O‐Insertion into Nonactivated CH Bonds: The first observation of O₂ cleavage by a P‐450 enzyme model in the presence of a thiolate ligand

Abstract

On reaction with '0-donors or O,, the synthetic P-450 analogue 2 undergoes 0-insertion at a nonactivated C-H bond of the covalently bound substrate. The mechanism of 0-insertion with 0, most likely involves homolytic cleavage of the 0-0 bond followed by 0-insertion via radical recombination.Introduction. -The cytochrome P-450 enzymes are heme proteins which play an important role in the metabolism of endogenous compounds and xenobiotics in both procaryotic and eukaryotic organisms [I] [2]. The geometry of the active site of one of these proteins is precisely known from a recent series of X-ray studies of the non-membrane-bound, camphor-hydroxylating P-450,,, [3]. These investigations confirmed earlier model studies concerning the coordination of a thiolate ligand to the Fe-atom on the face of the porphyrin opposite to the binding sites of an 0, and the substrate.Since the discovery of cytochrome P-450 catalyzed reactions some 30 years ago [4], the unique ability of these enzymes to insert an 0-atom regio-and stereospecifically into nonactivated C-H bonds has been a serious challenge to the organic chemist. To simulate these and other P-450 reactions, considerable progress was achieved by circumventing the problematic reductive cleavage of molecular 0, (see catalytic cycle, Scheme 1 ), and employing synthetic face-protected [5] or perhalogenated iron(II1) porphyrinates [6] as analogues of the resting state A and, e.g., iodosobenzene (1) as the 0-source. According to experiments by Groves and Wutanube [7] using peracids and iron-(1II)tetramesityl porphyrinate, this so-called 'shunt pathway' leads to an oxoiron(1V) porphyrinate radical cation B, which mimics the reactivity characteristic of P-450 enzymes, and, therefore, is believed to be an equivalent of the corresponding transient intermediate of the catalytic cycle in living cells (see reviews [S] [9]). However, in almost all studies using model porphyrins, the significance of the thiolate ligand to the reactivity of the iron porphyrinate was ignored*).We recently showed that the doubly-bridged iron porphyrinates 2 and 3 carrying thiolate ligands are active-site analogues of E . S complexes C of cytochrome P-450 with respect to spin states, CO binding, and UV spectroscopy [ 131 [ 141. To investigate whether these compounds are capable of P-450-like reactions, namely the 0-insertion into nonac-

β ‐Cyclodextrin‐Mediated Regioselective Hydrolysis of 5,10,15,20‐tetrakis[2,4‐bis(pivaloyloxy)phenyl]‐21H,23H ‐porphine

“…-In recent years, several face-protected metal tetraphenylporphyrin (TPP) derivatives have been prepared in order to study the oxygen binding [I], to investigate the redoxchemistry related to additional axial ligands coordinating to the metal [2], and to mimic the spectroscopy [3] and chemical reactivity of enzymes employing these complexes in their active site [4].…”

“…From all the synthetic concepts, aiming at P-450 models, the picket-fence and the doubly-bridged porphyrins became the most popular and useful for avoidingp -oxo-dimer formation in the presence of 0,. Accordingly, the latter approach was rather successful, since advanced P-450 enzyme model systems could be prepared, and even 0, cleavage and subsequent 0-insertion into non-activated C-H bonds was demonstrated which is characteristic of native P-450 enzymes [4].…”

Beyond Heme‐Thiolate Interactions: Roles of the Secondary Coordination Sphere in Cytochrome P450 Systems

“…While this complex was capable of performing P450 chemistry with hydrogen peroxide and other peroxy acids, it was unable to form a stable dioxygen adduct [25]. In another study it was demonstrated that a thiolate-iron porphyrin complex could cleave O 2 and insert an oxygen atom into non-activated C-H bonds [26]. This complex and others of its type, however, have lower redox potentials E o = −600 to −700 mV than P450 enzymes (e.g., −290 mV for CYP101A1 (P450cam)).…”

The novel and efficient direct synthesis of N,O-acetal compounds using a hypervalent iodine(iii) reagent: an improved synthetic method for a key intermediate of discorhabdins

“…This reagent is very easily prepared from pentafluoroiodobenzene and nitric acid. 7 Furthermore, we succeeded in the improved synthesis of the key intermediate of discorhabdins by using this method.…”