Übergangsmetall-katalysierte Allylsubstitution fluorierter Olefine und Synthese von geschützten Dipeptidmimetika

Im Rahmen dieser Arbeit wurden Trifluoracetate mit unterschiedlichen funktionellen Gruppen hoch regio- und hoch stereoselektiv in die entsprechenden Allylnitrile überführt, welche in guter Ausbeute und guter Z/E-Selektivität erhalten werden konnten. Die Umsetzung von Trifluoracetaten mit aromatische...

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Bibliographic Details
Main Author: Middel, Christoph
Contributors: Koert, Ulrich (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2022
Online Access:PDF Full Text
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Table of Contents: As part of this work, a method for the preparation of 3-fluoroallylnitriles was developed. Trifluoroacetates with different functional groups are converted into the corresponding allylic nitriles in a highly regio- and stereoselective manner, which could be obtained in good yield and good Z/E-selectivity. The reaction of trifluoroacetates with aromatic substituents conjugated to the fluoroolefine or an allyl carbamate group with a free NH proved challenging. However, when a trifluoroacetate with a PMB-protected allylic carbamate function was used, the corresponding nitrile could be successfully prepared. A nitrile could be converted into a carboxylic acid by two further reaction steps, so that access to PMB- and Boc-protected peptidomimetics was developed (Scheme 83). The configuration of the stereocenter was determined by a parallel synthesis of a scalemic Cbz-protected amino alcohol. On the one hand starting from a nitrile and on the other hand starting from acryloyl chloride according to a literature-known procedure and subsequent comparison of the flow properties on the chiral HPLC. Furthermore, a possible synthetic route for dipeptidomimetics with a second stereocenter was investigated. However, racemisation took place and hydrofluorination of an ynone using known methods was not possible, so that a different synthesis strategy would have to be chosen. Unfortunately, deprotection of the diprotected carboxylic acid under standard conditions was not successful and due to time constraints, only a few indications for further investigations could be collected. A regioselective palladium-catalysed terminal allylic substitution of trifluoracetates with dimethyl methylmalonate was also developed, giving the corresponding diester after a short reaction time in very good yield and Z/E-selectivity. However, the use of other nucleophiles turned out to be difficult and the investigation of other terminal trifluoroacetates as possible starting materials is still pending. Furthermore, a method for iridium-catalysed allyl substitution for the reaction of internal trifluoroacetates with dimethylmalonate was developed, which gives the corresponding products in good yields with excellent Z/E-selectivity. Due to time constraints, only a limited variation of nucleophile and fluoroolefines was possible but the reaction was shown to be highly regio- and stereoselective. The experimental determination of the stereocenter and a possible diastereoselectivity when using asymmetrical nucleophiles are still pending.