875930-44-2Relevant academic research and scientific papers
Exploring Electrochemical C(sp3)-H Oxidation for the Late-Stage Methylation of Complex Molecules
Ho, Justin S. K.,Lin, Song,Liu, Kaida,Mao, Kaining,Neurock, Matthew,Novaes, Luiz F. T.,Tanwar, Mayank,Terrett, Jack A.,Villemure, Elisia
, p. 1187 - 1197 (2022/02/05)
The magic methyl effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the magic methyl effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
Late-stage oxidative C(sp 3)–H methylation
Feng, Kaibo,Kohrt, Jeffrey T.,Oderinde, Martins S.,Quevedo, Raundi E.,Reilly, Usa,White, M. Christina
, p. 621 - 627 (2020/05/04)
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.
A new method for the preparation of nitrogen-containing cyclic compounds from p-nitrobenzenesulfonamide and alkyl bis(diphenylphosphinite)s by oxidation-reduction condensation using 1-azidoadamantane
Mukaiyama, Teruaki,Kuroda, Kiichi,Aoki, Hidenori
, p. 1644 - 1645 (2007/10/03)
A new and efficient method was established for the preparation of nitrogen-containing cyclic compounds from p-nitro-benzenesulfonamide, bisphosphinites, and 1-azidoadamantane in good yields under neutral conditions. Copyright
