N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.


Scheme 1:
General strategy for the enantioselective synthesis of N-containing heterocycles from N-tert-butanesulfinyl imines. Intoduction Chiral imines derived from tert-butanesulfinamide have been extensively used as electrophiles in a wide range of reactions. The presence of the chiral electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon [1][2][3]. The ready availability of both enantiomers of tert-butanesulfinamide in large-scale processes, the easy deprotection of the amine under mild acidic conditions, and a practical procedure for recycling the chiral auxiliary [4,5] have contributed to the widespread use of these imines as precursors of chiral compounds with a nitrogen atom bonded to a stereogenic center. The amine derivatives, resulting after removal of the tert-butanesulfinyl group, can be transformed into enantioenriched nitrogen-containing heterocycles [6,7] including natural alkaloids [8][9][10][11] and other compounds that show different types of biological activities [12,13]. The way to achieve these transformations is by intramolecular cyclizations, involving the free primary amine, and appropriate reactive positions (those positions bearing a leaving group) in the electrophile or in the carbonyl component of the starting imine (Scheme 1).

Synthesis of tert-butane N-sulfinyl imines
The first method developed for the synthesis of enantiomerically pure N-tert-butanesulfonamide 1 was reported by Ellman and co-workers [14,15]. In 1999, they described the synthesis of imines from the condensation reaction of aldehydes or ketones with tert-butanesulfinamides. In this work, the condensation with aldehydes was carried using Ti(OEt) 4 in tetrahydrofuran (THF), or CuSO 4 in dichloromethane at room temperature. The combination of MgSO 4 in the presence of a catalytic amount of pyridinium p-toluenesulfonate (PPTS) also worked well to perform these condensations [1,16]. For the formation of aldimines, other methodologies are described in the literature using condensation reagents such as Yb(OTf) 3 [17], Cs 2 CO 3 [18] and KHSO 4 [19]. However, for the synthesis of ketimines, Ti(OEt) 4 was the only effective reagent when performing the reaction at 60 °C in THF [16]. Ketimines were also synthesized with Ti(OEt) 4 , under microwave irradiation in a solvent-free system [20]. In hindered ketones, Ti(OiPr) 4 or Ti(OEt) 4 using vacuum or under a nitrogen flow were effective to tert-butanesulfinyl ketimine condensation (Scheme 2) [21].

Mechanism of addition of nucleophiles to N-sulfinyl imines
The p-toluenesulfinamide 5 was first described by Davis and co-workers in a racemic form [22], and subsequently, the compound was prepared and isolated as a single enantiomer [23,24], becoming an important tool in the asymmetric synthesis of aziridines [25,26], α-amino acids [27,28], β-amino acids [23,29] and branched α-amines [30,31]. The Darzens-type asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2-carboxylate esters (7 and 8) was described through the addition of lithium α-bromoenolates to enantiopure p-toluenesulfinamide 5. cisaziridine 7a was formed as the major diastereoisomer in 89% yield and the trans-isomer in 8% yield in a one-step procedure using lithium enolates of methyl bromoacetate 6a and sulfinyl imine 5. Lithium enolates of methyl α-bromopropionate gave trans-aziridine in 50% yield under the same conditions. The transition state is proposed with a six-membered chair-like transition containing a four-membered metallocycle. In cis-aziridine the enolate of methyl α-bromoacetate has E-geometry and the trans-aziridine 8a has Z-geometry [32,33]. In the transition Scheme 2: Methodologies for condensation of aldehydes and ketones with tert-butanesulfinamides (1).

Scheme 3: Transition models for cis-aziridines and trans-aziridines.
state, the metal cation of the enolate is being coordinated with both nitrogen and oxygen atoms of the sulfinimine [25,26] (Scheme 3).
In 1999, Ellman and co-workers described the reduction of sulfinyl imines using sodium borohydride (NaBH 4 ) [34] or o ʟ-selectride [35]. Davis-Ellman transition state models were proposed to rationalize organometallic additions to N-sulfinyl imines. The mechanism for obtaining these two stereoisomers was elucidated in the work published by Andersen and coworkers [36]. The origin of the reversal of the diastereofacial selectivity on the change of reducing agents is based on the operating transition states [37,38]. A cyclic transition state is proposed in the reaction with sodium borohydride. In this transition state, the oxygen of the sulfinyl group interacts with the boron atom, facilitating the release of the hydride, directing the attack to the Si-face of the imine with (R S ,E) configuration. When the reduction is performed with ʟ-selectride, with the Scheme 4: Mechanism for the reduction of N-tert-butanesulfinyl imines. poorly coordinating metal hydride, an open transition state operates due to the bulkiness of the isobutyl groups bonded to the boron atom. In this case, the attack of the hydride takes place to the less hindered Re-face of the imine (Scheme 4) [1,36].
The nucleophilic addition reactions to N-tert-butanesulfinyl imines were also described by Ellman and co-workers who reported the addition of allylmagnesium bromide to ketimines. The employment of Grignard reagents showed greater diastereoselectivity than reactions using organolithium and organocerium compounds. In some examples, the use of organolithium is feasible through the use of aluminum-derived additives [15]. In this study, the influence of solvents on diastereoselectivity was also observed. They found that the reactions performed in noncoordinating solvents, such as toluene and dichloromethane, took place with high diastereoselectivity. However, solvents such as ether and THF had a negative impact on stereoselectivity [15]. On the other hand, recent studies developed by Sirvent and Foubelo demonstrated the influence of the solvents in both the yield and diastereoselectivity in these reactions. They found that working in THF led to higher yields and poorer diastereoselectivities than when the reactions were performed in less coordinating solvents, such as diethyl ether and toluene [39].
Based on a broader analysis related to the effects of the solvent, metal and additives in 1,2-addition reactions to N-tert-butanesulfinyl imines of organometallic compounds, different transition models have been proposed to explain the stereochemical outcomes. The cyclic model justified by the Zimmermann-Traxler transition state [40][41][42] is the typical mechanism operating in reactions involving Grignard reagents in noncoordinating solvents, such as toluene and dichloromethane, while an acyclic model [43] is common in organolithium compounds in solvents such as THF. In the cyclic model, the bulky tertbutyl group occupies an equatorial position due to steric hindrance [1,14,44,45] (Scheme 5).
After this brief about the synthesis of enantiomerically pure N-tert-butanesulfonamide and applications in some nucleophilic additions, the next sections will describe the synthesis of several alkaloids according to the size of the heterocycles. We regret in advance that some contributions are excluded in order to maintain a concise format.

Review Asymmetric synthesis of aziridines
Saturated nitrogen-containing three-membered heterocycles have attracted increasing interest in recent years because compounds with this structural motif display quite diverse pharmacological activities. Chiral aziridines [51] also play an important role in asymmetric synthesis because they can act both as ligands [52][53][54][55] and as chiral auxiliaries [56]. The most widely used synthetic methods to form the aziridine ring [57][58][59][60][61] include intramolecular cyclizations in amines bearing potential leaving groups. Stereoselective syntheses of aziridines have been successfully carried out by combining a nucleophilic addition to N-tert-butanesulfinyl α-chloroimines, and an intramolecular cyclization, the chlorine atom being finally displaced.

