A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition.

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl ()-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

Ground State Generation and Cyclization of Aminium Radicals in the Formation of Tetrahydroquinolines.

This paper reports the first examples of ground state radical-mediated intramolecular C-H amination to afford 1-methyl-1,2,3,4-tetrahydroquinolines from -2,4-dinitrophenoxy derivatives of arylpropylamines. Whereas the photoactivation of -2,4-dinitrophenoxyamines for intermolecular reactions has been established, ground state chemistry provides the desired cyclization products in moderate to excellent yields using Ru(bpy)Cl (42-95% yields) under acidic conditions under an air atmosphere.

Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.

Oligonucleotides are rapidly emerging as powerful therapeutics for hard to treat diseases. Short single-stranded oligonucleotides can base pair with target RNA and alter gene expression, providing an attractive therapeutic approach at the genetic level. Whilst conceptually appealing, oligonucleotides require chemical modification for clinical use.

Nitrogen-Centered Radicals in Functionalization of sp Systems: Generation, Reactivity, and Applications in Synthesis.

The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp moieties without prefunctionalization, allowing for faster and more streamlined synthesis.

Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences.

Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene.

Modular, Step-Efficient Palladium-Catalyzed Cross-Coupling Strategy To Access C6-Heteroaryl 2-Aminopurine Ribonucleosides.

Two Pd-catalyzed methods to access 6-heteroaryl 2-aminopurine ribonucleosides from 6-chloroguanosine are described. First, Pd-132-catalyzed Suzuki-Miyaura cross-coupling using a series of boron substrates and 6-chloroguanosine forms 6-heteroaryl-2-aminopurines in a single step. The versatility of 6-chloroguanosine is further demonstrated using a modified Sonogashira coupling employing potassium iodide as an additive.

The Total Synthesis of the Bioactive Natural Product Plantazolicin A and Its Biosynthetic Precursor Plantazolicin B.

Herein, we describe our full investigations into the synthesis of the peptide-derived natural product plantazolicin A, a compound that demonstrates promising selective activity against the causative agent of anthrax toxicity, and its biosynthetic precursor plantazolicin B. This report particularly focuses on the challenging preparation of the arginine containing thiazole fragment, including the development of a robust, high yielding procedure that avoids the use of sulfurating agents. Extensive studies on the design of a coherent protecting group strategy and the establishment of a step-efficient dicyclization/oxidation approach allowed high levels of convergence for the construction of the oxazole fragments.

Total syntheses of linear polythiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B.

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.

Ruthenium-catalyzed C-H/N-O bond functionalization: green isoquinolone syntheses in water.

Ruthenium-catalyzed isoquinolone syntheses with ample scope were accomplished through carboxylate assistance in environmentally benign water as a reaction medium. The high chemoselectivity of the ruthenium(II) carboxylate complex also set the stage for the direct use of free hydroxamic acids for annulations of alkynes.

Metal-free direct arylations of indoles and pyrroles with diaryliodonium salts.

Direct arylations of indoles and pyrroles with differently substituted diaryliodonium salts were shown to efficiently proceed in the absence of metal catalysts.

Well-defined air-stable palladium HASPO complexes for efficient Kumada-Corriu cross-couplings of (hetero)aryl or alkenyl tosylates.

Palladium complexes of representative heteroatom-substituted secondary phosphine oxide (HASPO) preligands were synthesized and fully characterized, including X-ray crystal structure analysis. Importantly, these well-defined complexes served as highly efficient catalysts for Kumada-Corriu cross-coupling reactions of aryl, alkenyl, and even heteroaryl tosylates. Particularly, an air-stable catalyst derived from inexpensive PinP(O)H displayed a remarkably high catalytic efficacy, which resulted in cross-couplings at low catalyst loadings under exceedingly mild reaction conditions with ample scope.

Direct arylations of electron-deficient (hetero)arenes with aryl or alkenyl tosylates and mesylates.

A palladium catalyst derived from the ligand X-Phos enabled generally applicable direct arylations of electron-deficient heteroarenes and arenes with aryl and alkenyl tosylates or mesylates.