinylimines were also prepared by enantioselective oxidation of sulfenylimines. In 1997, Davis and co-workers described the use of enantiopure oxaziridines 49 for this purpose and obtained the desired products in 59−95% yield and enantiomeric excess up to 90% (improved to >97% by crystallization, Scheme 27). 208 Kagan's method was less efficient (80% yield, 13% ee). As preparation methods based on nucleophilic substitution were found more promising, this approach was abandoned.

S−N Bond Formation
Sulfinamides are conveniently obtained from other trisubstituted sulfinyl derivatives. Nonracemic sulfinates have been used in such conversions for over half of a century. In 1968, Colonna, Giovini, and Montanari prepared optically active ptoluenesulfinamides from the corresponding menthyl sulfinate and dialkylaminomagnesium bromides. 209 The reaction proceeded with an inversion of configuration. Later on, this auxiliary introduced by Andersen, 163 now commercially available, was used in the synthesis of other sulfinamides, mainly with the use of lithium amides. Davis and co-workers reacting this sulfinate with lithium amide followed by addition of aldehyde or ketone obtained the corresponding Nsulfinylimine with high enantioselectivity (Scheme 28). 208,210,211 In 2002, Senanayake's group introduced a versatile and stereoselective method for the synthesis of sulfinyl compounds with the use of N-activated oxathiazolidine oxides (Scheme 29). 212,213 Their subsequent reactions with organometallic compounds and lithium amide led to a variety of tertiary alkyl and aryl sulfinamides. 15 Reaction of N-acylated 1,2,3oxathiazolidine-2-oxide with Grignard compounds was also used to prepare chiral sulfinamides by Qin et al. 214 Nucleophilic substitution of enantioenriched tert-butane tertbutyl thiosulfinate (see Section 5.1) was established by Ellman and co-workers as a very convenient route to tert-butyl  178,184,186,187 No racemization during this step was observed, and the product could be obtained in multigram amounts. Compound 52 was identified as a valuable precursor for a range of enantiomerically pure tert-butanesulfinyl derivatives and, after removal of sulfinyl auxiliary, chiral nitrogen-containing compounds. As an example, reaction with aldehydes provided N-sulfinylimines; Grignard addition and cleavage with acid yielded optically active branched amines. 178 Various enantiomerically pure aldimines were prepared in a one-step condensation of sulfinamide 52 with aldehydes in the presence of dehydrating agents. 215 Also, ketimines were formed with a significant E/Z preference from respective ketones when Ti(OEt) 4 was applied as a Lewis acid (Scheme 30). 215,216 The procedure was later optimized, and tetrahydrofuran and cyclopentyl methyl ether (preferred in the case of more challenging ketones) were identified as optimal solvents. 217 The possibility of recovering the chiral auxiliary was investigated as well. 218 After the cleavage of imine with HCl, fast racemizing sulfinyl chloride was separated from chiral amine hydrochloride. The dynamic chiral resolution of this sulfinyl derivative treated with ethanol in the presence of quinine and proton sponge (both could be reused as well) in cyclopentyl methyl ether led to tert-butanesulfinamide in high yield and enantiomeric purity (up to 87% ee).
Alternatively, reduction of ketimines with NaBH 4 could be performed to give sulfinamides (66−86% yield, 80−94 de). 219 Both enantiomers of amine were obtained with high ee, with configuration dependent on the choice of reducing agent (NaBH 4 vs L-selectride). 220 Addition of alkyl, aryl, alkenyl, and allyl carbanions to aldimines and ketimines was performed, and the resulting sulfinamides were cleaved by HCl in methanol, yielding a variety of enantioenriched branched amines. 221 Other examples of the use of tert-butylsulfinyl auxiliary in asymmetric synthesis by Ellman's group included preparation of (among others) amino acids, 222−224 amino alcohols, 225−227 cyclic amines, 228,229 unsaturated amines, 2,230,231 nitriles, 232 aminophosphonates, 233 aminoboronates, 234 and total synthesis of natural products. 235,236 Novel urea and thiourea organocatalysts bearing N-sulfinyl fragment as a chirality source and an acidifying agent were developed in Ellman's laboratory. 237 They were obtained in condensation of isocyanates or isothiocyanates with tert-butanesulfinamide and used in asymmetric aza-Henry reaction. High stereoselectivity was observed for derivatives also containing aminoindanol moiety. Other sulfinylureas were found efficient in enantioselective additions to nitroalkanes. 238−242 Also enantiopure N-sulfinyl prolinamide was prepared via deprotonation of tert-butanesulfinamide and reaction with (S)-proline methyl ester, and its high efficiency in aldol reaction was demonstrated. 243 Ellman's group applied enantiopure tert-butanesulfinamide 52 to the preparation of chiral ligands. C 2 -Symmetric bis(N-sulfinylimine) derivatives and bis(sulfinyl)imidoamidine (SIAM) were tested in copperand zinc-catalyzed asymmetric Diels−Alder reaction (up to 98% de and up to 98% ee), 244 while N-sulfinylimine ligands bearing phosphine moiety were used in palladium-catalyzed allylic alkylation (yielding up to 96% ee), 245 and iridiumcatalyzed hydrogenation of stilbenes (up to 94% ee). 246 Later, Ellman and co-workers developed an improved synthesis of more electrophilic perfluorobutanesulfinamide 54 accomplished with the use of Senanayake's 2-aminoindanolderived sulfinyl transfer reagent 213 and a suitable Grignard reagent prepared from EtMgBr and C 4 F 9 I. 247,248 The sulfinate intermediate was treated with amine nucleophiles; NaHMDS led to the highest yield. The sulfinamide could be prepared on a gram scale in 67% yield and 99% ee using this two-step sequence (Scheme 31). Its condensation with ethyl glyoxylate provided N-sulfinyl imine ester, which was used in asymmetric transformations (Rh(III)-catalyzed C−H bond functionalization, aza-Diels−Alder reaction). 247,249 An alternative for tert-butane sulfinamide for the application in asymmetric synthesis was introduced by Li and coworkers. 250 The novel auxiliary combined properties of paratolyl-(aromatic chromophore) and tert-butyl-substituted (stability) derivatives. (R)-2-Phenyl-2-propyl sulfinamide 58 was prepared in four steps starting from the respective thiol, with H 2 O 2/ VO(acac) 2 /chiral Schiff base oxidation of disulfide as a key step for chiral induction (85% ee was further improved to >99% by washing with n-hexane, Scheme 32). This time, amidation of thiosulfinate was not straightforward and required the use of tert-butyldimethylsilyl amine (TBDMS-NH 2 ) followed by deprotection. Reaction of aldimines and ketimine derived from this sulfinamide with allylmagnesium bromide Chemical Reviews pubs.acs.org/CR Review proceeded with high diastereoselectivity, additionally increased by simple (group-assisted) purification. Sulfinyl chlorides are less convenient in the stereoselective synthesis of sulfinamides due to their instability and configurational lability. However, several enantiopure arylsulfinamides were obtained by Zhu and Shi by a spontaneous crystallization of products of reaction of sulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine. 251 (R,S S )-Diastereomers were isolated from the reaction mixture as solids in ca. 30% yield, while mother liquor was enriched in (R,R S ) isomers (50−58% de) and could be separated by chromatography. Enantiopure sulfinates were prepared from the corresponding sulfinamides using methanol and boron trifluoride etherate and later converted to primary (S S )-sulfinamides (which could not be obtained directly form tertiary counterparts).
A protocol for synthesis of sulfinamides from amines and sulfonyl chlorides reduced in situ with phosphine was developed by Harmata and co-workers. 252 The reaction showed broad substrate scope, although the use of chiral amines did not result in diastereoselection. We observed modest diastereoselectivity (up to 17% de) when we reacted tosyl and nosyl chlorides with enantiomerically pure amines (both commercially available and bicyclic derivatives prepared in our laboratory) under modified Harmata's conditions (Scheme 33). 253 Products were isolated as single stereoisomers by chromatographic separation.
Tang and co-workers converted N-phenyl tert-butane sulfinamide prepared by enantioselective oxidation of its sulfenyl counterpart (see section 6.1) into other derivatives (for which direct oxidation was not successful) via Nprotection and nucleophilic substitution with primary amines. 205 While yields were moderate (55−70%), almost complete inversion of configuration was observed (94−97% ee). Copper-catalyzed transamidations of primary sulfinamides with O-benzoylhydroxy-substituted secondary and primary amines were performed by Bolm and co-workers in 61−83% and 24−79% yield, respectively. 254 The use of enantiomerically pure amines led to 1:1 mixtures of diastereomers, which were separated by column chromatography to yield enantiopure sulfinamides.
N-Bromosuccinimide was used by Wei and Sun to activate tert-butylsulfinyl group in sulfoxides. 255 Reaction with nitrogen, oxygen, or carbon nucleophiles led to sulfinamides, sulfinates, and other sulfoxides, respectively, generally in high yield. Only racemic compounds were prepared.