Scheme 5:
Transition models for the addition of organomagnesium and organolithium compounds to N-tert-butanesulfinyl imines.
The first asymmetric synthesis of 2,2-dibromoaziridines 15 was achieved by performing the nucleophilic addition of the anion resulting from the deprotonation of bromoform with sodium hexamethyldisilazide (NaHMDS) to chiral N-tert-butanesulfinyl aldimines (RS)-14, at low temperature, and using DMF as solvent. After addition, a subsequent intramolecular cyclization involving the resulting amide and the vicinal carbon with bromine atoms took place. By contrary, when the reaction was carried out in THF, the elimination process was suppressed, leading exclusively to enantiomerically pure α-tribromomethylamines 16. The structure and configuration of aziridines 15 were determined unambiguously by single crystal X-ray analysis [64]. In order to explain the experimental results, a nonchelation controlled transition state was proposed. Based on computational studies, it is known that a kind of s-cis arrangement of the sulfinyl group is the most stable conformation of the imine, due to the contribution of the hydrogen bonding of the oxygen and the iminic hydrogen. In this scenario, the tribromomethyl anion attacked the less hindered Re face of the imine with (RS) configuration (Scheme 6). The applicability of sulfinyl imines was also shown by Garcia Ruano and co-workers. (S S )-tert-Butanesulfinyl imine 17b provided better diastereoselectivity to obtain aziridines 18b than (S S )-tert-butanesulfinyl imine 17a to obtain aziridines 18a (Scheme 7) [65].
Allylation of N-tert-butanesulfinyl imines 14 with allylic bromides in the presence of zinc or indium metals is a well-known reaction [66,67]. It is possible to control and predict the stereochemistry of the addition to get the corresponding homoallylamine derivative with a high level of stereocontrol. The reaction of chiral imine 14 with an excess of 1,3-dibromopropene (23) in THF at 50 °C for 2 h, and a 1000 rpm rotation speed, led to trans-vinylaziridines 22, in moderate yields and high diastereoselectivities. Those were the reaction conditions that Sun and co-workers found to be optimal for the formation of the vinylaziridines [68]. However, when the allylation was performed in the presence of indium metal, in a saturated aqueous solution of sodium bromide, a mixture of the bromoallylation and allylation products 25 and 26, respectively, were obtained [69]. The addition of the allyl unit to the imines proceeded with total facial diastereoselectivity, producing also preferably diastereoisomers with anti relative configuration. According to the mechanism depicted on Scheme 8, the allyl unit reacted at γ-position, taking place the addition to the Si face of the imines with R S configuration. The bromoallylated product 24 was obtained as a mixture of anti/syn diastereoisomers. Treatment of com-pounds 24 with potassium hexamethyldisilazide provided vinylaziridines 22 through an intramolecular cyclization step. This intramolecular nucleophilic substitution is a stereospecific process. In the case of aromatic compounds 24, trans-vinylaziridines were the only reaction products, meanwhile for aliphatic derivatives 24 (R = alkyl), trans-and cis-aziridines 22 were isolated in practically the same ratio as the anti/syn ratio of their precursors 24. This shows that the cyclization reaction is stereospecific (Scheme 8). Comparing both methodologies, the indium-mediated bromoallylation seemed to be superior, since aliphatic aldimines 14 were compatible with this approach.
The group of Stockman reported the synthesis of 2,2′,3-substituted aziridines 27 from N-tert-butanesulfinyl imines 14 and α-bromoesters 26 by applying an aza-Darzens methodology [70]. The reactions were performed in THF at −78 °C, using lithium hexamethyldisilazide as base. Aziridines with relative trans-configuration were obtained in good yields and excellent stereoselectivities with methyl α-bromo-α-phenylacetate (26, R 2 = Ph). Lower yields, and poorer diastereoselectivities were observed with less bulky methyl 2-bromo-2-butenoate (R 2 = CH 3 CH=), leading to an almost complete loss of cis/trans selectivity by the reaction with aliphatic aldimines 14. The absolute configuration of the reaction products was unambiguously determined after X-ray crystallographic analysis of some of the reaction products. In order to rationalize the observed stereochemical outcome, a six-membered cyclic transition state has been proposed. The addition to imine 14 with S S configuration takes place on the less hindered Re face, on the other hand, the cis/trans selectivity observed being a consequence of the E stereochemistry of both the imine 14 and the enolate derived from bromoester 26 (Scheme 9).
A two-step protocol carried out in a single synthetic operation was developed by Chen and Zhang to synthesize 3-substituted 2-chloroaziridines with relative cis configuration [71]. The reaction of chiral imines 14 in dichloromethane in the presence of 2 equivalents of phenyllithium at −78 °C to room temperature produced the expected 2-chloroaziridines with excellent yields and diastereoselectivities. Under the previously commented optimized reaction conditions, dichloromethyllithium is first generated, taking place a diastereoselective nucleophilic dichloromethylation of the imine. The addition took place almost exclusively to the Re face of the imine (R S )-14, which is the less sterically hindered in the most stable s-cis conformation (see Scheme 2). The second intramolecular N-alkylation step produced the 2-chloroaziridines 28 with relative cis configuration. The absolute proposed configurations were confirmed by X-ray crystallographic analysis (Scheme 10).
An interesting asymmetric vinylogous aza-Darzens reaction was employed to access cis-vinylaziridines 30 and 31. The group of Njardarson found that the reaction of different aromatic and aliphatic chiral imines (S S )-14 with the dienolate resulting from the deprotonation of bromomethyl butenolide 29 in THF at −78 °C led to a mixture of diastereomeric cis-vinylaziridines 30 and 31 with good yields in most cases. Lithium hexamethyldisilazide was the base of choice to perform the deprotonation, and it must be added very slowly to the reaction mixture in order to suppress self-dimerization of the butenolide [72]. The structures as well as the absolute and relative stereochemistry of reaction products 30 and 31 were also unambiguously determined following a single-crystal X-ray analysis (Scheme 11).
