Search Results (110)

Non-cephem drugs with 1,3-thiazine-derived rings are very rare, although a number of bioactive 1,3-thiazine derivatives are known. Similarly, 1,4-thiazepine-derived drugs are rare, but many 1,4-thiazepine derivatives show interesting biological activities. Therefore, our aim was the synthesis of such N,S-heterocycles using a versatile and short (1–3 steps) literature method. First, a three-component reaction of a cycloalkene, a thioamide, and an aldehyde provided 5,6-dihydro-4H-1,3-thiazines. Afterwards, Staudinger ketene–imine cycloaddition with chloroketene resulted in β-lactam-fused 1,3-thiazinanes. Finally, treatment with sodium methoxide induced ring expansion, yielding 4,5,6,7-tetrahydro-1,4-thiazepines. This synthetic pathway generates 3–5 new chiral centers with the help of pericyclic reactions, and almost every cycloaddition proceeded in a diastereoselective manner. Two-dimensional NOESY as well as single-crystal X-ray diffraction enabled unequivocal determination of the stereochemistry of all synthesized compounds. Full article

Fused polycyclic 1,7-naphthyridines are important N-heterocyclic scaffolds with potential applications in medicinal chemistry and materials science. Conventional methods for their synthesis often require harsh conditions or multiple steps, limiting functional group compatibility and scalability. Herein, we report a one-pot silver-catalyzed cyclization strategy that proceeds under mild conditions, tolerates diverse functional groups, and is amenable to gram-scale synthesis. The reaction features a simple workup involving celite filtration and standard purification. Preliminary studies indicate that these N-heterocycles exhibit promising photophysical and medicinal properties, highlighting their potential in light-emitting devices and therapeutic development. Full article

We report the first green and diastereoselective synthesis of novel thiophene bioisosteres designed to mimic the privileged pyrrolo[3,2-c]quinoline core of martinelline alkaloids. The key step features an intramolecular 1,3-dipolar cycloaddition of in situ generated non-stabilized azomethine ylides from sarcosine, which proceeds with excellent yield and diastereoselectivity. This sustainable protocol, leveraging ultrasonic irradiation, recyclable hydrotalcite catalysts, and the green solvent cyclopentyl methyl ether (CPME), efficiently constructs the complex tricyclic framework. The structure and stereochemistry of the novel bioisostere were unambiguously confirmed by X-ray crystallography. This method offers a valuable, eco-friendly approach for diversifying natural product-inspired libraries in medicinal chemistry. Full article

The Reformatsky reaction, first reported in 1887, has long been recognized as a fundamental method for carbon–carbon bond construction due to its mild conditions and functional group tolerance. Over the past few decades, this transformation has undergone a notable revival, with modern catalytic variants addressing limitations of stoichiometric protocols and expanding its role in complex molecule synthesis. Yet, despite its versatility, achieving stereoselective control remains a longstanding challenge. Herein we report the use of dichlorocyclopentadienyltitanium(III) (CpTiCl₂), generated in situ from CpTiCl₃ and manganese, as an efficient catalyst for Reformatsky-type couplings of aldehydes with α-haloesters and α-iodonitriles. Under mild conditions, CpTiCl₂ promotes the formation of β-hydroxy esters in high yields and with significant diastereoselective preference for the syn isomer (up to 100:0 syn:anti). This behavior contrasts sharply with the poor or anti-selective outcomes previously observed with titanocene(III) chloride (Cp₂TiCl). Mechanistic analysis suggests that the unique steric and electronic environment of CpTiCl₂—characterized by enhanced Lewis acidity and increased coordination vacancies—favors a Zimmerman–Traxler-type transition state that enforces syn stereocontrol. The methodology tolerates a wide variety of substrates, including aliphatic and aromatic aldehydes as well as α-iodonitriles, extending the scope of titanium-mediated Reformatsky chemistry. These findings establish CpTiCl₂ as a sustainable, selective, and robust organotitanium catalyst for stereoselective carbon–carbon bond formation, providing a promising alternative to the Nugent reagent and paving the way for new applications in complex molecule synthesis. Full article

