Cyclic Sulfamidates Research Articles

Catalytic Asymmetric Cycloadditions of Cyclic Sulfamidate Imines: Straightforward Access to Chiral N‐Heterocycles

AbstractChiral N‐heterocyclic compounds are key structures in natural compounds and pharmaceuticals, and they serve as essential building blocks of functional materials. Catalytic asymmetric cycloaddition reactions represent one of the most efficient synthetic strategies for constructing optically active heterocycles. Cyclic sulfamidate imines have recently come to be extensively studied and widely utilized in both organocatalytic and transition metal‐catalyzed asymmetric cycloadditions, where they have been shown to provide various N‐fused‐heterocycles and spiro‐cycles exhibiting high efficiencies with excellent stereoselectivities. This review highlights recent advancements in catalytic asymmetric cycloadditions of cyclic sulfamidate imines for the stereoselective synthesis of biologically active sulfamidate‐containing heterocycles since 2012 while focusing on the diverse reactivities of cyclic sulfamidate imines and the mechanisms of chiral induction in catalysis.

Synthesis of cyclic sulfamides via one pot alkylation/aza-Michael cascade reaction

A straightforward and transition metal-free method for the synthesis of cyclic sulfamides via base-promoted bis-alkylation of tert-butyl (N-alkylsulfamoyl)carbamates with electron-deficient allyl bromides is described. All obtained cyclic sulfamides underwent successful removal of tert-butoxycarbonyl protecting group.

Gold(I)−Catalyzed Synthesis of Cyclic Sulfamides via an Intramolecular Dehydrative Amination of Allylic Alcohols: A Strategy for 1,3‐Diamine Synthesis

AbstractA gold(I)‐catalyzed intramolecular dehydrative amination method has been developed to synthesize diverse cyclic sulfamides efficiently. Reactions proceed smoothly at room temperature using a combination of (IPr)AuCl (5 mol%) and AgBF4 (5 mol%). This method showcases a broad substrate scope, encompassing challenging seven‐membered ring structures, and exhibits functional group compatibility. Moreover, the reaction demonstrates high stereoselectivity, allowing the synthesis of enantiomerically enriched cyclic sulfamides from chiral secondary allylic alcohols. The synthesized cyclic sulfamides serve as valuable intermediates for generating 1,3‐diamines. This approach provides an improved route for cyclic sulfamide synthesis and a strategic entry point for obtaining essential 1,3‐diamine derivatives.

The Proton of Alcohols as Hydrogen Source in Diboron-Mediated Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Cyclic N-Sulfonyl Imines.

The proton of alcohols as the sole hydrogen source in diboron-mediated nickel-catalyzed asymmetric transfer hydrogenation of cyclic N-sulfonyl imines has been developed, providing the chiral cyclic sulfamidates in excellent enantioselectivities. The mechanistic investigations suggested that the proton of alcohols could be activated by tetrahydroxydiboron to form active nickel hydride species.

Photoinduced Metal- and Photosensitizer-Free Decarbonylative C-H Alkylation of Cyclic Sulfamidate Imines.

Photoinduced decarbonylative C-C bond formation with readily accessible aldehydes as alkyl sources is described. This protocol provides a sustainable alternative for the effective construction of diverse valuable 4-alkylated sulfonyl ketimines under metal- and photosensitizer-free conditions. Significantly, in this reaction, air serves as the green oxidant, and cyclic sulfamidate imines play a dual role of substrate and photocatalyst, thus affording a concise reaction system for C-H alkylation of cyclic sulfamidate imines.

Monofluoromethylation of Cyclic Sulfamidates and Sulfates with α‐Fluorocarbanions of Fluorobis(phenylsulfonyl)methane and Ethyl 2‐Fluoroacetoacetate

AbstractA regioselective fluoromethylation by ring‐opening of cyclic sulfamidates and sulfates with α‐fluorocarbanions and subsequent reductive desulfonylation is developed. Fluorobis(phenylsulfonyl)methane (FBSM) was explored as fluoromethide equivalent and the reaction was extended to the α‐fluorocarbanion of ethyl 2‐fluoroacetoacetate. This approach allows access to γ‐ and δ‐fluoroamines as well as γ‐ and δ‐fluoroalcohols in high yields.

δ-Acetoxy Allenoate as a 5C-Synthon in Domino-Annulation with Sulfamidate Imines: Ready Access to Coumarins.

