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Chiral sulfinamides are among the best known chiral auxiliaries in the stereoselective synthesis of amines and their derivatives. The most extensively used enantiopure tert-butanesulfinamide emerged as the gold standard among many others over the last two decades. The present review attempts to provide an overview of tert-butanesulfinamide mediated asymmetric N-heterocycle synthesis via sulfinimines and covers literature from 2010–2020. This methodology offers general access to structurally diverse piperidines, pyrrolidines, azetidines, and their fused derivatives that represent the structural motif of many natural products and therapeutically applicable compounds.

Ketamine has been extensively used as an anesthetic drug. Chiral auxiliaries such as tert-butanesulfinamide (TBSA) can be used for the asymmetric synthesis of (S)-ketamine. Condensation of TBSA with ketones provides tert-butanesulfinylimines in consistently high yields. The tert-butanesulfinyl group actuates the imine for nucleophilic addition, is a potent chiral directing group, and after nucleophilic addition is easily dissociated by intervention with acid solution. To prepare 2-(N-piperidinomethyl)-1-phenylcyclohexylamine (1), we started with the cyclohexanone and using Mannich reaction achieved an aminoketone. Then, we made the sulfiniylamin (2) by the condensation of TBSA with aminoketone. By using salts such as Ti(OEt)4, we obtained N-tert-butanesulfinylketimine in 85% yield. Next, we provided a new chiral center (3) using Grignard reagent as nucleophile at −78 °C (80% yield). Finally, after many steps, the (S)-ketamine synthesized under ozonolysis conditions, with good yield and enantioselectivity (75% yield and 75% ee).

Process development for a scalable and green synthesis of chiral tert-butanesulfinamide (TBSA) on a multikilogram scale is reported. The process is based on the identification of a chiral sulfinyl transfer agent, benzo[1,3]oxathiozin-2-one, that contains active and differentiated S–N and S–O bonds, allowing the synthesis to proceed under mild reaction conditions. This method is practical and overcomes the disadvantages of earlier methods deploying harsh reaction conditions and hazardous and toxic reagents.

An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.

A new chiral auxiliary for the diastereoselective alkylation of amino ester enolates that takes advantage of chiral information stored on the enolate side of the amino ester substrate has been developed. Chiral α-sulfinamido esters were alkylated under basic conditions in good yields (up to 90%) and good to high diastereoselectivities (generally >6:1) to provide unnatural mono- and α,α-disubstituted amino acid derivatives. This auxiliary allowed for the ready conversion of ester functionality without the need for esoteric reagents. Furthermore, the auxiliary is easily removed to provide enantiopure amino acids. Computational studies revealed that a chelated transition state governs electrophile addition from the convex face of a transient bicyclic intermediate. This method allows ready access to enantioenriched natural and unnatural amino acids.

We thank our Ministerio de Ciencia e Innovacion (MCINN; projects CONSOLIDER INGENIO 2010-CDS2007-00006, CTQ2011-24165), the Ministerio de Economia y Competitividad (MINECO; project CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2017-85093-P), the FEDER, the Generalitat Valenciana (PROMETEO 2009/039, PROMETEOII/2014/017), the University of Alicante, the Ministere de l'Enseignement Superieur et de la Recherche Scientifique Algerienne, Direction de la Cooperation et des Echanges Interuniversitaires, Programme de Formation Residentielle a l'Etranger au titre de l'annee universitaire 2016/2017: Programme National Exceptionnel (PNE) for continued financial support.

