Epoxides mimics

The diols (97) from asymmetric dil droxylation are easily converted to cyclic sii e esters (98) and thence to cyclic sulfate esters (99).This two-step process, reaction of the diol (97) with thionyl chloride followed by ruthenium tetroxide catalyzed oxidation, can be done in one pot if desired and transforms the relatively unreactive diol into an epoxide mimic, ue. the 1,2-cyclic sulfate (99), which is an excellent electrophile. A survey of reactions shows that cyclic sulfates can be opened by hydride, azide, fluoride, thiocyanide, carboxylate and nitrate ions. Benzylmagnesium chloride and thie anion of dimethyl malonate can also be used to open the cyclic sulfates. Opening by a nucleophile leads to formation of an intermediate 3-sidfate aiuon (100) which is easily hydrolyzed to a -hydroxy compound (101). Conditions for cat ytic acid hydrolysis have been developed that allow for selective removal of the sulfate ester in the presence of other acid sensitive groups such as acetals, ketals and silyl ethers. 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

To mimic the square-pyramidal coordination of iron bleomycin, a series of iron (Il)complexes with pyridine-containing macrocycles 4 was synthesized and used for the epoxidation of alkenes with H2O2 (Scheme 4) [35]. These macrocycles bear an aminopropyl pendant arm and in presence of poorly coordinating acids like triflic acid a reversible dissociation of the arm is possible and the catalytic active species is formed. These complexes perform well in alkene epoxidations (66-89% yield with 90-98% selectivity in 5 min at room temperature). Furthermore, recyclable terpyridines 5 lead to highly active Fe -complexes, which show good to excellent results (up to 96% yield) for the epoxidation with oxone at room temperature (Scheme 4) [36]. 

Asymmetric epoxidation systems using iron porphyrin heme-mimics are also known, however the labor-intensive and expensive syntheses is hmiting their applications [49]. 

In order to test this proposal, several theozymes were constructed.1101 Antibody 26D9 was originally elicited in response to a piperidine-N-oxide hapten (4, Figure 2), in which the polarized N-0 bond was meant to mimic the breaking C-0 bond of the epoxide in the cyclization transition state, and the 6-membered piperidine ring was used to represent the size and shape of the 6-endo transition state Hapten 4 was used as a template to create several... 

DNA binds and reacts with carcinogenic and similar compounds which alkylate it through cationic intermediates, in some cases extraordinarily fast 1371 and can in the process catalyse the hydrolysis of some substrates, like the bay-region diol epoxides derived from benzpyrene.1381 In the context of enzyme mimics these reactions are primarily of curiosity value DNA lacks the conformational flexibility and the chemical functionality to offer the prospect of efficient catalysis for ordinary reactions. 

Since the first two approaches are very well known and exploited, and excellent reviews and books on the topic are available [1], we will deal only with some of the most recent findings in chemical catalysis -excluding the Sharpless asymmetric epoxidation and dihydroxylation, to which the whole of Chapter 10 is devoted. Synthetic catalysts which mimic the catalytic action of enzymes, known as chemzymes, will be also considered. 

The enzyme could hydrogen bond to the oxygen of the epoxide ring and therefore mimic, to some extent, an acid-catalyzed reaction. This is illustrated below ... 

Metalloporphyrins have been used for epoxidation and hydroxylation [5.53] and a phosphine-rhodium complex for isomerization and hydrogenation [5.54]. Cytochrome P-450 model systems are represented by a porphyrin-bridged cyclophane [5.55a], macrobicyclic transition metal cyclidenes [5.55b] or /3-cyclodextrin-linked porphyrin complexes [5.55c] that may bind substrates and perform oxygenation reactions on them. A cyclodextrin connected to a coenzyme B12 unit forms a potential enzyme-coenzyme mimic [5.56]. Recognition directed, specific DNA cleavage... 

In the last decade, transition metal complexes (e.g. metalloporphyrins) have been used to catalyze epoxidation. These entities can reproduce and mimic all reactions catalyzed by heme-enzymes (cytochromes P-450)54. Synthetic metalloporphyrins are analogous to the prosthetic group of heme-containing enzymes which selectively catalyze various oxidation reactions. The metallo complexes of Fe, Co, Cr, Mn, Al, Zn, Ru, etc. possessing porphyrin ligands have been mostly studied55 -57. Porphyrin ligands (4) are planar and can possess several redox states of the central metallic ions and hence they can exist as oxo metals. 

