Hans-Günther Schmalz

Paraoxonase-1 is a major determinant of clopidogrel efficacy

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

New Developments in the Pauson–Khand Reaction

Catalytic and asymmetric variations, enones, enynes, and allene as other starting materials, and numerous applications in natural product synthesis are all evidence of the diversity of the Pauson-Khand reaction [Eq. (a)], which now definitely counts among the standard tools of organic synthesis.

Acyloxybutadiene Iron Tricarbonyl Complexes as Enzyme‐Triggered CO‐Releasing Molecules (ET‐CORMs)

Molecular hazardous materials transport: Enzyme-triggered CO-releasing molecules (ET-CORMs) offer new options for the delivery of CO. The cleavage of dienylester iron tricarbonyl complexes by an esterase under mild oxidative conditions generates CO, which causes a strong inhibiting activity of the compounds to inducible nitric oxide synthase as shown in a cellular assay.

A Modular Approach to Structurally Diverse Bidentate Chelate Ligands for Transition Metal Catalysis

A modular approach to a new class of structurally diverse bidentate P/N, P/P, P/S, and P/Se chelate ligands has been developed. Starting from hydroquinone, various ligands were synthesized in a divergent manner via orthogonally bis-protected bromohydroquinones as the central building block. The first donor functionality (L1) is introduced to the aromatic (hydroquinone) ligand backbone either by Pd-catalyzed cross-coupling (Suzuki coupling) with hetero-aryl bromides, by Pd-catalyzed amination, or by lithiation and subsequent treatment with electrophiles (e.g., chlorophosphanes, disulfides, diselenides, or carbamoyl chlorides). After selective deprotection, the second ligand tooth (L2) is attached by reaction of the phenolic OH functionality with a chlorophosphane, a chlorophosphite, or a related reagent. Some of the resulting chelate ligands were converted into the respective PdX2 complexes (X = Cl, I), two of which were characterized by X-ray crystallography. The methodology developed opens an access to a broad variety of new chiral and achiral transition metal complexes and is generally suited for the solid-phase synthesis of combinatorial libraries, as will be reported separately.

A [2 + 2 + 2]-cycloaddition approach toward 6-oxa-allocolchicinoids with apoptosis-inducing activity.

Following an A --> ABC strategy, a new synthesis of 6-oxa-allocolchicinoids was developed exploiting a microwave-promoted Co- or Rh-catalyzed intramolecular [2 + 2 + 2]-cycloaddition (alkyne cyclotrimerization) as a key step. The approach opens a short and efficient access to a variety of novel compounds, some of which were found to exhibit significant and selective apoptosis-inducing activities against BJAB tumor cells.

On the enantioselective deprotonation/silylation of prochiral mono- and 1,2-dimethoxybenzene-Cr(CO)3 derivatives

Abstract The ortho-deprotonation / silylation of mono- and 1,2-dimethoxy-benzene-Cr(CO)3 derivatives (5–9) was investigated. The monosilylated products were obtained with high enantioselectivity (up to 96% ee) when the chiral lithium amide 4 was employed as base under in situ quench conditions. In contrast, the monosilylated benzodioxole-Cr(CO)3 complex 14 was formed with low (

Total Synthesis of the Marine Antibiotic Pestalone and its Surprisingly Facile Conversion into Pestalalactone and Pestalachloride A

In 2001, Fenical and co-workers reported the isolation and structure elucidation of pestalone (1), a chlorinated, highly functionalized benzophenone produced by a marine fungus of the genus Pestalotia in response to bacterial challenge. Besides a moderate in vitro cytotoxicity against various tumor cell lines (mean GI50 = 6.0 mm), pestalone (1) was reported to exhibit highly potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng mL ) and vancomycin-resistant Enterococcus faecium (MIC = 78 ng mL ). This prompted Fenical to emphasize that “the potency of this agent toward drug-resistant pathogens suggests that pestalone should be evaluated in more advanced, whole animal models of infectious disease.” Consequently, pestalone (1) is considered a particularly promising molecule with antibiotic properties. Recently, Che and co-workers identified a few strongly antifungal metabolites (e.g. 3 and 4) from the plant endophytic fungus Pestalotiopsis adusta which they named the pestalachlorides. These compounds are structurally closely related to 1 and, interestingly, were obtained as racemates indicating a non-enzymatic biosynthesis or a particularly facile mode of racemization. Owing to their obvious biological potential, their limited availability from natural sources, and their challenging chemical structures, pestalone (1) and its congeners are interesting target molecules for chemical synthesis. Our first study in 2003 resulted in the synthesis of deformylpestalone, and little later a total synthesis of 1 (and its demethylated derivative 2) was communicated by Nishiyama et al. Remarkably, no further biological studies have been reported since then. We describe herein a highly efficient and practicable synthesis of 1 which makes it possible for the first time to prepare substantial amounts of this natural product for further chemical and biological studies. Moreover, we report some surprising transformations (including the onestep transformation of 1 to rac-3) shedding light on the possible “biosynthetic” relationship of 1 with the pestalachlorides. The strategy behind our synthesis is summarized in Scheme 1. As a key consideration, we intended to assemble the benzophenone scaffold from a 2,6-dibromobenzaldehyde

MEMORY OF CHIRALITY IN ELECTRON TRANSFER MEDIATED BENZYLIC UMPOLUNG REACTIONS OF ARENE-CR(CO)3 COMPLEXES

As density functional calculations suggest, Cr(CO)3 -complexed benzylic radicals (such as 2) exhibit a significant degree of configurational stablility. This was exploited in an efficient method for the electron transfer mediated transformations of readily available 1-arylalkanol-Cr(CO)3 derivatives 1 to afford alkylated products 3 in good yields and with a high degree of stereochemical retention.

NEUE ENTWICKLUNGEN DER PAUSON-KHAND-REAKTION

Katalytische und asymmetische Varianten, Enone, Enine und Allene als weitere Edukte und zahlreiche Anwendungen in der Naturstoffsynthese belegen die Vielseitigkeit der Pauson-Khand-Reaktion [Gl. (a)], die inzwischen einen festen Platz in der organischen Synthese einnimmt.

Radical cyclization of η6-arene-Cr(CO)3 complexes: A regio- and stereoselective entry to functionalized pseudopterosin precursors

Abstract The chiral 6,7-dimethoxytetralin-Cr(CO) 3 derivative rac - 10 , containing both a ketone and an olefin sidechain, was prepared from rac - 4 through a sequence of two successive benzylic deprotonation/alkylation steps. On treatment with samarium(II)iodide, rac - 10 selectively cyclized to the mono-demethoxylated hydrophenalene-Cr(CO) 3 derivative rac - 11 , a highly functionalized precursor for the synthesis of antiinflammatory pseudopterosins. This result displays the synthetic power of intramolecular radical additions to arene-Cr(CO) 3 complexes followed by single electron transfer (SET).