Novel Strategies in C-H Oxidations for Natural Product Diversification—A Remote Functionalization Application Summary

Abstract

Selectively activating the distal inactive C-H bond for functionalization is one of the on-going challenge in organic synthetic chemistry. In recent years, benefiting from the development of selective synthesis methods, novel methodologies not only make it possible to break non-traditional chemical bonds and attain more diversity in inactive sites, but also provide more possibilities for the diversification of complex natural products. Direct C-H bond functionalization approaches make it feasible to explore structure-activity relationship (SAR), generate metabolites and derivatives, and prepare biological probes. Among them, direct oxidation of inert C-H bonds is one of the most common methods for natural product diversification. In this review, we focus on the application of remote functionalization of inert C-H bonds for natural products derivatization, including the establishment of oxidation methods, the regulation of reaction sites, and the biological activities of derivatives. We highlight the challenges and opportunities of remote functionalization of inert C-H bonds for natural product diversification through selected and representative examples. We try to show that inert C-H bond oxidation, properly regulated and optimized, can be a powerful and efficient strategy in both synthetic and medicinal chemistry.

Bioinspired Synthesis of Pinoxaden Metabolites Using a Site-Selective C–H Oxidation Strategy

“…From the outset, we sought to develop a synthesis (of metabolites 2 – 4 ) that offered step-economy, cost savings, and scalability to meet our goals of sustainability. With rapid advancements and expansion of the toolbox of C–H oxidation methodologies, the ability to selectively oxidize a C–H bond of interest in a molecule without perturbing the surrounding framework carries considerable value. − Guided by this concept, we envisioned that we could use nature as a source of inspiration and hydrolyze the commercially available Pinoxaden “procide” ( 1 ) to generate the Pinoxaden “cide” form 6 (Scheme ). The cide form could be oxidized to provide tertiary alcohol 7 .…”

“…Preparation of 8-(2,6-Diethyl-4-methyl-pheny)-8-hydroxy-1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (7). To a solution of 1 (1.18 g, 2.96 mmol) in acetonitrile/methanol/ water (1:1:2, 150 mL) was added a 10 N solution of sodium hydroxide in water, and the solution was stirred at room temperature under ambient conditions for 2 h. The reaction was monitored by TLC (silica gel in ethyl acetate/methanol = 4:1).…”

Transition Metal-Catalyzed Direct Stereoselective Oxygenations of C(sp3)–H Groups

“…On the other hand, the stateof-the-art bioinspired catalytic C−H oxygenations assume the use of environmentally benign H 2 O 2 as the terminal oxidant of choice, which is evident as an advantage over stoichiometric C− H oxidations by dioxiranes or metal oxides, or oxidative transformations using high-molecular-weight inorganic and organic oxidants. 35,36 This contribution discusses the asymmetric oxygenations of aliphatic C(sp 3 )−H groups of organic molecules that have been reported to date, including (1) enantioselective hydroxylations of prochiral CH 2 groups, (2) oxidative desymmetrizations (through either ketonization or hydroxylation), via direct creation of new C−O bonds with the aid of synthetic catalysts, and (3) stereoselective late-stage C(sp 3 )−H oxygenations of complex molecules of relevance to drug discovery and development, in the presence of synthetic transition-metal based catalysts. For the purposes of this paper, a few examples of stereoselective oxygenations of complex chiral substrates in the presence of achiral catalysts are included, despite the fact that they formally do not match Kagan's definition of an "asymmetric catalytic transformation" (i.e., their enantioselectivity is not controlled by the catalyst chirality).…”

The Cascade [1,5]-Hydride Shift/Intramolecular C(sp3)–H Activation: A Powerful Approach to the Construction of Spiro-Tetrahydroquinoline Skeleton

“…Compared to classic transition metal-catalyzed coupling reactions, the direct modification of ubiquitous C–H bonds of simple organic compounds, without pre-activation and generation of a large number of wastes such as halides and tedious synthetic procedures, has attracted intense interest from the academic and industrial community ( Peng and Maulide, 2013 ; Zheng and You, 2014 ; Qin et al, 2017 ; Sauermann et al, 2018 ). Owing to its intrinsic advantages, numerous innovative and efficient synthetic methodologies have been successfully explored, offering a straightforward access to rapidly synthesize structurally complex molecules ( Hazelard et al, 2017 ; Karimov and Hartwig, 2018 ; Hong et al, 2020 ; Junrong et al, 2021 ). Among these powerful strategies, the transition metal-catalyzed C–H bond activation has long dominated the top topic in this field ( Cho et al, 2011 ; Kuhl et al, 2012 ; Chen et al, 2015 ; Gensch et al, 2016 ).…”