Two synthetic approaches to the Aspidosperma and Iboga classes of indole alkaloids are described. Section A discusses a possible synthetic route to the nine-membered ring alkaloid quebrachamine (93a). Nicotinic acid (75) was reduced to nipecotic acid hydrochloride (76), which was esterified to yield methyl nipecotate (77). Attempted preparation of 3-carbomethoxy-3-ethylpiperidine (67) by alkylation of (77) or of its p-bromobenzamide derivative (78) was unsuccessful„ The substituted piperidine (67) was then prepared by another synthetic sequence. Alkylations of methyl cyanoacetate led to methyl 3-chloropropylethylcyanoacetate (83). Catalytic reduction of the latter nitrile to the corresponding amine allowed cyclization to 3-carbomethoxy-3-ethylpiperidine (67). Reaction of 67 with 2-carboethoxy-3-(β-chloroethyl)-indole (66) provided 2-carboethoxy-3-[β-(3-carbomethoxy-3-ethyl-N-piperidyl)-ethyl]-indole (68). Attempted acyloin condensation of the latter to a nine-membered ring compound (69) was unsuccessful and led only to hydrolysis products. Section B describes the first total synthesis of the nine-membered ring compounds 4α- and 4β- dihydrocleavamine (152) and (153), isomeric with quebrachamine. Conversion of 2-ethyl 1,3-propanediol (106) to the monobenzyl ether (107) followed treatment with thionyl chloride provided 3-benzyloxy-2-ethyl- propyl chloride (108). Alkylation of malonic ester with the latter afforded diethyl 3-benzyloxy-2-ethylpropylmalonate (109 ). A second alkylation of 109 with ethyl bromoacetate yielded diethyl 2-(2-benzyloxymethylbutyl)-2-carboethoxysuccinate (113 ). Hydrolysis, decarboxylation and re-esterification of this triester provided the substituted succinic ester (71a) in high yield. The succinic ester (71a) was also prepared but in low yield by hydrolysis, decarboxylation and re-esterification of the malonic ester (109) followed by alkylation with ethyl iodoacetate,, Condensation of the succinic ester (71a) with tryptamine provided the succinimide (130) which was reduced with lithium aluminum hydride to the tertiary amine (131) in high yield. Mercuric acetate oxidation of the latter afforded a mixture of isomeric cyclized compounds one of which was the desired benzyl ether 72a. Catalytic debenzylation yielded the corresponding aminoalcohol (149) which was converted to the quaternary mesylate (73a) by treatment with methanesulfonyl chloride. Reductive cleavage of 73a with sodium in liquid ammonia yielded 4α- and 4β- dihydrocleavamine. The synthesis of the isomeric dihydrocleavamines coupled with other synthetic work provides a general entry into the Aspidosperma and Iboga alkaloids. / Science, Faculty of / Chemistry, Department of / Graduate

In Part I of this thesis, an investigation of the reaction of the alkaloid, catharanthine (12), with zinc in glacial acetic acid is presented. Four isomeric carbomethoxydihydrocleavamines (60-63) have been isolated and fully characterized. It is also shown that heating catharanthine in a mixture of acetic acid and sodium borohydride provides a very convenient method for the preparation of the previously unknown 188-carbomethoxy-cleavamine (64). A similar investigation is presented for some related chemistry of the Aspidosperma series. Minovine (72), when heated in a mixture of acetic acid and sodium borohydride, is readily converted to vincaminoreine (71) and vincaminorine. The reversibility of the latter reaction is demonstrated by the transannular cyclization of vincaminoreine to afford minovine. In Part II, Section A, of this thesis, the synthesis of possible precursors of the Aspidosperma, Vinca, and Iboga alkaloids are described. The synthesis of the methyl cyanoacetate adduct (52) and dimethyl maIonic ester adduct (53) was accomplished without difficulty. The other synthetic precursor, 96, was prepared by treating the chloroindolenine, 94, of the tetracyclic indole, 93, with methyl cyanoacetate and triethylamine. In Part II, Section B, of this thesis are also described the biosynthetic studies in Vinca rosea L. and Vinca minor L. plants. The biogenetic importance of the transannular cyclization reaction is described by evaluating appropriate nine-membered ring alkaloids as possible precursors of the Aspidosperma, Vinca, and Iboga alkaloids. To confirm that the transannular cyclization reaction is not important in the plant, a sequential incorporation of DL-tryptophan-3- C into Vinca minor L. plants is presented. The synthetic precursors, 52, 53 and 96, were also evaluated for their biogenetic importance. / Science, Faculty of / Chemistry, Department of / Graduate

