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). / Science, Faculty of / Chemistry, Department of / Graduate

Ozonization of Ʒβ, 20β -diacetoxy-5-pregnene-7-one (XII) gave methyl Ʒβ ,20β -diacetoxy-5-oxo-5,7-seco-6-norpregnan-7-oate (XIII). Treatment of the latter with sodium hydroxide yielded methyl 20β -acetoxy-5-oxo-5,7-seco-6-nor-Ʒ-pregnen-7-oate (XIV), which upon reduction gave methyl 20β -acetoxy-5-oxo-5,7-seco-6-norpregnan-7-oate (XV) in high yield (see Figure 20). Upon treatment of the latter with benzylamine, ring closure occurred and the enol lactam, 20β -acetoxy-N-benzyl-6-aza-4-pregnen-7-one (XVI) was formed. Catalytic reduction of the double bond followed by reduction of the carbonyl with lithium aluminum hydride yielded 20β -hydroxy-N-benzyl-6-aza-5§ -pregnane (XVIII) . / Science, Faculty of / Chemistry, Department of / Graduate

A synthetic approach to members of the Veratrum alkaloids and its application in the synthesis of verarine is described. The condensation of optically active 3β-acetoxy-5α-etiojerv-12-en-17-one (76), a known compound available from the degradation of hecogenin acetate, with the lithium derivatives of various substituted 2-ethylpyridines is outlined as a general scheme for synthesising the carbon skeleton of members of the Veratrum alkaloids. Condensation with the lithium derivative of 2-ethyl-5-methylpyridine (105) followed by acetylation of the product gave a mixture of four isomers possessing the verarine skeleton (106). The two major isomers designated "A" and "B" were separately converted to the ring D aromatic compounds (107) by heating with palladised charcoal and the products shown to be isomeric. Selective hydrogenation of the pyridine moiety in either ring D aromatised compound (107) gave a mixture of four isomers which contained the piperidine ring (108). These compounds were separated and then converted to the N-acetyl derivatives (110) via the 3-0,N-diacetyl derivatives (109). Degradation of veratramine (2) by a known procedure gave 3-0,N-diacetylverarine (117). Hydrogenation of the 5,6-double bond employing Adams catalyst in acetic acid gave a 1:1 mixture of the 5α,6- and 5β,6-dihydro compounds which were separated as the N-acetyl derivatives (120, 121). The N-acetyl derivative of one of the eight isomers obtained from hydrogenation of the isomeric aromatic compounds (107) has been identified as N-acetyl-5α,6-dihydroverarine (120). The conversion of this compound to verarine (Ӡ) was carried out on a quantity of material obtained from veratramine. Oxidation with Jones reagent led to N-acetyl-3-keto-5α,6-dihydroveiarine (111) which was converted to N-acetyl-Δ⁴-3-keto-5,6-dihydroverarine (112). Treatment of this α,β-unsaturated ketone with isopropenyl acetate gave the enol acetate (113) which was converted to N-acetylverarine (114). Removal of N-acetyl group gave verarine (3) which was identified by comparison with an authentic sample. This completes in a formal sense the total synthesis of verarine since hecogenin has been totally synthesised. The total synthesis of racemic 3β-acetoxy-5α-etiojervan-17-one from 6-naphthol by other members of this laboratory is mentioned and its comparison with the natural (+) 3β-acetoxy-5α-etiojervan-17-one is noted. / Science, Faculty of / Chemistry, Department of / Graduate