Dealkylation/Dearylation of Sulfoximines
Enantiopure sulfinamides were also obtained by dealkylation of sulfoximines with retention of configuration. First examples of this reactivity were reported in 1971. Schroeck and Johnson performed reduction with aluminum amalgam, 256 Tsujihara et al. 257 conducted pyrolysis of alkyl-substituted derivatives, and Williams et al. carried out tosylation. 258 Schroeck and Johnson also observed a similar conversion (reductive elimination of N(CH 3 ) 2 or OPh group, respectively) of sulfonimidamides and sulfonimidates. 256 More examples of stereoselective transformations of sulfoximines to sulfinamides caused by various triggers can be found in a recent review by Wiezorek et al. devoted to degradation of sulfoximines. 30 These reactions, though interesting for the study of stability and stereochemistry of involved derivatives, cannot be regarded as useful preparative routes for optically active sulfinamides.

Other Methods
Various methods based on transformation of substituents or involving rarely used sulfur reagents were described. A biocatalytic route to optically active sulfinamides was developed by Kazlauskas and co-workers. 259 Hydrolysis of racemic N-chloroacetyl and N-dihydrocinnamoyl arylsulfinamides were catalyzed by subtilisin E overexpressed in Bacillus subtilis, providing mainly (R) primary sulfinamides (Scheme 34). Their (S) counterparts could be formed after nonenzymatic hydrolysis of unreacted acylated sulfinamides. Yields were moderate, but an excellent enantioselectivity was observed in most cases. Gram-scale resolutions were also performed, and synthetically useful auxiliaries were obtained with 95−99% ee (after recrystallization). Enantioselective Narylation of racemic primary sulfinamides with aryl iodides catalyzed by chiral Cu(I) complexes was described by Liu et al. 260 Under optimized conditions, substituted sulfinamides were obtained in variable yield (37−93%) and medium stereoselectivity (5−60% ee).
Inspired by the rapid development in the sulfenate anion application in the preparation of sulfoxides (see section 3.1.2), Dai and Zhang decided to study electrophilic amidation of these anions generated from β-sulfinyl esters. 261 Optimization Chemical Reviews pubs.acs.org/CR Review of reaction conditions revealed CuI/bypy as the best catalytic system, lithium tert-butoxide as the most efficient base, with toluene as solvent. A variety of aliphatic and aromatic sulfinamides were prepared in 44−96% yield. The reaction could be performed in a gram scale; its asymmetric variant, however, was not described. Wang et al. reported on a cross-coupling of arylboronic derivatives with aminosulfur trifluorides (DAST reagents) to afford diverse aromatic sulfinamides in yields up to 92%. 262 The use of enantiopure tocopherol-derived boronic acid resulted in the 1:1 mixture of epimers; all other compounds were racemic.

STEREOSELECTIVE SYNTHESIS OF SULFOXIMINES
About 60 years ago, Bentley and co-workers identified a novel sulfinyl compound from the treatment of protein with nitrogen trichloride. 263−266 They were able to separate diastereomers of methionine sulfoximine and prepared other sulfoximines from sulfoxides using HN 3 . 267,268 Since then, these stable monoaza analogues of sulfones have been recognized as valuable auxiliaries, ligands, and catalysts in asymmetric synthesis, building blocks in pseudopeptides and, in the recent years, also as drug candidates.
Sulfoximines share many properties with sulfoxides: they are chemically and (if chiral), also configurationally stable. They bear sulfinyl group capable of high induction of chirality. However, the presence of a nucleophilic imine nitrogen atom which can participate in hydrogen bonding or metal coordination makes them special.
A recent growing interest in the synthesis and utilization of nonracemic sulfoximines prompted several research groups to write reviews, general, or focused on specific types, transformations, and applications. Bolm and co-workers prepared a chapter in the book on organosulfur chemistry. 14 Articles by this group dealt with properties and applications of fluorinated derivatives, 269 methods of sulfur atom imidation of sulfides and sulfoxides, 270 and routes of degradation of sulfoximines. 30 The importance of these compounds in the area of drug discovery is highlighted in articles by Bolm's group 271 and Lucking et al. 272,273 Harmata and Hong reviewed the chemistry of 2,1benzothiazines, cyclic sulfoximines studied thoroughly by Harmata's group. 274 Bull, Degennaro, and Luisi decided to highlight the progress made in preparation of N-unsubstituted derivatives. 275 Two reviews written in Chinese on synthesis and applications of sulfoximines can be added to the list. 276,277 In this section we shall focus on showing diverse synthetic strategies and efficient routes to variously substituted derivatives. In their review published in 2000, Reggelin and Zur stated that the most chemistry of optically active sulfoximines emanated from several "key intermediates", mainly S-methyl-S-phenyl-substituted compounds resolved through formation of diastereomeric salts with 10-camphorsulfonic acid. 278,279 Though resolutions (mainly kinetic) still remain important (see section 7.5), enantiomerically pure or enriched compounds can be now prepared using a variety of pathways developed in the recent years.

