Design and synthesis of novel biologically active flavones and isoflavones

The primary aim of this project was to develop different methodologies for the synthesis of novel 4-arylisoflavans and isoflavenes or analogues that structurally resemble isoflavonoids. In addition, the incorporation of fused-ring systems into the isoflavonoid scaffold to synthesize analogues of a bioactive natural product was also explored. The synthesized analogues were tested against cancer cells with results showing that a number of these compounds displayed promising anti-cancer effects. The construction of 4-arylisoflavan scaffold started with the preparation of phenyl propynyl ethers either by Williamson ether synthesis or Mitsunobu reaction, depending on the electronic nature of the propynyl aromatic systems which were introduced at the terminal alkyne via Sonogashira coupling. The intramolecular cyclization was carried out through an electrophilic borylative reaction followed by immediate esterification to furnish the benzopyran core with a boronic ester at 3-position. Subsequent Suzuki-Miyaura coupling reaction allowed for the attachment of various aromatic systems, giving access to 4-arylisoflavenes which were readily converted to cis 4-arylisoflavans by catalytic hydrogenation. The established methodology paved the way for flexible structural modification and possessed the advantage of preparing a large library of isoflavans in a short period of time. Attempts were also made to improve the bioactivities of 4-arylisoflavans by replacing the benzopyran core with 1,4-benzoxazine, which required the development of an alternative strategy. The synthesis of the benzoxazine ring was achieved by reduction of the nitro group and subsequent reductive amination of readily available precursors 2-(5-methoxy-2-nitrophenoxy)-1-arylethan-1-ones. An additional reduction step using NaCNBH3 was performed to increase amine conversion. The secondary amine present in the benzoxazine iv scaffold was substituted with either aromatic systems via Buchwald-Hartwig crosscoupling or different benzyl moieties. Subsequent functionalization such as amination and demethylation further expanded the substrate scope of 3,4-disubstituted benzoxazines. The synthesis of aza-analogues of 4-arylisoflavenes, or 3,4-disubstituted quinolines and their reduced analogues started with the construction of N-phenyl-2-propynylamines where the amine was protected with a tosyl group. Different aryl substituents were then introduced at the terminal alkyne through Sonogashira coupling reaction. Electrophilic iodocyclization furnished the quinoline scaffold for subsequent coupling at 3-position to afford the tosylated 3,4-diaryl-1,2-dihydroquinolines which were readily converted to desired 3,4-diarylquinolines by convenient deprotection. Furthermore, the catalytic reduction of the tosylated intermediates to generate the corresponding 1,2,3,4-tetrahydroquinolines was also explored.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2024

Author dc:creator

• Fu, Xiaoming

• natural product
• isoflavonoids
• anti-cancer
• organic synthesis
• fused-ring
• anzsrc-for: 3405 Organic chemistry

Statement dc:rights

• embargoed access
• CC BY 4.0

Licence

• http://purl.org/coar/access_right/c_f1cf
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/30458

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/102924