Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult‐to‐access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur‐selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S‐alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.     

Efficient Synthesis of Cyclic Sulfoximines from N-Propargylsulfinamides through Sulfur–Carbon Bond Formation

Cyclic sulfoximines were readily synthesized by the cyclization of N-propargylsulfinamides without using expensive and toxic metal catalysts. This cyclization proceeded without loss of optical purity of chiral sulfinamides through the unusual sulfur–carbon bond formation promoted by an inexpensive inorganic base. This stereospecific cyclization offers a general approach to the asymmetric synthesis of chiral cyclic sulfoximines as an emerging heterocycle in medicinal chemistry.     

Efficient Kinetic Resolution of Sulfur‐Stereogenic Sulfoximines by Exploiting CpXRhIII‐Catalyzed C−H Functionalization

Chiral sulfoximines with stereogenic sulfur atoms are promising motifs in drug discovery. We report an efficient method to access chiral sulfoximines through a C?H functionalization based kinetic resolution. A rhodium(III) complex equipped with a chiral Cp^x ligand selectively participates in conjunction with phthaloyl phenylalanine in the C?H activation of just one of the two sulfoximine enantiomers. The intermediate reacts with various diazo compounds, providing access to chiral 1,2‐benzothiazines with synthetically valuable substitution patterns. Both sulfoximines and 1,2‐benzothiazines were obtained in high yields and excellent enantioselectivity, with s‐values of up to 200. The utility of the method is illustrated by the synthesis of the key intermediates of two pharmacologically relevant kinase inhibitors.     

Enantioselective Synthesis of 1,2-Benzothiazine 1-Imines via RuII/Chiral Carboxylic Acid-Catalyzed C−H Alkylation/Cyclization

Sulfondiimines are diaza-analogues of sulfones with a chiral sulfur center. Compared to sulfones and sulfoximines, their synthesis and transformations have so far been studied to a lesser extent. Here, we report the enantioselective synthesis of 1,2-benzothiazine 1-imines, i.e., cyclic sulfondiimine derivatives from sulfondiimines and sulfoxonium ylides via C−H alkylation/cyclization reactions. The combination of [Ru(p-cymene)Cl₂]₂ and a newly developed chiral spiro carboxylic acid is key to achieving high enantioselectivity.     

Three‐Dimensional Heterocycles by Iron‐Catalyzed Ring‐Closing Sulfoxide Imidation

A general and atom‐economical method for the synthesis of cyclic sulfoximines by intramolecular imidations of azido‐containing sulfoxides using a commercially available Fe^II phthalocyanine (Fe^IIPc) as catalyst has been developed. The method conveys a broad functional group tolerance and the resulting three‐dimensional heterocycles can be modified by cross‐coupling reactions.     

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described_. The CCR generally requires dual Ni catalysis and MgBr₂ promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr₂ in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl₂ as a precatalyst and MgBr₂ with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh₃)₂Cl₂ as a precatalyst and ZnPh₂ does not require salt promotion and is stereoretentive. The reaction with Zn(CH₂SiMe₃)₂, however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh₃)₂Cl₂. Ni-Catalyzed and MgBr₂-promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh₂ and Zn(CH₂SiMe₃)₂ is stereoretentive with Ni(dppp)Cl₂ and Ni(PPh₃)₂Cl₂. CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.     

Synthesis of Chiral Sulfoximines via Iridium-Catalyzed Regio- and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand

Transition metal-catalyzed enantioselective C−H activation of prochiral sulfoximines for non-annulated products remains a formidable challenge. We herein report iridium-catalyzed enantioselective C−H borylation of N-silyl diaryl sulfoximines using a well-designed chiral bidentate boryl ligand with a bulky side arm. This method is capable of accommodating a broad range of substrates under mild reaction conditions, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative-scale C−H borylation for diverse downstream transformations, including the synthesis of chiral version of bioactive molecules. Computational studies showed that the bulky side arm of the ligand confers high regio- and enantioselectivity through steric effect.     

BINOL Phosphoric Acid‐Catalyzed Asymmetric Mannich Reaction of Cyclic N‐Acyl Ketimines with Cyclic Enones

A highly enantio‐ and diastereoselective Mannich reaction of cyclic N‐acyl ketimines generated in situ from 3‐hydroxyisoindolin‐1‐ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin‐1‐ones bearing adjacent quaternary and tertiary stereogenic centers.     

Increasing Complexity: A Practical Synthetic Approach to Three-Dimensional,Cyclic Sulfoximines and First Insights into Their in Vitro Properties

A short synthetic approach with broad scope to access five- to seven-membered cyclic sulfoximines in only two to three steps from readily available thiophenols is reported. Thus, simple building blocks were converted to complex molecular structures by a sequence of S-alkylation and one-pot sulfoximine formation, followed by intramolecular cyclization. Seventeen structurally diverse cyclic sulfoximines were prepared in high overall yields. In vitro evaluation of these underrepresented, three-dimensional, cyclic sulfoximines with respect to properties relevant to medicinal chemistry did not reveal any intrinsic flaw for application in drug discovery.     

