Stereoselective Synthesis of ß, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic ß, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Synthesis and in Silico Study of Novel Benzisoxazole-Chromene Derivatives as Potent Inhibitors of Acetylcholinesterase: Metal-Free Site-Selective C-N Bond Formation via Aza-Michael Reaction.

An efficient metal-free approach for site selective C-N coupling reaction of benzo[d]isoxazole and 2H-chromene derivatives has been designed and developed against AchE. This nitrogen containing organo-base promoted methodology, which is both practical and environmentally friendly, provides an easy and suitable pathway for synthesizing Benzisoxazole-Chromene (BC) possessing poly heteroaryl moieties. The synthesized BC derivatives 4 a-n was docked into the active sites of AChE to obtain more perception into the binding modes of the compounds. Out of them, compound 4 a and 4 l displayed potent activity and high selectivity against the AChE inhibition. Final docking results indicates that compound 4 l showed the lowest binding energy of -11.2260 kcal/mol with AChE. The synthesized BC analogs would be potential candidates for promoting suitable studies in medicinal chemistry research.

A DFT Investigation of the Reactivity of Guanidinium Salts in Tandem aza-Michael Addition/Intramolecular Cyclization.

A proposed mechanism of the reaction of guanidinium chlorides with dimethyl acetylenedicarboxylate in a tandem aza-Michael addition reaction/intramolecular cyclization was investigated by DFT M06-2X and B3LYP computational approaches. The energies of the products were compared against the G3, M08-HX, M11, and wB97xD data or experimentally obtained product ratios. The structural diversity of the products was interpreted by the concurrent formation of different tautomers formed in situ upon deprotonation with a 2-chlorofumarate anion. A comparison of relative energies of the characteristic stationary points along the examined reaction paths indicated that the initial nucleophilic addition is energetically the most demanding process. The overall reaction is strongly exergonic, as predicted by both methods, which is primarily due to methanol elimination during the intramolecular cyclization step producing cyclic amide structures. Formation of a five-membered ring upon intramolecular cyclization is highly favored for the acyclic guanidine, while optimal product structure for the cyclic guanidines is based on a 1,5,7-triaza [4.3.0]-bicyclononane skeleton. Relative stabilities of the possible products calculated by the employed DFT methods were compared against the experimental product ratio. The best agreement was obtained for the M08-HX approach while the B3LYP approach provided somewhat better results than the M06-2X and M11 methods.

Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner-Wadsworth-Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki-Miyaura cross-coupling from the corresponding brominated pyrazole-azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

Construction of N-Ferrocene Substituted Benzodihydrooxazoles via a Catalyst-Free Aza-Michael Addition/C(sp3)-O Bond Formation Tandem Reaction.

A catalyst-free aza-Michael addition/C(sp3)-O bond formation tandem reaction of substituted amino ferrocenes with quinone esters was developed, which provided a green and efficient strategy for the construction of a C(sp3)-O bond from C(sp3)-H, and a series of N-ferrocene-substituted benzodihydrooxazoles were smoothly produced in moderate to excellent yields (up to >99% yield). The mechanism experiments showed that quinone esters performed as both substrate and oxidant. The salient features of this transformation include good functional group tolerance, broad substrate scope and mild conditions.

Metal catalyst-free N-allylation/alkylation of imidazole and benzimidazole with Morita-Baylis-Hillman (MBH) alcohols and acetates.

A highly α-regioselective N-nucleophilic allylic substitution of cyclic MBH alcohols and acetates with imidazole or benzimidazole, in toluene at reflux with an azeotropic distillation, was successfully carried out with no catalysts or additives, affording the corresponding N-substituted imidazole derivatives in good yields. On the other hand, in refluxing toluene or methanol, the aza-Michael addition of imidazole onto acyclic MBH alcohols was performed using DABCO as an additive, leading to the corresponding 1,4-adducts in 70-84% yields.

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products.

An intriguing example of a crystallization-induced stereochemical switch in the configuration of aza-Michael reaction products is described. Depending on both the stereochemical purity and stoichiometric ratio of the chiral amine used, the reaction delivers crystalline diastereomers of a different stereochemistry. The optically pure diastereomer smoothly converts to its racemic epimer salt upon the addition of a complementary chiral amine.

Accelerated and Concerted Aza-Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High-Throughput Formats.