SO Bond Formation
Typical preparations of sulfoximines start from prochiral sulfide. Oxidation and imidation steps can be performed in different sequence (Scheme 35). However, introduction of NH or NR fragment into a sulfoxide was recognized as more attractive strategy than the oxidative transformation of sulfilimines (sulfilimides). They are relatively stable toward oxidation, and access to sulfoximines requires strong oxidizing agents, such as potassium permanganate, alkaline hydrogen peroxide, etc. 280 As far as we know, chiral oxidants have not been used for this transformation. However, chirality transfer is possible as sulfilimines can be obtained as single enantiomers. 281 Stereochemistry of oxidation of N-sulfonylsulfimines with alkaline solution of KMnO 4 was studied by Kresze and Wustrow, who observed retention of configuration. 282 Long reaction times are sometimes required for this oxidant, and yields can be small (for instance, only 10% for oxidation of thiane-derived sulfilimine). 283 However, permanganates are still chosen for certain preparations. For example, sulfilimines bearing perfluoroalkyl substituents were prepared from appropriate sulfoxides by treatment with nitriles; oxidation with KMnO 4 led to the corresponding racemic sulfoximines, either bearing N-acyl or NH fragment (depending on the environment). 284 An improvement was introduced to the method of preparation of the crop protection agent sulfoxaflor (known also under trade name Isoclast active). 285 The N-CN sulfilimine was prepared from pyridine sulfide treated with iodobenzene diacetate and H 2 NCN in acetonitrile and then oxidized. Various oxidation methods were tested, including RuCl 3 /NaIO 4 combination, but for practical and economic reasons, 40% aqueous NaMnO 4 was chosen. As the insecticide is used as a mixture of isomers (two stereogenic centers are present in the molecule), stereoselectivity of the reaction was not studied.
Various sulfoximines were also prepared by oxidation of sulfilimines with ruthenium tetroxide, generated in situ from NaIO 4 and substoichiometric amounts of RuO 2 . 286,287 Racemic N-cyanosulfilimines, prepared by Bolm and coworkers from sulfides and cyanogen amine, were easily oxidized with m-CPBA into corresponding sulfoximines, and the cyano group was cleaved by treatment with trifluoroacetic acid and methanolysis. 288 Later on, the enantioselective sulfimidation of sulfides with PhINTs catalyzed by transition-metal chiral complexes and bis-oxazoline ligands was studied (Scheme 36). 289 The best results (yield reaching Chemical Reviews pubs.acs.org/CR Review 99%, up to 82% ee) were noted for iron(III) acetylacetonates used as catalyst precursors. Oxidation of the obtained Ntosylsufilimines with NaIO 4 /RuCl 3 or m-CPBA led to optically active sulfoximines with high enantioselectivity, from which a protecting group could be easily removed. A chiral N-mesyloxycarbamate caused a stereoselective amination of thioethers in the presence of a chiral dirhodium-(II) carboxylate catalyst to yield the corresponding sulfilimines. 290,291 The possibility of preparation of sulfoximine through oxidation of sulfilimine with NaIO 4 with RuCl 3 as a catalyst was demonstrated; removal of chiral auxiliary with zinc in acetic acid yielded NH-sulfilimine as a single enantiomer (94%). Lebel and co-workers also applied iron catalyst in a similar preparation. 292 Increase of yield was possible thanks to application of continuous flow technology. 1-Butylimidazole was used as a base to form 1-butylimidazolium mesylate as an ionic liquid byproduct.
Alternatively, chlorination can be applied to increase oxidation state of sulfur atom. Furukawa, Oae, and co-workers found that alkaline hydrolysis of N-chlorinated sulfilimines resulted in formation of NH-sulfoximines in high yields (up to 95%). 293,294 N-Chlorosuccinimide and sodium hypochlorite were used as chlorinating agents for NH-sulfilimine; both reaction steps were shown to proceed with a retention of configuration.

SN Bond Formation
In a 2015 article by Bizet, Hendriks, and Bolm, methods for preparation of sulfoximines by imidation of sulfoxides (and sulfimides from sulfides) were comprehensively reviewed. 270 Efficiency of various imidating agents: N-haloamides and similar compounds (chloramine T, MSH), aziridine derivatives, dioxazolones, azides, and iminoiodinanes was compared. Uncatalyzed reactions typically gave lower yields in comparison with protocols engaging metal complexes: copper, silver, rhodium, ruthenium, and iron. Most imidations of sulfoxides were performed with racemic reactants. However, several research groups checked the stereospecifity of the reaction using enantiopure or enantiomerically enriched sulfoxide as a starting material. In each case, a complete retention of configuration was observed. An interesting example of kinetic resolution from Bolm's laboratory is noteworthy: racemic sulfoxides were treated with PhINTs in the presence of Fe(acacCl) 3 61 and a chiral bis-oxazoline ligand 62, yielding sulfoximines with up to 88% ee (and up to 43% yield, Scheme 37). 295 Among recent contributions from Bolm's laboratory, an efficient and stereospecific preparation of N-cyanosulfoximines from sulfoxides was described by Dannenberg et al. 296 Optimized reaction conditions included the use of cyanamide (2 equiv), potassium tert-butoxide (2 equiv) as base, and Nchlorosuccinimide (2 equiv) as oxidant, the set of reactants that were efficient for the synthesis of N-cyanosulfilimines from sulfides. 288 Reaction was performed in water at room temperature, with yields varying from 23 to 98%. Retention of configuration was observed for imination of a representative, enantioenriched sulfoxide (Scheme 38).
NH-Sulfoximines were synthesized in the reaction of sulfoxides and triflic acid salts of hydroxylamine catalyzed by Fe(II) complex. 297 No attempt was made to perform the reaction with enantioenriched sulfoxide or chiral iron catalyst.
The significant increase of yield (up to 91%) of imination of sulfoxides with NaN 3 or TMSN 3 was observed by Gutmann et al. when concentrated sulfuric acid was replaced by a fuming one. 298 The two-phase (H 2 O/CH 2 Cl 2 ) reaction could be performed under continuous flow conditions. However, the original optical purity of the reactant was not retained.
In 2015, Bull and co-workers described a rhodium-catalyzed transfer of carbamates to sulfoxides, yielding N-protected sulfoximines in good to excellent yields (54−98% under optimized conditions). 299 BocNH 2 and PhI(OAc) 2 were used to generate BocNIPh species in situ, Rh 2 (OAc) 4 acted as a catalyst, and MgO served as a base. Carbamate protection allowed performing good-yielding Suzuki coupling with S-aryl substituents; on the other hand, Boc and Cbz groups were easily removed to afford NH-sulfoximines. As shown in one example, both N-transfer and deprotection proceeded with a complete retention of configuration (Scheme 39); other reactions were performed with racemic samples.
In the search of a convenient electrophilic nitrene source, Bull, Luisi, and co-workers tested ammonium salts for a direct NH transfer under metal-free conditions. 300 The use of ammonium carbamate (4 equiv) and diacetoxyiodobenzene (3 equiv) in methanol at 25°C resulted in fast formation of sulfoximines from the corresponding sulfoxides. The reaction showed a wide substrate scope. Stereochemical outcome of the process was checked for three enantioenriched sulfoxides, for which a complete retention of configuration was observed (an example is shown in Scheme 39). Chemical Reviews pubs.acs.org/CR Review Later, the same group reported the use of similar set of reactants for the one-pot preparation of sulfoximines from sulfides 301 and conversion of thiols to sulfones and sulfonimidates (vide infra). 302 The possibility of performing the synthesis in a flow reactor was demonstrated as well. 303

