Designing Michaelases: exploration of novel protein scaffolds for iminium biocatalysis.

Biocatalysis is becoming a powerful and sustainable alternative for asymmetric catalysis. However, enzymes are often restricted to metabolic and less complex reactivities. This can be addressed by protein engineering, such as incorporating new-to-nature functional groups into proteins through the so-called expansion of the genetic code to produce artificial enzymes.

Modular Divergent Synthesis of Indole Alkaloid Derivatives by an Atypical Ugi Multicomponent Reaction.

We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma-type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three-component reaction showed full diastereoselectivity towards the cis-fused ring system, which can be rationalized by DFT calculations that moreover indicate that the reaction proceeds via a Passerini-type hydrogen bonding mechanism.

Dearomative Spirocyclization of Tryptamine-Derived Isocyanides via Iron-Catalyzed Carbene Transfer.

Tryptamine-derived isocyanides are valuable building blocks in the construction of spirocyclic indolenines and indolines via dearomatization of the indole moiety. We report the BuN[Fe(CO)NO]-catalyzed carbene transfer of α-diazo esters to 3-(2-isocyanoethyl)indoles, leading to ketenimine intermediates that undergo spontaneous dearomative spirocyclization. The utility of this iron-catalyzed carbene transfer/spirocyclization cascade was demonstrated by its use as a key step in the formal total synthesis of monoterpenoid indole alkaloids (±)-aspidofractinine, (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy--acetylcylindrocarine.

Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir.

In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps.

Dysregulation of ESX-5 Secretion by Novel 1,2,4-oxadiazoles.

The ESX-5 secretion system is essential for the viability and virulence of slow-growing pathogenic mycobacterial species. In this study, we identified a 1,2,4-oxadiazole derivative as a putative effector of the ESX-5 secretion system. We confirmed that this 1,2,4-oxadiazole and several newly synthesized derivatives inhibited the ESX-5-dependent secretion of active lipase LipY by ().

Iron-Catalysed Carbene Transfer to Isocyanides as a Platform for Heterocycle Synthesis.

An iron-catalysed carbene transfer reaction of diazo compounds to isocyanides has been developed. The resulting ketenimines are trapped in situ with various bisnucleophiles to access a range of densely functionalized heterocycles (pyrimidinones, dihydropyrazolones, 1H-tetrazoles) in a one-pot process. The electron-rich Hieber anion ([Fe(CO) NO] ) facilitates efficient catalytic carbene transfer from acceptor-type α-diazo carbonyl compounds to isocyanides, providing a cost-efficient and benign alternative to similar noble metal-catalysed processes.

The Use of Smartphone Serious Gaming Apps in the Treatment of Substance Use Disorders: Observational Study on Feasibility and Acceptability.

Background: Addiction is a worldwide problem with major health complications. Despite intensive treatment, relapse rates remain high. The prevalence of cognitive impairment is high in patients with substance use disorders (SUDs) and is associated with treatment dropout and relapse.

Enantioselective Total Synthesis of (-)-Limaspermidine and (-)-Kopsinine by a Nitroaryl Transfer Cascade Strategy.

We report an intramolecular conjugate addition/Truce-Smiles/E1cb cascade of 2-nitrobenzenesulfonamide-functionalized cyclohexenones as a new entry to the core scaffold of monoterpene indole alkaloids. The method was applied to the asymmetric total synthesis of (-)-limaspermidine, (-)-kopsinilam, and (-)-kopsinine, as well as the framework of the kopsifoline alkaloids, thus highlighting its complementarity to existing approaches involving the use of indole-based starting materials or the interrupted Fischer indole synthesis. Furthermore, we show that the cascade tolerates various substituents on the nitroarene, opening the way to other natural products as well as non-natural analogues.

Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides.

Transition metal-catalysed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes ( ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compounds allowing transformation towards numerous functional groups and organic compounds, including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the organic chemistry toolbox.

Synthesis of tetracyclic spiroindolines by an interrupted Bischler-Napieralski reaction: total synthesis of akuammicine.

Judicious substrate design allows interruption of the classical Bischler-Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. These complex polycyclic scaffolds are valuable building blocks for the construction of indole alkaloids, as showcased in a concise total synthesis of (±)-akuammicine.

Synthesis of Carbazoles and Dihydrocarbazoles by a Divergent Cascade Reaction of Donor-Acceptor Cyclopropanes.