Novel transannualr cyclisation reactions of nine-membered ring compounds like quebrachamine, dihydrocleavamine and carbomethoxydihydrocleavamine, previously described in this laboratory, provide an attractive entry into the Aspidosperma, Vinca and Iboga alkaloids. In this thesis two approaches to the synthesis of the nine-membered ring alkaloid, quebrachamine, are described. The first section of this thesis discusses the synthesis of model compounds suitable for evaluating the acyloin condensation for the synthesis of this alkaloid. For this purpose, 3-carbomethoxypiperidine (98) was prepared by three different routes. In sequence (a), nicotinic acid (109) was methylated to give methyl nicotinate (110), which on catalytic hydrogenation yielded (98). In sequence (b), nicotinic acid was reduced in the presence of dilute aqueous ammonia and 5% rhodium on charcoal to provide nipecotic acid (111). Esterification with diazomethane provided the desired piperidine (98). In sequence (c), the desired material was prepared by an esterification reaction of nipecotic acid hydrochloride (111,a). The formation of the intermediate arylhydrazone (108,a) was accomplished via a Japp-Klingemann reaction from diethyl ૪-chloropropylmalonate (108) and benzene-diazonium chloride. The arylhdrazone (108,a) was then treated under the conditions of the Fischer indole synthesis to provide 2-carboethoxy-3-(β-chloroethyl)-indole (97,a). Transesterification with methanol provided 2-carbomethoxy-3-(β-chloroethyl)-indole (97,b). The piperidine derivative (98) was coupled with (97,a) and (97,b) to provide the coupling products (99,R=Et) and (99,R=Me). Attempted acyloin condensations of these latter compounds to provide the nine-membered ring compound (100) are described. The second section of this thesis describes a new total synthesis of (dl)-quebrachamine via a completely different sequence. Diethyl ૪-benzyloxypropylethylmalonate (144) was prepared by the condensation between diethyl ethylmalonate and 1-chloro-3-benzyloxypropane (143.). Alkaline hydrolysis of (144) provided ૪-benzyl-oxpropylethyl malonic acid (145), whichwas decarboxylated to give 2-(૪-berizyloxypropyl)-butarioic acid (146). Esterification of (146) provided ethyl 2-(૪-benzyloxy-propyl)-butanoate (147), which by subsequent alkylation with triphenylmethyl sodium and ethyl bromoacetate gave ethyls[formula omitted]-(૪-benzyloxyprqpyl)–[formula omitted]-ethylsuccinate (148). Condensation of (148) with tryptamine provided N-β[-(3-indolyl)-ethyl]-[formula omitted]-(૪-benzyloxypropyl)-[formula omitted]-ethylsuccinimide (123), which was reduced with lithium aluminum hydride to yield N-[β-(3-indolyl)-ethyl]-3-(૪-benzyloxy-propyl)-3-ethylpyrrolidine (124). Thy uncyclised benzyl etheramine (124) was treated with an excess of mercuric acetate to provide a crude product which was immediately reduced with sodium borohydride to give a mixture of the isomeric cyclic benzyl ether amines (125). Catalytic debenzylation provided three separable aminoalcohols (164) A, B and C. The relatively abundant aminoalcohol B was converted to the quaternary ammonium salt (126) by treatment with methanesulfonyl chloride in pyridine. Ring cleavage of (126) with sodium and liquid ammonia yielded (dl)-quebrachamine (1). / Science, Faculty of / Chemistry, Department of / Graduate

Thesis (M. Phil.)--University of Hong Kong, 1988.

Thesis (Ph.D)---University of Adelaide, Dept. of Organic Chemistry, 1962. / Typewritten.

Thesis (Ph. D.)--University of Hong Kong, 1992.

Thesis (Ph. D.)--University of Hong Kong, 1995. / Includes bibliographical references (leaf 251-258).

