Synthetic studies towards the total synthesis of Zopfiellamide A / Nor Saliyana Jumali

Jumali, Nor Saliyana (2016) Synthetic studies towards the total synthesis of Zopfiellamide A / Nor Saliyana Jumali. PhD thesis, Universiti Teknologi MARA.

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Abstract

In this study, Zopfiellamide A was chosen as a target molecule due to its unique structure and its pharmacological importance. The synthetic strategy moving towards the synthesis of Zopfiellamide A was divided accordingly based on the C-5 and C-3 substitution groups. The first approached was focused on the insertion of C-5 substituents of Zopfiellamide A which is the construction of the quaternary carbon bearing the hydroxyl, isopropyl and carboxylic acid linked via the methylene group at C-5 position of the pyrrolidinone ring. Therefore, the C-3 position of the pyrrolidinone ring was protected by a methyl group. Methyl acetoacetate was dialkylated, brominated and cyclised with methylamine to form the required lactam skeleton. The synthesis of C-5 substituents involved olefination, Michael addition, alkylation and mono-decarboxylation to give decarboxylated product 30, which is closest to the target molecule 12. There were two more steps left, which are Qf-hydroxylation and hydrolysis of ester. The overall yield of reaction was about 30%. Meanwhile, the Cacylation on C-3 was done by preparing the studied template of pyrrolidine-2,4-dione template 38, via condensation, dieckmann cyclisation and decarboxylation reaction. The C-acylation reaction was performed using readily available acid chlorides including crotonyl, benzoyl, napthoyl, cinnamoyl, and fiiroyl chloride respectively. The reaction was carried out using strong and weak base, however, the product yield was very low, ranging from 1 to 14% yield to a complex mixture. Meanwhile, the chemical exploration of the pyrrolidinone intermediates produced during the reaction was also done using epoxidation, acid-catalyzed ring-opening and stereoselective reduction. The epoxidation of alkene 17 with mCPBA managed to give epoxide 31, and treatment with diluted acid was successfully gave diols 32. The reduction of alkene 17 with sodium borohydride in the presence of CaCl₂ and MnCl₂ was resulted in chemoselective but not stereoselective reaction. However, reduction with sodium borohydride in the presence of MgCl₂ and ZnCl₂ was found to be a chemoselective and stereoselective reaction. The reduction of Michael adduct 19 was successfully resulted in keto reduction and gave compound 35.

Item Type: Thesis (PhD)
Creators:
CreatorsID Num.
Jumali, Nor SaliyanaUNSPECIFIED
Divisions: Faculty of Applied Sciences
Item ID: 17884
Uncontrolled Keywords: Synthetic; Total synthesis; Zopfiellamide A
Last Modified: 10 Oct 2017 09:24
Depositing User: Staf Pendigitalan 5
URI: http://ir.uitm.edu.my/id/eprint/17884

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