Studies Toward the Total Synthesis of Panduratin and Bicuculline Natural Products

Abstract

Please see file attached under "Table of Contents".

This thesis describes the total synthesis of racemic panduratin A (8), 4-hydroxypanduratin A (9), nicolaioidesin B (20) (isopanduratin A), 4-hydroxyisopanduratin A (36), panduratin H (17), panduratin I (18) and studies towards synthesis of bicuculline (166).

The synthesis of the panduratin family members was achieved after first performing a model synthesis to successfully develop the required synthetic methodology. This involved a Diels-Alder reaction between cinnamaldehyde (48) and butadiene (42) followed by the addition of an organolithium derived from a bromobenzene.

This developed methodology allowed the generation of many panduratin analogues as well as several panduratin family members. Some of the analogues were tested against the dengue fever serotype 2 (DEN-2) protease along with 4-hydroxypanduratin A (9).

In addition to the synthesis of the panduratin family members and analogues, a regioselectivity study of high pressure Diels-Alder reactions between various cinnamates and E-ocimene (31) was also conducted to elucidate the steric and electronic factors responsible for the regioselectivity.

Following this study modified dienes with strong directing groups were synthesised in an attempt to shift the product distribution towards Diels-Alder product where the prenyl group was ortho to the electron withdrawing group of the cinnamate.

With respect to the synthesis of bicuculline (166) two approaches were employed. The first approach involved synthesis of a biaryl Z-alkene that could then undergo an intra-molecular tethered aminohydroxylation to afford the core of bicuculline. Biaryl alkene (245) was successfully synthesised through a Sonogashira coupling and subsequent reduction of the alkyne. Studies towards the remaining transformations remain ongoing.

The second approach to bicuculline (166) used a Suzuki coupling between MIDA boronate 259 and aryl iodide 230. The trans-alkene 229 was then converted to the epoxide followed by deprotection of the amine to facilitate a ring closure resulting in a crude sample that has been postulated to be bicuculline (166). Investigations into alternative ring closure conditions and purification strategies are ongoing.