sulfa-Michael Addition Research Articles

Sulfa-Michael Addition on Dehydroalanine: A Versatile Reaction for Protein Modifications.

Chemical modification of proteins has been widely applied in diagnostic and therapeutic processes. Here, we report a novel bioconjugation between sulfinic acids and amino acid dehydroalanine (Dha) in the context of both small molecules and proteins. This conjugation enables the rapid formation of sulfone linkages in a chemoselective and disulfide-compatible manner under biocompatible conditions with Dha residues chemically installed in proteins and thus provides a robust tool that is simple and has exquisite site selectivity for protein functionalization in a wide range.

Bicarbonate-binding catalysis for the enantioselective desymmetrization of keto sulfonium salts

Herein, an enantioselective desymmetrization of cyclic keto sulfonium salts through enantioselective deprotonation/ring opening process by anion-binding catalysis is presented. We report a squaramide/HCO3- complex as catalytic active species which is able to stereo-differentiate two enantiomeric protons, triggering the ring opening event taking advantage of the great tendency of sulfonium salts to act as leaving groups. Thus, this desymmetrization methodology give rise to β-methylsulfenylated sulfa-Michael addition type products with excellent yields and very good enantioselectivities. The bifunctional organocatalyst has been demonstrated to be capable of activating simultaneously the base and the keto sulfonium salt by DFT calculations and experimental proofs.

Quinoxaline-specific enantioselective sulfa-michael reaction catalyzed by chiral phosphoric acid

Highly enantioselective sulfa-Michael additions (SMA) between 2-alkenyl quinoxalines and aromatic thiols are accomplished using a low loading of chiral phosphoric acid catalyst (1 mol%). It was confirmed by an investigation of a lot of azaarenes that the two C=N units of quinoxalines are indispensable for controlling the reaction enantioselectivities. A series of non-terminal 2-alkenes substituted with aryls or alkyls, even other electro-withdrawing groups such as ketones, esters, or amides, selectively reacted and afforded the desired SMA products (48 examples) in good regioselectivities with high yields (up to 99%) and good ee values (up to 97%).

Recent Advances in Organocatalyzed Asymmetric Sulfa-Michael Addition Triggered Cascade Reactions.

The sulfa-Michael addition reaction is a crucial subset of the Michael addition reaction, and aroused the interest of numerous synthetic biologists and chemists. In particular, sulfa-Michael addition triggered cascade reaction has developed quickly in recent years because it offers an efficient method to construct C-S bonds and other bonds in one approach, which is widely applicable for building chiral pharmaceuticals, their intermediates, and natural compounds. This review emphasizes the recent advancements in sulfa-Michael addition-triggered cascade reactions for the stereoselective synthesis of sulfur-containing compounds, including sulfa-Michael/aldol, sulfa-Michael/Henry, sulfa-Michael/Michael, sulfa-Michael/Mannich and some sulfa-Michael triggered multi-step processes. Moreover, some reaction mechanisms and derivatization experiments are introduced appropriately.

NbCl5-catalyzed sulfa-Michael addition for constructing quaternary centers in enones.

A novel NbCl5-catalyzed sulfa-conjugate addition has been developed to construct quaternary centers in various enones. This new method enables a range of functionalized thiols to access different β-sulfido carbonyl compounds bearing a quaternary center. 27 novel β-sulfido ketones have been obtained with moderate to excellent yields. The preparative scale reactions also proceed well, showing no decrease in yield. We further studied the mechanism by DFT calculations. This methodology is significant in sulfur chemistry, especially in sulfa-conjugate addition, giving a new pathway to add thiols to tri-substituted enones.

Advances in Bifunctional Squaramide-Catalyzed Asymmetric Sulfa-Michael Addition: A Decade Update

AbstractThe application of bifunctional organocatalysts in organic chemistry has advanced remarkably owing to their high stability to moisture and air, relatively low toxicity, ease of handling, and recoverability. Among chiral bifunctional organocatalysts, squaramides have emerged as a privileged catalyst in recent years. This review article presents a comprehensive report on fine-tunable bifunctional chiral squaramide-catalyzed sulfa-Michael addition, which is based upon synchronous interplay of synergistic ‘electrophilic–nucleophilic’ dual activation strategies via multiple H-bonding interactions for the construction of both common and complex molecular entities bearing multiple stereocenters. Mechanistic discussions are kept brief, but significant understandings have been recorded. The contribution of squaramide catalyst to the construction of C–S bonds via sulfa-Michael addition has been applied in medicinal, natural, and industrial chemistry. Attention is focused on summarizing the progress made in chiral squaramide-catalyzed asymmetric sulfa-Michael addition and subsequent cascade/domino reaction sequences between 2011 and 2022.1 Introduction2 Quinine-Squaramide Organocatalysis3 Iminophosphorane-Squaramide Organocatalysis4 Chinchona-Squaramide Organocatalysis5 trans-1,2-Diaminocyclohexane-Squaramide Organocatalysis6 Conclusion

