Towards the total synthesis of meridamycins

Abstract

This thesis aims towards establishing a route for the synthesis of meridamycins with special focus on 3-normeridamycin. Meridamycins are non-immunosuppressive pipecolic acid natural products that have shown neuroprotective activity. The first member of the family was isolated in 1994 but, up to this day, there is no total synthesis reported. The structure of meridamycin has been published in several instances but recent analysis of the biosynthetic gene cluster has called into question the absolute configuration of its fourteen stereocentres. The aim of this project is the total synthesis of meridamycin firstly, to confirm the configuration of the stereocentres in this natural product and through that validate the method used to predict those stereocentres based only on gene cluster analysis and, secondly to explore the neuroprotective activity of meridamycin and its derivatives. The southern fragment of 3-normeridamycin was synthesized in the longest linear sequence of 16 steps in 3.1% overall yield from commercially available starting materials. The synthesis features a highly convergent assembly of the central region containing four asymmetric centres by performing two subsequent stereoselective boron-mediated aldol reactions on either side of the ethyl methyl ketone. The remaining keto group is then reduced by using Evans-Tischenko’s method and the proline-containing amino acid fragment is installed using a diazoamide Roskamp reaction, which, to our knowledge, is the first use of this type of reaction in the natural product synthesis. The synthesis of southern fragment was then finished by installing the “tricarbonyl” moiety and closing the lactol ring. Previously, synthesis of the C1-C9 part of the northern fragment was achieved by Dominik Göppert MSc. This work further elaborated the synthesis until C14. The highlights of the sequence are three boron-mediated transformations – firstly alkylating the terminal alkyne using Zweifel olefination, then performing a directed boron insertion to the distal position of the homopropargylic alcohol and finally attaching the C10-C14 fragment by lithiationborylation methodology. Overall, the C1-C14 section of the northern fragment of meridamycin was prepared in a four-step sequence from C1-C9 fragment in 14.9% yield. In the course of the work, the synthesis of the sourthern fragment of 3-normeridamycin was achieved and a significant progress was made towards completing the northern fragment.