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.