The stereoselective synthesis of diastereomeric 2-chloro-2aroylaziridines 36 and 32 was successfully accomplished through a three-component cascade coupling reaction of silyldichloro-methanes 33, arylnitriles 34 and chiral N-tertbutanesulfinyl aldimines (R S )-14. The process reported by Lu, Xu and co-workers started with the deprotonation of silyl com-pounds 33 with LDA at -78 °C, leading to the corresponding silyldichloromethyllium derivative, which reacted with arylnitrile 34. After nucleophilic addition and [1,3]-aza-Brook rearrangement, N-silyllithiumenamide 35 was formed. This strongly nucleophilic species could be traped by the chiral imine (R S )-14, producing 2-chloro-2-aroylaziridines via and aza-Darzens reaction [73]. Importantly, the structure of the final aziridine is determined by the silyl group, and the order of the addition of HMPA and imine 14 in the multicomponent coupling. When the bulky TBS group was used, and HMPA was added to the reaction mixture before the imine 14, aziridines 36 were formed. The addition of lithium metaloenamine took place through and open transition state to the Re face of the imine (R S )-14, followed by an intramolecular nucleophilic substitution to form the aziridines ring. On the contrary, aziridines 32 were obtained starting from dichloromethyltrimethylsilane (33, [Si] = TMS), and adding the chiral imine before HMPA to the reaction mixture. The nucleophilic addition of metaloenaime occurred through a cyclic transition state to the Si face of the imine (R S )-14. In this way, both cis-aziridines diastereoisomers 36 and 32 were formed from the same chiral imine 14 and arylnitriles 34 (Scheme 12). Chiral sulfinyl imines have been also used in the stereoselective synthesis of aziridines. The reaction of N-tert-butanesulfinyl trifluoromethyl ketimines (S S )-37 with dimethylsulfoxonium methylide 38 gave trifluoromethylated aziridines 39 in moderate to excellent yields (45-93%), and good diastereoselectivities (86:14 to >99:1 dr). The absolute configuration of compounds 39 was determined by X-ray crystallographic analy-sis, and it was found that the configuration of the newly generated stereocenter was R. Huang and co-workers proposed a cyclic transition state determined by the coordination of the nitrogen of the imine, and the oxygen atoms of the sulfoxonium and sulfinyl units to the sodium cation, which is present in the reaction medium [74]. The trifluoromethyl group occupies an equatorial position to avoid electrostatic repulsion with the lone pair of electrons of the sulfinyl group. The nucleophilic attack took place to the Si face of the ketimine 37 (Scheme 13).
Recently, Yang and co-workers described the diastereoselective synthesis of aziridines 42 in one-step using the Cu(I)/ʟproline complex as a catalyst and N-tert-butasulfinylamide in an aminotrifluoromethylation reaction of alkenes. All the aziridines 42 were obtained with high diastereoselectivity (dr > 25:1) and good yields (56-98%) from allylic sulfonamides 40 and Togni's reagent (41). The reaction mechanism is proposed based on DFT calculations. In this study, they observed an intramolecularly intermediate Cu(III) species, and the sulfinamide acts as a direction group and nucleophile [75] (Scheme 14).
A stereoselective synthesis of 1-substituted 2-azaspiro [3.3]heptanes 45 (n = 1) was reported by the group of Reddy [81] starting from ethyl cyclobutanecarboxylate 43 and chiral N-tertbutanesulfinyl aldimines (R S )-14. In this three-step procedure, a highly diastereoselective addition of the ethyl cyclobutanecarboxylate anion occurred first, followed by the reduction of the ester group, and an intramolecular nucleophilic substitution of the tosylate of the resulting primary alcohol (Scheme 15). This methodology was applicable to the synthesis of 1-phenyl-2azaspiro [3.4]octane (45, n = 2, R = Ph) and 1-phenyl-2azaspiro [3.5]nonane (45, n = 3, R = Ph). The structure and absolute stereochemistry of these compounds were assigned based on the single-crystal X-ray diffraction analysis of azaspiroheptane 45 with a 9-fenanthryl substituent at 1-position.
The same three-step procedure was applied by Reddy and co-workers to synthesize 1-substituted 2,6-diazaspiro [3.3]hep- tanes 48, starting in this case from 1-Boc-azetidine-3-carboxylate 46, instead of ethyl cyclobutanecarboxylate 43 [82]. This structural motif was found to have similar physicochemical properties as 2-substituted piperazines, which are key intermediates in drug discovery. The applied protocol was found to be practical for the asymmetric synthesis of a variety of aromatic, heteroaromatic, and aliphatic 1-substituted 2,6-diazaspiro [3.3]heptanes 48, with overall yields ranging from 74 to 94% (Scheme 16).
Asymmetric synthesis of β-lactams β-Lactam antibiotics are important drug class of antibacterial agents [83] and in the literature, several strategies are reported using the sulfinyl group [84][85][86][87][88]. In this context, an enantioselective synthesis of 4-substituted azetidin-2-ones 52 was also accomplished starting from chiral imines 14 and dimethyl malonate (49). A diastereoselective coupling of these components under solvent-free conditions was carried out, using sodium carbonate as base promoter. The resulting dimethyl 2-(1aminoalkyl)malonates 50 were obtained in moderate to good yields as single diastereoisomers in all cases except for aromatic aldimines. Compounds 50 could be easily transformed successively into β-amino esters 51, and the corresponding β-lactams 52 with high optical purity (Scheme 17) [89]. The absolute configurations of compounds 52 were obtained by the comparison of the signs of specific rotation of 52 with R = Ph(CH 2 ) 2 , with that of known (R)-4-(2-phenylethyl)azetidin-2-one. A 6/4-fused bicyclic transition state model was proposed to rationalize the stereochemical outcome, in which the sodium metal is chelated by the oxygen and the nitrogen atoms of sulfinyl imine (Scheme 17), occurring the nucleophilic attack to the Si face of the imines with R S configuration. of 54 was carried out by using 1.0 M HCl in EtOAc, and further removal of the Tr group by the employment of TFA in dichloromethane afforded the 2-oxoindolinyl amino ester derivative 55, the key intermediate for the synthesis of (-)-AG-041R, a gastrin/cholecyctokinin-B receptor antagonist. In addition, amino ester 55 was transformed into the fully unprotected amino acid 56 under basic conditions in MeOH, and after that, further treatment with of MsCl and NaHCO 3 in MeCN at 80 °C led to spiro-β-lactam derivative 57 in 72% combined yield (Scheme 18) [88].
In 2020, Pierce and co-workers developed a method for the synthesis of guanidinium alkaloid batzelladine D in enantiomeric and racemic form, along with a series of stereochemical analogues. The batzelladines are a family of polycyclic guani-dinium alkaloids that were isolated in the mid-1990s from the Caribbean sponge bataella sp. From a biological point of view, the batzelladines have received attention due to their reported activity as inhibitors of HIV gp120-human CD4 binding. Chiral N-tert-butanesulfinyl aldimine (S S )-58 was used as a precursor in the synthesis of (-)-batzelladine D 61 and (-)-13-epi-batzelladine D 62. The reaction of (S S )-58 with methyl bromoacetate in the presence on Zn and CuCl in THF, left, after removal of the sulfinyl group under acidic conditions, to β-amino ester ammonium chloride 59 in high yield. This compound was transformed into β-lactam 60 in 90% yield by treatment with LDA in THF at −78 °C [90]. Compound 60 was converted after 9 steps in target batzelladines D 61 and 62 (Scheme 19). The authors explored also the antimicrobial activity of these compounds against a series of pathogens with starting promising results.