In Part A of this thesis evidence is presented concerning the location and configuration of the bromine atom in each of the two isomeric monobromo derivatives (8a and 9a) of 5α,25R-spirostan (7, desoxytigogenin) and in each of the two isomeric monobromo derivatives (8b and 9b) of 3β-acetoxy-5α,25R-spirostan (tigogenin acetate) prepared by the action of bromine in acetic acid on the parent compounds. From a study of the mass spectra and nuclear magnetic resonance spectra obtained for the monobromotigogenins, it was established that the bromine atom was located at the C-23 site. In addition, the configuration of the bromine atom in each of the compounds studies was determined. In Part B of this thesis the syntheses of several derivatives of 4β-dihydrocleavamine (116) having a substituent at the C-18 site are described. The method employed an apparent SN₂’ displacement of chloride ion from the α-methyleneindoline form (118, R=H) of the chloroindolenine (113) of 4β-dihydrocleavamine. The chloroindolenine was prepared by the action of tertbutyl hypochlorite on 4β-dihydrocieavamine and was allowed to react with several nucleophiles under a variety of conditions. Using suitable conditions 18α-methoxy-4β-dihydrocleavamine (140), 18β-methoxy-43-dihydrocleavamine (141), 18β-hydroxy-4β-dihydrocleavamine (142), and 18β-cyano-4β-dihydrocleavamine (143) were prepared. The last compound was transformed into 18β-carbomethoxy-4β-dihydrocleavamine (139) by unexceptional means. This transformation provided a crucial link in the total syntheses of the Vinca alkaloid, coronaridine (45) and it C-4 epimer dihydrocatharanthine (46) In Part B of this thesis are also described the syntheses of dimeric compounds. The chloroindolenine of 4β-dihydrocleavamine was allowed to react with deacetylvindoline hydrazide (114) to give a dimer (115) . The coupling of the two units was shown to have taken place between the C-18 site of 4β-dihydrocleavamine and the C-15 site of deacetylvindoline hydrazide. The dimeric Vinca alkaloids isoleurosine A (110) and vincaleukoblastine (as the methiodide salt, 109) are coupled in the same manner. Isoleurosine A and vincaleukoblastine have in common a carbomethoxy group at the C-18 site of the dihydrocleavamine portion. The syntheses of two dimers (147 and 148) are described which also have this feature. The syntheses were accomplished in the manner of the previous coupling using the chloroindolenine (117, R=COOMe) of 18β-carbomethoxy-4β-dihydrocleavamine in place of the chloroindolenine of 4β-dihydrocleava;nine. In Part C of this thesis an effective method for preparing tritium and deuterium labelled indole alkaloids is described. Tritium labelled trifluoroacetic acid or trifluoroacetic acid-d was used. A combination of the methods of mass spectrometry and nuclear magnetic resonance spectroscopy was used to establish that the deuterium atoms were located primarily in the benzene portion of deuterium labelled 18α-carbomethoxy-4α-dihydrocleavamine (67) and 18β-carbomethoxycieavamine (73). Also in Part C of this thesis are described tracer experiments of a preliminary nature in Vinca rosea L. plants using [22-¹⁴ C]-18β-carbomethoxy-4β-dihydrocleavamine and [T-aromatic]-18β-carbomethoxycleavamine and tracer experiments in Vinca minor L. plants using [T-aromatic]-vincadine (74) and [T-aromatic]-vincaminoreine (75). / Science, Faculty of / Chemistry, Department of / Graduate

The total synthesis of trans-syn-cis-C-nor-2-methoxy-8, 11-dihydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11-undecahydro chrysene (87) is described. This compound has been synthesized from the C-nor-D-homo hydroxy aldehyde (67) via the olefin (71) by oxidative hydroboration. This sequence has the advantage of giving a much higher overall yield of (87). The conversion of the said compound (87), to the a-methyl ketone (74), a relay compound which has been used to synthesize verarine (76) is now nearing completion. Contrary to previous speculations⁸⁸, pyrolidene enamine methylation of model compounds (77,78) did not prove as fruitful as methylation of trapped enolates (figure 13). [diagram omitted] / Science, Faculty of / Chemistry, Department of / Graduate

A sequence leading to the total synthesis of trans-anti-trans- and trans-syn-cis-C-nor-2-methoxy-8,11-diketo-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11-undecahydrochrysene (LXXXI and LXXXII,respectively) from the known compound, 2-methoxy-8-keto-10a-methyl-5,6,8,9, 10,10a,11,12-octahydrochrysene (XLIII), is described. Oxidation of trans-anti-trans-2-methoxy-8β-acetoxy-10a-methyl-4b,5,6,6as7,8,9,10,10a,10b,11,12-dodecahydrochrysene (LXV) by means of t-butyl chromate led mainly to the 12-keto derivative (LXVIII). An olefinic bond at the 11,12 position (LXXI) was introduced by mild reduction of LXVIII with sodium borohydride followed by dehydration with phosphorus pentoxide. Subsequent reaction at the olefinic linkage by osmium tetroxide provided mainly the β-diol LXXII which upon treatment with periodic acid gave trans-anti-trans-11 ,12-seco-11,12-dioxo-2-methoxy-8β-acetoxy-10a-methyl-4b,5,6,6a,7,8,9, 10,10a,10b11,12-dodecahydrochry-sene (LXXIV). Intramolecular aldol condensation of IXXIV with sodium hydroxide gave the C-nor-D-homo diol aldehyde LXXIX. Oxidation of the latter with Jones reagent followed by deformylacion of the resulting diketo aldehyde IXXX provided the isomeric diketones LXXXI and LXXXII. It is felt that these latter substances show promise as useful intermediates for the total synthesis of Veratrum alkaloids. In another sequence designed as a model for the subsequent elaboration of LXXXI and LXXXII to the Veratrum alkaloid system, trans-anti-trans-anti-2-keto-8β-hydroxy-10a-methyl -2,3,4,4a, 4b, 5,6, 6a,7, 8,9,10,10a,10b,11,12-hexadecahydrochrysene (XCII) was methylated at C-1via the pyrrolidyl dienamine XCIII. A detailed discussion of the nuclear magnetic resonance spectra of the hydrochrysene compounds is also presented. / Science, Faculty of / Chemistry, Department of / Graduate

