UBC Theses and Dissertations

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UBC Theses and Dissertations

Studies related to the synthesis of bisindole alkaloids of the vinblastine-Vincristine family Balsevich, J. John


The work done towards this thesis is outlined in four sections. The first section involved evaluation of the 'chloro-indolenine coupling' of velbanamine derivatives with vindoline (10). Accordingly, 18S-carbomethoxycleavamine (19), chosen as starting material, was converted to 18S-carbomethoxy-3R-hydroxy-velbanamine chloroindolenine (55) in five steps. Attempted coupling of this derivative with vindoline in methanol containing hydrogen chloride was unsuccessful. Therefore, studies were undertaken to ascertain a reason for the lack of coupling. Consequently, internal quaternization of the tertiary nitrogen was established as a competitive side reaction. Based on these results the conditions of the coupling reaction were modified to eliminate this side reaction. Coupling of vindoline and 18S-carbomethoxy-3R-hydroxyvelbanamine chloroindolenine was thus attained, however, the only dimeric product obtained was 18'— eoivincadioline (74). The second section involved the study of the functional-ization of 3',4'-anhydrovinblastine (26) using aerial or ṯ-butyl hydroperoxide oxidation. Under the appropriate conditions the naturally occurring alkaloids leurosine (3) and Catharine (76) could be obtained. A study was carried out in regards to the mechanism of the oxidation with the result being implication of a radical mechanism. The third section involved the study of the reaction of 3',4'-anhydrovinblastine (and related derivatives) with potassium permanganate. From this reaction was obtained as the major product 3R-hydroxyvinamidine (83)—a derivative of the naturally occurring alkaloid vinamidine (82). Attempted deoxygenation of 3R-hydroxyvinamidine was unsuccessful. Therefore, vinamidine was prepared by potassium permanganate oxidation of 4'-deoxy-leurosidine (93). The fourth section relates to the preparation of vinblastine- vincristine analogs (for the purpose of elucidating structure-activity relationships). Thus, iodine/sodium bicarbonate oxidation of leurosine (3), vinblastine (1), and leurosidine (4) provided access to the corresponding 19'-oxo derivatives in fair to moderate yields. Oxidation of 19'-oxoleurosine (91) with Jones reagent at low temperature afforded 19',22-dioxoleurosine (98). Alternatively 19',22-oxoleurosine could be obtained from leurosine in better yield by first utilizing Jones oxidation to afford 22-oxoleurosine and then oxidation of this derivative with iodine/sodium bicarbonate. ṯ-Butyl hydroperoxide oxidation of 6,7-dihydro-3', 4'-anhydrovinblastine (100) afforded the novel analog 6,7-dihydroleurosine (101) , Jones oxidation of which yielded 22-oxo-6,7-dihydroleurosine ( 102).

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