Catalytic Enantioselective Aza‐Reformatsky Reaction with Cyclic Imines

A catalytic highly enantioselective aza‐Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral β‐amino esters with good yields and excellent enantioselectivities is reported. A readily available diaryl prolinol is used as a chiral ligand, ZnMe₂ as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five‐membered N‐sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral β‐amino esters.     

Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: potential scaffolds for peptide mimetics

The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to alpha- or beta-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.     

Modular asymmetric synthesis of functionalized azaspirocycles based on the sulfoximine auxiliary

A modular asymmetric synthesis of the functionalized azaspirocycles 6 (m = 2, n = 1), 7 (m = 1, n = 2), 8 (m = n = 2), 12, 20, and 24 from the cyclic allylic sulfoximines 1 is described. The synthetic strategy is based on the stereoselective construction of the carbocycle 4 containing the amino-substituted tertiary C atom from 1 followed by the generation of the azaspirocycle. Three different routes have been followed for the synthesis of the heterocyclic ring: N,C-dianion cycloalkylation, ring-closing metathesis, and N-acyl iminium ion formation.     

Synthesis of 1,5-P,N-phosphino-sulfoximines through phospha-Michael reaction of alkenyl sulfoximines and their evaluation as ligands in palladium-catalyzed allylic alkylation

We describe a modular synthesis of cyclic and acyclic 1,5-P,N-phosphino-sulfoximines by using a phospha-Michael reaction of the corresponding alkenyl sulfoximines with HPPh₂/KOtBu as key step, which proceeds with medium diastereoselectivity. The palladium-catalyzed allylic alkylation of racemic 1,3-diphenyl allyl acetate with malonate in the presence of a S_SR_CR_C-configured N-benzyl-substituted cyclic phosphino-sulfoximine gave the corresponding alkene with 97% ee in 98% yield. A comparative study of N-substituted phosphino-sulfoximines showed the selectivity of the Pd(0)-catalyst to be dependent not only on the chiral backbone of the ligand but also on the N-substituent and configuration of the sulfoximine group.     

Iron‐Catalyzed Imidative Kinetic Resolution of Racemic Sulfoxides

Kinetic resolution of racemic sulfoxides requires either custom substrates or shows moderate enantioselectivity, leading to achiral coproducts (such as sulfones) as an intrinsic part of the process. A new strategy is demonstrated that allows the resolution of racemic sulfoxides through catalytic asymmetric nitrene‐transfer reactions. This approach gives rise to both optically active sulfoxides and highly enantioenriched sulfoximines. By using a chiral iron catalyst and a readily available iodinane reagent, high selectivity factors have been achieved under very practical reaction conditions. With respect to the substrate scope, it is noteworthy that this unprecedented imidative kinetic resolution of racemic sulfoxides provides access to both aryl–alkyl and dialkyl sulfoximines in highly enantioenriched forms.     

Regio- and Enantioselective Substitution of Acyclic Allylic Sulfoximines with Butylcopper in the Presence of Lithium Iodide and Boron Trifluoride

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.     

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

An approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.     

Synthesis of Sulfoximidoyl‐Containing Hypervalent Iodine(III) Reagents and Their Use in Transition‐Metal‐Free Sulfoximidations of Alkynes

Well‐defined hypervalent iodine(III) reagents incorporating transferable sulfoximidoyl groups were obtained through ligand exchange reactions of methoxy(tosyloxy)iodobenzene (MTIB) with NH sulfoximines in good to excellent yields. The solid‐state structure of a representative product was characterized by X‐ray crystallography. Utilizing these reagents in synthesis provides a new, transition‐metal‐free approach towards N‐alkynylated sulfoximines.     

A Cyclization–Rearrangement Cascade for the Synthesis of Structurally Complex Chiral Gold(I)–Aminocarbene Complexes

A facile synthesis of chiral cyclic alkyl aminocarbene–gold(I) complexes from gold‐free 1,7‐enyne substrates was developed. The novel cyclization–rearrangement reaction sequence is triggered by the addition of (Me₂S)AuCl to different 1,7‐enynes and leads to structurally unique carbene–gold(I) complexes in high yields. These novel complexes are catalytically active and inhibit the proliferation of different human cancer cell lines.     

Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate their Self‐Assembly and Biological Activity

A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram‐positive bacteria and features self‐assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2‐chlorotrityl chloride resin through ether formation with the side‐chain alcohol. Subsequent elongation proceeds through Fmoc solid‐phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)‐3‐hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on‐resin head‐to‐tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self‐assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D ‐Asn8 analogue developed en route retains self‐assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self‐assembling properties and structure–activity relationships.     

Catalytic Asymmetric Transannulation of NH‐1,2,3‐Triazoles with Olefins

A convenient one‐pot asymmetric synthesis of 2,3‐dihydropyrroles from in situ generated triflated triazoles and olefins is described that further expands the utility of azavinyl carbene chemistry and provides access to an important class of cyclic enamides. Mechanistic investigations support the involvement of triflated cyclopropylaldimine intermediates in the formation of 2,3‐dihydropyrrole. To the best of our knowledge, this is the first example of a chiral Brønsted acid catalyzed rearrangement of cyclopropylimines into enantioenriched 2,3‐dihydropyrroles.