Entwicklung einer hoch modularen Synthese für die neuen, gegen Influenza wirkenden Naturstoffe Wickerol A und B
Zusammenfassung der Projektergebnisse
In collaboration with the group of Robert Spitale (University of California, Irvine) acrylonitrile derived probes, which should show selective Michael addition with the inosine moiety in RNA and offer the capability of attaching a biotin tag via a click reaction, were developed and synthesized. Pending the results of the biochemical experiments, we will submit for publication soon. A model system for Wickerols A and B, lacking the carbinol moiety and the methyl group on the 6-membered carbon bridge, has been prepared over 12 steps in 8.8% yield. This suggests that a concise, reductive approach towards the Wickerols, utilizing a carbonyl-ene ring closure as key feature could be feasible. During investigations towards an asymmetric approach, a scalable three step sequence of a 4-methyl-4-siloxy-substituted cyclohexenone was established in good yield (46% over 3 steps) and high enantioselectivity (ee > 98%). As Michael additions of carbon nucleophiles take place with high diastereoselectivity (dr > 20:1), this sequence could provide a valuable building block in the synthesis of complex natural products. One major problem of the asymmetric approach was the diastereoselective 1,4-addition to a highly biased hydrindenone in order to generate the quaternary carbon stereocenter. After extensive optimization of the copper source, additives, and nucleophilic metal source both diastereomers could be accessed with good selectivity (dr = 93:7 or dr = 4:96) in almost quantitative quield. As those delicate findings are barely known to the community, a publication of these results is also considered. The substituted hydrindanone could be converted to the desired [6-5-6] ring fused ester using similar chemistry as on the model system. An unforeseen challenge is the α-methylation of this compound. As all methylation attempts on this ester or its derivatives failed, it was homologated to the corresponding acrylonitrile, followed by reduction to the enal. Investigations of conjugate additions of methyl nucleophiles or their surrogates are currently ongoing.
