Aliphatic C-H Oxidations for Late-Stage Functionalization

Abstract

The atomistic change of C( sp³)-H to C( sp³)-O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C-H oxidation are an extension of this logic. The impact of developing undirected C-H oxidation reactions with controlled site-selectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses. This Perspective offers a historical view of why, as recently as 2007, it was thought that the differences between aliphatic C-H bonds of the same bond type (for example, 2° aliphatic) were not large enough to distinguish them preparatively with small-molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C-H hydroxylations and how the electronic, steric, and stereoelectronic rules for predicting site-selectivity that emerged have affected a shift in how the chemical community views the reactivity among these bonds. The discovery that site-selectivity could be altered by tuning the catalyst [i.e., Fe(CF₃-PDP)] with no changes to the substrate or reaction now gives scientists the ability to exert control on the site of oxidation on a range of functionally and topologically diverse compounds. Collectively, these findings have made possible the emerging area of late-stage C-H functionalizations for streamlining synthesis and derivatizing complex molecules.

Figure 1.

Atomistic change of C(sp³)–H to C(sp³)–O impacts a molecule’s properties. Introduction of a hydroxyl or ketone functionality can change (A) the smell and taste, (B) the pharmacological properties, and (C) the physical properties of small molecules (for example, solubility).

Figure 2.

Late-stage functionalization via Fe(PDP)- and Fe(CF₃-PDP)-catalyzed aliphatic C–H oxidation. (A) Traditional synthetic logic using existing functionality to introduce new functionality versus late-stage functionalization logic where new functionality is introduced remote from existing functionality. (B) The invention of Fe(PDP) and Fe(CF₃-PDP) catalysts for remote, late-stage aliphatic C–H oxidations. Site-selectivity operates under catalyst control: using the same molecule (artemisinin) and changing only the catalysts, preparative oxidation occurs at two distinct sites. (C) Fe(PDP) and Fe(CF₃-PDP) catalysis has been developed to enable late-stage oxidation of a wide range of natural products (terpenes, steroids, alkaloids, peptides, amides). ^aDirected sclareolide α-oxidation, ref . ^bAll yields are isolated yields based on 1 equiv of substrate. ^c2:1 alcohol:ketone ratio. ^d6:1 alcohol:ketone ratio. ^e2.5:1 C7ketone:C6alcohol ratio.

Figure 3.

Aliphatic C–H oxidation reactivity via hydroxyl radicals promoted with (A) iron salts (Fenton reaction) and (B) iron salts in the presence of pyridine and carboxylic acid additives (Gif reaction).

Figure 4.

Aliphatic C–H oxidations via stoichiometric dioxirane oxidants. (A) TFDO [methyl(trifluoromethyl)dioxirane] must be made and used at cryogenic temperatures (−20 °C) under conditions that exclude visible light and trace metals to avoid decomposition into free radicals. (B) Compounds housing functionality prone to decomposition in the presence of free radicals are not run under conditions that afford high conversion with TFDO (often requiring elevated temperatures). (C) Aliphatic C–H oxidations of steroids with TFDO and DMDO (dimethyldioxirane) occur at tertiary sites. Changes in site-selectivities happen only by changing the substrate and are not explained.

Figure 5.

Aliphatic C–H oxidation reactivity via organometallic intermediates. (A) The Shilov reaction converts methane to methanol and chloromethane using platinum salts. (B) A modification of the Shilov reaction that converts methane to methyl bisulfate features the ability to use platinum in catalytic amounts, with sulfuric acid acting as both the functionalization reagent and the stoichiometric oxidant. (C) Stoichiometric studies elucidated that the primary site-selectivities of reactions that proceed via organometallic intermediates are primarily due to a kinetic preference to proceed via an unhindered σ-complex and a thermodynamic preference to form the less sterically hindered C–M bond. (D) Reactivity challenges persist with the Shilov reaction, requiring suprastoichiometric amounts of substrate.

Figure 6.

Biomimetic aliphatic C–H oxidation and epoxidation reactivity with iron and manganese heme catalysts. (A) Reactivity and site-selectivity challenges. (B,C) The reactions are not stereospecific, leading to long-lived carbon-centered radical species that scramble stereochemistry and open cyclopropane rings. (D) Epoxidation experiments performed with stoichiometric manganese(oxo) porphyrin complexes show the presence of autoxidation products under both aerobic and anaerobic conditions, signifying an oxidant is formed with significant oxygen-centered radical character.

Figure 7.

Substrate directing group approaches for improving reactivity and controlling site-selectivity. (A) Intramolecular hydroxyl radical reactions require rigid substrates like steroids. (B) General design principles for directed organometallic C−H functionalizations. (C,D) Directed organometallic aromatic C−H functionalizations. (E,F) Directed organometallic aliphatic C−H oxidations.

Figure 8.

