Scalable C–H Oxidation with Copper: Synthesis of Polyoxypregnanes

See, Yi Yang; Herrmann, Aaron T.; Aihara, Yoshinori; Baran, Phil S.

doi:10.1021/jacs.5b09463

Cited by 119 publications

(132 citation statements)

References 44 publications

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“…The resulting reaction mixture was then decomplexed using Baran’s procedure (aqueous Na 4 EDTA solution) 22 and analyzed by 1 H NMR (Figure 3). …”

Section: Resultsmentioning

confidence: 99%

“…16,17 Baran and co-workers substantially improved the yields (70–90%) and shortened the reaction times (1.5 h at 50 °C) by increasing temperature, the amount of copper (1.3 equiv), and reductant loadings (2.0 equiv). 22 …”

Section: Resultsmentioning

confidence: 99%

“…The reaction conditions were subsequently improved (ascorbic acid as reductant, shorter reaction times, and higher yields) and applied to the first synthesis of highly oxygenated polyoxypregnane steroids with useful biological properties. 22 In these disclosures, it was proposed that the oxidation proceeded via formation of Cu 2 O 2 species, which are considered 2e − oxidants, limiting the reaction yields to 50% (in Baran’s approach, the reductant provided the electrons necessary to overcome the 50% threshold). However, the general uncertainty surrounding the mechanism has prevented further development of this potentially useful methodology, and advances have been limited to the above-mentioned examples.…”

Section: Introductionmentioning

confidence: 99%

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Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds

et al. 2017

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The use of copper in directed C−H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O−O cleavage to generate reactive RO• species, which are responsible for key C−H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.

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“…The resulting reaction mixture was then decomplexed using Baran’s procedure (aqueous Na 4 EDTA solution) 22 and analyzed by 1 H NMR (Figure 3). …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds

et al. 2017

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“…214,215 Starting with steroids containing C17 D-ring ketones, pyridyl imines are condensed ( 189 ) to direct Cu-catalyzed oxidations to occur at the C12–H to yield 190 (Figure 32). The achievement of selectivity at the C12 position is striking, given the electron withdrawing nature of the imine, which limits the inherent nucleophilicity of C12–H.…”

Section: C–h Oxidationmentioning

confidence: 99%

“…( B ) The proposed mechanism proceeds via bimetallic activation of O 2 to activate the C12–H bond. 214 …”

Section: Figurementioning

confidence: 99%

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

2017

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The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogs of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this review is on the recent studies of non-enzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

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Wang

et al. 2019

Green Oxidation in Organic Synthesis

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Scalable C–H Oxidation with Copper: Synthesis of Polyoxypregnanes

Cited by 119 publications

References 44 publications

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

Green Oxidative

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Scalable C–H Oxidation with Copper: Synthesis of Polyoxypregnanes

Cited by 119 publications

References 44 publications

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C–H Bonds

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C–H Bonds

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

Green Oxidative

Contact Info

Product

Resources

About

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds

Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp³ C–H Bonds