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.

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.

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.

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.

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.

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.

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.

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)).

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.

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).

Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4).

Inhibition of CYP 3A4 catalytic activity is a principal mechanism for in vivo drug-drug interactions, sometimes leading to severe toxic effects. Rapid in vitro testing for CYP 3A4 high affinity/high inhibition potential has become part of the standard investigations for new drug candidates. Unfortunately, the complexity of the kinetics associated with CYP 3A4 catalyzed reactions (multiple substrates binding, non Michaelis-Menten kinetics) make these tests either inaccurate or tedious.

The origin of the low-spin character of the resting state of cytochrome P450cam investigated by means of active site analogues.

Crown-capped iron(S-) porphyrins 1 x H2O and 2 x H2O and their corresponding Ba2+ complexes have been prepared as active site analogues of the resting state of cytochrome P450cam. cw-EPR studies and electronic structure calculations at the density functional theory (DFT) level of model systems suggest a functional role of the water cluster of P450cam.

A supramolecular enzyme model catalyzing the central cleavage of carotenoids.

Several bis-beta-cyclodextrin porphyrins have been prepared as supramolecular receptors of carotenoids. The binding constants of carotenoids to receptors were determined by quenching the fluorescence of the porphyrins on hydrophobic binding of carotenoids within the cavities of cyclodextrins. K(a)=8.

The Reaction Mechanism of the Enzyme-Catalyzed Central Cleavage of β-Carotene to Retinal.

Seeing things as they really are: The enzyme catalyzing the central cleavage of β-carotene (1) to retinal (2) is not, as previously thought, a dioxygenase. Incubation of the substrate analogue α-carotene in the presence of highly enriched O and H O revealed a monooxygenase mechanism.