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UBC Theses and Dissertations

The total syntheses of dregamine and epidregamine : a general route to 2-acylindole alkaloids Sung, Wing Lam


A general method for the total synthesis of 2-acylindole alkaloids is outlined and its application to the syntheses of dregamlne (34) and epidregamine (181) described. 2(S)-Amino-3(β-indolyl)-propan-l-ol (113), prepared from L-(-)-tryptophan (112) by lithium aluminum hydride reduction, was converted to its ditosylate (114). Reaction of the latter with potassium cyanide afforded 3(S)-tosylamino-4-(β-indolyl)-butanonitrile (115) which was transformed to 3(S)-amino-4(β-indolyl)-butanonitrile (116) by reductive cleavage. Formylation of (116) with methyl formate afforded 3(S)-(N-formylamino)-4-(β-indolyl)-butanonitrile (117). From this stage, a number of routes directed towards the synthesis of either a vobasine or sarpagine system were investigated. The only successful sequence involved initially a Bischler-Napieralski type reaction of (117) with polyphosphate ester (PPE) as the reagent whereupon the 3-dihydrocarboline derivative, 3(S)-cyanomethyl-3,4-dihydro-β-carboline (160) was obtained. The latter compound was then condensed with 3-methylenepentan-2-one (121) under acidic conditions to afford four isomeric 6(S)-cyanomethyl-3-ethyl-2-oxo-l,2,3,4,6,7,12,12b-octahydroindolo-(2,3-a)-quinolizines (159A-D). These isomers can be interconverted by acidic, basic or thermal methods, and therefore all of these compounds are useful for subsequent synthetic reactions. Base catalysed transannular cyclization of the 3(S), 12b(S)-isomer (159D) gave 16(R)- and 16(S)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxypericyclivine (164) and (165), the latter possessing the desired sarpagine skeleton. Both the nitriles (164) and (165) were utilized for the subsequent experiments. Reaction of (164) with cyanogen bromide provided the 3(R) and 3(S)-N-cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxyperivinols (173) and (174), while (165) under these conditions afforded the 3(S), 16(S)-diol (170). Manganese dioxide oxidation of both (173) and (174) afforded N-Cyano-16(R)-cyano-16-descarbomethoxy-19,20(S)-dihydro-15(R)-hydroxyperivine (175) and the latter was converted to N-cyano-16(S)-cyano-14,15-dehydro-16-descarbomethoxy-19,20(S)-dihydroperivine (172) by thionyl chloride dehydration and subsequent treatment with sodium hydroxide. The diol (170) in the other series was converted to the same ketone (172) through the same procedure. Sodium borohydride (pyridine) treatment of (172) accomplished the simultaneous reduction of the unsaturated carbonyl system and removal of the N-CN group to provide 16(S)-cyano-16-descarbomethoxy-19, 20(S)-dihydroperivinol (176) which was oxidised by manganese dioxide to give its corresponding ketone (177). Alkaline hydrolysis of the latter and subsequent esterification yielded 16-epi-19, 20(S)-dihydroperivine (179). The latter compound is identical with an authentic sample prepared from the alkaloid perivine (23) by hydrogenation and epimerization of the ester group. N-methylation of (179) by the Eschweiler-Clarke procedure and in turn, dregamine (34) after (181). provided 16-epidregamine (181) base-catalysed epimerization of (181).

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