Studies towards the total synthesis of Limnophilaspiroketone and the synthesis of alpha-modified enones of natural product derived model compound Limno-CP

摘要

Compounds with an alpha,beta-unsaturated carbonyl moiety and a phenol substituent are reported to exhibit anti-inflammatory and antioxidative activities. NF-kB and Nrf2 are important transcription factors of a complex signaling network, which mediate a multitude of different biological functions. However, they are also implicated in the pathogenesis of many inflammation-associated disorders and can therefore be addressed as molecular targets to alter or prevent undesired malignant events. Reactive cystein residues which are present in the transcription factors act as critical sensors for inducers and are involved in the fine-tuning of cellular homeostasis. Covalent modification or oxidation of the sulfhydryl groups by phenolic Michael acceptors results in an activation of anti-inflammatory Nrf2 and silencing of pro-inflammatory NF-kB respectively. The modulation of the function of the transcription factors can abrogate oxidative and electrophilic stress as well as inflammatory tissue injury.ududHerein, studies towards the total synthesis of the natural product limnophilaspiroketone, which belongs to the class of phenolic alpha,beta-unsaturated 3(2H)-furanones, are reported. Important key steps are an enantioselective epoxidation and diastereoselective cyanohydrin reaction which allowed for the formation of two quaternary stereocenters with the correct absolute configuration. A valuable and general strategy for the selective deprotection of a TMS acetylene in presence of a TMS ether was developed. udThe synthesis of spirocyclic Limno-CP, a simplified natural product derived model compound, was carried out successfully. Investigations on the formation of the spirocyclic framework revealed deeper insights in the mechanistic details of the cyclization reaction.udIn order to gain Michael acceptor specificity by fine tuning the reactivity of the alpha,beta-unsaturated carbonyl unit a library of 16 different, in alpha-position substituted compounds was synthesized from iPr-protected Limno-CP. NMR spectroscopic analysis was used to determine the electrophilicity of the alpha-carbon of the alpha,beta-unsaturated carbonyl subunit.udThe altered electronic properties of the enone entity could not be correlated to the observed reactivity towards nucleophiles. A 1,4-addition reaction with thiols or organocuprates was not observed. In contrast, with Limno-CP derivatives bearing chemically inert substituents alkyl lithium reagents effectively added in a 1,2-fashion to the carbonyl group, which lead to the corresponding alkylidene compounds.ud