Synthesis of [5:5] pyrazolidinone and [5:7] oxazepanone γ-Lactam ring systems / Fatin Nur Ain Abdul Rashid

Abdul Rashid, Fatin Nur Ain (2020) Synthesis of [5:5] pyrazolidinone and [5:7] oxazepanone γ-Lactam ring systems / Fatin Nur Ain Abdul Rashid. PhD thesis, Universiti Teknologi MARA.

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Abstract

γ-Lactam is an important structural motif that features in a variety of bioactive natural products and drugs. Due to the high synthetic value, considerable efforts have been devoted to develop various synthetic strategies to diversify the structural molecule, especially towards bicyclic γ-lactam. In this study, the synthetic strategy of bicyclic moiety of 3,4-fused [5:5] pyrazolidinone and [5:7] oxazepanone γ-lactam ring systems were successfully established. The synthetic strategy was divided into three main parts in which the first part concentrated on the construction of the key intermediates, γ-lactam or 2,3-dioxopyrrolidine ring moiety via multicomponent reaction (MCR‟s) of sodium diethyl oxalacetate salt, primary amine and aldehyde in refluxing ethanol. The approach successfully gave a series of 2,3-dioxo-4-carboxy-5-(substituted)pyrrolidines 100 in moderate yield. Later, this highly functionalized intermediate 100 was subjected to various chemical transformations that lead to the formation of new bicyclic γ-lactam and also other interesting heterocyclic compounds. The second part focused on the formation of 3,4-fused [5:5] pyrazolidinone γ-lactam bicyclic ring system. The key intermediate; 2,3-dioxopyrrolidine underwent nucleophilic addition reaction at C-3 position via insertion of hydrazine hydrate by refluxing in ethanol solvent. Subsequently, metal-catalyzed hydrogenation was performed using Pd/C as a catalyst to afford hydrazine γ-lactam 104 with cis-trans configuration as a major product. Eventually, intramolecular cyclization of hydrazine γ-lactam 104 in basic condition had furnished the desired [5:5] pyrazolidinone γ-lactam 109 in 3-18% overall yields. The final part of this study emphasized on the formation of 3,4-fused [5:7] oxazepanone γ-lactam bicyclic ring systems using the same approach as pyrazolidinone γ-lactam which included of nucleophilic addition, metal-catalyzed hydrogenation and intramolecular cyclization reaction. Nucleophilic addition of ethanolamine at C-3 position was performed using catalytic amount of acid in ethanolic solvent. Accordingly, metal-catalyzed hydrogenation was carried using Pearlman‟s catalyst followed by intramolecular cyclization to afford [5:7] oxazepanone γ-lactam 118 in 5-29% overall yields. In conclusion, not only 10 new bicyclic γ-lactam were successfully synthesized, but other interesting pyrrolidinone type compounds and various synthetic approaches were also been explored. The structures of all synthesized and intermediate compounds were confirmed using spectroscopic technique.

Metadata

Item Type: Thesis (PhD)
Creators:
Creators
Email
Abdul Rashid, Fatin Nur Ain
2015262372
Contributors:
Contribution
Name
Email / ID Num.
Thesis advisor
Mohammat, Mohd Fazli (Assoc. Prof. Dr.)
UNSPECIFIED
Subjects: T Technology > TP Chemical technology > Chemicals
Divisions: Universiti Teknologi MARA, Shah Alam > Faculty of Applied Sciences
Programme: Doctor of Philosophy
Item ID: 32507
Uncontrolled Keywords: Pyrazolidinone, Oxazepanone, γ-Lactam
URI: https://ir.uitm.edu.my/id/eprint/32507

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