In memoriam Andre S. Dreiding.

In his talk at the 49th Burgenstock Conference on Stereochemistry, the author paid tribute to Andre S. Dreiding, the founder of this event.

Asymmetric synthesis and biological activity of nor-α-tocopherol, a new vitamin E analogue.

The vitamin E analogues (2R,4'R,8'R)-nor-α-tocopherol (94 % de) and (2RS,4'R,8'R)-nor-α-tocopherol have been synthesized from (all R)-hexahydrofarnesol and phytol, respectively. According to in vitro experiments with murine macrophages nor-α-tocopherol is an anti-inflammatory compound more potent than α-tocopherol.

Recent biomimetic and organocatalytic syntheses of alpha-tocopherol.

We report here on our efforts to develop new strategies for the synthesis of alpha-tocopherol, the biologically most significant member of the vitamin E family. This review comprises five new methods to generate the chiral chromane of alpha-tocopherol with overall up to 29% yield from commercially available material and up to 94% de.

Bioorganic and bioinorganic chemistry.

The interdisciplinary projects in bioinorganic and bioorganic chemistry of the Department of Chemistry, University of Basel led to the preparation of new systems that mimic biologically important processes and to the discovery of compounds from natural sources which are very promising with respect to medical applications. The advances in these areas are reported here.

Synthesis and catalysis.

Research projects of the Department of Chemistry, University of Basel are reviewed ranging from the synthesis of complex natural products to the development of metalorganic catalysts and organocatalysts.

Asymmetric synthesis of alpha-tocopherol.

Alpha-tocopherol was synthesized from a chiral intermediate alpha-hydroxy ester by means of two ring-closing methods to yield the chromanol in 94% diastereomeric excess.

Synthesis and in vitro activity of heterocyclic inhibitors of CYP2A6 and CYP2A13, two cytochrome P450 enzymes present in the respiratory tract.

The synthesis of several heterocyclic compounds (1- or 2-substituted 1H-imidazoles and 2-substituted oxazoles, oxazolines and pyrazines) has been achieved. These compounds were tested as inhibitors of CYP2A6 and CYP2A13--two cytochrome P450 enzymes present in the respiratory tract--with a view to preventing the formation of carcinogenic metabolites of nicotine and inhibiting the metabolism of fragrances. 1-Substituted imidazoles bearing short alkyl chains displayed IC(50) values of around 2 microM for both enzymes, together with high vapour pressures.

Mechanistic insight into formation of oxo-iron(IV) porphyrin pi-cation radicals from enzyme mimics of cytochrome P450 in organic solvents.

Two new models for cytochrome P450 in which the thiolate axial ligand is replaced by a RSO(3)(-) group, form oxo-iron(IV) porphyrin pi-cation radicals as sole oxidation products in "peroxo shunt" reactions independent of the nature of the employed solvent (polar or non-polar) and electronic nature of the porphyrin rings. Although the properties of the solvent and push-pull effects from the porphyrin rings do not affect the mode of the O-O bond cleavage (heterolytic or homolytic) in these models, they strongly affect the rate and mechanism of each reaction step leading to the formation of the high-valent iron intermediates. This article reports the results of mechanistic studies involving the measurements of the rate of oxo-iron(IV) porphyrin pi-cation radical formation from the enzyme mimics of P450 for different oxidant concentration, temperature and pressure in selected organic solvents. Extraction of the appropriate rate constants and activation parameters for the reactions studied enable a detailed discussion of the effects of solvent and electronic nature of the porphyrin rings on the position of the first pre-equilibrium involving formation of the acylperoxo-iron(III) porphyrin intermediate, as well as on the rate of heterolytic O-O bond cleavage leading to the formation of the high-valent iron species. Furthermore, an unusual effect of solvent on the kinetics of oxo-iron(IV) porphyrin pi-cation radical formation in methanol is demonstrated and discussed in the present work.

Diastereoselective synthesis of alpha-tocopherol: a new concept for the formation of chromanols.

A diastereoselective synthesis of alpha-tocopherol 1 (93% de) was achieved via two key steps, (i) a highly diastereoselective Shi epoxidation of a trisubstituted alkene and (ii) an acid supported, "anti-Baldwin" epoxide ring opening under inversion of configuration leading to the 6-membered chromanol ring.

Low-temperature rapid-scan detection of reactive intermediates in epoxidation reactions catalyzed by a new enzyme mimic of cytochrome p450.

The use of synthetic iron(III) porphyrins as models for heme-type catalysts in biomimetic cytochrome P450 research has provided valuable information on the nature and reactivity of intermediates produced in the "peroxide shunt" pathway. This article reports spectroscopic detection of reactive intermediates formed in the epoxidation reaction of cis-stilbene with m-chloroperoxybenzoic acid catalyzed by a new mimic of cytochrome P450 with a substituted RSO3- group (1). The application of low-temperature rapid-scan stopped-flow techniques enabled the determination of equilibrium and rate constants for the formation and decay of all intermediates in the catalytic cycle of 1, including the rate constant for the formation (1*+)FeIV=O and for oxygen transfer to the substrate. Noteworthy, the reaction of (1*+)FeIV=O with cis-stilbene leads to an almost complete re-formation (95%) of the starting complex 1. The results show that complex 1 is a valuable catalyst with promising properties for further applications in a biomimetic approach toward mimicking oxygenation reactions of cytochrome P450.