Asymmetric synthesis of pyrrolidines
The pyrrolidine ring is more represented within natural products than the 3-and 4-membered nitrogen-containing heterocycles. This molecular array is also found in drugs and other biologically active molecules. For this reason, there are numerous examples of synthetic methodologies for these compounds in the literature. In most cases, the pyrrolidine ring is formed from an amine with a hydrocarbon chain that also carries a functional group at the appropriate distance that allows the cyclization process to take place. In the case of substituted pyrrolidines, the stereoselective synthesis is especially interesting, highlighting the 1,3-dipolar cycloaddition reactions with azomethine ylides as an example of transformation that take place with great stereocontrol, and allow the synthesis of polyfunctionalized pyrrolidines in a single reaction step [91,92]. On the other hand, natural amino acids proline and hydroxyproline are functionalized pyrrolidines that have found great application in organic synthesis as chiral organocatalysts in stereoselective processes [93,94].

Cyclizations involving a position in the starting chiral imine
Arylation of chiral sulfinyl imines with sodium tetraarylboronates 64 was found to proceed with high diastereoselectivity under rhodium catalysis. Reddy and co-workers applied this methodology to the synthesis of 2-substituted pyrrolidines 66 [95]. The arylation of chlorinated imine (R S )-63 was performed with 2 mol % of an air-stable rhodium catalyst in dioxane, in the presence of 2 equivalents of MeOH, at 65 °C, leading to compounds 65 with high diastereomeric ratio. Crude amides 65 were converted into the corresponding pyrrolidines 66 in high yield by stirring at room temperature for 1 h in presence of 2.0 equivalents of LiHMDS (Scheme 20). It is important to highlight that cyclization occurred without epimerization with such as strong base.
Isoindolines with substituents at 1 and 3 positions were synthesized from an aromatic N-tert-butanesulfinyl imine 67, bearing a Michael acceptor in the ortho-position. Fustero, Barrio and co-workers found that combining an asymmetric nucleophilic addition to the chiral imine, with an intramolecular conjugate aza-Michael reaction, the expected 1,3-disubstituted isoindolines were produced with high diastereoselectivity [96]. Importantly, depending on the base involved in the intramolecular aza-Michael reaction, it was possible to reach either cis-or trans-isoindolines, 69 and 70, respectively, from the same precursor 68. The authors proposed that the thermodynamically more stable cis-isomer 69 is formed when TBAF was used. Meanwhile, working under kinetic conditions (DBU as base), trans-isomer 70 was obtained (Scheme 21). The group of Stahl provided an elegant approach to the synthesis of 2,5-disubstituted pyrrolidines 73, from alkenyl sulfinamides 72 [97]. These substrates were prepared from chiral N-tert-butanesulfinyl imine (R S )-71. Nucleophilic additions to this imine took place with high diastereoselectivity to the Si face of the iminic carbon. After that, the combination of Pd(TFA) 2 , lithium acetate and DMSO as solvent led to optimal results in the oxidative cyclization process to produce pyrrolidines 73 as a single diastereoisomer, with relative cis-configuration (Scheme 22). This has been the first reported nucleophilic attack of the sulfinyl group to a π-allylpalladium intermediate.
The asymmetric synthesis of 3-hydroxy-5-substituted pyrrolidin-2-ones 77, with relative cis-configuration, was reported by the group of Huang and Wei [98]. A diastereoselective addition of Grignard reagents to chiral aldimine (R S )-74, and an intramolecular oxidative cyclization of aminoalcohols derivatives 76, are key steps of this approach. Both diastereoisomers of aldimines 74 (R S and S S ) were prepared from ᴅ-malic acid and the corresponding enantiomer of tert-butanesulfinamide. Importantly, the choice of the solvent was crucial for obtaining high diastereoselectivities in the Grignard addition step, in which dichloromethane was performing better than THF. On the other hand, diastereoselectivities for addition products 75 were higher working with (R S )-74 than its (S S ) diastereoisomer, indicating a mismatch between the chiral auxiliary and the stereocenter in this substrate. Concerning the oxidative cyclization reaction, pyridinium dichromate (PDC) provided low yields of expected lactam 77. Many oxidants were checked for this transformation to take place, and the Sarett reagent [CrO 3 ·(C 5 H 5 ) 2 ] in DMF was the best to produce lactams 77. The synthetic interest of these functionalized lactams was demonstrated in the synthesis of alkaloid (−)-preussin (78) from the appropriate precursor 77 in three steps (Scheme 23).
Similar strategies were employed to obtain similar heterocycles [99]. Other regio-and stereoisomeric 2-pyrrolidones 80 were also prepared by a stereoselective tandem Barbier process of 79 with alkyl and aryl bromide [100]. The process was performed in this case under Barbier reaction conditions. Namely, the formation of the nucleophile (organomagnesium reagent) is carried out in the presence of the electrophile (chiral imine 79). Surprisingly, both diastereomeric aldimines 79 (R S and S S ) gave similar results concerning the stereochemical outcome, suggesting that the chiral sulfonamide moiety was not involved in the stereocontrol during this tandem Barbier addition process. After addition of the organomagnesium reagent to the imine 79, cycli- zation involving the magnesium amide and the ester occurred without the need of an extra cyclization step to give, after N-Boc protection, 4-hydroxy-5-substituted pyrrolidin-2-ones 90, with relative trans-configuration (Scheme 24).

Cyclizations involving a position in the attacking nucleophile
The reaction of ethyl 4-bromocrotonate (81) with LDA at −78 °C and subsequent addition of chiral imines 14 afforded 3-pyrrolines 82 with high diastereoselectivity. Chogii and Njardarson proposed that after deprotonation of 81, the resulting dienolate reacted at α-position with the chiral imine 14. The addition was highly diastereoselective, being the configuration of the newly created stereogenic center dependent on the configuration of the sulfur atom of the starting imine 14. After nucleophilic addition, and subsequent elimination, 3-pyrrolines 82 were formed as single diastereomers [101]. The whole process could be considered a [3 + 2] annulation, and aziridines were not observed as competing reaction products (see above Scheme 11). In addition, hindered imines, ethers, sulfonates, heteroaryl substituents, and conjugated imines were all well tolerated (Scheme 25).
A SmI 2 -mediated coupling of allenoate 83 with chiral (R S )-14 provided γ-amino ester derivatives 84 in good yields and moderate diastereomeric ratios. Huang and Py found that the better yields and diastereoselectivities were found working in THF as solvent in the presence of t-BuOH and LiBr as additives [102].
The isopropyl-substituted derivative 84 was easily converted into the corresponding methylene lactam 85, upon removal of the sulfinyl unit under acidic conditions. Finally, ozonolysis of 85 yielded tetramic acid 86 in 60% yield (Scheme 26). The configuration of the newly generated chiral center in compounds 84 was assigned from the sign of the optical rotation of enantioenriched tetramic acid 86, which was previously characterized. Based on this, it can be stated that addition of the allenoate 83 takes place mainly to the Re face of imines with (R S )-configuration.
Excellent diastereoselectivities were also achieved in the indium-mediated allylation of chiral tert-butanesulfinyl glyoxylate imine derivatives 87 with ethyl 2-bromomethylacrylate (88). Working at room temperature without any additional solvent provided the highest yields in these coupling reactions, amino diesters 89 being isolated as single diastereoisomers (Scheme 27). Removal of the sulfinyl group under acidic conditions, and further treatment of the resulting ammonium salts with sodium ethoxide, yielded α-methylene-γ-butyrolactams 90, in a one-pot, two-step process [103]. A six-membered chair-like transition state model with the indium coordinated to the nitrogen atom of the imine, and the sulfinyl and R groups located at axial positions, in a kind of s-cis conformation, was proposed to rationalize the stereochemical outcome. By considering this working model, the nucleophilic attack took place to the Re face of imines with (Z,S S )-configuration (Scheme 27). The cycloaddition of chiral sulfinyl imines (R S )-14 with 2-(trimethysilylmethyl)allyl acetate (91) could also be promoted by Pd(0) to give methylenepyrrolidines 92. The group of Stockman demonstrated that Pd(PPh 3 ) 4 was the best source of Pd(0) and that the reaction worked well in different solvents, with dry THF giving the best diastereoselectivities and good yields at room temperature [104]. The configuration of the major diastereoisomer was assigned by X-ray crystallographic analysis. From this, authors rationalized the stereochemical outcome of the cyclization considering that the stereoinduction is derived from the dipole-dipole repulsion of the sulfinyl imine, which places the tert-butyl group on the Si face, and thus the cycloaddition occurs from the less sterically hindered Re face. The cyclization process worked also in tert-butanesulfinyl ketimines, but yields and diastereoselectivities were significantly lower (Scheme 28).
Recently, a series of alkaloids like dibenzoazaspirodecanes 97 have been synthesized by addition of 2-bromobenzylmagnesium bromide (94) to chiral N-tert-butanesulfinyl imines 93. These reactions proceeded with high levels of diastereocontrol. The resulting sulfonamide derivatives 95 were transformed into the target spiro compound 97 by performing successive desulfinylation and intramolecular palladium-catalyzed N-arylation. To rationalize the stereochemical course of the addition, DFT calculations were performed and they predicted correctly the observed experimental results considering a six-membered ring cyclic transition state. The addition took place to the Si-face of the imines with (R S )-configuration. Compounds 97 were also evaluated in a preliminary study in leukemia strains (Scheme 29) [105].
Li and Xu reported a method for the enantioselective synthesis of β,γ-unsaturated α-amino acids 100, by a Lewis acidpromoted diastereoselective Petasis reaction of vinylboronic acids 98, (R)-N-tert-butanesulfinamide and glyoxylic acid (99). They found that the best results were obtained working with InBr 3 as Lewis acid, in dichloromethane at room temperature [106]. Under these reaction conditions, sulfinyl imine is formed first along with the boronate by interaction of the correspond-

Asymmetric synthesis of piperidines
The six-membered nitrogen-containing rings are the most common heterocycles among natural products and also synthetic pharmaceutical drugs [107,108]. For this reason, the piperidine unit has attracted great attention among organic chemists [109]. Due to that, a large number of classical methodologies have been used for their synthesis, in which the key step is the generation of the six-membered ring, including the aldol reaction, the reductive amination, Mannich reaction, ring closing metathesis, Diels-Alder reaction with imines as dienophiles, aza-Prins cyclization, and intramolecular Michael reaction, among others [110][111][112][113][114][115]. Despite the considerable effort made to date in this field, the development of new methodologies that allow accessing these heterocycles in a stereoselective way, and taking into account environmental considerations as one of the most important points, continue to be of great interest [109,[116][117][118].

