title: Applications of σ-organomanganese compounds in the synthesis of potential antitumour agents

authors: Grigsby, Warren J.

abstract: Reported in this thesis are studies exploring the synthetic utility of tetra(carbonyl- κC)[3-methoxy-6-(2-phenyl-1-butanoyl- κO)-phenyl- κC]-manganese(I) 9 in organic synthesis, in particular, routes to both ortho-halogenated derivatives of Tamoxifen, a therapeutic drug for the treatment of hormone dependent breast cancer, and other potentially antiestrogenic compounds which may have therapeutic application.

Described are the syntheses of the ortho-halo-substituted Tamoxifen derivative Z-1-(2-bromo-4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1,2-diphenylbut-1-ene 26 and an analogue Z-1-(3-bromo-4-methoxyphenyl)-1,2-diphenylbut-1-ene 18.

The reaction of 9 with phenyl isocyanate gives E-6-methoxy-2-phenyl-3-(1-phenylpropylidene)-(3H)-isobenzopyrrolidinone 124 which is readily converted upon mild acid hydrolysis to the novel carboxylic acid and Tamoxifen analogue E-5-methoxy-2-(2-phenyl-1-phenylamino-1-butenyl)-benzoic acid 125.

The thermally-activated coupling of 9 in benzene with the alkynes PhC≡CPh, HC≡CPh, HC≡CSiMe₃, HC≡CCH₂CH₂OH, CH₃C≡C-nPr and MeO₂CC≡CCO₂Me was undertaken (equation above). An alkyne having a bulky substituent leads to formation of only one of two possible diastereoisomeric inden-1-ol products in benzene and petroleum spirit. In contrast, there is no such stereospecificity for the analogous coupling in the polar solvent acetonitrile. The Pd(II)-mediated coupling of PhC≡CPh with 9 gives moderate yields of the benzofulvenes E- and Z-5-methoxy-2,3-diphenyl-1-(1-phenylpropylidene)-indene 37 and 38 for which the crystal structures of both are reported.

Coupling of the alkenes H₂C=CHCOMe, H₂C=CHCO₂Me, CH₃CH=CHCO₂Me, H₂C=CHOCOMe, H₂C=CHPh and EtO₂CCH=CHCO₂Et with 9 was extensively investigated with or without promotion by Pd(II) or trimethylamine N-oxide (equation above), employing different solvents and reaction conditions. A development in this area results from the finding that when coupling is carried out in the presence of NiBr₂(PPh₃)₂ the yields and specificity of coupled products significantly increase.

In a separate study, titanium-mediated reductive dicarbonyl coupling of halo-substituted benzophenone derivatives with propiophenone gives ortho-brominated analogues of Tamoxifen. Titanium-mediated coupling also provides a route to the synthesis of Z-1-(2-N,N-dimethylaminoethyl)-4-(1,2-diphenylbut-1-enyl)pyridinium chloride 121, a novel Tamoxifen analogue. Some other Titanium-mediated coupling reactions of dicarbonyl compounds previously obtained by coupling of methyl propenoate and 3-buten-2-one with 9 are also studied as potential routes to substituted dihydronaphthalene and tetralone compounds.

Preliminary and tentative investigations are reported toward the synthesis of Tamandron analogues, a potential antitumour agent similar to Tamoxifen. Descibed is the synthesis of 9-hydroxy-6-methoxy-9a-methyl-9-(1-phenylpropyl)-1,2,3,4,4a,9,9a-heptahydro-1-fluorenone 128 a product derived from the coupling of 2-methyl-2- cyclohexenone with 9.

text: Applications of σ-organomanganese compounds in the synthesis of potential antitumour agents Reported in this thesis are studies exploring the synthetic utility of tetra(carbonyl- κC)[3-methoxy-6-(2-phenyl-1-butanoyl- κO)-phenyl- κC]-manganese(I) 9 in organic synthesis, in particular, routes to both ortho-halogenated derivatives of Tamoxifen, a therapeutic drug for the treatment of hormone dependent breast cancer, and other potentially antiestrogenic compounds which may have therapeutic application.

Described are the syntheses of the ortho-halo-substituted Tamoxifen derivative Z-1-(2-bromo-4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1,2-diphenylbut-1-ene 26 and an analogue Z-1-(3-bromo-4-methoxyphenyl)-1,2-diphenylbut-1-ene 18.