CO2-Switchable Single-Chain Polymeric Nanoparticles Enable Gas-Controllable Reaction Separation for Asymmetric Catalysis in Water

Water-soluble single-chain polymeric nanoparticles (SCPNs), which isolated catalytic sites within a hydrophobic interior, made water-incompatible organometallic catalysis highly efficient in water. However, it is still a great challenge to conveniently control their hydrophilicity, so as to combine reactivity and recovery of the catalytic SCPNs in aqueous systems. Herein, we have developed a series of catalytic SCPNs, which possessed CO2-switchable hydrophilic/hydrophobic behavior, to realize the gas-controlled reaction and separation for asymmetric sulfa-Michael addition (SMA) in water. A novel series of CO2-switchable random copolymers were thus synthesized by copolymerization of CO2-responsive amidine derivatives with hydrophobic chiral salen FeIII monomers via reversible addition-fragmentation chain transfer polymerization. Characterization suggested their CO2-controlled self-collapse behavior in water due to CO2-switched change in hydrophilicity/hydrophobicity of the amidine moiety. The resultant CO2-switchable SCPNs provided hydrophobic, catalytic compartments for asymmetric SMA in water upon CO2 addition, giving various chiral β-keto sulfides with almost quantitative yields (90–98%) and high enantioselectivities (93–99%). When CO2 is removed by N2 bubbling, they were collapsed and spontaneously precipitated from the aqueous system for steady reuse. The gas-controlled reaction-separation approach provides an energy-efficient way to combine reactivity and recovery of catalytic SCPNs in aqueous systems, which should be quite practical in large-scale industrial applications.

Eliminating Transition State Calculations for Faster and More Accurate Reactivity Prediction in Sulfa-Michael Additions Relevant to Human Health and the Environment.

Fast and accurate computational approaches to predicting reactivity in sulfa-Michael additions are required for high-throughput screening in toxicology (e.g., predicting excess aquatic toxicity and skin sensitization), chemical synthesis, covalent drug design (e.g., targeting cysteine), and data set generation for machine learning. The kinetic glutathione chemoassay is a time-consuming in chemico method used to extract kinetic data in the form of log(kGSH) for organic electrophiles. In this work, we use density functional theory to compare the use of transition states (TSs) and enolate intermediate structures following C–S bond formation in the prediction of log(kGSH) for a diverse group of 1,4 Michael acceptors. Despite the widespread use of transition state calculations in the literature to predict sulfa-Michael reactivity, we observe that intermediate structures show much better performance for the prediction of log(kGSH), are faster to calculate, and easier to obtain than TSs. Furthermore, we show how linear combinations of atomic charges from the isolated Michael acceptors can further improve predictions, even when using inexpensive semiempirical quantum chemistry methods. Our models can be used widely in the chemical sciences (e.g., in the prediction of toxicity relevant to the environment and human health, synthesis planning, and the design of cysteine-targeting covalent inhibitors), and represent a low-cost, sustainable approach to reactivity assessment.

Iminophosphorane Catalyst Permits Enantioselective Sulfa-Michael Addition to α,β-Unsaturated Amides

Key words sulfa-Michael addition - enamides - squareamides - iminophosphoranes

Organocatalytic Enantioselective Sulfa-Michael Additions to α,β-Unsaturated Diazoketones.

Enantioselective sulfa-Michael additions to α,β unsaturated diazocarbonyl compounds have been developed. Quinine-derived squaramide was found to be the best catalyst to promote C-S bond formation in a highly stereoselective fashion for alkyl and aryl thiols. The easy-to-follow protocol allowed the preparation of 22 examples in enantiomeric ratios up to 97:3 and reaction yields up to 94%. The mechanism and origins of enantioselectivity were determined through density functional theory (DFT) calculations.

Total Synthesis of (±)-Spiroaxillarone A via a Reversible Sulfa-Michael Addition.

A bioinspired strategy is described for the total synthesis of spiroaxillarone A, which exhibited significant antimalarial activity against resistant Plasmodium falciparum (IC50 = 2.32 μM). The key steps include an intermolecular ethanethiol Michael addition, o-quinone Michael addition, and subsequent β-ethanethiol elimination. This synthetic sequence provides a potential biosynthetic pathway of spiroaxillarone A.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional iminophosphorane catalyst. Low catalyst loadings (2.0 mol %) were achieved on a decagram scale, demonstrating the scalability of the reaction. Computational analysis revealed the origin of the high enantiofacial selectivity via analysis of relevant transition structures and provided substantial support for specific noncovalent activation of the carbonyl group of the α,β-unsaturated amide by the catalyst.

Total synthesis of thioamycolamide A using diastereoselective sulfa-Michael addition as the key step

The total synthesis of the antitumor natural product thioamycolamide A has been accomplished in 19.1% overall yield featuring a diastereoselective sulfa-Michael reaction.