A DMAP-catalyzed sequential benzannulation and lactonization strategy in which δ-acetoxy allenoate functions as a 5C-synthon in its reaction with cyclic sulfamidate imines is reported. This platform delivers π-extended coumarin frameworks under metal-free conditions via allylic elimination followed by Mannich coupling, proton shifts, C-N bond cleavage, and lactonization as key steps. The driving force for this domino reaction is the formation of the diene-ammonium intermediate and O-S bond cleavage. ESI-HRMS has been useful in gaining insights into the reaction pathway.

Metal‐free Oxidation of Cyclic Sulfamides to Imines with Dioxygen as an Oxidant

AbstractA novel metal‐free oxidation of aryl sulfamides to sulfonyl imines with dioxygen as an oxidant have been realized. The reactions proceeded in moderate to excellent yields. Mechanistic investigation suggests that alcohol compounds A can be the key intermediates for the formation of products 2.

Sulfamidate-Based Stereoselective Total Synthesis of (+)-Preussin Using Gold(I)-Catalyzed Intramolecular Dehydrative Amination: Dead End and Detour.

A sulfamidate-based stereoselective total synthesis of (+)-preussin has been developed. The key step involves a gold(I)-catalyzed intramolecular dehydrative amination of sulfamate esters tethered to allylic alcohols, which allows for the construction of the cyclic sulfamidate with high stereoselectivity. Further manipulation to highly constrained bicyclic sulfamidate and the following ring-opening process afford 3-hydroxypyrrolidine motif stereoselectively. The energy of the constrained bicyclic ring system is relieved by the subsequent ring-opening process, which leads to a stereoselective formation of the 3-hydroxypyrrolidine motif under mild reaction conditions. The success of this approach not only provides a new method for the total synthesis of enantiomerically pure (+)-preussin but also highlights the synthetic utility of sulfamidates in constructing valuable natural product architectures.

Novel pseudonucleosides and sulfamoyl-oxazolidinone β-D-glucosamine derivative as anti-COVID-19: design, synthesis, and in silico study

New pseudonucleosides containing cyclic sulfamide moiety and sulfamoyl β-D-glucosamine derivative are described. These pseudonucleosides are synthesized in good yields starting from chlorosulfonyl isocyanate and β-D-glucosamine hydrochloride in five steps; (protection, acetylation, removal of the Boc group, sulfamoylation, and cyclization). Further, novel glycosylated sulfamoyloxazolidin-2-one is prepared in three steps; carbamoylation, sulfamoylation, and intramolecular cyclization. The structures of the synthesized compounds were confirmed by usual spectroscopic and spectrometric methods NMR, IR, MS, and EA. Interesting molecular docking of the prepared pseudonucleosides and (Beclabuvir, Remdesivir) drugs with SARS-CoV-2/Mpro (PDB:5R80) was conducted using the same parameters for a fair comparison. A low binding affinity of the synthesized compounds compared to the Beclabuvir and other analysis showed that pseudonucleosides have the ability to inhibit SARS-CoV-2. After the motivating results of molecular docking study, the complex between the SARS-CoV-2 Mpro and compound 7 was subjected to 100 ns molecular dynamics (MD) simulation using Desmond module of Schrodinger suite, during which the receptor-ligand complex showed substantial stability after 10 ns of MD simulation. Also, we studied the prediction of absorption, distribution, properties of metabolism, excretion, and toxicity (ADMET) of the synthesized compounds. Communicated by Ramaswamy H. Sarma

Synthesis of Fluorescent Lanthipeptide Cytolysin S Analogues by Late-Stage Sulfamidate Ring Opening.

Nucleophilic ring opening of cyclic sulfamidates derived from amino acids is a common strategy for the synthesis of lanthionine derivatives. In this work, we report the regio-, chemo-, and stereoselective intramolecular S-alkylation of a cysteine residue with N-sulfonyl sulfamidates for the synthesis of cyclic lanthionine-containing peptides. The strategy involves the solid-phase synthesis of sulfamidate-containing peptides followed by late-stage intramolecular cyclization. This protocol allowed for the synthesis of four full-length cytolysin S (CylLS″) analogues, two α-peptides and two hybrid α/β-peptides. Their conformational preferences and biological activities were assessed and compared with those of wild-type CylLS″.

Covalent Tethers for Precise Amino Alcohol Syntheses: Ring Opening of Epoxides by Pendant Sulfamates and Sulfamides.

