Late-stage oxidative C(sp3)-H methylation.

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

Development of a Deactivation-Resistant Dialkylbiarylphosphine Ligand for Pd-Catalyzed Arylation of Secondary Amines.

Despite the prevalence of N-heteroarenes in small-molecule pharmaceuticals, Pd-catalyzed C-N cross-coupling reactions of aryl halides and amines containing these rings remain challenging due to their ability to displace the supporting ligand via coordination to the metal center. To address this limitation, we report the development of a highly robust Pd catalyst supported by a new dialkylbiarylphosphine ligand, FPhos. The FPhos-supported catalyst effectively resists N-heteroarene-mediated catalyst deactivation to readily promote C-N coupling between a wide variety of Lewis-basic aryl halides and secondary amines, including densely functionalized pharmaceuticals. Mechanistic and structural investigations, as well as principal component analysis and density functional theory, elucidated two key design features that enable FPhos to overcome the limitations of previous ligands. First, the ligated Pd complex is stabilized through its conformational preference for the O-bound isomer, which likely resists coordination by N-heteroarenes. Second, 3',5'-disubstitution on the non-phosphorus-containing ring of FPhos creates the ideal steric environment around the Pd center, which facilitates binding by larger secondary amines while mitigating the formation of off-cycle palladacycle species.

Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines.

We report a versatile and functional-group-tolerant method for the Pd-catalyzed C-N cross-coupling of five-membered heteroaryl halides with primary and secondary amines, an important but underexplored transformation. Coupling reactions of challenging, pharmaceutically relevant heteroarenes, such as 2-H-1,3-azoles, are reported in good-to-excellent yields. High-yielding coupling reactions of a wide set of five-membered heteroaryl halides with sterically demanding α-branched cyclic amines and acyclic secondary amines are reported for the first time. The key to the broad applicability of this method is the synergistic combination of (1) the moderate-strength base NaOTMS, which limits base-mediated decomposition of sensitive five-membered heteroarenes that ultimately leads to catalyst deactivation, and (2) the use of a GPhos-supported Pd catalyst, which effectively resists heteroarene-induced catalyst deactivation while promoting efficient coupling, even for challenging and sterically demanding amines. Cross-coupling reactions between a wide variety of five-membered heteroaryl halides and amines are demonstrated, including eight examples involving densely functionalized medicinal chemistry building blocks.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

Remote Oxidation of Aliphatic C-H Bonds in Nitrogen-Containing Molecules.

Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Brønsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non-directed C(sp(3))-H oxidations of tertiary, secondary, and primary amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

Comparison on properties between normal and A2 bovine milk fermented using commercial bacteria mixed with/without two probiotics from human milk.

The purpose of this study was to compare the structural and physical properties between normal bovine milk and A2 bovine milk fermented using commercial fermentation bacteria mixing with/without Lactiplantibacillus plantarum MWLp-12 and Limosilactobacillus fermentum MWLf-4 screening from human milk. Scanning Electron Microscopy (SEM), SDS-PAGE and inverted fluorescence microscope were used for analyzing the structural differences. Titratable acidity and pH, water holding capacity, rheology, texture performances, and chromaticity value were determined for evaluating differences in the physical properties. We found that A2 fermented milk had better viscosity characteristics and stable structure than normal fermented milk. Importantly, the significant differences in structure and physical properties would affirm that differences structures were existing in casein micelle between normal bovine milk and A2 bovine milk. In addition, the addition of MWLp-12 and MWLf-4 strains could enhance the proteolysis and bring in more pilotaxitic texture leading to the fermented milk possessing a greater texture performance. Therefore, this study will be an interest to the dairy industry for developing novel dairy products, and the two strains will be the potential probiotics to be applied on fermented milk preparation.

Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalization.

Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.