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Studies related to the synthesis of bisindole alkaloids of the Indole-Indoline type

University of British Columbia

The first part of this thesis describes the synthesis of 3,4- functionalized cleavamine templates bearing a C₁₈- carbomethoxy group. Thus hydroboration of 18β-carbomethoxycleavamine (29) produced two epimeric alcohols; 18α- and 18β -carbomethoxydihydrocleavamin -3 -ol (56 and 57). These compounds could be interconverted by using boron trifluoride etherate in benzene. One of these compounds (56) could be oxidized to the corresponding C₃ ketone which is a key intermediate for future work. The second part describes the research in the area of the so-called dimerization reaction. The generality of a procedure which had been used before was tested. When the chloroindolenine of 4(3-dihydrocleavamine and 18-carbomethoxy-43-dihydrocleavamine were each treated with vindoline in 1.5% methanolic hydrogen chloride,good yields of dimeric products were obtained. These materials have been shown by X-ray to be epimeric at C₁₈, to the natural dimers vincristine (VCR) and vinblastine (VLB). When these conditions were applied to the chloro- indolenines of 18β -carbomethoxycleavamine arid the 18α - and 18β -carbomethoxy-cleavaminols (56 and 57),good yields of dimers did not result. A detailed study, which has illuminated the mechanism of this reaction, was thus undertaken. As a result of this study, an improved procedure for the dimerization of such sensitive cleavamine templates was discovered. The insight gained from this study has permitted changes in the reaction conditions which have resulted in the isolation of two dimeric products from a single dimerization reaction. Previously, only one dimer had resulted from such reactions stereoselectively. Several new and exciting other approaches to the coupling of the indole and dihydroindole portions have been explored. Some of these have uncovered novel and useful avenues for eventually achieving the synthesis of the natural dimers such as VLB, VCR leurosine and leurosidine.

Text

2010-01-27

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http://hdl.handle.net/2429/19195

Chemistry

University of British Columbia

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