Inspired by naturally occurring bis-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type bis-1-arylisochromans containing a stereogenic ortho-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5′-linked heterodimeric bis-isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki–Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet–Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet–Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral ortho-quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target bis-isochromans against Bacillus subtilis and Enterococcus faecalis with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the bis-isochroman skeleton. Full article

Fused and spiro nitrogen-containing heterocycles play an important role as structural motifs in numerous biologically active natural products and pharmaceuticals. The review summarizes various approaches to the synthesis of three-, four-, five-, and six-membered fused and spiro heterocycles with one or two nitrogen atoms. The assembling of the titled compounds via cycloaddition, oxidative cyclization, intramolecular ring closure, and insertion of sextet intermediates—carbenes and nitrenes—is examined on a vast number of examples. Many of the reactions proceed with high regio-, stereo-, or diastereoselectivity and in excellent, up to quantitative, yield, which is of principal importance for the synthesis of chiral drug-like compounds. For most unusual and hardly predictable transformations, the mechanisms are given or referred to. Full article

This study reports an improved diastereoselective synthesis of substituted spiro[chromane-2,4′-pyrimidin]-2′(3′H)-ones via the acid-catalyzed condensation of 6-styryl-4-aryldihydropyrimidin-2-ones with resorcinol, 2-methylresorcinol, and pyrogallol. The optimized method allows for the isolation of diastereomerically pure products, with stereoselectivity controlled by varying acid catalysts (e.g., methanesulfonic acid vs. toluenesulfonic acid) and solvent conditions. The synthesized compounds were evaluated for antimicrobial and antioxidant activities. Notably, the (2S*,4R*,6′R*)-diastereomers exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains with minimal inhibition concentration down to 2 µg/mL, while derivatives containing vicinal bisphenol moieties demonstrated potent antioxidant activity, with IC₅₀ values (12.5 µg/mL) comparable to ascorbic acid. Pharmacokinetic analysis of selected hit compounds revealed favorable drug-like properties, including high gastrointestinal absorption and blood-brain barrier permeability. These findings highlight the potential of spirochromane-pyrimidine hybrids as promising candidates for further development in the treatment of infectious diseases and oxidative stress-related pathologies. Full article

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products. Full article

In the chemistry of bio-based furans, the Diels–Alder reaction plays an important role as a renewable route for the synthesis of fuels, fine chemicals, and monomers. Nonetheless, the unfavorable kinetic and thermodynamic parameters inherent to the Diels–Alder reaction involving furans as dienes often lead to the reversibility of cycloaddition, resulting in decreased equilibrium conversion and diastereoselectivity. In this study, we present a new strategy for overcoming the problem of reversibility in chemical reactions. We demonstrate that conducting the reaction under solvent-free conditions can facilitate the transition from a molten state formed by the initial reactants to a solid phase containing the reaction product along with an excess of the initial substrate. According to our results, such a liquid-to-solid transition of the reaction mixture can lead to exceptionally high conversion and diastereoselectivity in the furan–maleimide Diels–Alder reaction, particularly for challenging electron-poor furanic substrates. Our approach enables the reversible furan–maleimide Diels–Alder reaction to be performed in a cleaner and more environmentally friendly manner, free from the complexities associated with the use of solvents and the need for purification from side products. Full article