Cyclizations involving a position in the starting chiral imine
Enantiomeric N-tert-butanesulfinyl imines 104b derived from 3-(2-bromophenyl)propanal have been used as reaction intermediates in the synthesis of tetrahydroquinoline alkaloids (−)-angustureine (107) and (−)-cuspareine (108) reported by Sirvent et al. [119]. The diastereoselective addition of a Grignard reagent was a key step in this methodology. The addition proceeded with high diastereoselectivity in toluene, and the attack of the Grignard reagent occurred on the Re face of the imine with S configuration at the sulfur atom, through a chelated transition state. The reaction of chiral aldimine (S S )-104b with pentylmagnesium bromide gave compound 106 in 75% yield. Further successive N-desulfinylation, intramolecular palladium-catalyzed N-arylation, and final N-methylation led to (−)-angustureine (107) in high overall yield (Scheme 31). The same methodology was applied to the synthesis of (−)-cuspareine (108), starting in this case from enantiomeric imine (R S )-104b, and using 2-(3,4-dimethoxyphenyl)ethylmagnesium bromide as Grignard reagent.
The group of Prasad reported the diastereoselective synthesis of β-amino ketone derivatives from N-tert-butanesulfinyl imines and silyl enol ethers of aryl methyl ketone [123]. The synthetic interest in β-amino ketones was exemplified in the synthesis of alkaloid (+)-sedamine (125), which has been shown to display memory-enhancing properties and was also effective for the treatment of cognitive disorders. The reaction of the N-tertbutanesulfinyl imine (S S )-119 with trimethylsilyl enol ether derived from acetophenone 123 in the presence of TMSOTf at low temperature, produced β-amino ketone derivative 124 in high yield and diastereoselectivity (Scheme 34). A reduction of 124 gave a mixture of diastereomeric alcohols, and the one with (R)-configuration at the benzylic position was isolated in 54% yield. Further treatment of the alcohol with NaH furnished a cyclized product, which after desulfination and N-methylation led to expected (+)-sedamine (125) in 30% overall yield from ketone derivative 124.
The stereoselective synthesis of trans-5-hydroxy-6-substituted-2-piperidinones was also reported by the group of Wei, taking advantage of the addition of Grignard reagents to N-tert-butanesulfinyl α-alkoxy aldimines 126 [124]. In this one-pot approach, a successive nucleophilic addition-cyclization-desulfinylation took place, leading directly to piperidinones 127. The reactions were performed in THF at −78 °C for 3 hours. Yields ranged from moderate to excellent with aliphatic and aromatic organomagnesium compounds. Based on X-ray crystallographic analyses, the relative configurations of the products 127 were unambiguously assigned as trans-form. The stereocontrol was governed by the stereogenic center bearing the OTBS group at α-position of the imine, showing no influence on it the configuration of the sulfur atom of the sulfinyl unit. This methodology was applied to the asymmetric synthesis of (−)-CP-99,994 (128), the enantiomer of a promising clinical agent which displays a variety of biological activities, including neurogenic inflammation, pain transmission, and regulation of the immune response. Starting from α-alkoxy aldimines ent-126, the utility of this methodology was also demonstrated in the synthesis of alkaloid (+)-cassine (130), isolated from the leaves and twigs of Cassia excelsa, displaying antimicrobial activity. Methylmagnesium bromide was the Grignard reagent in this synthesis, with a 18% overall yield after seven steps from aldimine ent-126 (Scheme 35) [125].
The reaction of chiral α-siloxyl imine (S S )-126 with enolates derived from methyl ketones 131 was also investigated. The enolate was formed with LDA at −78 °C and reacted at the same temperature with imine (S S )-126 for 2.5 hours. The addition proceeded with high diastereoselectivity, followed by cyclization. Final acid treatment produced the removal of the sulfinyl group leading to trans-5-hydroxy-6-substituted ethanone-2piperidinones 132 in moderate to high yields, as a single diastereoisomer [126]. The diastereoselectivity of the addition was controlled in this case by both the α-siloxyl group and the chiral sulfinamide moiety. Interestingly, the utility of this approach was also demonstrated by the synthesis of (+)-febrifugine (133), a natural product isolated from Chinese medicinal plants Dichroa febrifuga Lour., and (+)-halofuginone (134), which is a pharmaceutical candidate developed from febrifugine for the treatment of human scleroderma (Scheme 36).
The reaction of chiral imine 135 with Grignard reagents in THF took also place with high diastereoselectivity. Starting imine 135 with two well-defined stereogenic centers at the hydrocarbon backbone were prepared as a mixture of (R S )-and (S S )diastereoisomers from ᴅ-glutamic acid. After nucleophilic addition to the imine, a successive cyclization-desulfinylation occurred to give the corresponding piperidinone. Final reaction with di-tert-butyl dicarbonate led to functionalized 2-piperidinones 136 [127]. These compounds are interesting reaction intermediates because they can be transformed by conventional reactions into, for instance, compound L-685,458 (137), an inhibitor of γ-secretase, with potential interest for the treatment of Alzheimer's disease and other neurological disorders (Scheme 37).
The diastereoselective synthesis of trans-5-hydroxy-6-substituted 2-piperidinones 139 was also achieved from O-benzyl protected aldimine 138 following the previously commented tandem Grignard reagent addition, subsequent cyclizationdesulfinylation, and final N-Boc protection. The stereochemical pathway is controlled exclusively again by the configuration of the stereogenic center bearing the benzyloxy group [128]. Interestingly, chiral δ-lactams 139 are synthetic intermediates that can be transformed into compound (+)-L-733,060 (140), a potent neurokinin substance P receptor antagonist. This compound displays a wide variety of biological activities, including inhibition of neurogenic inflammation, blocking In 2018, Wei and co-workers described the diastereoselective synthesis of 1-substituted isoquinolones using one-pot addition-cyclization-deprotection of the imine with Grignard reagents [130]. In this work, the addition to chiral imines 146, 148 and 150 was performed using 2,2'-dipyridyl-or 4-methylmorpholine (NMM) to promote the complexation with the Grig- In 2020, Kaczorek and Kawęcki described the stereoselective synthesis of 3-substituted dihydrobenzo[de]isoquinolones 154 in both enantiomeric forms in one step. In this study, they reported an addition-cyclization-substitution reaction employing (Rs) and (Ss) N-tert-butylsulfinyl imine 14 and Grignard reagents using THF or CH 2 Cl 2 as solvent at 40 °C. The 3-substituted dihydrobenzo[de]isoquinolinones 154 were obtained with good yield and with enantiomeric excess of 46-99%. The mechanism was explained by stereoselective addition of the Grignard reagent to the N-sulfinyl imine 153a derived from 152, in a subsequent cyclization to obtain the intermediate 156 then, a substitution at the sulfur atom occurred to form 154a and 157 [131] (Scheme 41).