An alkylation/olefination cascade of indolecarboxaldehydes and phosphonate-functionalized donor-acceptor cyclopropanes affords functionalized dihydrocarbazoles and cyclohepta[]indoles in formal (3 + 3) and (4 + 3) cycloadditions. A minor modification to the reaction conditions also allows access to the fully aromatic heterocyclic scaffolds by thermal loss of an electron-rich aryl moiety.

Palladium-Catalyzed Cascade to Benzoxepins by Using Vinyl-Substituted Donor-Acceptor Cyclopropanes.

A palladium-catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported. A key feature of the reaction is the use of a phosphonate group as an acceptor moiety on the cyclopropane, exploiting its propensity to undergo olefination with aldehydes. Subsequent O-allylation enabled the formation of a range of substituted benzoxepinsWith a novel chiral ligand, the products were obtained in generally good yield and with reasonable enantioselectivity.

Synthesis of Carbazoles by a Diverted Bischler-Napieralski Cascade Reaction.

An unforeseen twist in a seemingly trivial Bischler-Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

Recent Advances in Palladium-Catalyzed Isocyanide Insertions.

Isocyanides have long been known as versatile chemical reagents in organic synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C building blocks, whose inherent -substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products.

Diastereoselective Synthesis of β-Lactams by Ligand-Controlled Stereodivergent Intramolecular Tsuji-Trost Allylation.

The diastereoselective synthesis of highly substituted β-lactams by intramolecular Tsuji-Trost allylation is reported. Judicious selection of the ligand on palladium allows selective access to either the isomer (in generally good to excellent yield with very high diastereomeric excess) or isomer (with yields and diastereoselectivity ranging from modest to excellent depending on the substrate). The reaction proceeds under exceedingly mild conditions (rt, no additives) with a broad range of substrates, which are readily accessible by the Ugi reaction.

Synthesis of Quinazolin-4-ones by Copper-Catalyzed Isocyanide Insertion.

Herein, we report a novel copper-catalyzed imidoylative cross-coupling/cyclocondensation reaction between 2-isocyanobenzoates and amines efficiently producing quinazolin-4-ones. The reaction utilizes Cu(II) acetate as an environmentally benign catalyst in combination with a mild base and proceeds well in anisole, a recommended, sustainable solvent. Additionally, the reaction does not require dry conditions or inert atmospheres for optimal performance.

Synthesis of Densely Functionalized Pyrimidouracils by Nickel(II)-Catalyzed Isocyanide Insertion.

A robust nickel-catalyzed oxidative isocyanide insertion/C-H amination by reaction of readily available -uracil-amidines with isocyanides affording polysubstituted pyrimidouracils has been reported. The reaction proceeds in moderate to quantitative yield, under mild conditions (i.e.

Mild and Practical Indole C2 Allylation by Allylboration of in situ Generated 3-Chloroindolenines.

C2 allylation of indole derivatives is a challenging but important transformation given the biological relevance of the products. Herein we report a selective C2 allylation strategy that proceeds via allylboration of in situ-generated 3-chloroindolenines. The reaction is mild, practical, and compatible with a wide range of C3-substituted indoles.

Catalytic Asymmetric Synthesis of Diketopiperazines by Intramolecular Tsuji-Trost Allylation.

We report the intramolecular Tsuji-Trost reaction of Ugi adducts to give spiro-diketopiperazines in high yield and with high enantioselectivity. This approach allows the catalytic asymmetric construction of a broad range of these medicinally important heterocycles under mild conditions, in two steps from cheap, commercially available starting materials.

Base Metal Catalyzed Isocyanide Insertions.

Isocyanides are diverse C building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as inputs for multicomponent reactions (MCRs) and other one-pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals.

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization.

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.

Identification of novel GNAS mutations in intramuscular myxoma using next-generation sequencing with single-molecule tagged molecular inversion probes.

Background: Intramuscular myxoma (IM) is a hypocellular benign soft tissue neoplasm characterized by abundant myxoid stroma and occasional hypercellular areas. These tumors can, especially on biopsy material, be difficult to distinguish from low-grade fibromyxoid sarcoma or low-grade myxofibrosarcoma. GNAS mutations are frequently involved in IM, in contrast to these other malignant tumors.