Synthetic Models of the Active Site of Cytochrome P‐450. 1st Communication. The Synthesis of a Doubly‐Bridged Iron(II)‐Porphyrin Carrying a Tightly Bound Thiolate Ligand

Abstract

The doubly-bridged iron(I1)-tetraphenylporphyrin derivative 6, carrying a sterically fixed S-ligand in the 'proximal'position and the substrate at the 'distal' site, was synthesised as an enzyme model for cytochrome P-450. Compound 36, the CO complex of 6, displays a split Sorer band (403 and 457 nm) similar to the native cytochrome P-450.Introduction. -The significance of cytochrome-P-450-catalysed oxygenations in the metabolism of endogenous compounds and xenobiotics [ 11 [2] has stimulated intensive research focussing on 1 ) the investigation of the reaction mechanisms of P-450 monooxygenases from bacterial [3], plant [4], and mammalian [5] [6] sources, and 2) the synthesis and application of iron-tetraphenylporphyrin derivatives, structurally related to the active site of these enzymes [7-91. The results of these investigations led to the formulation

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

“…The identification of 6 and 7 confirms our earlier suggestion [13] that P-450 model compounds with thiolate ligands not rigidly attached to the porphyrin moiety will be oxidized at the S-atom when 0, is used, but not when the oxidant is PhIO or a peroxo compound [15]. Since it was impossible to induce 0-insertion with sulfonate 6, it is evident that 7 originates from 4.…”

Cationic Ruthenium‐Cyclopentadienyl‐Diphosphine Complexes as Catalysts for the Allylation of Phenols with Allyl Alcohol; Relation between Structure and Catalytic Performance in O‐ vs. C‐Allylation

“…The NMR and mass spectra of the products 3-6 were in agreement with the data found in the literature. [32] GLC Method…”

Remote Effects Modulating the Spin Equilibrium of the Resting State of Cytochrome P450cam –An Investigation Using Active Site Analogues

“…In the event, the porphyrin, tentatively assigned as aa-25 was bridged with 1,11-dibromoundecane in the presence of Cs 2 CO 3 in hot DMF under high-dilution conditions (Scheme 5). It is known that eleven carbon atoms are sufficient to span the porphyrin plane [25] and furthermore the ab- Accordingly, the correct atropisomer was identified and the synthesis continued with the bridging of aa-25 with activated and protected thiophenylene 17 under high-dilution conditions in hot DMF in the presence of Cs 2 CO 3 (Scheme 6). The latter reagent acts on one hand as a base to preform the bisphenolate and on the other hand has a templating effect for macrocyclisation.…”

“…The latter reagent acts on one hand as a base to preform the bisphenolate and on the other hand has a templating effect for macrocyclisation. [25] The dimesylate 17 was synthesised from the corresponding diol 29 which was obtained via hydroboration reaction of diallylthiophenol carbamate 28. [25] The distal acetylamino groups were hydrolysed by refluxing 30 in a mixture of 6 M HCl and MeOH to give bis(aminophenyl) porphyrin 12 in high yield.…”

“…By this strategy it is possible to have access to model compounds mimicking different active sites of enzymes having a heme cysteinate cofactor like cytochrome P450 s, chloroperoxidase (CPO) and nitric oxide synthase (NOS). [18,25,26] In the case of the bis(tetrahydrofuranyl) model 11 the amino groups were acylated with tetrahydrofurancarbonyl chloride 13 which was obtained from the corresponding acid 14 by treatment with oxalyl chloride (Scheme 7). Cleavage of the thiocarbamate protecting group of 31 liberated the thiophenol function and subsequent iron insertion using FeBr 2 in the presence of 2,6-lutidine as base in refluxing toluene completed the synthesis of bis(tetrahydrofuranyl) model 11.…”