Shape–molecular recognition strategies for controlling site-selectivity in aliphatic C–H oxidations with manganese porphyrins. Panel B: Reproduced with permission from ref . (Stereochemistry at C20 of cholesterol corrected.) Copyright 1988 ACS.

Figure 9.

Functional group–molecular recognition strategies for controlling site-selectivity in aliphatic and benzylic C–H oxidations with manganese catalysts. Panel A: Reproduced with permission from ref . Copyright 1997 ACS. Panel B: Reproduced from ref . Copyright 2001, with permission from Elsevier. Panel C: From ref . Reproduced with permission from AAAS.

Figure 10.

Our guiding hypothesis for developing catalysts for site-selective C–H hydroxylations: the discovery of metal(oxo) intermediates that abstract hydrogen to form weak metal O–H bonds and will proceed via endothermic pathways with late, product-like transition states that may afford sensitivity to differences in the C–H bonds’ chemical environment within complex molecules.

Figure 11.

(A) Biomimetic aliphatic C–H hydroxylation reactivity using non-heme iron catalysts Fe(TPA) and Fe(MEP). (B) Aliphatic C–H oxidations catalyzed by Fe(MEP) are stereospecific, and H₂O labeling studies indicate that they proceed via iron carbonyls. (C) The first example of preparative oxidation catalyzed by a non-heme iron complex is in the epoxidation of terminal olefins.

Figure 12.

Discovery of Fe(PDP) catalysis for preparative aliphatic C–H oxidations. Table from ref . Reproduced with permission from AAAS.

Figure 13.

Mechanistic considerations with Fe(PDP) hydroxylations. (A) Proposed mechanism for Fe(PDP)-mediated C(sp³)–H hydroxylation. (B) The site-selectivity in C–H cleavage with the Fe(PDP) oxidant is not solely based on BDE. (C) Oxidations with Fe(PDP) do not scramble stereocenters or open cyclopropane rings, indicating that no long-lived carbon-centered radicals are formed. (D) Evidence for a stepwise mechanism is seen in Fe(PDP) oxidation of a taxane derivative where a ring-contracted nortaxane product is formed. Carboxylic acids on the substrate can direct oxidation away from the site that is intermolecularly favored with Fe(PDP). Collectively this suggests that Fe(PDP) oxidations proceed via a carboxylate-bound oxidant through a late, product-like C–H cleavage step and a rapid hydroxyl rebound step.

Figure 14.

Fe(PDP) is proposed to discriminate C(sp³)–H bonds on the basis of their different electronic, steric, and stereoelectronic environments.

Figure 15.

Fe(PDP) and Fe(CF₃-PDP) catalysts discriminate between aliphatic C–H bonds on the basis of their electronic properties. (A) General trends for electronically driven site-selectivities are established. (B) Fe(PDP) affords preparative yields of mono-oxidized products at the more electron-rich site in substrates housing two electronically distinct tertiary C–H sites. (C) Fe(PDP) and Fe(CF₃-PDP) afford preparative yields of mono-oxidized product at the site most remote from an electron-withdrawing group in substrates housing multiple electronically distinct secondary C–H sites. ^aCombined isolated yields for regioisomeric oxidation products.

Figure 16.

Generality of electronic rules for site-selectivity established with Fe(PDP) for radical and metallocarbene-mediated C–H functionalizations. ^aCalculated yield of major product. ^bGC yields. ^c53% selectivity. ^d3 equiv of substrate; yield based on substrate.

Figure 17.

Fe(PDP) and Fe(CF₃-PDP) catalysts discriminate between aliphatic C–H bonds based on their steric properties. Preparative yields of mono-oxidized products are seen in Fe(PDP)- and Fe(CF₃-PDP)-catalyzed oxidations of (A) a menthol derivative, (B) trans-1,2-dimethylcyclohexane, (C) and an androsterone derivative. Small radical and dioxirane reagents show either no or alternate selectivities.

Figure 18.

Fe(PDP) discriminates between aliphatic C–H bonds on the basis of their stereoelectronic properties. (A) Oxygen functionality hyperconjugatively activates adjacent methylene sites to furnish preparative yields of mono-oxidized products with Fe(PDP) oxidations and light-promoted radical xanthylation. (B,C) Cyclopropane rings that act as hyperconjugative activators in Fe(PDP) catalysis are opened with radical reagents. (D) Ring-strain release (release of torsional strain) promotes oxidation at C3 of substituted cyclohexane rings with Fe(PDP) catalysis.

Figure 19.

First examples of predictable, site-selective late-stage aliphatic C–H oxidations on complex molecules that are not steroids: (A) artemisinin (2007), (B) gibberellic acid derivative (2007), and (C) dihydropleuromutilone (2010). (D) Analogous site-selectivities are seen in 2018 with rhodium nitrene-based C–H aminations.

Figure 20.

