Repository logo

Studies towards the synthesis of perhydropyrrolo[2,1-j]quinoline and perhydropyrido[2,1-j]quinoline ascidian alkaloids.

Thumbnail Image



Journal Title

Journal ISSN

Volume Title



Cylindricines A-K [1-11], lepadifonnine [12] and fasicularin [13] are tricyclic ascidian alkaloids exhibiting the perhydropyrrolo[2,1 :j]quinoline and perhydropyrido[2,1-j]quinoline ring systems. The structural features and biological activity of these alkaloids make them ideal targets for total synthesis. The first aim of this project was to construct the azabicycles [111] and [112] that resemble the spirocyclic core of these alkaloids. The synthesis began with the C ring intact and the attempted construction of the B ring using Diels-Alder methodology. A key step was the Eschenmoser coupling reaction between thiolactams [105] and [106] to give the vinylogous amides [107] and [108]. All attempts to convert the vinylogous amides to the corresponding dienes proved to be unsuccessful, due to the fact that the preferred site for deprotonation was ~ to nitrogen and not a to the carbonyl group. Due to time constraints we moved to our second aim, the enantioselective synthesis of the B and C rings offasicularin [13]. Significant progress was made towards our second goal. (5S)-5-Hydroxytetrahydro2(lH)pyridinone [127], which represents the C ring of fasicularin, was successfully synthesized in 5 steps from L-glutamic acid [113]. This lactam was O-protected with tertbutyldiphenylsilyl group to afford (5S)-5-tert-butyldiphenylsilyloxy-2-piperidinone [114]. Thionation of lactam [114] gave the thiolactam [160]. Conjugate addition of this thiolactam to methyl acrylate gave methyl 3-[(5S)-5- {[tert-butyl(diphenyl)silyl]oxy}-2-thioxotetrahydro1(2H)-pyridinyl ]propanoate [163], which underwent a Eschenmoser coupling reaction with bromoacetone to gIve methyl 3-[(5S)-5-{ [tert-butyl(diphenyl)-silyl]oxy} 2-[(£)-2oxopropylidine] tetrahydro-2(1H)-pyridinyl]propanoate [164]. Unfortunately conversion of [164] into the corresponding diene using KHMDS and TBSCI was unsuccessful. The reaction conditions caused the cleavage of the methyl acrylate protecting group on nitrogen, affording the secondary E-vinylogous amide [167]. This constituted an important serendipitous discovery - methyl acrylate can be used to protect the nitrogen atom of enaminones and can be removed by KHMDS to access secondary E-enaminones that are otherwise difficult to synthesise. Another route pursued was to introduce the hexyl chain in the A ring of fasicularin by means of an SN2 reaction between lactam [114] and mesylate [116]. The stereodefined (lR)1-(2-{[tert-butyl-(dimethyl)sily]oxy}ethyl)heptyl methanesulfonate [116] was successfully x synthesized in 5 steps from l-octyne [115]. Unfortunately the subsequent SN2 reaction with lactam [114] failed when we using t-BuOK and THF and time constraints prevented us from attempting this coupling reaction using alternative conditions.


Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2002.


Theses--Chemistry., Alkaloids., Ascidiacea.