There are many compounds with a 1,2,3,4-tetrahydroisoquinoline structural motif bearing substituents at 1-position which display a wide range of biological activities. However, compounds bearing substituents at 3-position are less represented in nature and among pharmaceutical drugs. A multistep methodology to synthesize 1,2,3,4-tetrahydrosioquinolines 185 bearing substituents at 3-, 6-and 7-positions in a highly enantioselective fashion starting from chiral N-tert-butanesulfinyl imines (R S )-14 was reported by Sirvent et al. [137]. The key step of this synthesis is a [2 + 2 + 2] cyclotrimerization by means of Wilkinson catalyst of azadiyne system 180, which was accessible from imine 14 by consecutive diastereoselective indium-promoted propargylation, selective N-propargylation and final oxidation of the sulfinyl group. Sulfinyl imines (R S )-14 could be also precursors of tetrahydroisoquinolines with substituents at different positions of the aromatic ring, by combining allylation and propargylation processes as the first steps of this new strategy. The resulting azaenynes 179 and 181 were efficiently transformed by a ruthenium-catalyzed ringclosing metathesis into cyclic 1,3-dienes 182 and 186, respectively. The best results were obtained by performing the metathesis with Hoveyda-Grubbs second generation catalyst in the synthesis of cyclodiene 182, and with Grubbs first generation catalyst for compound 186. When these dienes reacted with dimethyl acetylenedicarboxylate in toluene at 100 ºC, followed by dehydrogenation of the resulting [4 + 2] adduct with DDQ, the expected 7,8-or 5,6-bis(methoxycarbonyl)substituted 1,2,3,4-tetrahydrosioquinolines 184 and 187, were obtained, respectively (Scheme 45). Turlington and co-workers reported a stereoselective synthesis in three steps of 2-substituted 1,2,5,6-tetrahydropyridines 196 starting from chiral N-tert-butanesulfinyl imines (R S )-14 [139]. The synthesis commenced with addition of the organolithium compound resulting from the deprotonation of 4-chloro-1butyne (194) to the imine. The propargylamine derivatives 195 were obtained in high yields and diastereoselectivities (>20:1 dr, in most cases). The lowest diastereoselectivity was found for pyridyl-substituted imine 14 (R = 3-pyridyl, 4:1 dr), due probably to competitive coordination of the lithium acetylide by the heteroatoms present in these imines. Reduction of the triple bond with Lindlar catalyst to provide olefin with cis-configuration, and cyclization using LiHMDS led to 1,2,5,6tetrahydropyridines 196 (Scheme 47).
Many methods have been provided to generate thermodynamically stable cis-2,6-disubstituted piperidines, but the synthesis of trans-derivatives remains elusive. In this regard, Bhattacharjee and co-workers reported a highly efficient large-scale synthesis of 2,6-trans-piperidine derivative 199 from easily available starting material [140]. Key steps of the synthesis are the diastereoselective addition of 4-pentenylmagnesium bromide to chiral imine (S S )-14 (R = 4-BrC 6 H 4 ). Two diastereoisomers 197 were isolated in 94% yield and moderate diastereoselectivity. The major component of the mixture was transformed into compound 198 through a Hoveyda-Grubbs second generation cross metathesis with ethyl acrylate. Another key step was the intramolecular aza-Michael reaction promoted by cesium carbonate as base in dimethylacetamide (DMA), leading to 2,6trans-piperidine derivative 199 in high yield (Scheme 48). This compound was an intermediate in the synthesis of a novel class of anti-infective agents.
The base-promoted decarboxylative Mannich coupling of chiral imines (R S )-14 [derived from an aldehyde R 1 CHO and (R)-tertbutanesulfinamide] with these reagents provided β-amino ketone derivative 200 in high yields and diastereoselectivities [120]. These compounds were easily transformed into cis-2,6-disubstituted piperidin-4-ones 201 through a ʟ-proline organocatalyzed intramolecular Mannich reaction with a second aldehyde (R 2 CHO). Almost no diastereoselectivity was observed when R 1 and R 2 were aromatic rings. On the other hand, aliphatic aldehydes gave in general excellent enantiomeric ratios (>90:10). It is important to note that the order of reaction of carbonyl compounds R 1 CHO and R 2 CHO with tert-butanesulfinamide to form chiral imine 14, or in the intramolecular organocatalyzed condensation, determined the absolute configuration of compounds 201 [141]. tions proceeded with high facial diastereoselectivity. The resulting β-nitroamine derivatives 204 were easily transformed into 5-nitro-6-substituted piperidine-2-ones 205, upon removal of the sulfinyl group with concomitant δ-lactam formation. Further transformation of the nitro group under Nef-type reaction conditions led to enantioenriched 6-substituted piperidine-2,5-diones 206 [142]. Interestingly, from compounds 205, and following a two-step process, involving conjugative addition to ethyl acrylate with formation of 207 as a single diastereoisomer, and final reduction of the nitro group with Raney-nickel, 1,7diazaspiro [4.5]decane-2,8-diones 208 were accessed in a highly stereoselective fashion (Scheme 50) [143].
A large number of biologically active natural products and synthetic pharmaceutical drugs contain the 3-aminooxidole motif. Chen and Xu demonstrated that the zinc-mediated allylation of chiral oxindole sulfinyl imines (R S )-53 with allylic bromides proceeded smoothly at room temperature in a mixture of THF and HMPA, and a wide range of highly enantiomerically enriched 3-allyl-substituted 3-aminooxindoles 209 were prepared. The observed diastereofacial selectivity was rationalized by considering an acyclic transition state model. The addition of the allylic reagent occurred to the less hindered Re face of the imine with (R S )-configuration. N-Allylation of compounds 209, followed by ring-closing metathesis with Grubbs second generation catalyst, and removal of the sulfinyl group, led to chiral spirocyclic aminooxindoles 210 in reasonable yields (Scheme 51) [144].
Azaspirocyclic alkaloids with interesting pharmacological properties have been isolated from skin extracts of dendrotabic frogs, and also from methanol extracts of ants of the species Carabella bicolor. Amongst these alkaloids, (−)-histrionicotoxin displays a potent noncompetitive acetylcholine antagonist activity. It was found that perhydrohistrionicotoxin analogues display similar biological properties. In this regard, Peralta-Hernández and Cordero-Vargas reported the synthesis of an advanced synthetic intermediate 213 of perhydrohistrionicotoxin [145]. The diastereoselective nucleophilic addition of a lithium acetylide to cyclic chiral N-tert-butanesulfinyl imine 211 is a key step in this strategy. The addition proceeded with total stereocontrol to give a single diastereoisomer, and further removal of the silyl group provided propargylamine derivative 212. Partial hydrogenation of this compound under Lindlar conditions led to terminal olefin, which reacted with ethyl iodoacetate in refluxing dichoroethane, in the presence of 1.6 equivalents of lauroyl peroxide (DLP), as thermal initiator of the radical process. A spirolactam was isolated in 45% yield, taking place under the essayed reaction conditions successively a radical addition of the enolate to the terminal alkene, lactonization and removal of the sulfinyl group. Final deprotection of the hydroxy group led to compound 213, a precursor of the 6-(R) epimer of perhydrohistrionicotoxin (Scheme 52).
Chiral aromatic sulfinyl imines 214 with a 2-haloethyl substituent at ortho-position were effective synthetic intermediates in the stereoselective preparation of 1-aryl-1,2,3,4-tetrahydroisoquinolines, which are compounds that display interesting biological activities. For instance, solifenacin (216), a competitive muscarinic acetylcholine receptor antagonist currently used in the treatment of overactive bladders, was prepared from (R S )-214a (X = Br) by addition first of phenylmagnesium bromide at -40 °C in toluene. A 93:7 diastereomeric mixture was obtained and the major diastereoisomer was easily isolated after column chromatography. Subsequent intramolecular cyclization in the presence of NaH in DMF at room temperature gave the pure diastereomer 215, a precursor of solefinacin (216) [146]. Diastereoselective allylation of chlorinated derivative (R S )-214b (X = Cl) with allylmagnesium bromide in dichloromethane gave the corresponding homoallylic sulfinamide as a 9:1 mixture of easily separable diastereoisomers, and the major component of the mixture was further cyclized to give product 217, which was transformed after 5 steps into almorexant (218), a non-peptide antagonist of the human orexin receptor, which plays a major role in controlling the sleep/wake cycle [147]. The same precursor (R S )-214b (X = Cl) and strategy was followed in the first steps of the synthesis of compound 220, used as neuroprotective agents in the treatment of neurological diseases, such as epilepsy and ischemia. In this case, the addition of 4-chlorophenylmagnesium bromide to (R S )-214b gave the expected product with 93:7 ratio of diastereoisomers. An intramolecular cyclization of the major diastereoisomer afforded 219 in high yield (Scheme 53) [146].