Fluorescent probes for rapid screening of potential drug-drug interactions at the CYP3A4 level.

Steroid derivatives bearing fluorescent groups such as anthracene, dansyl, deazaflavin, and pyrene attached to C6 were synthesized. These compounds are unique inhibitors of cytochrome P450 3A4 (CYP3A4) and display similar IC(50) values in the microM range for the CYP3A4 substrates midazolam, testosterone, and nifedipine. On binding to CYP3A4, the fluorescence of the dansyl, deazaflavin, and pyrene probes is quenched by photophysical interaction of the fluorophore with the heme. The addition of drug candidates with binding constants in the nM-microM range causes displacement of the probes from the active site, and hence leads to restoration of fluorescence. Accordingly, relative affinities of drug candidates to CYP3A4 can be easily and accurately determined by fluorescence measurements.

Thermodynamic and kinetic studies on the binding of nitric oxide to a new enzyme mimic of cytochrome p450.

A new model for the P450 enzyme carrying a SO(3)(-) ligand coordinated to iron(III) (complex 2) reversibly binds NO to yield the nitrosyl adduct. The rate constant for NO binding to 2 in toluene is of the same order of magnitude as that found for the nitrosylation of the native, substrate-bound form of P450(cam) (E.S-P450(cam)). Large and negative activation entropy and activation volume values for the binding of NO to complex 2 support a mechanism that is dominated by bond formation with concomitant iron spin change from S = (5)/(2) to S = 0, as proposed for the reaction between NO and E.S-P450(cam). In contrast, the dissociation of NO from 2(NO) was found to be several orders of magnitude faster than the corresponding reaction for the E.S-P450(cam)/NO system. In a coordinating solvent such as methanol, the alcohol coordinates to iron(III) of 2 at the distal position, generating a six-coordinate, high-spin species 5. The reaction of NO with 5 in methanol was found to be much slower in comparison to the nitrosylation reaction of 2 in toluene. This behavior can be explained in terms of a mechanism in which methanol must be displaced during Fe-NO bond formation. The thermodynamic and kinetic data for NO binding to the new model complexes of P450 (2 and 5) are discussed in reference to earlier results obtained for closely related nitrosylation reactions of cytochrome P450(cam) (in the presence and in the absence of the substrate) and a thiolate-ligated iron(III) model complex.

A supramolecular fluorescence sensor for pyrovanadate as a functional model of vanadium haloperoxidase.

A novel basket-shaped tris(pyrene guanidinium) receptor was synthesized which binds pyrovanadate and pyrophosphate with Ka > 107 M-1. The binding of both anions is associated with quenching of the excimer fluorescence of the pyrenes. The supramolecular vanadate complex catalyzes the bromination of activated C-H bonds and hence is an enzyme mimic of vanadium haloperoxidases.

Reactivity of a new class of P450 enzyme models.

P450 enzyme models carrying a SO3(-) ligand coordinating to iron have been synthesized and characterized. These complexes show characteristics very similar to those of iron-heme cofactors of P450 enzymes. Their reactivity towards different reactions catalyzed by P450 enzymes such as epoxidation of double bonds, hydroxylation of non-activated C-H bonds, N-dealkylation of amines, and cleavage of diols (C-C-bond cleavage) has been investigated.

Metalloporphyrines as active site analogues--lessons from enzymes and enzyme models.

Research at the interface of enzyme chemistry and organic chemistry of metal complexes is particularly rewarding employing metal porphyrins as cofactor surrogates. Three examples are discussed: active site analogues of cytochrome P450 and chloroperoxidase (CPO), both heme-thiolate proteins, and enzyme models of beta-carotene monooxygenase, a non-heme iron protein. In all cases, catalytically active synthetic systems could be established displaying chemical reactivity close to the native proteins. Further, it is demonstrated that enzymatic reaction mechanisms can be elucidated by means of active site analogues (CPO) and information can be obtained from enzyme models that is useful to explain certain aspects of Nature's sophisticated approach to develop very efficient catalysts.

The first supramolecular orthovanadate receptor -- structural mimics of vanadium haloperoxidase.

Tris(2-guanidinium-ethyl)amine (1) was prepared as a supramolecular receptor of hydrogen orthovanadate (HVO(4)(2-)) to mimic the active site of vanadium haloperoxidase (V-HPO). Both (1)H and (51)V NMR titration indicated 1:1 complex (5) formation between (1) with HVO(4)(2-) with a binding constant of 1.1 x 10(3) M(-1). Similar as V-HPO, a UV band at 307 nm was observed upon binding of HVO(4)(2-) to (1). According to DFT calculations UV transitions >300 nm observed for both the enzyme and its mimic are due to V-N interactions.