S−C Bond Formation
Sulfoximines can be obtained from other tetrasubstituted sulfinyl derivatives: sulfonimidoyl halides, sulfonimidamidates, and sulfonimidamides. Reggelin and co-workers developed a strategy based on preparation of two epimers of cyclic sulfonimidamidate (71 and 72, see also section 9.1) and their reaction with organometallic reagents, which proceeded with an inversion of configuration (Scheme 40). 304 This synthetic precursor was also applied in the preparation of the first bis(NH-sulfoximine) in a diastereomerically pure (but racemic) form. 305 Epimers of the same sulfinimidamidate were used in a one-pot synthesis of enantiopure cyclic oxathiazine Soxides 306 and other enantiopure sulfoximines. 278 A synthesis based on the use of sulfonimidates was also reported in 2018. 307 They were shown to react with a variety of organometallic (mainly Grignard) compounds in THF. Yields were moderate to high; as only racemic reactants were used, stereochemical aspects of the transformation were not discussed.
Harmata and co-workers concentrated their attention on the preparation of derivatives of cyclic sulfoximine, 2,1-benzothiazine, a compound which found numerous applications in asymmetric synthesis. 274 Reaction of sulfonimidoyl chloride 73 with alkynes under Lewis acid catalysis afforded 2,1benzothiazines in 46−75% yield (Scheme 38). 308 These cyclic sulfoximines were also obtained when alkenes were used instead of alkynes, and good yield was in certain cases (for example, cyclohexene addition) accompanied by high diastereoselectivity (Scheme 41). 309 Reaction of sulfonimidoyl chloride with mono-, di-, and trisubstituted olefins in the presence of AlCl 3 provided benzothiazines bearing two stereogenic centers with variable diastereoselectivity. 310 The effect of alkene substitution on the reaction outcome was studied.
Also noncyclic sulfoximines were prepared from sulfonimidoyl chlorides or fluorides, as exemplified by the reaction of the latter with TMSCF 3 , leading to trifluoromethylated product. 311 Diarylsulfoximines were prepared by Takata and co-workers from sulfonimidoyl chlorides (in turn obtained by treatment of sulfinyl chlorides with chloramine-T) and aromatic hydrocarbons catalyzed by Lewis acids. 312 Synthesis of sulfoximines can start from trisubstituted derivatives, sulfinamides, or imines derived therefrom. Enantiopure N-tert-butylsulfinylimines bearing fluorinated alkyl substituents were applied in a [3+2]-cycloaddition reaction with arynes, yielding cyclic sulfoximines with excellent diastereo-and enantioselectivity (the configuration of sulfur stereocenter was retained, Scheme 42). 313 A reverse process of conversion of cyclic sulfoximines into sulfonamides was investigated as well.
Stockman and co-workers prepared a series of cyclic sulfoximines from nonracemic mesityl-or tert-butyl sulfinylimines via an aza-Darzens-type aziridination with 2-bromobut-2-enoic acid methyl ester; the formed vinyl aziridines spontaneously rearranged into diastereomerically pure products. 314 The reaction could be performed either with isolation of the aziridine intermediate or in a one-pot fashion, typically in higher yield.
In very recent reports by Aota et al., a stereospecific synthesis of sulfoximines by a S-selective alkylation or arylation of sulfinamides was described. 315,316 Protection of nitrogen atom with a pivaloyl group and the proper choice of reaction conditions (2 equiv of alkyl iodide or bromide, 1.1−1.2 equiv of NaH, 1.1−1.2 equiv of 15-crown-5 in dioxane, 11−168 h) allowed preparation of sulfoximines in 31−96% (but in most cases >80%) yield with a retention of configuration (Scheme 43). 315 The protecting group could be removed by LiAlH 4 treatment. Interestingly, starting with tert-butyl sulfinamide opened the route to both enantiomers of various derivatives Chemical Reviews pubs.acs.org/CR Review with two similar alkyl chains via de-tert-butylation of sulfoximine obtained in the first step with TFA followed by the second alkylation. The reaction was conducted on a gram scale as well. A similar strategy was used for CuI-catalyzed arylation of sulfinamides with aryliodonium salts and N,Ndicyclohexylmethylamine in DMSO: conversion of N-pivaloyl tert-butane sulfinamide proceeded in 53−90% yield. 316 De-tertbutylation with potassium tert-butoxide (85%) and second arylation (68−91%) yielded the desired enantiopure diaryl sulfoximines. The same group described also a stereoselective preparation of five-membered cyclic sulfoximines by cyclization of optically pure N-propargylsulfinamides. 317

Formation of SO and SN Bonds
In 2017, three groups independently reported a convenient one-pot protocol for the synthesis of NH-sulfoximines from sulfides. Reactants which were found efficient for the conversion of sulfoxides to sulfoximines, diacetoxyiodobenzene (phenyliodine diacetate, PIDA), and ammonium carbamate were successfully applied by Bull, Luisi, and co-workers in nitrogen and oxygen transfer to sulfides (Scheme 44). 301 Preparation of NH-sulfoximines from sulfides treated with PIDA and H 2 NCOONH 4 was also described by Reboul and co-workers, 318 and modified reaction conditions allowed extension of the methodology for derivatives bearing perfluoroalkyl substituents (Scheme 44). 319 A similar procedure, but with ammonium carbonate ((NH 4 ) 2 CO 3 ) as the source of ammonia, was developed by Li and co-workers (Scheme 44). 320 An asymmetric variant of this versatile, operationally simple method offering a broad substrate scope and performed under mild conditions (at room temperature under air) is of high demand, but it has not been announced yet.
The sulfoximination protocol was applied by Reboul's group in the last step of the synthesis of drug candidate atuveciclib. 321 An attempted stereoselective synthesis via enantiomerically enriched sulfoxide resulted in (S)-enantiomer with only 20% ee. The authors attributed this unsatisfactory result to the low enantioselectivity of sulfoxidation step for which Kagan's conditions were applied.