The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO2 F followed by fluoride exchange by a catalyst. We report catalyst-free Aza-Michael addition to install SO2 F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼104 relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high-throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet-assisted accelerated reactions in combination with high-throughput experimentation for characterization of reaction scope.

Benefits of time-resolved nonuniform sampling in reaction monitoring: The case of aza-Michael addition of benzylamine and acrylamide.

Monitoring of chemical reactions is best carried out using methods that sample the test object at a rate greater than the time scale of the processes taking place. The recently proposed time-resolved nonuniform sampling (TR-NUS) method allows the use of two-dimensional (2D) nuclear magnetic resonance (NMR) spectra for this purpose and provides a time resolution equivalent to that achievable using one-dimensional spectra. Herein, we show that TR-NUS acquired data eliminates 2D spectral line disturbances and enables more accurate signal integration and kinetics conclusions. The considerations are exemplified with a seemingly simple aza-Michael reaction of benzylamine and acrylamide. Surprisingly, the product identification is possible only using 2D spectra, although credible monitoring requires TR-NUS.

Facile Synthesis of 3-Substituted Thiazolo[2,3-α]tetrahydroisoquinolines.

It was found that 4-hydroxy-2-butenoic ester (11) could not react with 3,4-dihydro-isoquinoline (4a). Individual addition reactions of γ-mercapto-α,ß-unsaturated esters (18) and -unsaturated amide (19) with 3,4-dihydroisoquinolines (4) were carried out under appropriate conditions to provide the corresponding thiazolo[2,3-α]isoquinoline derivatives with good yields (up to 87%) and significant diastereomeric selectivity. The mechanism of the crucial reaction was discussed.

Organocatalytic synthesis of 5-hydroxyisoxazolidine catalyzed by camphor sulfonyl hydrazines through aza-Michael addition/cyclization.

A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addition reaction between N,O-protected hydroxyamines and enals. Moderate yields with moderate to good enantioselectivities (up to 96% enantiomeric excess [ee]) were achieved. It provides an alternative asymmetric approach to preparing isoxazolidine derivatives.

Multicomponent Domino Reaction in the Asymmetric Synthesis of Cyclopentan[c]pyran Core of Iridoid Natural Products.

The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development.

Design, and facile synthesis of 1,3 diaryl-3-(arylamino)propan-1-one derivatives as the potential alpha-amylase inhibitors and antioxidants.

Diabetes is the most prevalent metabolic disorder causing a high rate of mortality and morbidity. Recently alpha-amylase is reported to be good drug design target for the treatment of diabetes mellitus. We have designed 116 molecules based on aza-Michael adduct of trans-chalcone as 1,3 diaryl-3-(arylamino)propan-1-ones which were studied by molecular docking and among them best six derivatives were synthesized easily via aza-Michael addition on trans-chalcone using KOH as a catalyst and evaluated for alpha-amylase inhibition along with antioxidant activity. It was observed that all compounds have alpha-amylase inhibitory activity but at different extents. The molecule 3e is the most potent alpha-amylase inhibitor of this series. 3a is the second most potent compound, whereas only one molecule 3d has shown antioxidant activity.

One-Pot Catalytic Enantioselective Synthesis of 2-Pyrazolines.

A scalable, one-pot, enantioselective catalytic synthesis of 2-pyrazolines from beta-substituted enones and hydrazines is described. Pivoting on a two-stage catalytic Michael addition/condensation strategy, the use of an aldehyde to generate a suitable hydrazone derivative of the hydrazine was found to be key for curtailing background reactivity and tuning the catalyst-controlled enantioselectivity. The new synthetic method is easy to perform, uses a new and readily prepared cinchona-derived bifunctional catalyst, is broad in scope, and tolerates a range of functionalities with high enantioselectivity (up to >99:1 e.r.). The significant scalability of this methodology was demonstrated with the synthesis of more than 80 grams of a pyrazoline product with 89 % catalyst recovery.

Modular Bi-Directional One-Pot Strategies for the Diastereoselective Synthesis of Structurally Diverse Collections of Constrained ß-Carboline-Benzoxazepines.

The development of robust and efficient strategies to access structurally diverse drug-like compound collections remains an important challenge for small molecule probe development and drug discovery. Following a build/couple/pair strategy we have established bidirectional approach to unprecedented benzoxazepines by employing a Pictet-Spengler/aza-Michael addition cascade and Schiff base/aza-Michael addition/reduction protocols, respectively. The corresponding ß-carboline-fused benzoxazepines and peripherally substituted benzoxazepines are isolated in high diastereoselectivity, good to excellent yields and have, to the best of our knowledge, never been reported.

