3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Enaminone-based approaches to the synthesis of alkaloids possessing the pyrrolo[1,2-a]azepine core(2018) Mthembu, Siyanda ThabaniThis thesis illustrate strides taken toward the construction of the pyrrolo[1,2-a]azepine 4 nucleus via enaminone chemistry developed in this University for creating pyrrolizidine 1, indolizidine 2 and quinolizidine 3 alkaloids. The pyrrolo[1,2-a]azepine 4 core is a fused pyrrolidine and azepine system found in lehmizidine, Stemona, Cephalotaxus alkaloids and other alkaloids. A concise background is given on the nature of enaminones, how they are accessed with strong emphasis on the Eschenmoser sulphide contraction reaction and their versatile reactivity, followed by literature review of this University background on synthesis of alkaloids containing 1, 2 and 3 nuclei. The aims and strategies presented are preceded by literature review of lehmizidine, Stemona, Cephalotaxus alkaloids and some reported synthesis. A range of attempts and successes are reported in chapter 2 for making four-carbon chain length enaminones (via N-alkylation, condensation, thionation, Eschenmoser sulphide contraction and tandem acylation/Michael addition reactions) crucial in creating azepane onto pyrrolidine in an acylation or alkylation ring closing steps yielding lehmizidine like compounds (E)-ethyl 8-oxo- 2,3,5,6,7,8-hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylate 144 and (E)-ethyl 2,3,5,6,7,8- hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylate 147. Vice versa, the synthesis of two carbon chain length N-alkyl vinylogous amides is demonstrated leading to the formation of pyrroles, ethyl 2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 222, ethyl 2-(4-nitrophenyl)- 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 223 and ethyl 2-(4-methoxyphenyl)- 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 224 in Knoevenagel condensation reactions similar to those described by Garreth Morgans and Stefania Scalzullo in their PhD theses. The synthesis of 1-benzoyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2,3-dione 233 and 1-(4-methoxybenzoyl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2,3-dione 235 in a double acylation reaction between NH vinylogous amides and oxalyl chloride is also demonstrated. In chapter 3, the synthesis of vinylogous urethanes for making the Cephalotaxus core via Nalkylation, condensation, thionation, Eschenmoser sulphide contraction and tandem acylation/Michael addition reactions are described. A variety of attempts of the arylation reaction on vinylogous urethanes are demonstrated leading to a comparison study to ascertain carbon chain length dependency of the step. The synthesis of pyrido[1,2-a]azonine nucleus of Sessilifoliamide alkaloids, which are a subset of the Stemona alkaloids demonstrated in chapter 4 is in line with our fascination with bigger ringed alkaloids. The synthetic route is presented leading the formation of compounds 1-benzoyl-3- methyl-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 337, 3-methyl-1-(4- nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 338 and 1-(4- methoxybenzoyl)-3-methyl-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 339.Item Enaminones in the synthesis of azabicyclic models for alkaloids(2008-10-06T13:36:45Z) Mthembu, Siyanda ThabaniThe purpose of this project was to investigate whether methodology developed in these laboratories for preparing 5/6 and 6/6 azabicyclic systems with bridged head nitrogen can be extended to 7/6, 8/6, 9/6 and 13/6 azabicyclic systems. The methodology entails the use of enaminones as central to the formation of the azabicyclic systems. The synthetic route adopted began with the Beckmann rearrangement reaction and/or the Schmidt reaction of cyclic ketones to make lactams, which were then thionated by Curphy or Brillon procedures. The Michael reaction of NH thiolactams with tert-butyl acrylate was followed by Eschenmoser sulfide contraction to afford the enaminones 132 which were utilised in the ring-closing step. This involved hydrolysis of the tert-butyl ester and cyclisation via a mixed anhydride. Ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 170b, 1-(4- nitrobenzoyl)-3,4,6,7,8,9-hexahydroquinolizin-2-one 172a, 1-benzoyl- 3,4,7,8,9,10-hexahydropyrido[1,2-a]azepin-2(6H)-one 173d, 1-(4-nitrobenzoyl)- 3,4,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-2-one 174a, and 1-(4- nitrobenzoyl)-3,4,7,8,9,10,11,12,13,14,17,16-dodecahydropyrido[1,2-a]azacyclotridecin- 2(6H)-one 176a were synthesised in good yields, but yields of 8-(4- nitrobenzoyl)-2,3,5,6-tetrahydroindolizin-7(1H)-one 171a and 1-(4-nitrobenzoyl)- 3,4,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-2(6H)-one 175a were not satisfactory. In a much shorter synthetic route that involves enaminone chemistry as well, NH vinylogous amides were synthesised by the Eschenmoser sulfide contraction and used in the aza-annulation reaction with acryloyl chloride. Structural isomers (to compounds mentioned above) 8-(4-nitrobenzoyl)-2,3,6,7-tetrahydroindolizin- 5(1H)-one 178a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin- 4(6H)-one 180a, 1-benzoyl-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-4(6H)-one 180b, 1-(4-nitrobenzoyl)-2,3,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-4-one 181a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)- one 182a and 1-(4-nitrobenzoyl)-2,6,7,8,9,10,11,12,13,14,15,16- dodecahydropyrido[1,2-a]azacyclo-tridecin-4(3H)-one 183a were synthesised in good yields. 1-(4-Nitrobenzoyl)-2,3,6,7,8,9-hexahydroquinolizin-4-one 179a was obtained in low yield, and apparently as two conformational isomers.