Chemical studies towards the synthesis of janolusimide, a marine neurotoxin from janolus cristatus / Nurulhuda Kamaruddin

Janolusimide 19 was chosen to be the synthetic target molecule due
to having a unique tripeptide structure besides showing a neurotoxin
activity. Our synthetic approach towards the synthesis of janolusimide
involved the construction of a core lactam system derived from
L-valine using EDC.HCl followed by dimethylation using four different
conditions. Dimethylation at C-3 position of 133 affords (5S)-3,3-
dimethyl-5-isopropylpyrrolidine-2,4-dione 26 in 72% yield using TBAF
as a phase transfer catalyst. In this dimethylation step, a characteristic of
ambident anion also can be observed. Multiple positions of alkylation had
occurred due to enolate’s ambident character of which C,O-alkylated and
O-alkylated side products were observed. While the effort to synthesize
the dipeptide chain was carried out using aldol reaction, N-alkylation of
26 and N-acylation of a template, 2-pyrrolidinone 139 and lactam 26 with
several electrophiles. Four general protocols (Method A-D) to N-acylate
2-pyrrolidinone and lactam 26 were examined..