The development of new catalysts for asymmetric organic transformations is a broad and important research goal in modern synthetic organic chemistry. The use of chiral ligands as a source of asymmetric induction in metal-catalyzed reactions has been a traditional focus of this field. One class of chiral ligands is those which incorporate enantiomerically pure sulfinamides. Chapter 1 provides an overview of this area of research. Also included are examples of sulfinamide-based ligands for reactions involving stoichiometric metals, as well as a few examples of sulfinamide-based organocatalysts that have been reported in the literature. The literature reviewed serves as an important foundation for the research described in Chapters 2 and 3.Asymmetric organocatalysis, the use of chiral small molecules as metal-free catalysts, has developed into an area of intense research in the past decade. One mode of substrate activation by organocatalysts is hydrogen bonding. The urea/thiourea scaffold is one of the most effective and well developed types of hydrogen bonding organocatalysts. The acidity (and corresponding strength of the hydrogen bonding interaction) of the hydrogen bond donor is an important consideration for the development of efficient catalysts. Chapter 2 details the development of organocatalysts that incorporate an N-sulfinyl urea as a hydrogen bond donor. In these catalysts, the sulfinyl substituent serves both to acidify the urea N-H bond and to act as a source of asymmetric induction by virtue of the sulfur-based chirality that is presented proximal to the hydrogen bond donor. The application of these catalysts to two different nucleophilic addition reactions is described.Organocatalysts that incorporate a nucleophilic amine have also been developed extensively in recent years. One of the earliest reported examples of this type of catalysis was the use of proline as a catalyst for the enantioselective intermolecular aldol reaction via a nucleophilic enamine intermediate. While the amine may be considered the primary catalytic site, the carboxylic acid has also been implicated in the catalytic cycle, and is proposed to provide a key hydrogen bonding interaction in the enantiodetermining step of the reaction. Chapter 3 describes the development of an N-sulfinyl proline amide as a novel and superior catalyst for the aldol reaction, again demonstrating the utility a sulfinyl N-H as a chiral hydrogen bond donor.

Organic disulfanes (also named disulfides) play a vital role in chemistry and biology.1–4 In particular, unsymmetrical disulfanes are a class of important molecules with bioactivities,1–4 such as a...

A series of tert-butanesulfinamide type compounds, which were decorated with phenol receptors, were found to recognize chlorine ion, nitrate ion, and acetate ion by 1H NMR titration experiments. The results indicated that the interaction between subject molecule and anion was enhanced with the increase of the acidity of the phenolic O–H group. Furthermore, the tert-butyl group seemed to play a role in the anion recognition.

An asymmetric synthesis of mexiletine and structural analogs was developed using chiral tert-butanesulfinamide to convert precursor ketones to chiral amines. Starting from α-aryloxy ketones, a two-step condensation–reduction procedure provided chiral N-tert-butanesulfinyl amines as immediate precursors to mexiletine or structural analogs. Reduction of the intermediate N-tert-butanesulfinyl imine showed substrate- and reagent-derived stereoselectivity. Following removal of the chiral auxiliary, mexiletine and structural analogs were obtained in high enantiopurity using this approach.

Mannich-type reactions of chiral delta-chloro-N-tert-butanesulfinyl-substituted imidates across N-sulfonyl aldimines resulted in the efficient and anti-stereoselective synthesis of new beta-(sulfonylamino)-N-sulfinyl imidates (dr > 99:1). These compounds were then successfully cyclized to give 2-aryl-N-sulfonylpiperidine-3-(N-sulfinyl) carbimidates in high yields. These proved to be useful intermediates for the synthesis of chiral methyl 2-arylpiperidine-3-carboxylates as well as cis-3-amino-2-aryl-N-sulfonylpiperidines.

The benzofuran skeleton is commonly found in a wide variety of natural products that display a wide range of biological activities. For this reason, benzofuran has a high potential for use as a scaffold in both chemical and pharmaceutical syntheses of natural products. This work describes the development of a novel asymmetric synthetic method of benzofuran-derived β-amino esters via K2CO3-promoted domino reactions of ortho-hydroxyl aromatic N-tert-butylsulfinyl imines and diethyl bromomalonate. A small library of target compounds was prepared under optimized reaction conditions in moderate to good yields with high distereoselective and enantioselective properties. The newly generated chiral carbon center was of an (S)-configuration as determined by x-ray diffraction.

An operationally simple and efficient strategy for a highly potent Dipeptidyl Peptidase-4 (DPP-4) inhibitor, sitagliptin has been developed employing readily available precursors. The chiral β-amino acid core of sitagliptin has been constructed through a Barbier type allylation of chiral sulfinyl imine or a Mannich type addition of diethyl malonate. This approach is more convenient, exquisitely selective and practical.