Since H202 is easier to handle than 02, we will focus on the use of the former. Many metals can be used for this transformation [50]. Among them, iron compounds are of interest as mimics of naturally occurring non-heme catalysts such as methane monooxygenase (MMO) [51a] or the non-heme anti-tumor drug bleomycin [51b]. Epoxidation catalysts should meet several requirements in order to be suitable for this transformation [50]. Most importantly they must activate the oxidant without formation of radicals as this would lead to Fenton-type chemistry and catalyst decomposition. Instead, heterolytic cleavage of the 0—0 bond is desired. In some cases, alkene oxidation furnishes not only epoxides but also diols. The latter transformation will be the topic of the following section. 

Non-heme iron catalysts containing multidentate nitrogen ligands such as pyri-dines and amines have been studied by various groups [42a, 52-54], Jacobsen and coworkers presented an MMO mimic system for the epoxidation of aliphatic alkenes in which the catalyst self-assembles to form the active species [54] (Scheme 3.5). Interestingly, small amounts of an additive (one equivalent of acetic acid) increased the catalytic performance, presumably due to the intermediate formation of peroxya-cetic acid [55, 56]. The reactions proceeded quickly even with terminal aliphatic alkenes, which are generally considered difficult substrates. Another catalyst system available for the epoxidation of terminal alkenes uses phenanthroline as ligand [57]. 

Acetone is the important product of the mimic s monooxygenase activity. It is synthesized at high temperature, 220 °C or higher. The yield of acetone noticeably increases with contact time and temperature, reaching 15 wt.%. In this case, two ways of acetone formation (catalytic isomerization of epoxide and direct synthesis from C3H6) are also probable. 

The catalyst indicated extremely high resistance to the effects of oxidants and their intermediates and relatively high temperature, e.g. it preserves the ability to epoxidize during the whole time of the biomimic tests. Owing to the mentioned properties of the mimic, kinetic regularities of current monooxygenase reaction were studied in a broad range of reaction parameters with reproducible results. 

The mechanism of such mimics is discussed in detail in the literature [1], It is indicated that monooxygenase, including epoxidation, are conjugated with the catalase process. The mandatory parameter of chemical conjugation in such chemical systems is the determinant value, calculated by the following equation ... 

These iron porphyrin derivatives selectively catalyzed cyclohexane hydroxidation, where (FeTNMCPP)Cl displayed the higher stability. Cyclooctane epoxidation on the same mimic proceeded with multiple oxidant addition. 

In order to mimic an entire catalytic cycle, a second O was removed from the oxide overlayer (equivalent to performing a second epoxidation cycle) and O2 dissociation was examined on this doubly reduced oxide overlayer. The most favorable dissociation route identified, with a barrier of 0.40 eV, proceeds through the transition state labeled (d) in Fig. 9, and involves O2 initially adsorbed parallel to the surface. 

The existence of a cytosolic epoxide hydrolase was first indicated by its ability to hydrolyze analogs of insect juvenile hormone not readily hydrolyzed by microsomal epoxide hydrolase. Subsequent studies demonstrated a unique cytosolic enzyme catalytically and structurally distinct from the microsomal enzyme. It appears probable that the cytosolic enzyme is peroxisomal in origin. Both enzymes are broadly nonspecific and have many substrates in common. It is clear, however, that many substrates hydrolyzed well by cytosolic epoxide hydrolase are hydrolyzed poorly by microsomal epoxide hydrolase and vice versa. For example, l-(4 -ethylphenoxy)-3,7-dimethy I -6,7-epoxy-//7//i,v-2-octene, a substituted geranyl epoxide insect juvenile hormone mimic, is hydrolyzed 10 times more rapidly by the cytosolic enzyme than by the microsomal one. In any series, such as the substituted styrene oxides, the trans configuration is hydrolyzed more rapidly by the cytosolic epoxide hydrolase than is the cis isomer. At the same time, it should remembered that in this and other series,... 

The N-alkylation reaction represents a bifurcation of the normal alkene epoxidation reaction cycle and, therefore, N-alkylation is a suicide event that leads to catalytic inhibition in the native system. With synthetic tetraarylporphyrins that mimic the N-alkylation reaction, the use of halogen-substituted catalysts that are stable toward oxidative degradation (26, 27) provide the most useful model systems because the heme model remains intact for a significantly greater number of turnovers than the partition number. The partition number is the ratio of epoxidation cycles to N-alkylation cycles, i.e., N-alkyl porphyrins are formed before the heme is oxidatively destroyed. 

The additional key transformation in a nine-step synthesis of the Pancratistatin mimic involved silica gel-catalyzed opening of an epoxide and hydrolysis of an acetonide (Scheme 112) <2005JOC3490>. The yields of condensation products depend on reaction conditions that were used (1) silica gel surface at 70 °C (2) 0.1 equiv of InCh in CH2CI2 (3) InCh-doped silica at 70 °C (4) 10% aq InCh-treated silica at 70 °C (5) rt, TLC plate silica. 

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