Synthese des Isochinocyclin Aglycons

Ziel war die Synthese des Isochinocyclin Aglykons. Zunächst wird ein pentacyclisches Lacton hergestellt, um daran die finalen Schritte zum Aufbau der Heterocyclen durchzuführen. Um das Lacton zu erreichen wurde ausgehend von Acrolein in 4 Stufen ein Dien hergestellt. Das dazugehörige Dienophil war...

Full description

Saved in:
Bibliographic Details
Main Author: Dischmann, Mike
Contributors: Koert, Ulrich (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

The objective was the synthesis of isoquinocycline aglycone. Key intermediate was the pentacyclic lactone which was established in several steps, followed by an introduction of the pyrrolo-pyrrol-heterocycle. Starting point for the synthesis was acrolein which was converted in 4 steps into a diene. The corresponding dienophile for a Diels-Alder reaction was available from a diol in 3 steps. The following Diels-Alder reaction and acid catalysed aldol-condensation gave a bicyclic enone. For the following Hauser-annulation it was necessary to synthesize a cyanolactone. Therefore m-anisic acid was converted into a furanone in 4 steps. The Hauser-annulation product was oxidized by exposure to air followed by a methylation of the phenolic hydroxyl-function to obtain a methoxyether. The primary silylether was cleaved and the resulting alcohol was oxidized with Dess-Martin reagent to an aldehyde, followed by oxidation with NaClO2 to obtain a carboxylic acid. The acid was converted into an epoxide via iodo-lactonization followed by transesterification with methanol. The epoxide was opened in acidic aqueous acetone to generate the desired pentacyclic lactone. It was reduced to tetramethoxyanthracene which was converted to reduced silylether. The attempt to create the desired pyrrolo-pyrrol substructure was the addition of an alkyne and sequently introducing nitrogen and finally closing the E-ring while the F-ring is already in place. Therefore a silylether was added to the lactone to obtain the addition product in a 1:1 mixture of hemi acetal and alkynone. Both epimers could be converted into an imidate by using [Ni(0)(CN)4]2-. The product was converted into ditosylate by first tosylating the imidato-nitrogen and then changing the TBS-ether into a tosylate. The ditosylate was treated with ammonia to generate an amidine. In this step the spiro-center equilibrates and from imidate, so two amidines were obtained. Isoquinocycline amidine was oxidized with CAN into its anthracycline form and was finally thermally closed in 2,6-lutidine to obtain the pyrrolo-pyrrol. The desired isoquinocycline aglycone was obtained by cleaving the TBS-ether with TBAF, the N-tosylate with HF in triethylamine and the methoxy-protection groups with BCl3. Based on the known pentacyclic lactone the isoquinocycline aglycone was synthesized in 13 linear steps with an overall yield of 2.12%. In combination with the presented optimized synthesis of lactone it was possible to synthesize the isoquinocycline aglycone in 29 linear steps in 0.68 % yield.