Enaminone-based approaches to the synthesis of alkaloids possessing the pyrrolo[1,2-a]azepine core
Date
2018
Authors
Mthembu, Siyanda Thabani
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Abstract
This 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.
Description
A thesis submitted to the Faculty of Science, University of the
Witwatersrand, Johannesburg.
In fulfilment of the requirements for the Degree of Doctor of Philosophy
February 2018.
Keywords
Citation
Mthembu, Siyanda Thabani (2018) Enaminone-based approaches to the synthesis of alkaloids possessing the pyrrolo[1,2-a]azepine core, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/26053>