A general scaffold for the synthesis of cysiherbaine and its analogues

Abstract

Dysiherbaine 1 and a select number of structurally related compounds have been shown to have selective effects on ionotropic glutamate receptors (iGluRs). iGluRs are essential components in the central nervous system (CNS); playing an important role in memory and learning. They also play a role in a number of neurological disorders, including schizophrenia, epilepsy, Rasmussen¡¯s encephalitis and stroke; along with neurodegenerative disorders such as Alzheimer¡¯s, Parkinson¡¯s and Huntington¡¯s diseases. This dissertation describes the synthesis of key molecule 4 and future directions for its use. The molecule will serve as the branch point for the synthesis of other analogues. We designed a 12 step route to this molecule that utilizes highly stereo- and regioselective reactions. The molecule 4 will provide dysiherbaine and a series of analogues without having to design a new total synthesis for each analogue. While there are a number of syntheses of dysiherbaine reported, they are not appropriate for the easy variation of the important C8-amino C9-alcohol pharmacophore. The molecule 4 has a double bond between the C8 and C9 position as the key reactive functional group. The principal reactivity that will be used to synthesize derivatives of this molecule involves the double bond. Addition reactions of electrophilic reagents to the double bond are the most typical, and include hydroxylation, hydrogenation, halogenation, alkylation, amination, etc. This will be a unique and simple way to make dysiherbaine and analogues with just few steps from molecule 4. Finally, this work will provide unique molecules that will enhance the understanding of the structure and function of ionotropic Glu receptors in the CNS.