Improving Physical Properties via CH Oxidation: Chemical and Enzymatic Approaches

• Published in: Angewandte Chemie (International ed.) Vol. 53; no. 45; pp. 12091 - 12096
• Main Authors: Michaudel, Quentin, Journot, Guillaume, Regueiro-Ren, Alicia, Goswami, Animesh, Guo, Zhiwei, Tully, Thomas P., Zou, Lufeng, Ramabhadran, Raghunath O., Houk, Kendall N., Baran, Phil S.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 03.11.2014; WILEY‐VCH Verlag; Wiley
• Subjects: Biocompatibility; Biological Products - chemistry; Carbon - chemistry; Chemistry; Chemistry, Multidisciplinary; CH activation; Handles; Hydrocarbons; Hydrogen - chemistry; medicinal chemistry; Natural products; Oxidation; Oxidation-Reduction; Physical properties; Physical Sciences; Production methods; radical reactions; Science & Technology; Solubility; Strategy; terpenoids; CHROMIUM(VI) OXIDE; STRAIN RELEASE; terpenoids; CATALYZED OXIDATION; oxidation; radical reactions; TRITERPENES; FUNCTIONALIZATION; C-H activation; HIV-INFECTION; BETULINIC ACID; ALKYL HYDROPEROXIDES; DIACETATE; medicinal chemistry; PHOTOCHEMICAL REACTION; CH activation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201407016

Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle‐type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of CH oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water‐soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds. A handle on [O]: A variety of CH oxidation methods were explored on the betulin skeleton to improve the solubility of this bioactive, yet poorly water‐soluble, natural product. The innate reactivity of the molecule, as well as the molecular handles present on the core, allowed oxidations at different positions. Solubility enhancement was observed for many of the synthesized compounds.