The reaction of 9 with phenyl isocyanate gives E-6-methoxy-2-phenyl-3-(1-phenylpropylidene)-(3H)-isobenzopyrrolidinone 124 which is readily converted upon mild acid hydrolysis to the novel carboxylic acid and Tamoxifen analogue E-5-methoxy-2-(2-phenyl-1-phenylamino-1-butenyl)-benzoic acid 125.

The thermally-activated coupling of 9 in benzene with the alkynes PhC≡CPh, HC≡CPh, HC≡CSiMe₃, HC≡CCH₂CH₂OH, CH₃C≡C-nPr and MeO₂CC≡CCO₂Me was undertaken (equation above). An alkyne having a bulky substituent leads to formation of only one of two possible diastereoisomeric inden-1-ol products in benzene and petroleum spirit. In contrast, there is no such stereospecificity for the analogous coupling in the polar solvent acetonitrile. The Pd(II)-mediated coupling of PhC≡CPh with 9 gives moderate yields of the benzofulvenes E- and Z-5-methoxy-2,3-diphenyl-1-(1-phenylpropylidene)-indene 37 and 38 for which the crystal structures of both are reported.

Coupling of the alkenes H₂C=CHCOMe, H₂C=CHCO₂Me, CH₃CH=CHCO₂Me, H₂C=CHOCOMe, H₂C=CHPh and EtO₂CCH=CHCO₂Et with 9 was extensively investigated with or without promotion by Pd(II) or trimethylamine N-oxide (equation above), employing different solvents and reaction conditions. A development in this area results from the finding that when coupling is carried out in the presence of NiBr₂(PPh₃)₂ the yields and specificity of coupled products significantly increase.

In a separate study, titanium-mediated reductive dicarbonyl coupling of halo-substituted benzophenone derivatives with propiophenone gives ortho-brominated analogues of Tamoxifen. Titanium-mediated coupling also provides a route to the synthesis of Z-1-(2-N,N-dimethylaminoethyl)-4-(1,2-diphenylbut-1-enyl)pyridinium chloride 121, a novel Tamoxifen analogue. Some other Titanium-mediated coupling reactions of dicarbonyl compounds previously obtained by coupling of methyl propenoate and 3-buten-2-one with 9 are also studied as potential routes to substituted dihydronaphthalene and tetralone compounds.

Preliminary and tentative investigations are reported toward the synthesis of Tamandron analogues, a potential antitumour agent similar to Tamoxifen. Descibed is the synthesis of 9-hydroxy-6-methoxy-9a-methyl-9-(1-phenylpropyl)-1,2,3,4,4a,9,9a-heptahydro-1-fluorenone 128 a product derived from the coupling of 2-methyl-2- cyclohexenone with 9.

year: 1993

title: Suboptimal Choice Behaviour across Different Reinforcement Probabilities

authors: Yang, Le

abstract: Six adult roosters’ choice behaviour was investigated across a series of five experimental conditions and a series of replication of the same five experimental conditions. Stagner and Zentall (2010) found that pigeons prefer to choose an alternative with highly reliable discriminative stimuli but with less food reward over an alternative with non-discriminative stimuli but with more food reward. The current research systematically changed the probability of reinforcement associated with the discriminative stimulus through a series of experimental conditions. Experimental sessions were completed with six adult roosters. The experimental procedure was based on Stagner and Zentall’s (2010) experiment in which the suboptimal alternative with discriminative stimuli was associated with 100% reinforcement on 20% of the trials, and non-reinforcement on 80% of the trials; the optimal alternative with non-discriminative stimuli was associated with both 50% reinforcement on all trials. This research modified the probabilities of reinforcement associated with the discriminative alternative. In the first experimental condition, the probability of getting access to reinforcement was the same (50%) for each discriminative stimulus, thus, what was seen for the first time was that both alternatives were associated with non-discriminative stimuli. To insure reliability, a replication of the conditions was done after the first five experimental conditions were completed. The results showed that four of the roosters had suboptimal choice behaviour in the first five experimental conditions; however, only two of them maintained such suboptimal behaviour in the replication conditions. This result does not support the idea that the suboptimal choice behaviour with strong discriminative stimuli is a robust effect.

