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: Cartesian genetic programming for trading: a preliminary investigation

authors: Mayo, Michael

subjects: Cartesian Genetic Programming

abstract: In this paper, a preliminary investigation of Cartesian Genetic Programming (CGP) for algorithmic intraday trading is conducted. CGP is a recent new variant of genetic programming that differs from traditional approaches in a number of ways, including being able to evolve programs with limited size and with multiple outputs. CGP is used to evolve a predictor for intraday price movements, and trading strategies using the evolved predictors are evaluated along three dimensions (return, maximum drawdown and recovery factor) and against four different financial datasets (the Euro/US dollar exchange rate and the Dow Jones Industrial Average during periods from 2006 and 2010). We show that CGP is capable in many instances of evolving programs that, when used as trading strategies, lead to modest positive returns.

text: Cartesian genetic programming for trading: a preliminary investigation In this paper, a preliminary investigation of Cartesian Genetic Programming (CGP) for algorithmic intraday trading is conducted. CGP is a recent new variant of genetic programming that differs from traditional approaches in a number of ways, including being able to evolve programs with limited size and with multiple outputs. CGP is used to evolve a predictor for intraday price movements, and trading strategies using the evolved predictors are evaluated along three dimensions (return, maximum drawdown and recovery factor) and against four different financial datasets (the Euro/US dollar exchange rate and the Dow Jones Industrial Average during periods from 2006 and 2010). We show that CGP is capable in many instances of evolving programs that, when used as trading strategies, lead to modest positive returns.

year: 2012

title: Studies on the conservation of waterlogged wood in New Zealand

authors: Wallace, Roderick Thomas

abstract: This thesis is a study of properties of certain New Zealand woods recovered from waterlogged environments. The woods are those which were commonly used by the pre-european Maori to make artefacts, and the properties are those which affect the way these artefacts can be conserved after they have been removed from wet archaeological sites.
The properties studied were (a) the species of wood used (b) the forms and shapes of the timbers (c) the densities (d) directional shrinkages, and (e) directional penetrabilities of each wood. The results of this research are intended to aid conservators to correctly treat the artefacts. 
The research began with studies of (a) New Zealand wet site archaeology, (b) the structure and properties of wood in general, and (c) the techniques used to conserve waterlogged wood worldwide.
This was followed by a survey of circa. 1000 wooden Maori artefacts from Museums involving the identification, by thin section microscopy, of wood species. 30 wood types from 22 tree species were found to have been widely used. A collection was made of samples of each type in different states of decay. 
Each sample was tested for density, directional shrinkage and directional penetrability.
The penetrability was measured by vacuum impregnation of water into wood blocks. Results were compared to those from sound oak (Quercus robur), a wood which has been studied intensively by conservators in Europe. 
Detailed summaries of the conservation properties of 26 wood types are given. This reveals that while some New Zealand woods are easy to conserve others provide considerable problems. The latter woods are all highly durable in wet sites, extremely dense, have high shrinkages and are highly impenetrable. These will require special types of treatment to avoid damage during conservation.

text: Studies on the conservation of waterlogged wood in New Zealand This thesis is a study of properties of certain New Zealand woods recovered from waterlogged environments. The woods are those which were commonly used by the pre-european Maori to make artefacts, and the properties are those which affect the way these artefacts can be conserved after they have been removed from wet archaeological sites.
The properties studied were (a) the species of wood used (b) the forms and shapes of the timbers (c) the densities (d) directional shrinkages, and (e) directional penetrabilities of each wood. The results of this research are intended to aid conservators to correctly treat the artefacts. 
The research began with studies of (a) New Zealand wet site archaeology, (b) the structure and properties of wood in general, and (c) the techniques used to conserve waterlogged wood worldwide.
This was followed by a survey of circa. 1000 wooden Maori artefacts from Museums involving the identification, by thin section microscopy, of wood species. 30 wood types from 22 tree species were found to have been widely used. A collection was made of samples of each type in different states of decay. 
Each sample was tested for density, directional shrinkage and directional penetrability.
The penetrability was measured by vacuum impregnation of water into wood blocks. Results were compared to those from sound oak (Quercus robur), a wood which has been studied intensively by conservators in Europe. 
Detailed summaries of the conservation properties of 26 wood types are given. This reveals that while some New Zealand woods are easy to conserve others provide considerable problems. The latter woods are all highly durable in wet sites, extremely dense, have high shrinkages and are highly impenetrable. These will require special types of treatment to avoid damage during conservation.

year: 1985