Studies in the fields of steroids and alkaloids
Creators: name: Cretney, Walter James
Publisher: name: University of British Columbia
Year: 2011

description: In Part A of this thesis evidence is presented concerning the location and configuration of the bromine atom in each of the two isomeric monobromo derivatives (8a and 9a) of 5α,25R-spirostan (7, desoxytigogenin) and in each of the two isomeric monobromo derivatives (8b and 9b) of 3β-acetoxy-5α,25R-spirostan (tigogenin acetate) prepared by the action of bromine in acetic acid on the parent compounds. From a study of the mass spectra and nuclear magnetic resonance spectra obtained for the monobromotigogenins, it was established that the bromine atom was located at the C-23 site. In addition, the configuration of the bromine atom in each of the compounds studies was determined. In Part B of this thesis the syntheses of several derivatives of 4β-dihydrocleavamine (116) having a substituent at the C-18 site are described. The method employed an apparent SN₂’ displacement of chloride ion from the α-methyleneindoline form (118, R=H) of the chloroindolenine (113) of 4β-dihydrocleavamine. The chloroindolenine was prepared by the action of tertbutyl hypochlorite on 4β-dihydrocieavamine and was allowed to react with several nucleophiles under a variety of conditions. Using suitable conditions 18α-methoxy-4β-dihydrocleavamine (140), 18β-methoxy-43-dihydrocleavamine (141), 18β-hydroxy-4β-dihydrocleavamine (142), and 18β-cyano-4β-dihydrocleavamine (143) were prepared. The last compound was transformed into 18β-carbomethoxy-4β-dihydrocleavamine (139) by unexceptional means. This transformation provided a crucial link in the total syntheses of the Vinca alkaloid, coronaridine (45) and it C-4 epimer dihydrocatharanthine (46) In Part B of this thesis are also described the syntheses of dimeric compounds. The chloroindolenine of 4β-dihydrocleavamine was allowed to react with deacetylvindoline hydrazide (114) to give a dimer (115) . The coupling of the two units was shown to have taken place between the C-18 site of 4β-dihydrocleavamine and the C-15 site of deacetylvindoline hydrazide. The dimeric Vinca alkaloids isoleurosine A (110) and vincaleukoblastine (as the methiodide salt, 109) are coupled in the same manner. Isoleurosine A and vincaleukoblastine have in common a carbomethoxy group at the C-18 site of the dihydrocleavamine portion. The syntheses of two dimers (147 and 148) are described which also have this feature. The syntheses were accomplished in the manner of the previous coupling using the chloroindolenine (117, R=COOMe) of 18β-carbomethoxy-4β-dihydrocleavamine in place of the chloroindolenine of 4β-dihydrocleava;nine. In Part C of this thesis an effective method for preparing tritium and deuterium labelled indole alkaloids is described. Tritium labelled trifluoroacetic acid or trifluoroacetic acid-d was used. A combination of the methods of mass spectrometry and nuclear magnetic resonance spectroscopy was used to establish that the deuterium atoms were located primarily in the benzene portion of deuterium labelled 18α-carbomethoxy-4α-dihydrocleavamine (67) and 18β-carbomethoxycieavamine (73). Also in Part C of this thesis are described tracer experiments of a preliminary nature in Vinca rosea L. plants using [22-¹⁴ C]-18β-carbomethoxy-4β-dihydrocleavamine and [T-aromatic]-18β-carbomethoxycleavamine and tracer experiments in Vinca minor L. plants using [T-aromatic]-vincadine (74) and [T-aromatic]-vincaminoreine (75).