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Studies in steroids and alkaloids

University of British Columbia

In part I of this thesis are described our studies in the area of aza steroids. These investigations involve chemical and spectroscopic studies of these compounds. Lithium aluminum hydride reduction of 3β-hydroxy-11-aza-5a, 22β-spirost-8(9)-en-12-one (72) provides the enamine, (73), which upon subsequent conversion to its iminium salt, (75), and borohydride reduction yields 11-aza-5a, 8ξ, 9a, 22β-spirostan-3β-o1 (76). This reaction furnishes a convenient sequence for reduction of the 8, 9-double bond in 11-aza steroid derivatives. Degradation of the sapogenin side chain then allows entry into 11-aza pregnane derivatives. The synthetic sequence provides the first examples of 11-aza steroid analogues in which ring C is six-membered and completely saturated. A detailed discussion of the mass spectra of 6- and 11-aza steroid derivatives is presented. In part II of this thesis is described our work which relates to a synthetic approach to the Iboga and Aspidosperma alkaloids. The first section involves the synthesis of 2-carbomethoxy-3-[a-hydroxy-β-(3-carbomethoxy-N-piperidyl)-ethyl]-indole (78) and 3-[β-(3-carbomethoxy-N-piper-dyl)-ethyl]-indole-2-acetic acid methyl ester (93). The Hoesch reaction was used for the synthesis of 2-carbomethoxy-3-chloroacetylindole (75) from 2-carbomethoxy-indole (74) and chloroaceto-nitrile. Treatment of 75 with 3-carbomethoxy piperidine (76) yielded 2-carbomethoxy ‒3 ‒ (3-carbomethoxy-N-piperidyl)-acetylindole (77). The latter compound was reduced with sodium borohydride or by catalytic hydrogenation with Raney nickel to 78. Prolonged hydrogenation of 77 or 78 with Raney nickel catalyst provided 2-carbomethoxy-3-[a-hydroxy-β-(3-carbomethoxy-N-piperidyl)-ethyl]-4, 5, 6, 7-tetrahydro-indole (79). Similarly 2-carbomethoxy-indole (74) was reduced to 2-carbomethoxy-4, 5, 6, 7-tetrahydro- indole (80) by hydrogenation with platinum oxide catalyst. The Hoesch reaction was also used for the synthesis of 3-chloro-acetylindole-2-acetic acid methyl ester (89) from indole-2-acetic acid methyl ester (88) and chloroacetonitrile. Treatment of 89 with 2-carbomethoxy piperidine (76) provided 3-(3-carbomethoxy-N-piperidyl)-acetyl-indole-2-acetic acid methyl ester (92). The latter substance was reduced with diborane to 93. The second section provides the synthesis of 1, 2 , 3, 5, 6, 11, 11b (ξ)-heptahydro-2ξ-(ɜ-chloropropyl)-2ξ-ethyl-3-oxo-indolo(2, 3-g)indolizine (118). The fundamental reaction involved condensation of tryptamine with either ethyl a-keto-ʏ-(ʏ-benzyloxypropyl)-ʏ-ethyl-glutarate (70b) or ethyl-a-(ʏ-benzyloxypropyl)-a-ethyl-syccinate (70a). When glutarate 70b was condensed with tryptamine the amides 110 and 111 were obtained. On the other hand, the succinate 70a reacted with tryptamine to afford the desired N-[β- (3-indolyl)-ethyl-a- (ʏ-benzyloxypropyl)-a-ethyl-succinimide (112). Treatment of the latter substance with boron tribromide yielded N-[β-(3-indolyl)-ethyl]-a-(3-hydroxypropyl)-a-ethyl-succinimide (115), which was subsequently converted to N-[β-(3-indolyl)-ethyl]-a-(3-chloropropyl)-a-ethyl-succinimide (116) with thionyl chloride. Cyclization of the latter substance with phosphorus pentoxide afforded 2, 3, 5, 6, 11-pentahydro-2ξ-(3-chloropropyl)-2ξ-ethyl-3-oxo-indolo(2, 3-g) indolizine (117), which on hydrogenation with platinum oxide yielded 118. The glutarate 70b and the succinate 70a involved in the above syntheses were obtained via a series of established reactions, starting from benzyl ʏ-chloropropyl ether (101).

Text

2011-09-27

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http://hdl.handle.net/2429/37644

Chemistry

University of British Columbia

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