The initial work toward a synthetic entry into the hexacyclic cevane nucleus (7) is described, and the specific application of this work to the total synthesis of verticine (12) is discussed. Hecogenin acetate (74) was converted to C-nor-D-homo-(25 R)-5α-spirost-13(18)-en-3β-ol-3-acetate (79) via a known procedure, and hydroboration of the double bond gave the corresponding 13β-hydroxymethyl compound (80(a)). The mass spectral fragmentation of the spiroketal system is discussed. The stereochemistry at C-13 of the hydroborated compound (80(a)) was reversed by oxidation of the primary alcohol to the aldehyde, epimerization, and reduction. Acetylation gave the diacetate (85) which was used in investigation of the spiroketal side chain degradation. The Baeyer-Villiger oxidation sequence developed by W.F. Johns was used in the spiroketal degradation. 13α-Acetoxymethyl-17-acetyl-18-nor-5α-etiojerv-16(17)-en-3β-ol-3-acetate (110) was obtained with considerable difficulty in low yield from this sequence, A model compound, 17-acetyl-5α, 13β-etiojerv-16(17)-en-3β-ol (111), was employed to test the feasibility of attachment of a heterocyclic portion via a reaction developed by Schreiber and Adam. Reduction of the double bond and epimerization of the methyl ketone gave the ketone (120), which was then condensed with 2-lithio-5-methylpyridine. The structure of the condensation product was established by its n.m.r. and mass spectra. / Science, Faculty of / Chemistry, Department of / Graduate

A synthetic approach toward the synthesis of vindoline (3) and a reinvestigation of the total synthesis of vincaminoridine (4) and epivincaminoridine (4a) is described. The synthetic sequence involves alkylation with benzyl chloride of the monosodium salt of propane-l,3-diol to give y-benzyloxypropanol (197). Treatment of 197 with thionyl chloride afforded benzyl-y-chloropropyl ether (198). Alkylation of ethyl diethyl malonate with 198 provided diethyl Y~DenzyloxyProPyletnyl malonate (134). Basic hydrolysis of 134 gave y-benzyloxypropylethyl malonic acid (199), which upon decarboxylation provided 2-(y-benzyloxypropyl)-butanoic acid (200). The monoacid (200) was esterified with ethanol to provide ethyl tx-(y-benzyloxypropyl)-butanoate (135). Alkylation of 135 with allyl bromide gave ethyl-a-(y-benzyloxypropyl)-a-allyl-butanoate (201), which upon treatment with osmium tetroxide and sodium periodate gave ethyl a(y-benzyloxypropyl)-a-(a-formylmethyl)-butanoate (140). Condensation of 140 with 6-methoxy tryptamine afforded the tetracyclic lactam (150) . Lithium aluminum hydride reduction of the latter, followed by hydrogenolysis of the benzyl group gave two isomeric tetracyclic alcohols (204) . These intermediates were converted via their mesylate derivatives to the quaternary salts (205), which upon treatment with potassium cyanide gave the isomeric cyanides (216). Acid hydrolysis of 216 gave the corresponding carbomethoxy derivative (151). Alkylation of 151 with methyl iodide provided dl-vincaminoridine (4) and dl-epivincaminoridine (4a) . Transannular cyclization of the latter substances gave the pentacyclic aspidosperma-type system (195) . The degradation sequence involved acid hydrolysis of vindoline (3) to provide desacetyl vindoline (224), which upon catalytic hydrogenation gave desacetyldihydrovindoline (225) . Pyrolysis of 225 afforded the ketone (86), which upon treatment with dimethyl carbonate provided the g-ketoester (226) . Treatment of the sodium enolate of 226 with oxygen-hydrogen peroxide gave the hydroxy ketoester (227). Treatment of desacetyldihydrovindoline (225) with N,N-thiocarbonyldiimidazole gave the thiocarbonate derivative (230), which upon desulfurization with Raney nickel afforded the unsaturated ester (231) . Catalytic hydrogenation of 231 gave the saturated ester (232) , which upon treatment with lithium diisopropyl amide and oxygen-hydrogen peroxide provided the hydroxyester (234). The saturated ester 232 was converted to the alcohol derivative (237) by reduction with aluminum hydride. Oppenauer oxidation of 237 gave the aldehyde (238). Finally potassium permanganate oxidation of the unsaturated ester (231) gave 5-membered lactam (240), 6-membered lactam (241), N -formyl-5-membered lactam (242), ct and NQ-formyl-6-membered lactam (243) . / Science, Faculty of / Chemistry, Department of / Graduate

