Authors: Peters, Hartwig
Title: Neue metallorganische Synthesen von Heterocyclen und ihre Anwendung in der Naturstoffsynthese
Language (ISO): de
Abstract: This thesis is concerned with the first application of the aza-Heck reaction developed by Narasaka and coworkers in natural product synthesis. By means of this reaction the first formal total synthesis of butyl-orthocycloprodigiosin was achieved. Butyl-orthocycloprodigiosin is a member of a class of natural products with cytotoxic and distinct immunosuppressive properties. It has been know in the literature since 1975 but until the publication of this thesis no total synthesis has been presented. The ensuing synthesis of butyl-orthocycloprodigiosin commences with the multigram scale preparation of cyclononadienone. Although this compound has already been described in the literature no detailed method for it's synthesis has been reported. The synthetic sequence starts with ring enlargement of cyclooctanone by means of ethyldiazoacetate. Decarboxylation of the product formed gives cyclononanon which is protected as the ethyleneketal and dibrominated in both alpha-positions. Elimination of HBr and hydrolysis of the ketal affords cyclononadienone as the major building block. This compound is reduced with DIBAH and the symmetric cyclononadienol thus produced is acetylated yielding the cyclononadienyl acetate. The application of a palladium mediated pi-allyl-alkylation transforms the cyclononadienyl acetate in an unprecedented manner into the symmetric cyclononadienyl acetatoacetate. After decarboxylation the resulting cyclononadienyl acetone is transformed into the oxime and the oxime is acylated with pentafluorobenzoylacetate. The oximester thus synthesised is the substrate for the aza-Heck-reaction which is conducted with 10 mol % of a mixture of palladium acetate and tri-orthotolylphosphane in DMF and triethylamine as a mandatory base at 110 °C. The reaction product is a bicyclic dihydropyrrole which can be selectively isomerized to the core pyrrolophane of the natural product. This pyrrolophane is transformed, favoured by stereoelectronic effects, into the required pyrrolophane ketone by means of a hydroboration/oxidation procedure with diborane and the Dess-Martin-periodinane as the key reagents. The subsequent Wittig-reaction can be achieved by application of a butylphosphorane in boiling toluene. Hydrogenation with Crabtree's catalyst finishes the introduction of the butyl substituent. For the selective oxidation of the remaining methyl group on the pyrrolering a new method based on a CAN-oxidation was developed, which transformed the methyl group in one step and excellent yield into an aldehyde and thus completed the formal total synthesis of butylorthocycloprodigiosin. During model studies towards this synthesis a asymmetric version of the aza-Heck-reaction was discovered. Although the yields are low, the enantiomeric excess of the reaction is very promising.
Subject Headings: Pyrrolchemie
Immunsuppressiva der Naturstoffsynthese
Issue Date: 2003-06-13
Provenance: Universität Dortmund
Appears in Collections:Max-Planck-Institut für molekulare Physiologie

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