We describe the development of the first ring opening of epoxides using pendant sulfamates and sulfamides. These reactions are promoted by a base and proceed under mild conditions to afford oxathiazinanes and cyclic sulfamides with excellent diastereoselectivity and regiocontrol. The reactions scale well, and the products serve as synthons for ring-opening reactions.

Swapping Copper-Catalytic Process: Selective Access to Pyrazoles and Conjugated Ketimines from Oxime Acetates and Cyclic Sulfamidate Imines.

A powerful CuCl-catalyzed sequential one-pot reaction of aryl methyl ketoxime acetates with cyclic N-sulfonyl imines followed by elimination in the presence of base is reported. This hydrazine-free method conveniently makes C-C and N-N bonds via a radical cleavage of the N-O bond, delivering a special class of C3-hydroxyarylated pyrazoles in good yields. Surprisingly, while employing CuI as a catalyst instead of CuCl, the reaction proceeds through a non-radical pathway which embodies a new tactic for the high-yielding access to value-added conjugated N-unsubstituted ketimines. Moreover, additive-free approach to sulfamidate-fused-pyrazoles was achieved by successfully catalyzing addition and oxidative N-N bond-making reactions by CuI and CuCl, respectively. Significantly, our novel technique could convert the prepared ketimines into the pharmacologically recognized 6H-benzo[c]chromene frameworks.

Conformationally Restricted β-Sheet Breaker Peptides Incorporating Cyclic α-Methylisoserine Sulfamidates.

Peptides containing variations of the β-amyloid hydrophobic core and five-membered sulfamidates derived from β-amino acid α-methylisoserine have been synthesized and fully characterized in the gas phase, solid state and in aqueous solution by a combination of experimental and computational techniques. The cyclic sulfamidate group effectively locks the secondary structure at the N-terminus of such hybrid peptides imposing a conformational restriction and stabilizing non-extended structures. This conformational bias, which is maintained in the gas phase, solid state and aqueous solution, is shown to be resistant to structure templating through assays of in vitro β-amyloid aggregation, acting as β-sheet breaker peptides with moderate activity.

Kukhtin-Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars.

Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin-Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin-Ramirez adducts, followed by a base-promoted reductive N-S bond cleavage. The mild reaction conditions of the protocol enable the formation of amino alcohols including analogs that bear multiple functional groups.

Selective Reduction Leading to 3,5-cis-3-Aminosugars: Synthesis and Stereoselective Glycosylation.

Synthesis of 3,5-cis-3-amino glycals with a cis-fused cyclic sulfamidate group has been achieved by selective reduction of sulfamidate ketimine groups. The efficient access to the structurally unique glycals allowed the subsequent divergent synthesis of various naturally occurring 3-amino-2,3,6-trideoxysugars. In addition, Lewis acid-promoted glycosylation of the glycals provided a simple solution for the stereoselective installation of O- and C-linked aglycons on the amino sugar scaffolds.

Amphiphilic Polyfluorinated Amino Ethers from Cyclic Sulfamidates.

Regioselective ring opening of cyclic sulfamidates was achieved by means of nucleophilic polyfluorinated alkoxides to access achiral and chiral β- and γ-ORF amines and α-amino esters. Subsequent transformations provide free amines ready for incorporation into bioactive substances through amide bond formation or nucleophilic aromatic substitution.

From Data to Prediction: Thermal Risk Analysis of Cyclic Sulfamidates

From Data to Prediction: Thermal Risk Analysis of Cyclic Sulfamidates

Synthesis of Versatile Enantiopure Morpholine Fragments from Chiral-Pool Starting Materials

Key words morpholines - cyclic sulfamidates - chiral pool - building blocks - bioisosterism - asymmetric synthesis

Thermal Safety and Structure-Related Reactivity Investigation of Five-Membered Cyclic Sulfamidates

Five-membered cyclic sulfamidates are very valuable electrophiles in organic synthesis and readily used on a multikilogram scale. However, their thermal degradation is underreported and might lead to unforeseen and undesirable safety events. In addition, ring or nitrogen substitution can have a tremendous influence on cyclic sulfamidate reactivity toward bases and therefore impact the overall safety assessment of a process. An understanding of such behavior is therefore of high importance in the industry while designing a synthetic route, as a change of, e.g., a protecting group can increase the thermal safety of a step on scale. We report herein the thermal degradation investigation as well as the structure-related reactivity exploration of cyclic sulfamidates, including their use in combination with strong bases. The design of a predictive model to rapidly assess the thermal hazard based on collected data and selected molecular descriptors is also presented.