Desymmetrization of Achiral or Racemic Sulfoximines. Kinetic Resolution
Desymmetrization of N-trialkylsilyl dimethyl sulfoximines was performed by their treatment with chiral bases and reacting the resulting anion with electrophiles, thus yielding enantioenriched derivatives difficult to obtain by other methods. 322 Under optimized conditions, with chiral lithium amide prepared in situ, several electrophiles were tested with variable yield (6−86%) and enantioselectivity (18−70% ee).
The desymmetrization strategy was later used for the preparation of S,S-dialkyl sulfoximine 77, an optically active myristic acid analogue. 323 However, a simple generation of anion from dimethyl derivative 75 followed by addition of dodecyl iodide resulted in a racemic product and a strategy was modified, finally yielding the desired sulfoximine with 58% ee (Scheme 45). The target compound was prepared in high enantiomeric purity using enantioselective oxidation of 4bromophenyl methyl sulfide (Kagan's method was applied), followed by a displacement of aryl group by Grignard reagent, iron-catalyzed imination, and deprotection of nitrogen atom.
Kinetic resolution of NH-sulfoximines utilizing their amidation with enals catalyzed by chiral N-heterocyclic carbene catalysts was described by Dong et al. 324 A broad variety of aryl-substituted sulfoximines afforded amides with reasonable yield and excellent stereoselectivity (up to 59% yield, up to 96% ee), and unreacted sulfoximines in up to 56% yield and up to 99% ee; both enantiomeric forms of each product could be obtained). The reaction could be performed on a gram scale, which was demonstrated by the efficient preparation of sulfoximine further transformed into optically active Betrixaban analogue, an inhibitor of human Factor Xa.
A stereodifferentiation of variety of sulfoximines upon annulation with diazo compounds catalyzed by rhodium(III) complex bearing a chiral Cp x ligand was independently described by the groups of Li 325 and Cramer. 326,327 A possible inversion of stereoselectivity caused by the change of solvent or suitable additives was noticed.

Modifications of Sulfoximines
Typical modifications of optically active sulfoximines concern substitution of imine nitrogen atom (however, they were also introduced into pseudopeptides by Bolm and co-workers using reactions of S-methyl substituent 328−330 ). New attempts are usually performed with racemic substrates, but in many cases tests with enantiomerically pure compounds prove a retention of configuration of stereocenters. For example, in N-arylation Palladium-and copper-catalyzed arylations of NH-or Nbenzylsulfoximines developed in Bolm's laboratory allowed preparation of chiral ligands for asymmetric synthesis. 333,334 This group obtained also chiral thiourea organocatalysts from (S)-S-methyl-S-phenylsulfoximine by a direct reaction with isothiocyanate. 335 Protocols for preparation of N-alkyl (acylation and reduction with complexed boranes) 336 and Nalkynyl derivatives (through the reaction with methoxy-(tosyloxy)iodobenzene) were described as well. 337,338 To avoid using stereochemically labile sulfonimidoyl chlorides in the synthesis of enantiomerically pure benzothiazines, Harmata and Pavri adapted the N-arylation protocol developed by Bolm. 331,339 The reaction between enantiopure NH-sulfoximine and ortho-bromobenzoates or analogous cinnamate derivative resulted in N-arylation; ring closure upon addition of a base such as sodium or potassium hydride yielded substituted 2,1-benzothiazines as single isomers (Scheme 47). The reaction could be performed in a one-pot version when o-bromobenzaldehydes were used as reactants. Benzothiazines were also obtained in the reaction of methyl phenylsulfoximine with o-bromocinnamates followed by baseinduced cyclization. 340,341 Products were formed as single stereoisomers in a highly stereospecific process.
Harmata and co-workers described a palladium-catalyzed microwave-assisted reaction of aryl chlorides with NHsulfoximine, which allowed preparation of a series of arylated sulfoximines and benzothiazines in good to excellent yields in a relatively short time. 342 When aryl dichlorides were used, under various reaction conditions, only products of monosubstitution were observed. 343

SULFONIMIDOYL HALIDES
The title compounds, which can be regarded as halides of sulfonimidic acid, are relatively unstable (at least chlorides and bromides), moisture-sensitive compounds prepared as intermediates in the synthesis of other tetrasubstituted sulfinyl derivatives. Their chemistry was reviewed by Levchenko and co-workers in 2000. 344 Here, we present several papers devoted to the preparation of these compounds, but they will also appear in other sections, especially in the one concerning sulfonimidamides.
Most frequently, sulfonimidoyl chlorides are obtained from sulfinyl chlorides, sulfinamides, but also from other tetrasubstituted sulfinyl derivatives. Their first successful preparation was reported by Levchenko and Kirsanov in 1960. 345 Johnson and co-workers developed a new method of preparation of these compounds by oxidation of sulfinamides with chlorine or N-chlorobenzotriazole 82, 346,347 later replaced by tert-butyl hypochlorite (Scheme 48). 348 Retention of configuration during this transformation was established (due to the priority rules, this means that when chlorine substituent takes place of lone pair of electrons, (S)-sulfinamide was converted to (R)sulfonimidoyl chloride). 349 Stereospecific conversions of sulfonimidoyl chloride to sulfinamidate and sulfonimidamides was associated with inversion of configuration.
Jones and Cram reported on the preparation of epimeric Ncarbomenthoxy-p-toluenesulfonimidoyl chlorides using two methods and proved that also imination of sulfinyl chloride proceeds with retention of configuration. 28 A cycle of stereospecific transformations involving several sulfinyl derivatives was proposed.
Roy investigated the possibility of preparation of sulfonimidoyl chloride from other tetrasubstituted sulfinyl compounds. 350 He reacted N-silylated sulfonamides with phosphorus chlorides and observed formation of the corresponding chlorides under appropriate conditions. He also obtained the first detectable sulfonimidoyl bromide. Correlation of configuration was not the part of the study.
Sulfonimidoyl fluorides have been recognized as more stable analogues of their chloride counterparts, which makes them more convenient as reaction intermediates that can be isolated without the need of immediate use. Unfortunately, the stereochemical course of the reactions in which they were prepared was not studied. First, sulfonimidoyl fluorides were prepared by Johnson and co-workers from the respective chlorides and diverse fluoride sources (NaF, KF, TBAF). 351 These derivatives were used in the synthesis of sulfoximines. Novel sulfonimidoyl fluorides were prepared by van Leusen et al. by treatment of the corresponding chlorides with KF or KHF 2 . 352 N-Tosyl derivatives exhibited shelf stability; partial resolution to enantiomers by crystallization was achieved for Chemical Reviews pubs.acs.org/CR Review one derivative. Fluorides were converted to the corresponding (racemic) isocyanides as well. Selectfluor was found useful as a fluoride source in conversion of cyclic sulfoximine to the cyclic fluorinated 1oxo-2H-1,2,4-benzothiadizine derivative, which was characterized by X-ray study. 353 Quite recently, Sharpless and coworkers applied thionyl tetrafluoride 83 in a two-step reaction; in the first step, primary amines were treated with SOF 4 , which resulted in difluoride intermediate. Its reaction with alkyllithium yielded the desired products (Scheme 49). 354