Synthesis of dual-action parthenolide prodrugs as potent anticancer agents.

Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC50 values ranging from 0.2 to 5.2µM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).

One-Pot Lipase-Catalyzed Enantioselective Synthesis of (R)-(-)-N-Benzyl-3-(benzylamino)butanamide: The Effect of Solvent Polarity on Enantioselectivity.

The use of the solvent engineering has been applied for controlling the resolution of lipase-catalyzed synthesis of ß-aminoacids via Michael addition reactions. The strategy consisted of the thermodynamic control of products at equilibrium using the lipase CalB as a catalyst. The enzymatic chemo- and enantioselective synthesis of (R)-(-)-N-benzyl-3-(benzylamino)butanamide is reported, showing the influence of the solvent on the chemoselectivity of the aza-Michael addition and the subsequent kinetic resolution of the Michael adduct; both processes are catalyzed by CalB and both are influenced by the nature of the solvent medium. This approach allowed us to propose a novel one-pot strategy for the enzymatic synthesis of enantiomerically enriched ß-aminoesters and ß-aminoacids.

Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and ß-Trifluoromethyl ß-Aryl Nitroolefins.

The aza-Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza-Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza-Michael reaction between primary alkyl amines and ß-trifluoromethyl ß-aryl nitroolefins. In contrast to classical conjugate-addition reactions, a strategy of HOMO-raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).

Synthesis of Saxitoxin Biosynthetic Intermediates: Reveal the Mechanism for Formation of its Tricyclic Skeleton in Biosynthesis.

The synthesis and biosynthesis of the complex saxitoxin (STX) structure have garnered significant interest. Previously, we hypothesized that the tricyclic skeleton of STX originates from the monocyclic precursor 11-hydroxy-IntC'2 during biosynthesis, although direct evidence has been lacking. In this study, we identified conditions to synthesize a proposed tricyclic biosynthetic intermediate, 12,12-dideoxy-decarbamoyloxySTX (dd-doSTX), along with its 6-epimer (6-epi-dd-doSTX) and a bicyclic compound, in a single step from di-Boc protected 11-hydroxy-IntC'2. The reaction mechanism involves successive aza-Michael addition of a guanidino amine to the conjugated olefin. Notably, both dd-doSTX and 6-epi-dd-doSTX were detected in a toxin-producing cyanobacterium, suggesting that the biosynthetic enzymes may generate these compounds via similar mechanisms.

Design and synthesis of fosmidomycin analogs containing aza-linkers and their biological activity evaluation.

BACKGROUND: The enzymes involved in the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway are attractive targets of a new mode of action for developing anti-infective drugs and herbicides, and inhibitors against 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC), the second key enzyme in the pathway, have been intensively investigated; however, few works are reported regarding IspC inhibitors designed for new herbicide discovery. RESULTS: A series of fosmidomycin (FOS) analogs were designed with nitrogen-containing linkers replacing the trimethylene linker between the two active substructures of FOS, phosphonic acid and hydroxamic acid. Synthesis followed a facile three-step route of sequential aza-Michael addition of α-amino acids to dibenzyl vinylphosphonate, amidation of the amino acid carboxyl with O-benzyl hydroxylamine, and simultaneous removal of the benzyl protective groups. Biological activity evaluation of IspC and model plants revealed that some compounds had moderate enzyme and model plant growth inhibition effects. In particular, compound 10g, which has a N-(4-fluorophenylethyl) nitrogen-containing linker, exhibited the best plant inhibition activities, superior to the control FOS against the model plants Arabidopsis thaliana, Brassica napus L., Amaranthus retroflexus and Echinochloa crus-galli. A dimethylallyl pyrophosphate rescue assay on A. thaliana confirmed that both 10g and FOS exert their herbicidal activity by blocking the MEP pathway. This result consistent with molecular docking, which confirmed 10g and FOS binding to the IspC active site in a similar way. CONCLUSION: Compound 10g has excellent herbicidal activity and represents the first herbicide lead structure of a new mode of action that targets IspC enzyme in the MEP pathway. © 2023 Society of Chemical Industry.