Total Synthesis of Daphlongeranine B
Date du début: 1 mars 2013,
Date de fin: 28 févr. 2015
"The Daphniphyllum alkaloids are a huge family of architecturally complex natural products found in evergreen trees and shrubs native to south-east Asia. To date, more than 200 members have been isolated and structurally characterised; some of them have been shown to possess interesting biological activity, such as cytotoxic- or antioxidative properties. However, not least due to their limited availability – both from natural sources and via chemical total syntheses – the biological functions and pharmacological properties of Daphniphyllum alkaloids have been only poorly studied until now. From an organic chemist`s point of view, members of the Daphniphyllum - family present highly attractive targets for synthetic approaches. Apart from their potential use as drugs or drug candidates, their fascinating, polycyclic skeletons present a vast playground to elaborate innovative synthetic strategies and tactics. Daphlongeranine B was isolated from the fruits of Daphniphyllum longeracemosum in 2007 and was shown to exhibit in vitro platelet aggregation. Its unprecedented hexacyclic core with seven stereogenic centres, three of which are fully substituted, presents a formidable and as yet unmet synthetic challenge. We are proposing the first total synthesis of Daphlongeranine B taking advantage of a series of partly unprecedented, powerful catalyst- and substrate controlled reactions and also cascade sequences. Their application will allow us to construct the target molecule in a nineteen-step route, starting from simple starting materials. Our proposed synthetic strategy features a novel tandem aminomethylation-alkynylation sequence, an unprecedented gold-catalysed 5-endo-dig hydroamination, a diastereoselective epoxidation followed by semipinacol rearrangement and a highly diastereoselective Michael-addition / Pd (0) catalysed vinylation cascade."
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