Applications of σ-organomanganese compounds in the synthesis of potential antitumour agents
Permanent link to Research Commons versionhttps://hdl.handle.net/10289/15641
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.
The University of Waikato
All items in Research Commons are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
Missing page 180
- Higher Degree Theses