An expedient asymmetric synthesis of TRPV1 antagonist 1 has been developed and demonstrated on multikilogram scale. The enabling route to 1 is detailed herein and characterized by the following key transformations: an aldol-cyclodehydration sequence to install the chromanone, and an auxiliary-mediated diastereoselective reductive amination.

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of ( R )- tert -butanesulfinamide and glyoxylic acid with molecular sieves in CH 2 Cl 2 was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give ( R )-2-(( R )- tert -butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of ( Z )-crotylboronic acid pinacol ester produced no product; however, that of ( E )-crotylboronic acid pinacol ester produced (2 R, 3 S )-2-(( R )- tert- butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.

Organic disulfanes (also named disulfides) play a vital role in chemistry and biology.1–4 In particular, unsymmetrical disulfanes are a class of important molecules with bioactivities,1–4 such as a...

A highly diastereoselective Michael addition of (R)-N-tert-butanesulfinyl imidates 8 to α,β-unsaturated pyrazolidinone 3a has been developed to afford pyrazolidinones 10 possessing three contiguous stereocenters with good to excellent yield and excellent diastereoselectivity. A two-step conversion of reduction and cyclization provides the bicyclic pyrazolopiperidine 12 in a good yield. A series of pyrazolopiperidine derivatives 18 with a quaternary carbon center at C-3a are stereoselectively synthesized via alkylation or Michael addition.

The valuable 2-(tert-butyldisulfanyl)heterocycles were effectively synthesized from 2-mercaptoheterocycles and tert-butanesulfinamide via unusual condensation. The reaction between 2-mercapto sulfur-containing heterocycles and tert-butanesulfinamide was performed under ligand-free CuI-catalyzed conditions. The synthetic processes described herein are simple, cost-efficient, and practical. Furthermore, a plausible mechanism is proposed for this transformation.

two chiral sulfur compounds, tert-butyl tert-butanethiosulfinate (1) and tert-butanesulfinamide (2), with inversion of configuration, have been studied by raman optical activity (roa) and electronic circular dichroism combined with density functional theory calculation. with the ss linkage in 1, the couplings between the two tertiary carbon atoms often generate large roa signals, whereas the tertiary carbon atom itself generally makes a large contribution to roa signals in 2 for similar vibrational modes. the conformational dependence of roa parameters provides probing conformation around the ss bond from a new perspective. the simultaneous use of electronic circular dichroism and roa is warranted to extract reliable conformational information. roa provides a suitable candidate for the stereochemical study of chiral sulfur compounds, especially its capability of sensing the conformation around the ss bond. chirality 24:731740, 2012. (c) 2012 wiley periodicals, inc.

Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes.

1,2-Amino alcohols have been converted into morpholines by using sulfinamides as temporary protecting/activating groups on the amine. We have developed a procedure for the selective synthesis of monoprotected N-sulfinyl amino alcohols through a double sulfinylation/hydrolysis strategy. Following the reaction of the sulfinamides with bromoethyldiphenylsulfonium triflate, protected morpholines were obtained in high yields. Subsequent treatment with HCl liberated the morpholine hydrochloride salts. The usefulness of this high yielding and efficient methodology has been demonstrated in the formal synthesis of the antidepressant drug (S,S)-reboxetine.

A practical process for recycling the tert-butanesulfinyl group upon deprotection of N-tert-butanesulfinyl amines has been achieved. Treatment of N-tert-butanesulfinyl amines with HCl in cyclopentyl methyl ether results in complete conversion to tert-butanesulfinyl chloride and the corresponding amine hydrochloride salt, which is isolated by filtration in analytically pure form and in quantitative yield. Treatment of the resulting sulfinyl chloride solution with aqueous ammonia then provides analytically pure tert-butanesulfinamide in 97% yield. Alternatively, the tert-butanesulfinyl chloride solution can be treated with ethanol and catalytic quinidine as a sulfinyl transfer catalyst to provide a cyclopentyl methyl ether solution of ethyl tert-butanesulfinate with 88% ee. Addition of NaNH(2) in ammonia followed by simple trituration of the product with octane provides tert-butanesulfinamide with 99% ee and in 67% overall isolated yield based upon the starting N-tert-butanesulfinyl amine.

