Studies towards an enantioselective total synthesis of (+)-20-epi-ibophyllidine

• Main Author: Καζιάλες, Άννα
• Other Authors: Ρασσιάς, Γεράσιμος
• Format: Thesis
• Language: English
• Published: 2017
• Subjects: Natural products; Indole alkaloids; Φυσικά προϊόντα; Αλκαλοειδή ινδολίου; 581.63

Τhe objective of this project is the study of the enantioselective total synthesis of (+)-20-epi-ibophyllidine, a natural product that belongs to the Ibophyllidine family and the Pandoline group of indole alkaloids. Ibophyllidine alkaloids share the conserved pentacyclic framework of the Aspidosperma-type indole alkaloids and vary in stereochemistry and substitution at C20. A distinct architectural variation from the common Aspidosperma skeleton that is found among Ibophyllidines, is the pyrrolidine D-ring instead of the more commonly encountered piperidine D-ring. The few reported strategies towards Ibophyllidine natural products synthesis, are in the majority biomimetic, non-enantioselective and demand inversion of stereochemistry at one or more stereocenters. The aim of this work is the study of the enantioselective total synthesis of (+)-20-epi-ibophyllidine, based on a novel key-sequence. The proposed sequence may provide the desired structural complexity with high regio and stereochemical control, having three out of four stereocenters readily installed. The enantioselective total synthesis of (+)-20-epi-ibophyllidine may be completed, utilizing well-established chemical transformations in 18 steps longest linear sequence, whereas the scope of this strategy can potentially be extended to address various indole alkaloids. During the course of this project and based on the retrosynthetic analysis outlined in Scheme 3, we attempted the synthesis of the suitable precursor of the aforementioned key-sequence. The synthesis begins with the terpene myrcene and consists of cheletropic addition of sulfur dioxide to myrcene, selective oxidative cleavage of the olefinic bond, suitable asymmetric α-substitution of the desired carbonyl compound and one carbon chain extension. Finally, N-heterocyclization with a suitable dihalide and isomerization of the double bond of the resulting pyrroline may provide the desired synthetic intermediate. In fact, the proposed synthesis was successful up to the C-C bond formation step, that due to the high sensitivity towards basic reagents demands further research.