Abstract:
Aldehyde deformylation is a crucial transformation in biological systems, playing a significant role in the biosynthesis of hormones and long-chain hydrocarbons, with molecular oxygen serving as the primary oxidant. In humans, cytochrome P450 aromatase enzyme catalyzes the conversion of androgens to estrogens. This process involves the deformylation of C19 aldehyde attached to ring A and B in the steroid structure, leading to the aromatization of ring A. This reaction is essential for estrogen biosynthesis and has important medical implications. Accordingly, aromatase inhibitors are commonly used in the treatment of estrogen-dependent breast cancer. Although heme peroxo species have been proposed as key oxidants in enzymatic deformylation reactions, the potential role(s) of the heme Fe(III)-superoxo adduct therein has not been thoroughly investigated. In synthetic model studies, metal(III)-peroxo complexes have been widely studied as biomimetic models, demonstrating efficient aldehyde deformylation. However, this study aims to explore the ambiphilic nature of aldehyde substrates and compare their reactivity with primarily electrophilic heme superoxide as supposed to nucleophilic heme peroxo species. The results indicate that heme superoxide alone is insufficient to induce aldehyde deformylation; instead, a base is required, presumably help to generate the enolate form of the aldehyde substrate, which then undergoes reactivity heme-superoxide. Detailed kinetic analyses reveal the importance of α-hydrogen of 2-phenylpropanaldehyde (2-PPA) on its reactivity with heme superoxide. Moreover, the relevant kinetic isotope effect (KIE) confirms that α-hydrogen abstraction is the rate-limiting step, and the inorganic and organic final products have been characterized using spectroscopic techniques. ¹⁸O-labeling studies indicate that the primary oxidizing agent in solution is indeed the heme superoxo adduct. These findings enhance our understanding of the ambiphilic nature of aldehyde substrates and offer insights into understanding the convoluted mechanism of aldehyde deformylation that is important with respect to both enzymatic and synthetic applications.