A stereoselective approach to the core structure ofpolyoxin and nikkomycin antibiotics has been developed. The key steps of this approach include diastereoselective nucleophilic addition of 2-lithiofuran to tert-butanesulfinyl imine derived from (S)-tert-butanesulfinamide and ribosyl aldehyde for the generation of C-5 stereocenter, and the use of triflic acid to remove tert-butylsulfonyl group. Significantly, the synthesis provides a method for large-scale preparation of polyoxin and nikkomycin analogues because of simple operation, excellent yield and high stereoselectivity.

The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon–nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions.

N-tert-Butanesulfinyl aldimines 3 and ketimines 4 are exceedingly versatile intermediates for the asymmetric synthesis of amines. The N-tert-butanesulfinyl imines are prepared in high yields by condensing enantiomerically pure tert-butanesulfinamide 1, which is readily available in either configuration, with a wide range of aldehydes and ketones. The tert-butanesulfinyl group activates the imines for the addition of many different classes of nucleophiles, serves as a powerful chiral directing group, and after nucleophilic addition is readily cleaved by treatment of the product with acid. A wide range of highly enantioenriched amines, including alpha-branched and alpha,alpha-dibranched amines, alpha- and beta-amino acids, 1,2- and 1,3-amino alcohols, and alpha-trifluoromethyl amines, are efficiently synthesized using this methodology. In addition, N-tert-butanesulfinyl imine derivatives provide a new family of ligands for asymmetric catalysis.

A collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular SN2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl3-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.

High yielding and highly diastereoselective methods for 1,2-additions of organometallic reagents to N-tert-butanesulfinyl aldimines (2) and N-tert-butanesulfinyl ketimines (3) are described. The additions of alkyl, aryl, alkenyl, and allyl carbanions to a diverse set of imines with different steric and electronic properties are demonstrated. Acidic methanolysis of the sulfinamide products (4 and 6) delivers highly enantioenriched α-branched and α,α-dibranched amines. Since a broad range of sulfinyl imines are easily accessible from aldehydes and ketones, a wide variety of enantioentriched amines may be prepared.

Experimental details for the first general methods for the one-step preparation of N-tert-butanesulfinyl imines (tert-butanesulfinimines) (2) from aldehydes and ketones is described. To effect the condensations of tert-butanesulfinamide (1) with aldehydes, the Lewis acidic dehydrating agents MgSO4, CuSO4, or Ti(OEt)4 are employed. Aldehyde condensations mediated by MgSO4 proceed in high yields (84−96%) when an excess of aldehyde is used. In contrast, only a slight excess of aldehyde (1.1 equiv) relative to tert-butanesulfinamide provides sulfinimines in high yields when the more Lewis acidic dehydrating agent CuSO4 is used. The CuSO4-mediated procedure is effective for a wide range of aldehydes, including sterically demanding aldehydes, such as isobutyraldehyde (90%), and electron-rich aldehydes, such as p-anisaldehyde (81%). The still more Lewis acidic Ti(OEt)4 and Ti(O-i-Pr)4 also afford N-tert-butanesulfinyl aldimines from especially unreactive aldehydes, such as pivaldehyde (82%). In addition, Ti(OEt)...

The first example of the catalytic asymmetric oxidation of tert-butyl disulfide (1) is described. The product, tert-butyl tert-butanethiosulfinate (2) is obtained with 91% enantiomeric excess in yields of ≥92% on scales as large as 1 mol. The application of H2O2 as stoichiometric oxidant in the presence of 0.25 mol % of VO(acac)2 and 0.26 mol % of a chiral Schiff base ligand, 6a, is both convenient and cost-effective. Thiosulfinate ester 2 is chemically and optically stable and serves as an excellent precursor to chiral tert-butanesulfinyl compounds by the stereospecific nucleophilic displacement of tert-butyl thiolate. Addition of LiNH2 in liquid ammonia and THF provides tert-butanesulfinamide (3; 91% yield). A single recrystallization provides enantiomerically pure 3 in 71−75% overall yield from disulfide 1. Enantiomerically pure thiosulfinate ester 2 also reacts readily and stereospecifically with Grignard reagents, organolithiums, lithium amides, and lithium imine salts to provide enantiomerically pur...