Mechanisms of asymmetric sulfa-Michael additions between phenylacetylene and thiolacetic acid: A DFT investigation

Mechanisms for asymmetric sulfa-Michael additions between phenylacetylene and thiolacetic acid have been investigated with M06-2X-D3/ma-def2-TZVP level, and SMD model was taken to simulate the solvent effect of toluene. The computational results suggest that(E)-S-styryl ethanethioate is the only product, and Gibbs free energy surface points out that the reaction between thiyl radical and terminal carbon atom of phenylacetylene is favorable. The yielded path of S-(1-phenylvinyl) ethanethioatehas a higher barrier and could not happen. Fukui function and dual descriptor can be used to predict the reactive sites, and localized orbital locator isosurfaces and electron spin density isosurface graphs can analyze the structures and reveal the substances.

Visible Light Mediated Photocatalyst Free C-S Cross Coupling: Domino Synthesis of Thiochromane Derivatives via Photoinduced Electron Transfer.

An efficient visible light mediated photocatalyst free C-S cross-coupling reaction has been developed for the synthesis of thiochromane derivatives through photoinduced electron transfer (PET). This methodology was further utilized for the synthesis of thiochroman-4-ol through intermolecular three-component cross-coupling reaction. The reaction proceeds via C-S bond formation through EDA complex/thioester cleavage/inter-or intramolecular sulfa-Michael addition followed by aldol reaction sequence. The EDA complex formation between aryl iodides and xanthate has been substantiated using spectroscopic experiments and DFT calculations.

A green and novel method for synthesis of β-sulfonyl esters under solvent-free conditions

A manipulative simple and efficient green methodology for the synthesis of β-sulfonyl esters from sulfonyl hydrazides and acrylic esters promoted by DABCO (1,4-diazabicyclo[2.2.2]octane) is described. The reaction is conducted through sulfa-Michael addition reaction in the absence of solvent at 75°C within 2–3 h. The effects of different bases, molar ratio of DABCO, temperature and time parameters on yield of reaction were investigated.

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst.

Cinchona alkaloid-derived organocatalysts are widely employed in various asymmetric transformations, yielding products with high enantiopurity. In this respect, a bifunctional quinine-derived sulfonamide organocatalyst was developed to catalyze the asymmetric sulfa-Michael reaction of naphthalene-1-thiol with trans-chalcone derivatives. The target sulfa-Michael adducts were obtained with up to 96% ee under mild conditions and with a low (1 mol %) catalyst loading. Selected enantiomerically enriched sulfa-Michael addition products were subjected to oxidation to obtain the corresponding sulfones.

“Free of Base” Sulfa-Michael Addition for Novel o-Carboranyl-DL-Cysteine Synthesis

The sulfa-Michael addition reaction was applied for the two-step synthesis of o-carboranyl cysteine 1-HOOCCH(NH2)CH2S-1,2-C2B10H11 from the trimethylammonium salt of 1-mercapto-o-carborane and methyl 2-acetamidoacrylate. To avoid the decapitation of o-carborane into its nido-form, the “free of base” method under mild conditions in a system of two immiscible solvents toluene-H2O was developed. The replacement of H2O by 2H2O resulted in carboranyl-cysteine containing a deuterium label at the α-position of the amino acid 1-HOOCCD(NH2)CH2S-1,2-C2B10H11. The structure of the protected o-carboranyl cysteine was determined by single-crystal X-ray diffraction. The obtained compounds can be considered as potential agents for the Boron Neutron Capture Therapy of cancer.

Diastereodivergent Synthesis of 2-Ene-1,4-hydroxy Sulfides from 2-Sulfinyl Dienes via Tandem Sulfa-Michael/Sulfoxide-Sulfenate Rearrangement

The highly diastereoselective sulfa-Michael addition of thiolates to enantiopure 2-sulfinyl dienes leads to anti or syn 2-ene-1,4-hydroxy sulfides in good yields and selectivities dependent on the reaction conditions in a diastereodivergent process. Synthetic applications of these enantiopure hydroxy sulfides by subsequent sigmatropic rearrangements have been outlined.

Organocatalyzed Sulfa-Michael Addition of Thiophenols on Trisubstituted α-Fluoroacrylates, a Straightforward Access to Chiral Fluorinated Compounds

In this manuscript, a simple and efficient sulfa-Michael addition reaction of aryl thiols to trisubstituted α-fluoro-α,β-unsaturated esters both in racemic and, for the first time, in enantioselective version is reported. The commercially available dimer of cinchona derivatives (DHQ)2PYR was used as a catalyst. This strategy showed a great tolerance for various substrates and substituents, providing fair to excellent yields, moderate to excellent diastereoselectivities (2:1 to >99:1), and low to good enantioselectivities (2 to 87%). The reaction has been applied to the synthesis of fluorinated analogues of diltiazem and tiazesim, both therapeutic agents.