Tetrahedron Letters最新文献

Pyridine spirocycles play an important role in drug design and development. In this paper, a novel spirocyclic cyclopentapyridine compound was synthesized. Based on retrosynthesis analysis, commercially available 2-chloro-6-methoxypyridine was used as the starting material for the synthesis of the target molecule, accomplished through an eight-step reaction process. Particular emphasis was placed on the two most challenging steps: selective Negishi coupling and carbonyl reduction.

The total synthesis of (±)-3-thiaglutamate is reported. Central to our strategy is an thiol addition to an imine to form the thioaminal of the natural product. The resulting thioaminal product is then subjected to triflic acid global deprotection to produce 3-thiaglutamate as a triflate salt. This work constitutes the first total synthesis of 3-thiaglutamate and demonstrates that the hemithioaminal group in 3-thiaglutamate can be stabilized under acidic conditions.

Neutral dual hydrogen bond donors (HBDs) are effective catalysts that enhance the electrophilicity of substrates or the Lewis/Brønsted acidity of reagents through an anion-binding mechanism. Despite their success in various enantioselective organocatalytic reactions, their application to transition metal catalysis remains rare. Herein, we report the activation of gold(I) precatalysts by chiral ureas, leading to enantioselective hydroarylation of allenes with indoles. Experimental and computational studies support an anion-binding mechanism for gold(I) precatalyst activation. Noncovalent interactions were identified as the source of enantiodifferentiation, providing insights into the cooperativity between achiral phosphine ligands and chiral ureas.

Here, we report a solvent-controlled tandem Knoevenagel-epoxidation reaction capable of efficiently and selectively synthesizing α-formamidoepoxide and epoxidized benzylidene derivatives of malononitrile dimers. By carefully selecting the solvent system, we demonstrate the tunability of this reaction towards different product outcomes, thereby providing a switchable synthetic platform for various epoxy derivatives. The reaction proceeds under mild conditions with short reaction times, high efficiency, and good tolerance towards diverse functional groups. Furthermore, this method is scalable to gram-scale production.

We report here a cascade synthetic approach to prepare 3,3′-bis(indolyl)methanes (BIMs) and analogues from single reactant 1H-indole-3-carbaldehydes under the reductive condition using NaBH₄. Uniformly, in another strategy, 1H-indole-3-carbaldehydes produced BIMs as a cascade product under Grignard reaction conditions. This is the first application of organometallic and reductive nucleophilic condition, where indole-3-carbaldehydes underwent NaBH₄ reduction/ methyl Grignard addition to form 1°/2° alcohol followed by elimination and subsequent addition of another molecule of indole aldehyde provided symmetric BIMs as unambiguous cascade products (22 analogues) in good to excellent yields.

A novel and concise approach has been developed for the total synthesis of (S)-tolvaptan, which is used for the treatment of hyponatremia. The key intermediate, benzazepinone has been synthesized in three steps through ortho-acylation of N-Pivalamide protected aryl amine followed by an intramolecular haloamine cyclization. The total synthesis of (S)-tolvaptan from p-chloroaniline has been accomplished in seven steps with 43% overall yield.

Herein, we report a urea-based DES that acts as an amine source in the synthesis of N-substituted styryl quinazolinone from anthranilic acid via N-acylation, cyclization, and subsequent sp³ CH functionalization under a green reaction medium. The salient features of this approach are gram-scale synthesis, mild reaction conditions, and a metal-free methodology. Additionally, post-functionalization and photophysical properties were evaluated.

PPARγ is a member of nuclear receptor superfamily, which possesses a large Y-shaped cavity in the ligand-binding pocket. GW9662 is a well-known PPARγ antagonist which covalently reacts with the Cys285 residue via nucleophilic substitution. In contrast to its irreversibility, the ability of GW9662 to prevent other ligands from accessing the ligand-binding pocket is partly defective. By focusing on this incompleteness, we develop an integrated approach to create a new PPARγ agonist by using a structure of GW9662 as a scaffold for linking with a fragment compound. A screening of 1,040 compounds identified a partner ligand which synergistically activates PPARγ transcription in combination with GW9662. We introduced an azido or alkyne group to GW9662 or the identified fragment hit, respectively, and then connected the two structures via copper-catalyzed azide-alkyne cycloaddition. A coupling reaction provided a series of hybrid structure with triazole linker, among which the compounds with a bent configuration function as a partial PPARγ agonist. These results highlight a potential utility of GW9662 for the decoration with a fragment compound to develop a covalent agonist for PPARγ activation.

Schweinfurthin G, one of the most potent of the schweinfurthins containing a hexahydroxanthene moiety, was found to exhibit strong cytotoxicity against A549 and KB cell lines with the IC₅₀ values of 0.8 μM and 0.6 μM, respectively. In this paper, a new series of schweinfurthin G derivatives modified on the isoprenyl side-chain were synthesized from schweinfurthin G using multicomponent reactions. The cytotoxicity of all the synthetic compounds was evaluated against four human cancer cell lines (KB, Hep3B, A549, MCF7) and one non-cancerous cell line (HEK293), which enabled to perform in-depth structure–activity relationships on a still poorly explored part of the molecule.

Organic molecules containing 1,2-diphosphonate moiety are of great value in organic synthesis. Diphosphoryl acetylenes (or named as ethyne-1,2-diyldiphosphonates) are a class of molecules utilized for synthesis of diverse phosphorus compounds applicable in multiple fields. However, present stoichiometric methods for the preparation of diphosphoryl acetylenes generally requires multiple steps or harsh conditions. Herein, we report a facile synthesis of diphosphoryl acetylenes, in which the readily available ethynyl phosphonates couple with dialkyl phosphonates through cheap copper catalysis. A series of diphosphoryl acetylenes in symmetric or unsymmetric fashions are facilely prepared. This protocol demonstrates advantages of mild reaction conditions, inert atmosphere-free, cheap catalyst, base-free, and high efficiency to serve as a practical method for synthesis of diphosphoryl acetylenes.