Chemical studies towards the total synthesis of pachydermin and bioactive metabolites derived from Chamonixia pachydermis / Noor Hidayah Pungot

Pachydermin 1, an oxylated tetramic acid with 3-chloro-4-hydroxyphenyl substituent, was isolated from the New Zealand basidiomycete Chamonixia pachydermis and was chosen as an attractive target for synthesis. Its degradation product was found to exhibit mild antibacterial activity against Bacillus subtilis, thus its derivatives are anticipated to have similar biological potentials. In this study, the main synthetic strategy was divided into three parts. The first part was to develop the synthesis of pachydermin utilizing N-benzylated β,β-diketoester 11 as the key structural moiety. The β,β-diketoester 11 was initially synthesized via nucleophilic substitution of ethyl iodoacetate with benzylamine to yield a benzylated glycine ethyl ester which accordingly, underwent condensation with methyl malonyl chloride followed by Dieckmann cyclisation to give the desired β,β-diketoester 11 with an overall yield of 71%. In the second part, insertion of an oxalyl subunit using ethyl chlorooxoacetate as well as other acyl or alkyl subunits at the C-3 position of the pyrrolidinedione ring via acylation or alkylation reactions furnished the required intermediates of pachydermin and its derivatives. Alkene functionalities at the C-5 position were subsequently introduced using different alkyl or aryl aldehydes with different non-nucleophilic bases which include diisopropylamine and lithium bis(trimethylsilyl)amide (LHMDS) in anhydrous tetrahydrofuran. Selective demethoxycarbonylation using lithium iodide in DMF was also performed on a precursor of pachydermin, 139, to successfully give a mixture of decarboxylated product 143 which is an essential intermediate of pachydermin and 144, in 30% yield. Unlike 143, product 144 has an additional methyl substituent at the C-3 position of the ring moiety. Nevertheless, synthesis of 143 was achieved in six steps with an overall yield of 2%.