Chemoselective methylene oxidation in aromatic molecules

Abstract

Despite significant progress in the development of site-selective aliphatic C-H oxidations over the past decade, the ability to oxidize strong methylene C-H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF₃-PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic and biaryl moieties. Late-stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C-H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

Figure 1 |. Enzymatic and small molecule approaches for C–H oxidation.

A chemoselective small molecule catalyst capable of strong methylene C–H bond oxidations in the presence of the more oxidatively labile π-functionality of aromatic groups was previously unknown. a. Cytochrome P450 enzymes (CYPs) achieve such chemoselective oxidation of methylene C–H bonds by restricting the substrate’s approach to the iron oxidant, however these enzymes are challenging to use preparatively. b. The two major pathways of aromatic oxidation with the iron(oxo) oxidants generated in CYPs are electron transfer (top) or epoxidation followed by hydride shift (e.g. the “NIH shift”, bottom). c. Small molecule catalyst Mn(CF₃–PDP) 1 achieves chemoselective hydroxylation of strong methylene C–H bonds in presence of aromatic functionalities. This reactivity is orthogonal to other oxidants that perform weaker bond oxidations (for example benzylic C–H) in the presence of aromatic functionality as demonstrated with an ethinylestradiol derivative (the site of oxidation is highlighted in yellow). d. The crystal structure of the Mn(CF₃–PDP)Cl₂ precatalyst shows the bulky ligand framework thought to be critical for the high chemoselectivity achieved with Mn(CF₃–PDP)(CH₃CN)₂•(SbF₆)₂ catalyst [Mn(CF₃–PDP)] 1.

Figure 2 |. Chemoselective methylene C–H oxidation.

a. Aromatic substrates with heteroaromatic or 3° amine substituents^a. Mn(CF₃–PDP) 1 catalyzed remote 2° C–H oxidation in the presence of aromatic functionality with basic nitrogen containing heterocycles or heteroaromatics. b. Aromatic dipeptides. Mn(CF₃–PDP) 1 oxidation of peptides containing amino acids with mildly deactivated aromatic groups. This enables for the first time intramolecular functionalizations with arene π-nucleophiles to furnish medicinally relevant tricyclic cores. Isolated yields are average of two-three runs. Site of oxidation is highlighted in yellow. Ns, 4-nitrophenylsulfonyl. ^aHBF₄•OEt₂ protected as described in ref. followed by slow catalyst addition protocol (method C): both H₂O₂ (10 equiv.) and Mn(CF₃–PDP) 1 (10 mol%) were simultaneously added over 3 hours. See methods section for more details. ^bMethod C used at 0 °C. ^cWithout HBF₄ complexation under optimal condition with 1. ^d25 mol% Fe(CF₃–PDP) 6, slow addition protocol (ref. 28). ^eMethod B used. ^fStarting material recycled once. ^gMethod A used with AcOH (15 equiv.) and H₂O₂ (5.0 or 7.5 equiv.) at –36 °C. ^hCrude hemiaminal, TfOH (2.0 equiv.), 90 °C, 2 hours.

Figure 3 |. Late-stage methylene hydroxylation of synthetic and natural product, aromatic drugs derivatives.

a. Derivatives of the HIV-1 drug efavirenz and a γ-secretase modulator analogue that house oxidatively sensitive π-functionality such as aryl halides, acetylenes, piperidine, and tertiary amines are oxidized with Mn(CF₃–PDP) 1 at remote methylene sites in preparative yields. Antidepressant citalopram is oxidized to a hemiacetal and arylated with an arene π-nucleophiles via an intermediate oxocarbenium. b. Drug candidate piragliatin, identified as a metabolite of drug lead 65, required de novo synthesis to furnish quantities for further evaluation. Mn(CF₃–PDP) 1 catalysis enables an advanced lead intermediate to be rapidly transformed to piragliatin. c. Sequential Mn(CF₃–PDP) 1 catalyzed 2^o benzylic/2^o aliphatic C–H oxidation of an ethinylestradiol derivative. 2° benzylic oxidation can be tuned with oxidant to give ketone 70 or diastereomerically pure alcohol 71 that undergo further diastereoselective C12 β methylene hydroxylation to alcohols 73 and 74 (crystal structures confirm the 12β configuration). In contrast, TFDO furnishes oxidation at the doubly activated 3° benzylic site. All reactions run with limiting substrate and isolated yields reported as an average (2–3 reactions, using 1). See the Supplementary Information Section VIII and IX for more details. Ac, acetyl; Piv, pivaloyl. ^a Method A used at 0 °C. ^b HBF₄•OEt₂ protected, ref. followed by method C at 0 °C. ^c Method A using 2 equiv. H₂O₂; arylation protocol, ref. . ^d LiOH•H₂O (5 equiv.); oxalyl chloride (1.1 equiv.); 2-aminopyrazine (2.2 equiv.), pyridine (2.2 equiv.). ^e Method A with modifications: 1 (5 mol%; 2 mol% for gram scale), ClCH₂CO₂H (7.5 equiv.), H₂O₂ (10 equiv. for 70 or 2 equiv. for 71), 4:1 MeCN:CH₂Cl₂ at –36 °C. ^f Ac₂O (2.4 equiv.), NEt₃ (2.4 equiv.), CH₂Cl₂, 86%. ^g Method A with 4:1 MeCN:CH₂Cl₂ at 0 °C. ^h TFDO: 72 (0.05 mmol) in CH₂Cl₂ (0.5 mL) at –20 °C. TFDO (0.4 M solution, 0.25 mL, 2 equiv.) added at –20 °C and stirred for 40 minutes in dark.