Sclareolide sequential C–H oxidation was first demonstrated with Fe(PDP) catalysis and later as a “privileged substrate” for electrophilic metallonitrene and radical C(sp³)–H functionalizations.

Figure 21.

Examples of site-selective aliphatic C–H functionalization reactivity prior to 2007 lacked preparative utility.

Figure 22.

Designing the Fe(CF₃-PDP) catalyst to predictably alter site-selectivities. By narrowing the approach trajectory to the active oxidant, Fe(CF₃-PDP) weighs the steric environment of C–H bonds more heavily than their electronic/stereoelectronic environment. Reproduced with permission from ref . Copyright 2013 ACS.

Figure 23.

Catalyst-controlled site-selectivities with Fe(CF₃-PDP). (A) When electronic and steric preferences at sites on the substrate diverge, Fe(CF₃-PDP) overrides electronic preferences in favor of sterics and is selective. (B) In cases where Fe(PDP) selects for a site based on favorable electronics and moderate sterics, Fe(CF₃-PDP) overturns that selectivity in favor of the more sterically accessible site.

Figure 24.

Catalyst controlled site-divergence. (A) Predictable site-divergent selectivities in natural product artemisinin using Fe(PDP) or Fe(CF₃-PDP). (B) Prior to Fe(PDP), site-selective oxidations on artemisinin had only been reported with enzymes. (C) Site-divergence in the cyanthiwigin core. The modest yields for tertiary hydroxylation underscores the importance of finding the “matched” version of the chiral Fe(PDP) catalyst with chiral substrates. Panel A: Reproduced with permission from ref . Copyright 2013 ACS.

Figure 25.

Reactivities and selectivities with radical chlorinations and azidations and metallonitrene C–H aminations in (A) artemisinin and (B) the cyanthiwigin core.

Figure 26.

Development of a predictive, quantitative model for site-selective aliphatic C-H oxidations with Fe(PDP) and Fe(CF₃-PDP). (A) Parameterization of electronic, steric, and stereoelectronics properties of C-H bonds enables development of a site-filter that identifies likely sites for oxidation with PDP catalysts that are remote from existing functionality, relatively unhindered, and stereoelectronically activated. (B) Development of a predictive model entails mathematically correlating the substrate properties with the empirically observed site-selectivities as a function of catalyst. (C) Predicted site-selectivity on a nectaryl derivative. (D) Predicted site-selectivity on a finasteride derivative. (E) A linear correlation was found between the predicted and observed site-selectivities as a function of catalyst. Panels B/E: Reproduced with permission from ref . Copyright 2013 ACS.

Figure 27.

Fe(PDP)- and Fe(CF₃-PDP)-catalyzed oxidative diversification of amino acids and peptides. (A) Four chiral pool amino acids are transformed into 21 chiral unnatural amino acids. (B) Late-stage oxidative derivatization of one peptide transforms it into eight peptides with preserved α-chirality.

Figure 28.

Late-stage oxidation of internal proline residues. (A) A tripeptide with an internal proline residue undergoes Fe(CF₃-PDP) oxidation to a glutamic acid residue. (B) Internal prolines may be incorporated into linear peptides to facilitate cyclization and then transformed at a late-stage via Fe(PDP) oxidation to linear residues (e.g., an ornithine derivative).

Figure 29.

Late-stage C–H oxidations with Fe(PDP) to streamline total syntheses of densely functionalized natural products: (A) gracilioether F (Brown 2014, ref 21) and (B) scaparvin (Snyder 2017, ref 23).

Figure 30.

Strategies for expanding basic nitrogen tolerance in aliphatic C–H oxidations. (A) Imides are tolerated with no protection. (B,C) Tertiary amines can be masked via protonation as HBF₄ salts or via BF₃ complexation (not shown) to promote remote C–H oxidation. (D) Amides and lactams (not shown) can be masked as imidate salts to promote remote C–H oxidations.

Figure 31.

Application of late-stage C–H oxidation to rapidly identify drug metabolites and produce them on a preparative scale is a future opportunity. (A) Piragliatin, a drug candidate for diabetes, was discovered via a MetID study of the lead compound. (B) Independent total syntheses were required to identify the structures of the possible cyclopentane ring metabolites and fully evaluate their biological activities.

Figure 32.

Atomistic change of C(sp³)–H to C(sp³)–N and C(sp³)–C impact a molecule’s properties. (A) The first broad-spectrum penicillin derivative (ampicillin) differs from penicillin G by the introduction of a benzylic amine. (B) The introduction of a methyl group, often alpha to heteroatoms, can significantly boost the potency of drug candidates and is referred to as the “magic methyl effect”.

Figure 33.

A Mn(ClPc)-catalyzed intermolecular benzylic C(sp³)–H amination that shows site-selectivity and chemoselectivity trends analogous to those established with Fe(PDP) hydroxylation catalysis.