Late-stage oxidative C(sp3)-H methylation

Abstract

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 molecules^1-3. 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.

Fig. 1 |. C(sp³)–H methylation.

a, The magic methyl effect boosts potency of drugs and furnishes biological probes. b, This oxidative methylation proceeds through an electrophilic intermediate. Challenges included over-oxidation, unselective oxidation, elimination and unselective methylation pathways. c, Late stage oxidative methylation of antibiotic tedizolid. d, Oxidative C-H methylation is demonstrated on 16 different pharmaceutically relevant cores. Using only 1 equivalent of substrate, methylation proceeds site-selectively and with functional group tolerance to afford preparative yields in 41 examples (including 18 complex bioactive molecules).

Fig. 2 |. Reaction development.

a, Optimization of the oxidative methylation reaction. For achiral substrates, (R,R)- and (S,S)-1 can be used interchangeably. b, Exposure of hemiaminal to mild C–H hydroxylation developed here (0.5 mol% 1, 2 equiv. H₂O₂) gives little overoxidation to the imide. The previous forcing condition (10 mol% 1, 5 equiv. H₂O₂) results in imide as the major product. ^aNo methylation. ^bMixture of hemiaminal (64%-71%) and hemiaminal acetate from AcOH (13%-18%). ^c1 equiv. ^d2 equiv. ^eTFAA (1 equiv.), TMSOTf (1 equiv.). ^fMsCl (1 equiv.), NEt₃ (1 equiv.), NaHCO₃ wash; AlMe₃ (3 equiv.), −78 °C, 2 h; rt 1 h. ^gMeMgBr (3 equiv.), −78°C, 3 h.

Fig. 3 |. Ten different heterocyclic cores, commonly found in pharmaceuticals, were explored in the Mn(CF₃PDP) 1-catalyzed C–H hydroxylation and methylation.

Twenty-two heterocycles including lactams, oxazolidinones, pyrrolidines, piperidines, azepane, azabicycloheptane, quinolines, and isochroman were oxidatively methylated in preparative overall yields (54% average) using limiting substrate. General oxidation: substrate, catalyst (0.5 mol%), AcOH in MeCN, −36 °C; H₂O₂ (2 or 5 equiv.) in MeCN syringe pump 1 h. Mixture passed through silica plug, EtOAc flush, concentrated prior to isolation or methylation. For insoluble substrates, CH₂Cl₂ added to MeCN and/or 0 °C. ^aDAST Activation: crude in CH₂Cl₂ (0.2 M), DAST (1 equiv.) added at −78 °C; room temperature (rt) for 1 h; cooled to −78 °C, AlMe₃ added, stirred 2 h; rt for 1 h. ^bBF₃ Activation: crude in CH₂Cl₂ (0.2 M), −78 °C, AlMe₃ (3 equiv.) and BF₃•OEt₂ (2 equiv.) sequentially added, stirred 1 h; rt for 3 h. ^cTriethylaluminum. ^d2 mol% (S,S)-1. ^eAlMe₃ −78 °C, 3 h. ^f1 mol% (S,S)-1. ^gFor facile purification, hemiaminal isolated before methylation. 10 mol% (S,S)-1, rt, starting material recycled 1x.

Fig. 4 |. Application of oxidative methylation for late stage functionalization.

a, Selective methylation of drugs, drug precursors, intermediates and natural products underscores the power of this method for late stage applications. Generally, 0.5 to 5 mol% (S,S)-1 and 2 or 5 equiv. H₂O₂ were used for oxidation. Higher catalyst and oxidant loadings were applied when conversions were low. b, Methylation of an RORc inverse agonist precursor rapidly furnishes the analogue with 13-fold potency boost. c, Methylation of antibiotic tedizolid acetate furnishes Me-tedizolid. d, Methylation of linear aniline in S1P₁ antagonist methyl ester occurs at a position where magic methyl effect was observed to contribute to a 2135-fold potency boost. e, Remote methylation of a carbocycle on an abiraterone analog. ^aDAST activation. ^bBF₃ activation. ^cTMSOTf activation: TFAA, rt, 1 h; cooled to −78 °C, AlMe₃ and TMSOTf sequentially added, 2 h; then rt, 1 h. ^dDeoxo-Fluor activation. ^eMesylation activation: MsCl and Et₃N added, rt, 1 h; NaHCO₃ wash, dried, condensed; redissolved in CH₂Cl₂, AlMe₃ added at −78 °C, stirred 2 h; then rt, 1 h. ^fOxidation intermediates isolated before methylation. ^g1 M NaOH/MeOH. ^hStarting material recycled 1x. ⁱFor insoluble substrates, CH₂Cl₂ added to MeCN and/or 0 °C. ^jHBF₄ protection, ref. 40. ^k10 mol% (S,S)-Mn(PDP)(SbF₆)₂. ^l10 mol% (S,S)-1. ^mPhSH, Cs₂CO₃; Boc₂O. ⁿMg, NH₄Cl; formaldehyde, formic acid. ^o10 mol% (RR)-1. ^p2 equiv. TMSOTf. ^qTMSOTf (1.2 equiv.), 0 °C, 1 h, then MeMgBr (3.0 equiv.) −78 °C, 4 h, repeated once.