PREPARATION OF OPTICALLY ACTIVE
SULFONIMIDATES Similarly to sulfoximines and sulfonimidamides, sulfonimidates have been known for over half a century and recently rediscovered, mainly as intermediates in the synthesis of sulfoximines. To fulfill these roles, they are not always required in enantiomerically pure form, and thus certain preparative methods rather neglect the fate of stereogenic center. Possible applications of these compounds are limited by their observed slow conversion to corresponding sulfonamides at elevated temperature. 355

S−O Bond Formation
Typical preparations of sulfonimidates involve oxidative introduction of alkoxy group into sulfinamides. It is often, but not necessarily, realized in two steps. Already, in the 1970s, Johnson and co-workers prepared enantiopure sulfonimidates in a two-step procedure involving reaction of (S)-Nmethylbenzenesulfinamide 84 with chlorine followed by treatment of obtained sulfonimidoyl chloride 85 with sodium phenoxide (Scheme 50). 29 (S)-Sulfonimidate 87 was formed as a result of retention of configuration in the first step and inversion in the second one. Scheme 50 shows other possible conversions involving also sulfonimidamide 86 and sulfoximine 88, confirming that typically interconversions of tetrasubstituted derivatives are associated with the change of configuration, in contrast to those between three-and foursubstituted chiral sulfinyl compounds.
In 1993, Roy reported a conversion of racemic N-silylated sulfonimidoyl chlorides and bromides to the corresponding sulfonimidates in yields up to 78%. 350 A quantitative desilylation with methanol resulted in NH-sulfonimidates. 356 Thermally induced, Lewis acid-catalyzed polycondensation of these compounds as well as of certain silylated derivatives was observed, yielding poly(oxothiazene) polymers with an NS backbone.
Sulfinamides bearing hydroxyl group in the N-substituent were shown to undergo cyclization to sulfonimidates. Reggelin and co-workers developed an efficient stereoselective synthesis of enantiomers of cyclic sulfonimidate that could be used as precursors for enantiopure sulfoximines (Scheme 40). 304,357,358 The synthesis started from (S)-O-trimethylsilylvalinol and sodium salt of p-toluenesulfinic acid. The most efficient route included separation of epimeric sulfinamides by crystallization prior to the conversion of sulfonimidoyl chlorides with t-BuOCl; a fast, DBU-induced cyclization appeared at −78°C, which precluded the loss of enantiomeric purity. 357 Sulfonimidates were prepared by Malacria and co-workers through the reaction of sulfinamides with alcohols and iodosylbenzene (Scheme 51). 359 The reaction proceeded smoothly for primary alcohols serving also as solvents (71− 94% yield after 1 h in room temperature). When the reaction was conducted in acetonitrile with 3 equiv of alcohols, yields were slightly lower (39−95%) due to the competitive oxidation to sulfonamide. Also, secondary sulfinamide was efficiently converted to the corresponding sulfonimidate in 52% yield. Stereospecifity of the transformation was checked with two enantiomerically pure sulfinamides, which yielded the corresponding products with 62 and 72% ee, mainly with retention of configuration. 360 This observation was confirmed by the conversion of enantiopure sulfinamides bearing an additional stereogenic center: diastereomeric products were formed with 51−76 de. X-ray structure of the major isomer of resulting sulfonimidate proved that configuration of sulfur stereocenter was retained.
The above method was limited to N-alkyl derivatives. In 2006, Felim et al. reported the modified protocol which allowed preparation of N-aryl sulfonimidates, and better results were obtained when PhIO was replaced by more stable PhI(OAc) 2 (or its phenyl-substituted derivatives) with MgO as a base. 361 Similarly, a series of 27 sulfonimidates were prepared by oxidation of sulfinamides with PhIO in the presence of alcohols (15 min at room temperature, yields up to 93%). 307 The resulting (racemic) compounds were further converted to sulfoximines (see section 7.4).

Other Methods
In a recent report of Luisi, Bull, and co-workers, thiols were reacted with ammonium carbamate and diacetoxyiodobenzene in methanol, yielding the corresponding sulfonamides or sulfonimidates, depending on reaction conditions (Scheme 52; shorter reaction time and an increase of the amount of ammonium carbamate resulted in higher yields of sulfonimidate). 302 In this convenient one-pot protocol, a direct formation of both sulfur−oxygen and sulfur−nitrogen bonds was observed. Factors which would induce stereoselectivity of the process were not checked; all reactants, including a variety of thiols, were achiral, and chiral additives were not tested. A possibility of transformation of sulfonimidate to sulfoximine was demonstrated by the reaction of electron-rich 4methoxyphenyl sulfonimidate with morpholine (80% yield, racemic).

STEREOSELECTIVE PREPARATION OF SULFONIMIDAMIDES
Sulfonimidamides belong to the group of intrinsically chiral sulfinyl compounds. Their story is very similar to other tetrasubstituted derivatives, sulfoximines and sulfonimidates; first prepared in the 1960s by Levchenko and co-workers, long forgotten, in the 21st century they have experienced an impressive revival. 362 It is connected with the discovery of their potential as biologically active substances, with possible pharmaceutical and agricultural applications 363 but also as chiral auxiliaries for asymmetric synthesis. The progress in the synthesis of sulfonimidamides was reviewed in a 2018 article by Nandi and Arvidsson. 362 Since then, several new publications have been issued. They will be presented in this section, together with representative examples of important contributions to the field.
Enantiopure sulfonimidamides were obtained either from other optically active sulfinyl derivatives or by separation of obtained isomers by HPLC. As the access to the starting material with two sulfur−nitrogen bonds is limited, one of these connections is formed in most preparations. The majority of described transformations involve sulfinamides and sulfonamides, and other tetrasubstituted derivatives (sulfonimidoyl halides or sulfonimidates) may serve as intermediates. Various approaches can differ by the substitution of imine and amine nitrogen atoms in the final product; postsynthetic modifications can change this pattern without altering the configuration of stereogenic sulfur atom.