This review probes the recent developments in stereoselective reactions within the area of sulfoxonium ylide chemistry since the early 2000s. An abundance of research has been applied to sulfoxonium ylide chemistry since its emergence in the early 1960s. There has been a continued effort since then with work in traditional areas, such as epoxidation, aziridination and cyclopropanation. Efforts have also been applied in novel areas, such as olefination and insertion reactions, to develop stereoselective methodologies using organocatalysis and transition metal catalysis. The growing research area of interrupted Johnson–Corey–Chaykovsky reactions is also described, whereby unexpected stereoselective cyclopropanation and epoxidation methodologies have been developed. In general, the most observed mechanistic pathway of sulfoxonium ylides is the formal cycloaddition: (2 + 1) (e.g., epoxides, cyclopropanes, aziridines), (3 + 1) (e.g., oxetanes, azetidines), (4 + 1) (e.g., indanones, indolines). This pathway involves the formation of a zwitterionic intermediate through nucleophilic addition of the carbanion to an electrophilic site. An intramolecular cyclization occurs, constructing the cyclic product. Insertion reactions of sulfoxonium ylides to X–H bonds (e.g., X = S, N or P) are also observed, whereby protonation of the carbanion is followed by a nucleophilic addition of X, to form the inserted product. Full article

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by X-ray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (K_i = 599 nM) and high selectivity over μ, δ, σ₁, and σ₂ receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket. Full article

This research employs 2-methylene-tetrahydronaphtalene-1-ones and N-cyclopropylanilines as starting materials, integrating photocatalysis and organic phosphoric acid catalysis to synthesize 2-amino-spiro[4.5]decane-6-ones via a [3 + 2] cycloaddition approach. This method boasts the advantage of mild reaction conditions that are photocatalyst-free and metal catalyst-free. It achieves 100% atom conversion of the substrates, aligning with the principles of green chemistry. Additionally, it attains a high diastereoselectivity result of up to 99:1, demonstrating good stereoselectivity. In the derivatives of 2-methylene-tetrahydronaphtalene-1-ones, substrates with alkane rings of different sizes or thiophene replacing the phenyl ring are also amenable to this method, enabling the synthesis of different [4.4], [4.5], and [4.6] spirocyclic compounds. In the derivatives of N-cyclopropylanilines, substrates with para-fluoro and meta-fluoro substitutions are also amenable to this method. Finally, a preliminary mechanistic investigation was conducted, proposing a plausible reaction mechanism pathway initiating from the intermediate N-cyclopropylanilines with chiral phosphoric acid. Full article

A novel class of chiral sulfonium salts, derived from L- and D-methionine, was designed and successfully employed for the diastereoselective synthesis of epoxy amides. This new methodology of asymmetric epoxidation was exploited for the stereoselective construction of fused polycyclic ethers, which are structural motifs present in a great variety of natural products of marine origin. This methodology proved to be useful for the synthesis of the tricyclic A–C system contained in yessotoxin and adriatoxin, and also in many other related natural products of marine origin belonging to the fused polycyclic ether toxins. Full article

The ability to recognize hidden symmetry in a highly asymmetric world is a key factor in how we view and understand the world around us. Despite the fact that it is an intrinsic property of the natural world, we have an innate ability to find hidden symmetry in asymmetric objects. The inherent asymmetry of the natural world is a fundamental property built into its chemical building blocks (e.g., proteins, carbohydrates, etc.). This review highlights the role of asymmetry in the structure of the carbohydrates and how these stereochemical complexities present synthetic challenges. This survey starts with an overview of the role synthetic chemistry plays in the discovery of carbohydrates and their 3D structure. This review then introduces various de novo asymmetric synthetic approaches that have been developed for the synthesis of carbohydrates and, in particular, oligosaccharides. The two most successful strategies for oligosaccharide synthesis rely on diastereoselective palladium-catalyzed glycosylation. The first uses an Achmatowicz reaction to asymmetrically prepare pyranose building blocks along with a substrate-controlled Pd-glycosylation. The other strategy couples a ligand-controlled Pd-glycosylation with a ring-closing metathesis for oligosaccharide assembly. Full article

The chiral oxazolidine moiety is an important core in asymmetric synthesis due to its ability to participate in various stereoselective chemical reactions and because it forms part of more complex and important active compounds. Therefore, in this letter we report a convenient diastereoselective and practical strategy for the synthesis of chiral methyl 2-((4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetates, starting from (R)-(–)-2-phenylglycinol and methyl propiolate, which were obtained via two simple chemical and stereoselective reactions. Full article