Asymmetric synthesis of pyrrolizidines, indolizidines and quinolizidines
Bicyclic systems containing bridgehead nitrogen, such as 1-azabicyclo[3.3.0]octanes, 1-azabicyclo[4.3.0]nonanes and 1-azabicyclo [4.4.0]decanes are structural motifs frequently encountered in alkaloids, which can come from quite diverse sources, such as bacteria, fungi, plants and animals, among others. Many of these natural products display extremely potent biological activities and their syntheses, along with that of structurally related analogs, remain of great interest for chemists and pharmacologists. Relevant contributions regarding the synthesis of these bicyclic compounds, involving chiral N-tert-butanesulfinyl imines, are compiled in the following paragraphs.

Initial stereocontrol by allylation of sulfinyl imines
The allylation of chiral N-tert-butanesulfinyl imines is of great synthetic interest because in this reaction together with a new functionality (amino derivative group), a carbon-carbon bond is formed. In addition, the double bond of the allylic moiety can participate in a number of further synthetically useful transformations, including the generation of functional groups prone to participate in intramolecular cyclization processes involving the nitrogen atom of the starting imine. Interestingly, the allylation of these imines can be carried out in a stereoselective fashion with different allylating reagents [66,148,149].
Pyrroloisoquinoline alkaloid (−)-crispine A (223) was isolated from Carduus crispus plants which were used in folk medicine for the treatment of different inflammatory diseases, such as bronchitis, stenocardia, gastroenteritis, and rheumatism. In addi- tion, it also shows promising biological activity against human cancer cell lines. The allylation of chiral imine (R S )-214 with allylmagnesium bromide in dichloromethane at −78 °C was the key step in the synthesis reported by Reddy and co-workers of this alkaloid. The allylated product was obtained in 80% yield as 9:1 mixture of diastereoisomers, and the major diastereoisomer was separated from the mixture and cyclized to give tetra-hydroisoquinoline 217 (see above, Scheme 53). The formation of the 5-membered ring to produce target (−)-crispine A (223) was accomplished in six additional steps which comprise removal of the sulfinyl group and subsequent N-Boc protection to give 221, hydroboration-oxidation to produce terminal alcohol derivative 222, and formation of the mesylate, removal of the Boc group, and final cyclization (Scheme 54) [150].
A similar strategy was described by the same authors for the stereoselective synthesis of (−)-harmicine and other tetrahydroβ-carboline alkaloids. The allylation of chiral imine (R S )-225 with allylmagnesium bromide in dichloromethane at −78 °C was the key step for the synthesis reported by Reddy and co-workers that led to compound 226 in 81% yield (dr > 99:1). After a sequence of similar steps of removal of the sulfinyl group, protection of the amine, hydroboration-oxidation and formation of the mesylate, removal of the Boc group, and final cyclization, the (−)-harmicine (228) was obtained in 72% yield in the last step [151] (Scheme 55).  T3, T4, T7, T8; 231, 233, 235 and 237, respectively) was prepared from 5-bromopentanal. Importantly, to prepare tetraponerines T5-T8, with a pentyl group at C5-position, a cross-metathesis reaction involving the allyl group of the second aminoallylation with cis-3-hexene was carried out in order to elongate the side chain [152,153]. The anticancer activity of tetraponerines T5-T8 against four different carcinoma human cell lines was also investigated, observing a promising cytotoxic activity of tetraponerine T7 (236) against breast carcinoma cell line MCF-7 [152].
Taking advantage of this highly diastereoselective indiummediated amino allylation of carbonyl compounds, an efficient stereocontrolled synthesis of phenanthroindolizidines 246 and phenanthroquinolizidine 7-methoxycryptopleurine 248 was accomplished by Antón-Torrecillas et al., using 2-(phenanthren-9-yl)acetaldehydes 243 as starting materials. The initially formed homoallylamine derivatives 244 were transformed first into pyrrolidines 245 (hydrobroration-oxydation-intramolecular Mitsunobu N-alkylation), and after removal of the sulfinyl group, and a Pictet-Spengler reaction involving formaldehyde, the expected phenanthroindolizidine 246a and the alkaloid (−)-tylophorine (246b) were obtained (Scheme 57) [154]. On the other hand, key chiral homoallyllic sulfinamine intermediate 244b was also transformed in four steps into enantioenriched 7-methoxycryptopleurine 248, a rhodium-catalyzed linear hydroformylation being one of the steps involved in the formation of piperidine derivative 247. Cytotoxic evaluation of both enantiomers of 7-methoxycryptopleurine demonstrated that the compound with (R)-configuration shown in Scheme 57 was much more potent than its antipode against four cancer cell lines examined [155]. Phenanthroquinolizidines with a quaternary center at C-14a position, bearing a methyl group instead of the proton, were prepared following the same methodology, and using the corresponding methyl ketone as starting material. These compounds displayed also cytotoxic activity against different human cancer cell lines [156]. Indium-mediated allylation of sulfinyl imines was also the source of the stereocontrol in the synthesis of benzo-fused 1-azabicyclo[j.k.0]alkanes 253 and 255 reported by Sirvent et al.. The starting chiral imines (S S )-250 derived from aliphatic aldehydes, with a 2-bromophenyl substituent, and (S)-tertbutanesulfinamide. When the allylation was carried out with ethyl 2-(bromomethyl)acrylate (249), and after removal of the sulfinyl unit, the resulting free amine derivative led to α-methylene-γ-butyrolactams 252. On the other hand, dihydropyridin-2ones 254 were obtained after sequential allylation with allyl bromide 251, desulfinylation, acylation with acryloyl chloride, and ring-closing metathesis. Lactams 252 and 254 were easily transformed into target polycyclic compounds 253 and 255 by performing an intramolecular N-arylation using Ullmann-type reaction conditions (Scheme 58) [157].
The group of Wei reported a diastereoselective approach for the synthesis of trans-4-hydroxy-5-allyl-2-pyrrolidinone 80 through an indium-mediated allylation of α-chiral aldimine (R S )-79 (see above Scheme 24) [100]. Allyl pyrrolidone 80 was an intermediate in the synthesis of alkaloids (+)-epohelmins A (258) and B (260). These natural products were isolated from an unidentified fungus, and inhibited recombinant lanosterol synthase with low IC 50 values, with potential use as anticholesteraemic drugs to complement or even substitute the now widely used members of the statin family. The second five-membered ring of the pyrrolizidinic system in (+)-epohelmin A (258) was constructed from alcohol 257, upon forming the corresponding mesylate, subsequent removal of the Boc group, promoting cyclization, and final desilylation. Compound 256 was the last common intermediate in the diastereodivergent approach to both epohelmins, the corresponding epimer 259 was the precursor of (+)-epohelmin B (260) by applying the same reaction conditions as for (+)-epohelmin A (258, Scheme 59) [158].
Fustero and co-workers described for the first time the use of N-tert-butanesulfinamide in a desymmetrization-type process involving an intramolecular aza-Michael reaction for obtaining the advanced intermediates 271a and 271b in the total synthesis of (−)-hippodamine (273) and (+)-epi-hippodamine (272). The condensation reaction between the symmetric ketone 267 and (R)-N-tert-butanesulfinamide in the presence of titanium(IV) ethoxide followed by the reductive amination with NaBH 4 and double-direction cross-metathesis reaction led to 268a in 50% yield and 268b in 49% yield. These compounds were submitted to the desymmetrization process by an intramolecular aza-Michael reaction using NaH in THF. The applied conditions yielded a mixture of cis-269 and trans-269 diastereoisomers as major product (cis/trans 3:1) and a small amount of other possible isomer 270 was detected (269a/270a 95:5) and (269b/270b 96:4). The addition of nitrogen nucleophile occurred to the Si face of the conjugated ester, opposite to the bulky tert-butyl group gave cis-269a,b as major isomer (Scheme 61). The sulfoxide auxiliary was removed under acid conditions, and after a basification process with saturated aqueous NaHCO 3 , a second intramolecular aza-Michael reaction took place to the products 271a and 271b with excellent yields and high diastereoselectivity. Since 271a,b is C 2 -symmetric, the cyclization of cis-269a,b or trans 269a,b as soon as 270a,b gave the same isomer 271. Consequently, 271a was obtained in 90% ee and 271b in >99% ee, as determined by chiral HPLC analysis. After three steps, a mixture of (−)-hippodamine (273) and (+)-epi-hippodamine (272) were obtained in high yield which was separated by column chromatography [160] (Scheme 61).

