Studies On The Biomimetic Synthesis Of Manzamine Marine Alkaloids

The manzamine alkaloids are complex polycyclic marine natural products composed of more than 100 members that have been isolated from marine sponges and characterized by processing a diverse range of bioactivities including insecticidal, antibacterial and antimalarial. Recently, much attention has been attracted to these unique alkaloids because of their unprecedented polycyclic ring system and extraordinary bioactivities.Biosynthetic pathways of the manzamines have been proposed since their discovery including “acrolein” C3 species scenario by Baldwin in 1992 and “malondialdehyde” C3 species scenario by Marazanon in 1998. However, biomimetic synthesis studies based on those hypotheses were frustrated by the extremely low yield of the key step and tedious synthetic sequences. It was worthwhile to revisit this interesting biosynthetic question in a fresh view by design a strategic biomimetic approaches to the chemical synthesis of the manzamine alkaloids.This thesis aims at the studies of the total synthesis of Keramaphidin B, a member of the manzamines which is proposed as an important biosynthetic intermediate. Our strategic design is based on the use of Michael-Aldol-Mannich annulation cascade as the core step for the construction of the unique ring system. It consists of the following three parts:(1) An effective and convergent synthesis of the key C10 and C26 intermediates were accomplished by using the Wittig and Claisen condensation as key reactions;(2) To validate our hypothesis, a model reaction were successfully established to study the key tandem Aldol-Michael-Aldol reaction;(3) The feasibility of the key tandem Michael-Aldol-Mannich annulation was probed experimentally to provide chemical basis for the new biosynthetic hypothesis of the manzamines.