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of ( R )- tert -butanesulfinamide and glyoxylic acid with molecular sieves in CH 2 Cl 2 was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give ( R )-2-(( R )- tert -butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of ( Z )-crotylboronic acid pinacol ester produced no product; however, that of ( E )-crotylboronic acid pinacol ester produced (2 R, 3 S )-2-(( R )- tert- butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.

Optically pure tert-butanesulfinyl aldimines 1 were prepared by direct condensation of chiral tert-butanesulfinamide 3 with aldehydes 2 in high yields in the presence of KHSO 4 . The main advantage of KHSO 4 is that it is applicable to the condensation reactions of a variety of aldehydes, including electron deficient and electron rich (hetereo)aromatic aldehydes, as well as aliphatic aldehydes.

The products are obtained in an enantiopure form with mostly excellent diastereoselectivities.

Experimental details for the first general methods for the one-step preparation of N-tert-butanesulfinyl imines (tert-butanesulfinimines) (2) from aldehydes and ketones is described. To effect the condensations of tert-butanesulfinamide (1) with aldehydes, the Lewis acidic dehydrating agents MgSO4, CuSO4, or Ti(OEt)4 are employed. Aldehyde condensations mediated by MgSO4 proceed in high yields (84−96%) when an excess of aldehyde is used. In contrast, only a slight excess of aldehyde (1.1 equiv) relative to tert-butanesulfinamide provides sulfinimines in high yields when the more Lewis acidic dehydrating agent CuSO4 is used. The CuSO4-mediated procedure is effective for a wide range of aldehydes, including sterically demanding aldehydes, such as isobutyraldehyde (90%), and electron-rich aldehydes, such as p-anisaldehyde (81%). The still more Lewis acidic Ti(OEt)4 and Ti(O-i-Pr)4 also afford N-tert-butanesulfinyl aldimines from especially unreactive aldehydes, such as pivaldehyde (82%). In addition, Ti(OEt)...

(1S,2R)-(−)-cis-1-Amino-2-indanol 3,5,-Di-tert-butyl salicyladehyde (1S,2R)-1-[(2-Hydroxy-3,5-di-tert-butylbenzylidiene)amino]indan-2-ol (RS)-(+)-tert-Butyl-tert-butanethiosulfinate Vanadyl bis-acetylacetonate Di-tert-butyl disulfide Hydrogen peroxide Ammonia Iron(III) nitrate nonahydrate Lithium Chloroacetic acid (RS)-(+)-2-Methyl-2-propanesulfinamide Keywords: tert-butanesulfinamide; hydrogen gas; chiral amines; oxidation; natural gas odorant; thiol odor

A three-step procedure for the preparation of enantiopure tert-butanesulfinamide 6 in 51% overall yield is described starting from (1R,2S)-N-Cbz-1,2-diphenylaminoethanol. The key step is the reaction of tert-butylmagnesium chloride with N-Cbz-4,5-diphenyl-1,2,3-oxathiazolidine-2-oxide 2 to afford the optical pure tert-butylsulfinyl-4,5-diphenyl-1,3-oxazolidinone 5 via an 1,5-alkoxy anion rearrangement, which is then subject to ammonia hydrolysis with LiNH(2) in liquid ammonia to give (R)-tert-butanesulfinamide 6.

tert-Butanesulfinyl imines are exceedingly versatile intermediates for the asymmetric synthesis of amines. Aldimines 15 and ketimines 16 are prepared in high yields under mild conditions by condensing enantiomerically pure tert-butanesulfinamide 10, either enantiomer of which is readily synthesized in large scale from inexpensive reagents, with a wide range of aldehydes and ketones. The tert-butanesulfinyl group activates the imines for the addition of many different classes of nucleophiles, serves as a powerful chiral directing group, and after nucleophilic addition function as a versatile protecting group of the amines, which is readily cleaved by treatment with acid. A wide range of highly enantioenriched amines, including α-branched amines, α, α-dibranched amines, α- and β-amino acids, 1, 2- and 1, 3-amino alcohols, and α-trifluoromethylamines are efficiently synthesized using this methodology.