Stereocontrol synthesis through addition of Grignard reagents to N-sulfinyl imines
The group of Lindsley developed new methodologies for the enantioselective synthesis of different azabicyclic systems. These methodologies are based on the diastereoselective addition of Grignard reagents to chiral sulfinyl imines, and applied to the syntheses of the indolizidine alkaloid (+)-grandisine D (279) [161], and pyrrolizidine alkaloid (+)-amabiline (283) [162], starting from imine 274. The addition of a masked acetal organomagnesium compound to sulfinyl imine 274 provided compound 275 in high yield and diastereoselectivity, which after reaction with the appropriate alkylating reagent led to 276 and 280. These compounds were prone to undergo ring-closing metathesis, generating 6-and 5-membered ring systems, respectively. After several steps, acetal derivatives 278 and 282 were transformed into (+)-grandisine D (279) and (+)-amabiline (283). Treatment under acidic conditions of 278 and 282 produced removal of the sulfinyl group and hydrolysis of the acetal, revealing the masked aldehyde. In the final step, an intramolecular hydroamination allowed the formation of the five-membered ring, to complete the construction of the azabicyclic arrays (Scheme 62). The indolozidine alkaloids grandisines were isolated from leaves of the Australian rain forest tree Elaeocarpus grandis, and these alkaloids display selective human δ-opioid receptor affinity. Meanwhile, hepatotoxic (+)-amabiline (283) was found in the seeds and flowers of Borago officinalis.
The addition of alkynyl or alkenyl Grignard reagents to chiral sulfinyl imine (S S )-126 led to 6-substituted trans-5-hydroxy-2piperidinones with high diastereoselectivity, which is controlled mainly for the configuration of the stereocenter bearing the silyloxy group with alkenyl reagents, and by the coordination of the silyloxy substitution and stereochemistry of the sulfinamide with alkynyl organomagnesium compounds. The addition of vinylmagnesium bromide to (S S )-126 led, after N-Boc protection to 2-piperidinone 284, a precursor of diolefin 285, which through ring closing metathesis allowed the synthesis of quinolizidinone 286, from which (−)-epiquinamide (266) was prepared after three steps. On the other hand, the reaction of imine (S S )-126 with ethynylmagnesium bromide provided compound 288, which was transformed into the N-allyl-substituted piperidinone 289. Again, a ring-closing metathesis allowed the formation of the bicyclic indolizidinone system 290, an ad- Scheme 63) [163]. This alkaloid was found in the fungus Rhizoctonia leguminicola and in plants such as the Australian Swainsona canescens and the North American locoweed Astragalus lentiginosus. It displays a wide range of biological activities, including alteri neoplastic growth and metastasis.

Stereocontrol synthesis through Mannich, nitro-Mannich and Mukaiyama-Mannich reactions of N-sulfinyl imines
Heterocyclic compounds can be obtained through strategies using Mannich reactions [164][165][166]. It was previously commented that the addition of ethyl 4-nitrobutanoante (203) to chiral sulfinyl imines under basic solvent-free conditions proceeded with high facial diastereoselectivity (Scheme 64 [143]). When the reaction was performed with the imine of 5-bromopentanal, (R S )-76, the nitro-Mannich adduct 292 was formed in 86% yield as a 1:1 mixture of diastereoisomers, considering the stereocenter bearing the nitro group. Taking advantage of this methodology, Benlahrech et al. reported the synthesis of (+)-C(9a)-epi-epiquinamide (294) [167]. Desulfinylation of compound 292 led to quinolizidine derivative 293, taking place two consecutive cyclizations involving the resulting free amino group, the ester and the alkyl bromide functionalities. Although compound 292 was isolated in a 1:1 dr, quinolizidine 293 was formed as a 6:1 mixture of diastereoisomers, due to a rapid epimerization under basic conditions, leading to the thermodynamic most stable isomer. Sequential reductions of the nitro group, the lactam and final N-acetylation of the primary amine were the last steps of this synthesis (Scheme 64).
Andrade [8,169,170] and Zhao reported an elegant and efficient methodology for the rapid assembling of chiral N-tertbutanesulfinyl imine (R S )-303 with methyl 2-ethylacrylate to give tricyclic derivative 305, in high yield and diastereoselectivity. Treatment of (R S )-303 with LiHMDS in THF at -78 °C led to the formation of lithiodienamine intermediate 304, which reacted with methyl 2-ethylacrylate, leading to the Michael addition product, and the resulting enolate participated in an intramolecular Mannich reaction to form a six-membered ring. Final addition of an excess of allyl bromide yielded tetrahydrocarbazole 305 in 90% yield. After convenient functional group transformation, diolefin 306 was submitted to ring-closing metathesis to form tetracycle 307. Further removal of the sulfinyl group and N-alkylation with 2-bromoethanol gave compound 308, which is an ideal substrate for the construction of the fivemembered ring leading to spiro compound 309, upon reaction with potassium tert-butoxide (Bosch−Rubiralta spirocyclization). Treatment of 309 with LDA at -78 °C and quenching the resulting metalloenamine with methyl cyanoformate furnished (−)-tabersonine (310), and selective hydrogenation of 310 led to (−)-vincadifformine (311). In addition, double hydrogenation of 309 produced (−)-aspidospermidine (312) in 75% yield. All these alkaloids are members of the Aspidosperma family (Scheme 67) [171,172].

Asymmetric synthesis of lysergic acid
In 2013, Liu and colleagues used N-tert-butanesulfinamide in the total synthesis of (+)-lysergic acid (323). The first step was the aminoallylation of aldehyde 317 with allyl bromide and sulfinamide (R S )-1 by means of indium metal, leading to homoallyl derivative 318. Further steps included an N-alkylation and ring-closing metathesis with Grubbs second generation catalyst to generate tetrahydropyridine 320 in high yields. Removal of the silyl protecting group, followed by oxidation of the resulting terminal alcohol and palladium-catalyzed coupling of the aldehyde with 3-chloro-2-iodoaniline afforded indole derivative 322, which is an advanced precursor of target (+)-lysergic acid (323, Scheme 69) [174].

Conclusion
Important progress has been made in the development of methodologies that make use of stable N-tert-butanesulfinyl imines as chiral reagents in diverse synthetic transformations, being possible to recover the chiral auxiliary at the end of the reaction. The great value of enantiomerically enriched amines as synthetic intermediates in the route to complex organic molecules, in-cluding natural products (mostly, alkaloids), has boosted the development of nucleophilic addition protocols to these Davis-Ellman N-sulfinyl imines, since the pioneering work of Davis`s group and subsequent work of Ellman`s group. Interestingly, the existing working models facilitate the prediction of the major diastereoisomer in most cases, making this technology attractive with the aim of synthetic applications.