Preparation of Sulfonimidamides from Sulfinamides
The first synthesis of optically active sulfonimidamide was reported by Johnson and co-workers. 349 Chlorination of sulfinamide (S)-84 followed by reaction with dimethylamine resulted in product (R)-86 in 56% overall yield with inversion of configuration (Scheme 50).
More recently, conversion of sulfinamides to sulfonimidamides was studied by Bolm's group. García Manchenõ and Bolm investigated chlorination of p-tolylsulfinamides con-nected with immediate transformation of transient sulfonimidoyl chlorides by the amine nucleophile into the respective racemic sulfonimidamides in 50−97%. 364 Two enantiopure Nbenzoyl-and N-tert-butyloxycarbonyl-protected sulfonimidamides were efficiently prepared in several steps starting from the commercially available sodium 4-toluenesulfinate 89 (Scheme 53). 365 Its conversion to enantiopure sulfinamide (S)-51 was achieved using menthol auxiliary. Oxidative chlorination of this sulfinamide with tert-butyl hypochlorite followed by reaction of transient (R)-sulfonimidoyl chlorides 92 and 93 with aqueous ammonia resulted in formation of enantiopure N-substituted (S)-sulfonimidamides 94 and 95 in 78% and 97% yield, respectively. Their configuration was confirmed by X-ray diffraction measurement. Amino-functionalized sulfonimidamides were prepared by oxidative chlorination of sulfinamides with t-BuOCl followed by the reaction with amine or bisamine. 366 Alternatively, a reaction of Nbenzoyl-protected sulfonimidamide with aziridinium salts obtained from aminoalcohols was performed. In the first case, enantiopure reactants were used and products were obtained as single stereoisomers, while the second method afforded separable mixtures of diastereomers. Applied in copper-catalyzed asymmetric Henry reaction, they led to product formation in reasonable yields and up to 95% ee.
A direct amination of N-arylsulfinamides with N-benzoyl derivatives of secondary amines (piperidine, piperazine, or morpholine) catalyzed by CuBr was also reported by Bolm and co-workers. 254 Chiral amines were not tested, and racemic products were obtained in 35−96% yield.
Oehlrich and co-workers described a synthesis of sulfonimidamides bearing a CF 3 substituent from the corresponding sulfinamides. Their oxidative fluorination by the action of NCS and TBAF led to sulfonimidoyl fluoride intermediates, more stable as compared to their chloride counterparts; a subsequent reaction with amines led to the desired sulfinyl derivatives. 367 Trifluoromethylated sulfonimidamides were also prepared by the same group from a bench-stable solid sulfoximine precursor. In both cases, the process could be conducted in a flow reactor. Unfortunately, stereoselectivity of the substitution was not the issue that deserved attention. 368 Cathers and Schloss reported on the synthesis of dipeptides containing sulfonimidamides as mimics for transition states for metalloproteases and aspartic acid. 369 Sulfinyl phthalimide prepared by oxidation of the respective sulfenyl derivative with m-CPBA was first treated with L-phenylalanine methyl ester to afford a separable mixture of diastereomers. Sulfinamide was then reacted with chlorine, followed by substitution of chloride Chemical Reviews pubs.acs.org/CR Review with ammonia, which yielded a sulfonimidamide with a free NH 2 group. Two more derivatives contained glycine benzyl ester and leucine methyl ester, the latter converted upon the crystallization attempt into a cyclic sulfonimidamide. The configuration of sulfur stereocenter in these compounds was, however, not studied. Inspired by the work of Bull, Luisi, and co-workers, 300 Lucking's group applied ammonium carbamate combined with PhI(OAc) 2 for NH transfer to tertiary sulfinamides. 370 NHsulfonimidamides were formed in good yields (Scheme 54) and, as suggested by one experiment with enantiomerically enriched substrate, also in a stereospecific manner (though configuration of the product was not established).

Preparation of Sulfonimidamides from Sulfonamides
Sulfonamides can be also converted to sulfonimidamides by a formal replacement of O by a NR fragment. Typically, sulfonimidoyl chlorides serve as intermediates of such preparations, as exemplified by the synthesis described by Chen and Gibson (Scheme 55). 371 Yields varied from 20 to 89%; enantiomerically pure derivatives were obtained only by chiral HPLC separation of a racemic sample. Sulfonimidamide derivatives of amino acids were prepared by chlorination of sulfonamides with Ph 3 PCl 2 , followed by the reaction with enantiopure amino acid esters. 372 Diastereomers formed in ca. 2:1 ratio were separated by column chromatography. Alternatively, a removal of N-tert-butyldiphenylsilyl (TBDPS) protecting group was performed yielding five-membered cyclic sulfonimidamides; preparative HPLC led to individual stereoisomers, and configuration of one of them was established by X-ray study.
A novel approach to the synthesis of sulfonimidamides was recently proposed by Grygorenko and co-workers who prepared a stable and versatile imidosulfuric diamide from the corresponding sulfonamide and used it in reactions with amines. 373 A variety of sulfonimidamides were obtained in 83− 94% yield, but only as racemates because no attempt was directed toward enantioselective variant of the reaction.