text: Suboptimal Choice Behaviour across Different Reinforcement Probabilities Six adult roosters’ choice behaviour was investigated across a series of five experimental conditions and a series of replication of the same five experimental conditions. Stagner and Zentall (2010) found that pigeons prefer to choose an alternative with highly reliable discriminative stimuli but with less food reward over an alternative with non-discriminative stimuli but with more food reward. The current research systematically changed the probability of reinforcement associated with the discriminative stimulus through a series of experimental conditions. Experimental sessions were completed with six adult roosters. The experimental procedure was based on Stagner and Zentall’s (2010) experiment in which the suboptimal alternative with discriminative stimuli was associated with 100% reinforcement on 20% of the trials, and non-reinforcement on 80% of the trials; the optimal alternative with non-discriminative stimuli was associated with both 50% reinforcement on all trials. This research modified the probabilities of reinforcement associated with the discriminative alternative. In the first experimental condition, the probability of getting access to reinforcement was the same (50%) for each discriminative stimulus, thus, what was seen for the first time was that both alternatives were associated with non-discriminative stimuli. To insure reliability, a replication of the conditions was done after the first five experimental conditions were completed. The results showed that four of the roosters had suboptimal choice behaviour in the first five experimental conditions; however, only two of them maintained such suboptimal behaviour in the replication conditions. This result does not support the idea that the suboptimal choice behaviour with strong discriminative stimuli is a robust effect.

year: 2015

title: Ko Waikato-Maniapoto te iwi

authors: Ngaia, Te Ingo Karangaroa Terehia

subjects: Waikato Maniapoto

abstract: Nō te ūnga mai o Tainui waka, i Whangaparāoa, ka tīmata i reira te tautapa haere a Tainui waka i tōna rohe, i tāna tere i Te Ika-ā-Māui. Nāwai rā ka tau ki tōna tumu i roto o Kāwhia Moana, Kāwhia Kai, Kāwhia Tāngata, i te taha hauāuru o Te Ika-ā-Māui. I roto i ngā rautau i muri mai i te ūnga o Tainui waka me ngā tūpuna i tere mai i te waka, ka tīmata ngā tūpuna te mātoro haere i te whenua hou me te whakanoho i ngō rātou whānau. Ka tupu i koneki ngā hapū me ngā iwi i heke mai i ngā waka. I roto i ngā tātai whakapapa o Tainu waka, e mārama mai ana ngā kāwai heke ki ngā iwi o Waikato me Maniapoto hoki. Ka whai mana ngā rangatira o ngā iwi nei i ngō rātou kāinga me ngā pānga whenua i noho ai rātou.
I hua tuatahi ai te iwi o Waikato-Maniapoto i roto i ngā pakanga me ngā whakaipoipotanga mo ngā kāinga me ngā pānga whenua, kai, moana hoki. Nā ngā pūkenga wānanga, pakanga hoki, i whakawehe, i kotahi ai rānei ngā iwi.
I te taenga mai o te Pākehā ki te pēhi i ngā tikanga a te Māori, ka huri te aro o te Pākehā ki te whakahau me te whakawai i ngā rātou tauira hou ki runga i ngā iwi.
Ka whakaturengia ngā ingoa o ngā tikanga hou, nā te Kāwanatanga Pākehā hou nei i whakamana, ā, i whakaū ngēnei tikanga hou kia pēhia ngā tikanga taketake ake a te Māori. Ka huri a Waikato-Maniapoto iwi ki te aru i ngā tauira hou ki te whakawhanake i ngā uri whakatupu i roto i te ao hou. Hoi, i mau tonu i a Waikato-Maniapoto te wairua me ngā tikanga i heke iho ki ngōna uri.
Ka whakaūngia te wairua me ngā tikanga o ngā mātua tūpuna ki roto i te tauira hou o te Kīngitanga. Ka mahi ngātahi te Kīngitanga me te iwi o Waikato-Maniapoto ki te whakatinana i tōna kaupapa, arā, hei pupuru i te toto; hei pupuru i te whenua; ā, hei pupuru i te mana Māori motuhake. I roto i te Kīngitanga nga 
hanganga iwi hou i puta hei kōkiri i ngā rautaki whakawhanake i te iwi whānui i roto i te ao hou nei.
Huhua noa atu ngā uri o Waikato-Maniapoto i whai wāhi i runga i ngā tūranga whakawhanake i te iwi whānui mā te whakaū i te mana Māori motuhake i roto i te reo me ngā tikanga o Waikato-Maniapoto iwi me ngōna kaupapa. Ko te whakahua i ngā hononga iwi kia whai whanaungatanga, kia whai tūrangawaewae te whakatinanatanga o te whakapono ā-wairua nei ki ngā taonga tuku iho o Waikato-Maniapoto. Ka whai mana, ka tūturu te kīanga a Waikato-Maniapoto i roto i te whakamana a ngā uri i ngā kōrero whakapapa o te iwi o Waikato-Maniapoto me te whakamana i te kīanga nei i ngā reanga whakapapa.

