Catalytic Photoinduced Intramolecular Decarboxylative and Desulfonylative sp3 Allylation Enabled by Sulfinate Salts.

Herein, we describe a catalytic intramolecular decarboxylative/desulfonylative sp3 allylation triggered by sulfinate salts under light irradiation. The reaction is likely enabled by a non-classical, radical-polar crossover mechanism, allowing rapid and reliable access to valuable allyl architectures from readily accessible precursors. The protocol is characterized by its operational simplicity and scalability, employing abundant, commercially available catalysts.

Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement.

Despite the many methods available for the synthesis of furans, few methods remain that allow for the custom-made assembly of fully substituted furans. Here we report a powerful protocol to rapidly construct tetrasubstituted, orthogonally functionalized furans under mild reaction conditions. The developed method involves the regioselective ring-opening of readily available 2,5-dihydrothiophenes followed by an oxidative cyclization to provide the heterocycle. The selective oxidation at sulfur is promoted by N-chlorosuccinimide as an inexpensive reagent and proceeds at ambient temperature in high yield within 30 min. The obtained furans serve as exceptionally versatile intermediates and were shown to participate in a series of valuable postmodifications. The fate of the initial sulfonium intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene sesquiterpenoids (pleurotins A, B, and D).

Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-Contraction of Sulfilimines.

We present a modular, synthetic entry to polysubstituted pyrroles employing readily available 2,5-dihydrothiophenes. Ring-opening of the heterocycle provides access to a panel of 1,3-dienes which undergo pyrrole formation in the presence of inexpensive chloramine-T trihydrate. The transformation is conducted in an open flask and proceeds at ambient temperatures (23 °C) in nondry solvents. A careful adjustment of the electronics and sterics of the 1,3-diene precursor allows for the isolation of key intermediates. DFT studies identified a reaction mechanism that features a 6π-electrocyclization of a sulfilimine intermediate followed by spontaneous ring-contraction to reveal the pyrrole skeleton.

Beyond the Isoprene Pattern: Bifunctional Polyene Cyclizations.

Polyene cyclizations are capable of producing molecular complexity in a single step. While classical systems are limited to simple alkyl substitution patterns only, bifunctional polyenes take advantage of the unique reactivity of higher-functionalized alkenes. Here, we highlight the potential of these variants for the synthesis of structurally complex polycycles involving unprecedented termination steps. We also want to provide a stimulus for the development of novel modes of cyclization that involve bifunctional units to enable efficient synthesis of yet inaccessible natural products.

Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides.

Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophene products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and vic-quarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58%. In addition, we showcase its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.

BRCA-1 depletion impairs pro-inflammatory polarization and activation of RAW 264.7 macrophages in a NF-κB-dependent mechanism.

BRCA-1 is a nuclear protein involved in DNA repair, transcriptional regulation, and cell cycle control. Its involvement in other cellular processes has been described. Here, we aimed to investigate the role of BRCA-1 in macrophages M(LPS), M(IL-4), and tumor cell-induced differentiation. We used siRNAs to knockdown BRCA-1 in RAW 264.7 macrophages exposed to LPS, IL-4, and C6 glioma cells conditioned medium (CMC6), and evaluated macrophage differentiation markers and functional phagocytic activity as well as DNA damage and cell survival in the presence and absence of BRCA-1. LPS and CMC6, but not by IL-4, increased DNA damage in macrophages, and this effect was more pronounced in BRCA-1-depleted cells, including M(IL-4). BRCA-1 depletion impaired expression of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the phagocytic activity of macrophages in response to LPS. In CMC6-induced differentiation, BRCA-1 knockdown inhibited TNF-α and IL-6 expression which was accompanied by upregulation of the anti-inflammatory markers IL-10 and TGF-ß and reduced phagocytosis. In contrast, M(IL-4) phenotype was not affected by BRCA-1 status. Molecular docking predicted that the conserved BRCA-1 domain BRCT can interact with the p65 subunit of NF-κB. Immunofluorescence assays showed that BRCA-1 and p65 co-localize in the nucleus of LPS-treated macrophages and reporter gene assay showed that depletion of BRCA-1 decreased LPS and CMC6-induced NF-κB transactivation. IL-4 had no effect upon NF-κB. Taken together, our findings suggest a role of BRCA-1 in macrophage differentiation and phagocytosis induced by LPS and tumor cells secretoma, but not IL-4, in a mechanism associated with inhibition of NF-κB.

Regiodivergent sp3 C-H Functionalization via Ni-Catalyzed Chain-Walking Reactions.

The catalytic translocation of a metal catalyst along a saturated hydrocarbon side chain constitutes a powerful strategy for enabling bond-forming reactions at remote, yet previously unfunctionalized, sp3 C-H sites. In recent years, Ni-catalyzed chain-walking reactions have offered counterintuitive strategies for forging sp3 architectures that would be difficult to accomplish otherwise. Although these strategies have evolved into mature tools for advanced organic synthesis, it was only recently that chemists showed the ability to control the motion at which the catalyst "walks" throughout the alkyl chain. Specialized ligand backbones, additives and a judicious choice of noninnocent functional groups on the side chain have allowed the design of "a la carte" protocols that enable regiodivergent bond-forming scenarios at different sp3 C-H sites with distinct topological surface areas. Given the inherent interest in increasing the fraction of sp3 hybridized carbons in medicinal chemistry, Ni-catalyzed regiodivergent chain-walking reactions might expedite the access to target leads in drug discovery campaigns.

A modular synthesis of tetracyclic meroterpenoid antibiotics.

Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels-Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2-sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.

One-Pot Synthesis of 5-Hydroxy-4H-1,3-thiazin-4-ones: Structure Revision, Synthesis, and NMR Shift Dependence of Thiasporine A.

An annulation of arylthioamides with 3-bromopyruvic acid chloride to 5-hydroxy-4H-1,3-thiazin-4-ones has been developed. The initial condensation affords two regioisomeric thiazolinone intermediates in a temperature-dependent manner. The synthesis of the 2-aminophenylthiazinone derivative led to the revision of the previously proposed structure of thiasporine A. Synthesis of the revised structure and NMR analysis revealed that thiasporine A had been isolated as a carboxylate.