Part A of this thesis provides a resume1 of the synthesis of various radioactively labelled forms of secodine C76) and provides an evaluation of these compounds, as well as some radioactively labelled forms of tryptophan C25), as precursors in the Biosynthesis of apparicine (81), uleine C83), guatam-buine (90) , and olivacine (88) in Aspidosperma australe. Only apparicine (81) could be shown to incorporate these precursors to a significant extent. Degradation of apparicine (81) from Aspidosperma pyricollum provided evidence for the intact incorporation of the secodine system. Part B discusses the synthesis of 16-epi-stemmadenine (161), which provides an entry into the stemmadenine system with, radioactive labels at key positions in the molecule. The synthesis involved the degradation of strychnine (29) to Wieland-Gumlich aldehyde (130) by a previously established sequence of reactions. Initial conversion of Wieland-Gumlich aldehyde to nor^fluorocurarine (134) succeeded by a previously described route, although some study was necessary for determining the conditions by which the Oppenauer oxidation of 2B,16a-cur-19-en-17-ol (137) could selectively yield either 23,16a-cur-19-en-17-al (133) or nor-fluorocurarine (134). When nor-fluoro-curarine (134) could not be converted to the desired stemmadenine system, Wieland^GxunlictL aldehyde was converted to methyl 18-hydroxy^2&,16a-cur-19-en-17^oate (156) by a previously established procedure. Conversion of this compound to methyl 2 6/, 16a-cur-19- en-17-^oate 0.571 was accomplished by successive treatment with, hydrogen bromide and zinc in acetic acid. The ester 157 was converted to its- N Ca I *s£ o rmy-1 derivative 158 by reaction with methyl formate and sodium hydride. Treatment of this product with dry formaldehyde and sodium hydride in dimethyl sulfoxide led to the formation of the unexpected but nevertheless useful tetrahydrooxazine derivative 159. Hydrolysis of the tetrahydrooxazine moiety was accomplished with methanolic hydrogen chloride, resulting in the isolation of 2g,16g-carbo-methoxy-cur-19-en-17-ol (160) . Oxidation of compound 160 with lead tetraacetate followed immediately by treatment with sodium borohydride in methanolic acetic acid provided 16-epi-stemmaden-ine C161). Hydride reduction of the C-16 ester function in 161 and authentic stemmadenine (6a) led to the same diol 175 thereby providing the required interrelationship between the synthetic and natural compounds. This sequence also established the previously unknown configuration of stemmadenine (6a) about C-16 and provided an obvious pathway for the synthesis of stemmadenine via the saturated aldehyde 133. Also discussed in Part B is the lead tetraacetate oxidation of the ester 157 to akuammicine (66), representing the first total synthesis of that compound. Part C discusses the synthesis of 16-epi-stemmadenine (161) labelled with tritium in the aromatic ring. Simultaneous 3 administration of this material and stemmadenine-Car- H) (6a) to separate portions of A., pyricolluro root sections established that, while the latter was incorporated into apparicine (81), no incorporation could be detected in the. case of the former. / Science, Faculty of / Chemistry, Department of / Graduate

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. / Science, Faculty of / Chemistry, Department of / Graduate