text: Ko Waikato-Maniapoto te iwi Nō te ūnga mai o Tainui waka, i Whangaparāoa, ka tīmata i reira te tautapa haere a Tainui waka i tōna rohe, i tāna tere i Te Ika-ā-Māui. Nāwai rā ka tau ki tōna tumu i roto o Kāwhia Moana, Kāwhia Kai, Kāwhia Tāngata, i te taha hauāuru o Te Ika-ā-Māui. I roto i ngā rautau i muri mai i te ūnga o Tainui waka me ngā tūpuna i tere mai i te waka, ka tīmata ngā tūpuna te mātoro haere i te whenua hou me te whakanoho i ngō rātou whānau. Ka tupu i koneki ngā hapū me ngā iwi i heke mai i ngā waka. I roto i ngā tātai whakapapa o Tainu waka, e mārama mai ana ngā kāwai heke ki ngā iwi o Waikato me Maniapoto hoki. Ka whai mana ngā rangatira o ngā iwi nei i ngō rātou kāinga me ngā pānga whenua i noho ai rātou.
I hua tuatahi ai te iwi o Waikato-Maniapoto i roto i ngā pakanga me ngā whakaipoipotanga mo ngā kāinga me ngā pānga whenua, kai, moana hoki. Nā ngā pūkenga wānanga, pakanga hoki, i whakawehe, i kotahi ai rānei ngā iwi.
I te taenga mai o te Pākehā ki te pēhi i ngā tikanga a te Māori, ka huri te aro o te Pākehā ki te whakahau me te whakawai i ngā rātou tauira hou ki runga i ngā iwi.
Ka whakaturengia ngā ingoa o ngā tikanga hou, nā te Kāwanatanga Pākehā hou nei i whakamana, ā, i whakaū ngēnei tikanga hou kia pēhia ngā tikanga taketake ake a te Māori. Ka huri a Waikato-Maniapoto iwi ki te aru i ngā tauira hou ki te whakawhanake i ngā uri whakatupu i roto i te ao hou. Hoi, i mau tonu i a Waikato-Maniapoto te wairua me ngā tikanga i heke iho ki ngōna uri.
Ka whakaūngia te wairua me ngā tikanga o ngā mātua tūpuna ki roto i te tauira hou o te Kīngitanga. Ka mahi ngātahi te Kīngitanga me te iwi o Waikato-Maniapoto ki te whakatinana i tōna kaupapa, arā, hei pupuru i te toto; hei pupuru i te whenua; ā, hei pupuru i te mana Māori motuhake. I roto i te Kīngitanga nga 
hanganga iwi hou i puta hei kōkiri i ngā rautaki whakawhanake i te iwi whānui i roto i te ao hou nei.
Huhua noa atu ngā uri o Waikato-Maniapoto i whai wāhi i runga i ngā tūranga whakawhanake i te iwi whānui mā te whakaū i te mana Māori motuhake i roto i te reo me ngā tikanga o Waikato-Maniapoto iwi me ngōna kaupapa. Ko te whakahua i ngā hononga iwi kia whai whanaungatanga, kia whai tūrangawaewae te whakatinanatanga o te whakapono ā-wairua nei ki ngā taonga tuku iho o Waikato-Maniapoto. Ka whai mana, ka tūturu te kīanga a Waikato-Maniapoto i roto i te whakamana a ngā uri i ngā kōrero whakapapa o te iwi o Waikato-Maniapoto me te whakamana i te kīanga nei i ngā reanga whakapapa.

year: 2010