Total synthesis of Daphlongeranine B

• Applicant: Dr. Christopher Rose
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2012 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227522062

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 significant biological activity. Due to their extremely limited natural supply, however, their biological functions and pharmacological properties have been poorly studied until now. For this reason ¿ and, more importantly because of their fascinating, polycyclic skeletons - the Daphniphyllum alkaloids have recently been gaining growing interest as targets for total syntheses.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 wish to exploit this synthesis opportunity taking advantage of a series of powerful catalyst- and substrate controlled reactions and also cascade sequences, which will allow us to construct the target molecule in a seventeen-step route. Starting from simple starting materials, our proposed synthetic route 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.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Darren J. Dixon