Cyclopropenones and Cyclobutenediones in the Synthesis of Biologically Active Heterocycles

  • Bimod Thapa

Student thesis: Doctoral Thesis


Squaric acids and 1,2,4-oxadiazoles have interesting properties such as hydrogen bond acceptor and donor sites which are useful in drug design. Furthermore, they have also been shown to act as bioisosteres of different functional groups and therefore may be exploited as biologically active compounds. This thesis reports the synthesis of various squaramides and oxadiazoles to connect them and form an analogue of the marine cytotoxic compound Phidianidine B. Amino cyclopropenones also contain both hydrogen bond acceptor and donor sites which could be explored in drug design. The cycloaddition of cyclopropenones to cyclic imines generates pyrrolo-fused compounds. There is great literature interest in the pyrroloisoquinoline alkaloids such as the antitumour compound Crispine A and in the pyrrolizidinone bacterial natural products such as the Jenamidines. This thesis reports that pyrroloisoquinolines can be synthesised by reacting the dihydroisoquinolines with cyclopropenones and goes onto describe an approach to the pyrrolizidinones. To access these pyrrolizidinones, amino substituted cyclopropenones were required. These were synthesised using a modified literature method in three steps from tetrachlorocyclopropene. Attempted reaction of aminocyclopropenone (Ar = Ph, R3 = R4 = iPr), with cyclic imines under various conditions gave no reaction, but in ethanol resulted in the formation of the ring opened enamino ester (Ar = Ph, R3 = R4 = iPr, X = O, R’ = Et). Enamino esters are versatile building blocks for synthesis, and the core itself is present in a plethora of biologically active compounds. Thus, this reaction was further explored using different N-substituted cyclopropenones (R3 = R4 = iPr or, Bn, Ar = Ph, 2,4-dimethoxyphenyl or, 2,4-xylyl) and other alcohols (R’ = alkyl, aryl) and thiols giving a range of enamino esters and thioesters in moderate to excellent yields. The results of investigations into the reactions of cyclopropenones with 4-vinyl-1-azetines is also discussed. This process goes through a cascade of cycloaddition and aza-Cope rearrangement to give the azabicyclo[4.2.1]nonene core, which is present in some natural products. This thesis reports the optimisation of this reaction and the subsequent scope studies in moderate yields. Finally, nine different compounds synthesised in the duration of this project have been studied for their biological activity against human male colon cancer line HCT116. Overall, the compounds showed good biological activity against the HCT116 cell line and can be used as a good starting point towards a series of compounds to test against these cancer cell lines and perform SAR studies.
Date of Award9 Jun 2023
Original languageEnglish
SupervisorKarl Hemming (Main Supervisor) & Andrew Laws (Co-Supervisor)

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