Late-stage oxidative C(sp(3))-H methylation

doi:10.1038/s41586-020-2137-8

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2137-8
	Late-stage oxidative C(sp(3))-H methylation
	Fessler, Evelyn 1,2; Eckl, Eva-Maria 1,2; Schmitt, Sabine 3; Mancilla, Igor Alves 1,2; Meyer-Bender, Matthias F.1,2; Hanf, Monika 1,2; Philippou-Massier, Julia 1,2; Krebs, Stefan 1,2; Zischka, Hans 3,4; Jae, Lucas T.1,2
	2020-03-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	580 期号:7805 页码:621-+
文章类型	Article
语种	英语
国家	USA
英文关键词	Frequently referred to as the ' magic methyl effect' , the installation of methyl groups-especially adjacent (alpha) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules(1-3). However, existing methylation methods show limited scope and have not been demonstrated in complex settings(1). Here we report a regioselective and chemoselective oxidative C(sp(3))-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(sp(3))-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 manganese-catalysed oxidative C(sp(3))-H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the ' magic methyl effect' .
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000528161700001
WOS关键词	GLYCOSYL FLUORIDES ; AMINO-ACIDS ; POTENT ; CONVERSION ; DISCOVERY ; NITROGEN ; FUNCTIONALIZATION ; SELECTIVITY ; ACTIVATION ; ALKYLATION
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281258
专题	地球科学资源环境科学气候变化
作者单位	1.Ludwig Maximilians Univ Munchen, Gene Ctr, Munich, Germany; 2.Ludwig Maximilians Univ Munchen, Dept Biochem, Munich, Germany; 3.Tech Univ Munich, Inst Toxicol & Environm Hyg, Sch Med, Munich, Germany; 4.German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Mol Toxicol & Pharmacol, Neuherberg, Germany
推荐引用方式 GB/T 7714	Fessler, Evelyn,Eckl, Eva-Maria,Schmitt, Sabine,et al. Late-stage oxidative C(sp(3))-H methylation[J]. NATURE,2020,580(7805):621-+.
APA	Fessler, Evelyn.,Eckl, Eva-Maria.,Schmitt, Sabine.,Mancilla, Igor Alves.,Meyer-Bender, Matthias F..,...&Jae, Lucas T..(2020).Late-stage oxidative C(sp(3))-H methylation.NATURE,580(7805),621-+.
MLA	Fessler, Evelyn,et al."Late-stage oxidative C(sp(3))-H methylation".NATURE 580.7805(2020):621-+.