Other Preparations
Toth et al. prepared a series of sulfonimidamide−urea conjugates and evaluated their biological activity. 374 These compounds were obtained as racemates from sulfides, disulfides, thiols, or sodium sulfinates, which were converted into the corresponding N-sulfinyl thioureas; their oxidative chlorination with t-butyl hypochlorite followed by amination afforded the target compounds. The use of (1S,2R)norephedrine in the last step yielded a mixture of epimers which were separated to give enantiopure derivatives.
Sulfonimidamides were also obtained from unprotected sulfoximines in a copper-catalyzed dealkylation/amination process in which S-methyl or S-benzyl substituent was replaced by amines under O 2 atmosphere. 375 Yields were in certain cases high, however, the use of optically active sulfoximine resulted in racemic product.
Willis and co-workers developed a one-pot protocol using sulfinylamines, in particular a stable sulfinyltritylamine, as a starting point for sulfonimidamide synthesis. 376 Three steps: treatment with organometallic compound, chlorination, and the reaction with amine led to the protected sulfonimidamides in 49−80% yield. The use of chiral amine led to separable mixture of diastereomers; other stereochemical aspects were not considered.
Enantiopure imidazolyl and 1,2,4-triazolyl sulfonimidoyl derivatives were prepared from sulfonimidoyl chlorides as reported by Kluge et al. 377 Also, 1,2,3-triazole ring was introduced as a substituent of sulfur atom via click reaction of the corresponding azide by Nandi and Jesin. 378 To overcome the drawbacks of previous methods (e.g., limited functional group tolerance), Bolm's group described a new one-pot approach, involving sulfonimidate formation from N-tritylsulfinylamine, 4-fluorophenyldiazonium tetrafluoroborate, and 1-hydroxybenzotriazole in the presence of a base (Nmethylpiperidine was found optimal) in dimethyl carbonate chosen as solvent (Scheme 56). 379 Relatively stable sulfonimidates were converted to sulfonimidamides by the action of primary and secondary aliphatic amines. The method was found versatile, with high tolerance for various functional groups, although without any control of stereochemistry.
Bull, Luisi, and co-workers studied reaction of ammonium carbamate and iodosylbenzene with sulfenamides, a rarely used starting material, prepared from disulfides and amines. 380 A one-pot formation of SO and S−N bonds proceeded smoothly (45−95% yield after 1 h reaction in 2-propanol at 25°C, with 2.5 equiv of PhIO as oxidant, 2.0 equiv of NH 2 COONH 4 , and 1.0 equiv of acetic acid additive, Scheme 57). The obtained racemic products could be further functionalized.

Modifications of Sulfonimidamides
Numerous modifications involving either imine or amine nitrogen atoms of prepared sulfonimidamide have been reported by several research groups. It is assumed that such reactions do not affect the sulfur stereocenter, and usually this Chemical Reviews pubs.acs.org/CR Review has not been checked or simply racemic mixtures have been used in these transformations. Apparently enantiopure final products are not necessary for certain applications.
Several recent examples will be briefly described as the protocols can be easily adapted for synthesis of optically active compounds. Arvidsson's group focused their attention on preparation of NH sulfonimidamides. 381 Three methods were developed for deprotection of morpholine-substituted and imine-protected sulfonimidamidates under acidic, nucleophilic, and basic conditions. An efficient palladium-catalyzed arylation of imine nitrogen with aryl halides was also described. Arvidsson and co-workers reported also copper-catalyzed arylation using aryl boronic acids 382 (a similar reaction was independently described by Battula et al. 383 ), and N-acylation with aryl or heteroaryl halides and carbon monoxide released in situ from Mo(CO) 6 in the presence of palladium catalyst, DBU, and triethylamine. 384 Recently, N-trifluoromethylthiolated sulfonimidamides were prepared and their cytotoxic activity studied. 385 Microwave-assisted, copper-catalyzed N-arylation of sulfonimidamides was also described by Malacria and co-workers. 386 Even though hydroxyproline was used as ligand, the obtained products were racemic. The same team converted sulfonimidamides bearing NH 2 group into nitrenes by the reaction with PhIO; these nitrogen-transfer agents were trapped by sulfides, sulfoxides, or olefins in the presence of Cu(II) salt. 387 Reaction with enantiopure sulfoxide gave a mixture of separable diastereomers; otherwise diastereoselectivity was low in the case of sulfimide formation, while up to 50% de was noted for aziridination.
In 2018, 47 N-functionalized tertiary sulfonimidamides were prepared by Lucking and co-workers by arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation, and aminocarbonylation of the NH group. 388 Their hydrolytic and metabolic stability were checked, indicating the potential of application in biological systems.
Modifications of sulfonimidamides were also introduced by Bolm and co-workers. 389,390 Enantiopure derivatives were tested in asymmetric reactions. Novel organocatalysts were obtained in good yield from protected (S)-proline and two enantiomers of N-tosylsulfonimidamide. 391 High diastereoand enantioselectivity was observed when these compounds were applied in solvent-free asymmetric aldol reaction. N-Phosphorylation of single enantiomers of sulfonimidamides resulted in novel phosphoramidites (SIAPhos), which were used to prepare neutral rhodium and iridium complexes, the latter found efficient in asymmetric hydrogenation of enamides (70−92% ee). 392 Kinetic resolution of racemic sulfonimidamides was described by Liang et al., who applied these compounds for amination of benzylic C−H bonds catalyzed by a chiral Rh(II) complex. 393 A strong matched effect was observed between (S)-enantiomers of sulfinyl compound and the catalyst. The reaction of various benzylic substrates with racemic sulfonimidamide and PhI(OCOt-Bu) 2 in the presence of (S)-form of rhodium complex resulted in formation of (1R,S S ) product in 56−77% yield, 88−99% de, and 97−99% ee, , accompanied by recovery of unreacted substrate with (R s ) configuration.

SUMMARY
Undoubtly, chiral sulfinyl compounds have proved their usefulness and versatility in modern stereoselective synthesis, serving as precursors, catalysts, and ligands in various preparations of important target molecules, mainly for biomedical applications. These derivatives, despite a common structural feature, constitute an omnifarious family. Consequently, certain methods of their preparation in enantiomerically pure form are similar, while part of synthetic routes remain applicable only for particular representatives. A possibility of mutual interconversions between various sulfinyl compounds is therefore worth emphasizing, because one precursor can be quite often transformed into other derivatives in a stereospecific manner without significant loss of optical purity (which can be in many cases improved by crystallization). More and more such chiral sulfinyl transfer agents have become easily available (in a short synthesis or from commercial sources), in both enantiomeric forms, and virtually any substitution pattern can be achieved. On the other hand, preparative methods based on catalytic enantioselective oxidation or imination of achiral organosulfur compounds involve chirality multiplication and are beneficial from the economic point of view. The possible disadvantages and difficulties (e.g., contamination by traces of toxic metals which can preclude biomedical applications) can be overcome if chiral organic molecules are applied as catalysts.
The development of synthetic methods is often inspired by the increased interest in a given family of compounds resulting from possible applications (both synthetic and biomedical). Quite often, a series of independent reports are published in a short period of time, followed by subsequent papers describing modifications and improvements. In the case of sulfinyl compounds, it can be observed that new approaches have been introduced mainly without much stress on stereochemical issues, which are included on the later stage. This raises hopes on further progress in the field, as asymmetric variants of newly introduced methods are needed. One recent example can be added to those cited in the previous sections. A one-pot synthesis of unsymmetrical sulfoxides was developed based on subsequent reactions of two organometallic reagents with DABSO (DABCO-bis(sulfur dioxide)) used as a source of sulfinyl group. 394 A potential of this methodology and other protocols in which chiral sulfinyl compounds are obtained as racemic mixtures should serve as a driving force in future research in the field.

Notes
The authors declare no competing financial interest.