The first part of this thesis describes a sequence which provides a total synthesis of cleavamine (23) and catharanthine (12). Dihydrocatharanthinol (76) obtained by lithium aluminum hydride reduction of dihydrocatharanthine (34) was converted to its tosylate derivative. The latter intermediate upon heating in benzene containing two equivalents of triethylamine underwent an interesting fragmentation reaction to provide a seco-diene (78) containing the cleavamine ring system. Reaction of this diene with osmium tetroxide provided a tetrol (96) which could be converted to cleavamine on the one hand and the C₄-functionalized cleavamine derivatives on the other. Thus treatment of the tetrol with sodium borohydride allowed the hydrogenolysis of the carbinol amine function and provided a triol (97). The vicinal diol present in 97 was cleaved by means of periodate and the resultant 2-acylindole chromophore was further converted by borohydride to a 4,18-dihydroxy dihydrocleavamine derivative (99). Reductive removal of the C₁₈ hydroxyl function by means of lithium aluminum hydride provided isovelbanamine (100). Acid catalyzed dehydration of the latter yielded cleavamine (23) while isomerization under aqueous acidic conditions provided velbanamine (22).
To complete the total synthesis of catharanthine (12), cleavamine was reacted with t-butyl hypochlorite and the resultant chloroindolenine was then subjected to nucleophilic attack by cyanide ion to provide 18ϐ-cyanocleavamine. Basic hydrolysis of the nitrile function followed by esterification provided 18ϐ-carbomethoxycleavamine (60). This compound upon reaction with mercuric acetate was cyclized to catharanthine.
The second part of this thesis establishes the utility of both the chloroindolenine and the C₁₈-hydroxy analogues of the cleavamine systems to the synthesis of dimeric compounds structurally similar to the natural dimeric alkaloids. Treatment of either of these analogues with vindoline under mild acidic conditions yielded the appropriate dimers containing the indole and dihydroindole units present in vincaleukoblastine.
The dimerization reaction was shown to be stereospecific and led in each case to the same stereochemistry at C₁₈, of the resulting dimers / Science, Faculty of / Chemistry, Department of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/34749 |
| Date | January 1970 |
| Creators | Bylsma, Feike |
| Publisher | University of British Columbia |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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