Iron biomimetic synthesis

The mechanism of penicillin biosynthesis from the Arnstein tripeptide, 8-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV), has been extensively studied and reviewed by many chemists. Most of the biosynthetic mechanisms have been ascertained by Baldwin and Bradley using an excellent enzymatic technique.55 However, the first step in the biosynthesis of penicillin, conversion of the Arnstein tripeptide to a cis-P-lactam intermediate, is still a fascinating mechanistic problem. Although Baldwin et al. recently proposed a mechanism involving an iron-bound thioaldehyde formation route via a Pummerer-type cyclization, the intermediate for this mechanism has not been identified. The mechanism of selective formation of the cw-P-lactam ring is still also unknown (Fig. 39).56 These types of biomimetic reactions have been chemically studied. An example of an unsuccessful intramolecular Pummerer cyclization of the sulfoxide involving a cysteine moiety under standard Pummerer conditions was reported by Wolfe et al.57 Although Kaneko reported the conversion of the very simple 3-phenylsulfinyl propionamide into a P-lactam with TMSOTf/triethylamine,58 a successful biomimetic synthesis of... 

Dithiocarbamates, in Ru and Os half-sandwiches, 6, 493 Dithiocarbenes, Pt complexes, 8, 439 Dithiocarboxy ligands, in molybdenum carbonyls, 5, 447 Dithiolate-bridged compounds in dinuclear iron compounds with Fe-Fe bonds, 6, 238 as iron-only hydrogenase biomimetic models, 6, 239 Dithiolate diamides, with Zr(IV), 4, 784 Dithiolene—uranium complexes, synthesis and characterization, 4, 212 Ditopic receptors, characteristics, 12, 489 Ditungsten complexes, associated reactions, 5, 748 Divinyllead diacetates... 

Iron-only hydrogenase, dithiolate-bridged compounds as biomimetic models, 6, 239 Iron oxide films, synthesis, 12, 51 Iron-palladium nanoparticles, preparation, 12, 74 Iron-platinum bimetallic clusters, with isocyanide clustes,... 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

The biomimetic approach to the synthesis of new siderophores has not been restricted to studies in the USA Kontoghiorghes241 242,269) has synthesized hydroxypyridones (34, 35) and demonstrated their ability to mobilize iron(III) from ferritin. Intragastric administration of l,2-dimethyl-3-hydroxy-pyrid-4-one (34) proved to be as effective as intramuscular DFOA in mobilizing iron from the iron-overloaded rat. This effectiveness of an orally administered chelating agent is particularly noteworthy. 

The goal of diiron model chemistry is to develop small molecule systems that accurately reproduce spectroscopic, structural, and more ambitiously, reactivity aspects of driron metaUoproteins. Despite being structurally similar, diiron enzymes carry out a variety of catalytic processes see Iron Proteins with Dinuclear Active Sites)Advancements in the synthesis and characterization of small molecule mimics for nonheme diiron enzymes have been tremendous in the last decade. Biomimetic studies have been carried out in efforts to reproduce the structural and functional aspects of these biocatalysts. Although this has been a challenging endeavor, much information regarding the structural and mechanistic aspects of catalytic intermediates has been obtained. 

Biomimetic oxidation catalysis has largely focused on complexes with planar tetradentate ligands such as manganese or iron porphyrins and related macrocyclic trans-chelates[5]. There is considerable interest in the synthesis of multinuclear metal complexes since these molecules might be useful as building block for magnetic molecular materials[6] and model compounds for understanding the properties of metalloproteins[7]. 

The development of more sustainable methodologies is of particular interest to afford carbonyl compounds with industrial and biological interest. In this context, iron-based alcohol oxidations may be of great use. Since cytochrome P450 was presented as an active catalyst in the synthesis of carbonyl compounds,biomimetic synthetic complexes have also been used in this context, e.g. TPA-Fe =0. In the proposed mechanism, the oxidation of the alcohol takes place via a-CH hydrogen-atom abstraction, followed by an electron transfer to yield the corresponding carbonyl compound and an iron(ii) complex that could be reoxidised toward the active catalytic species, L-0=Fe(iv) (Scheme 13.27). 

As mentioned in the Introduction, the group 3 biomimetic approach (see Scheme 1) has been the most popular route to the trichothecene skeleton. Two different moieties have served as the electrophilic site for biomimetic cyclization. When the cyclization proceeds via an allylic carbonium ion (127) (Path A, Scheme 9), the desired trisubstituted olefin (126) is obtained directly. On the other hand, the Michael acceptor (128) (PathB) yields, upon cyclization, a ketone (129) which must then be transformed into the olefin (126), a process which shows good but not complete regioselectivity. Hence, Path A, which can also be entered from the enone (128), is the superior route. Further analysis of Scheme 9 reveals that the primary stereochemical challenge of the biomimetic approach is to control the relative stereochemistry at the two quaternary centers C-5 and C-6. Within the context of trichothecene synthesis, a number of useful protocols have been devised for this purpose and include photocyclization (99), selective ring contraction (134), Diels-Alder cycloaddition (117,125) conjugate addition (27,120), and interconversion of dienyl iron complexes (114). 

Ott, S. Kritikos, M. Akermark, B. Sun, L. C. Synthesis and structure of a biomimetic model of the iron hydrogenase active site covalently linked to a ruthenimn photosensitizer. Angew. Chem. Int. Ed. 2003, 42, 3285-3288. 

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