In part I of this thesis is described the structural determination of thamnosin, a minor component obtained from Thamnosma montana Torr. and Frem. Thamnosin, C₃₀H₂₈O₆, was shown by NMR and IR spectra to posess a coumarin chromophore and the mass spectrum suggested that this substance was cleaved under electron impact into two equal halves. Catalytic hydrogenation of thamnosin gave its dihydro-derivative and thereby indicated the presence of one easily reduced olefinic linkage. The UV spectrum of the latter suggested that two 6-alkyl-7-methoxycoumarin chromophores were present. The cleavage of thamnosin into lower molecular weight fragments was achieved by osmium tetroxide hydroxylation of the double bond followed by periodic acid oxidation of the resulting diol. The two aldehydic products (C₁₁H₈O₄ and C₁₉H₂₀O₄) which were obtained from this reaction were subsequently characterized. The smaller fragment was identified as 7-methoxycoumarin-6-aldehyde by direct comparison with an authentic sample. The other fragment, C₁₉H₂₀O₄ was initially shown by spectroscopic evidence, to possess a 6-substituted 7-methoxycoumarin system. The nature of the substituent at C-6 was subsequently identified as cyclohexene derivative bearing two methyl groups and a tertiary formyl functions. Summation of the above and other evidence allowed a structural assignment to thamnosin. It is seen that this substance represents a novel system which has not been previously obtained in nature. A detailed discussion of the mass spectra of thamnosin and its derivatives is presented. Part II describes a possible synthetic route to the vobasine- and sarpagine-type alkaloids. Three different approaches to the preparation of 5-dehydro salts and to ring closure of corynanthenoid bases via transannular cyclizations were attempted. Firstly, oxidation of sitsirikine (121) and dihydro-corynantheic acid ethyl ester (126) by mercuric acetate predominantly gave 3-dehydro salts (122) and (127), respectively, while the formation of 5-dehydro salts was not significant to form the bridge between C-16 and C-5 via transannular cyclization. Secondly, mercuric acetate, oxidations of 3-benzyl-derivatives of corynanthenoid bases followed by transannular cyclizations were attempted. Preparation of the isomeric 3ɤ- and 3β-benzylyohimbines was accomplished by the reaction of benzyl magnesium bromide with 3-dehydro-yohimbine perchlorate. The stereochemistry of these compounds was established by NMR and mass spectra. Accordingly, 3ɤ-benzyl-derivattves of dihydrocorynantheine, dihydrocorynantheic acid ethyl and methyl ester and the tetracyclic methyl ketone (157) were prepared. Oxidation of these derivatives by mercuric acetate proceeded but transannular cyclization was not successful. Thirdly, oxidation of 3,4-seco-corynantheinoid bases by mercuric acetate was attempted. Dihydrocorynantheal ethylene aectal methiodide (173) was treated with sodium in liquid ammonia to give 3,4-seco-N[subscript: b]-methyldihydro-corynantheal ethylene acetal (174), which could be oxidized by mercuric acetate to the dehydro salt. However subsequent hydrolysis of the ethylene acetal was not successful. / Science, Faculty of / Chemistry, Department of / Graduate

The Strychnos skeleton (e.g. preakuammicine, 56) has been postulated in the literature to rearrange to Aspidosperma (e.g. vindoline, 5) and Iboga (e.g. catharanthine, 6) bases via the intervention of Δ⁴‧²¹ -dehydrosecodine (76). Part A of the thesis describes the syntheses and biosynthetic evaluation of two close relatives, 16,17-dihydrosecodin-17-ol (90) and secodine (107), of the fugitive acrylic ester (76). In the synthetic sequence, condensation of 3-ethylpyridine with 2-carboethoxy-3-(3-chloroethyl)-indole (80) followed by the reduction of the resulting pyridinium chloride (82) gave N[β-{3-(2-hydroxymethylene)-indolyl}-ethyl]-3'-ethyl-3'-piperideine (84). The benzoate ester (85) of alcohol (84) was treated with potassium cyanide to afford N-[β-{3-(2-cyanomethylene)-indolyl}-ethyl]-3'-ethyl-3'-piperideine (86). This latter compound upon treatment with methanol and hydrogen chloride gas gave N- [β-{3- (2-carbomethoxymethylene)-indolyl}-ethyl]-3’-ethyl-3'-piperideine (88). Formylation of the ester (88) with methyl formate followed by reduction of the resulting enol (89) gave 16,17-dihydro-secodin -17-61 (90). Feeding of [¹⁴C00CH₃]-16,17-dihydrosecodin-17-ol (90) into Vinca minor L. revealed no significant activity into the isolated alkaloids. The substance in fact appeared to be a toxic component with marked deterioration of the plant occurring within 24 hours. In another investigation, synthetic 16,17-dihydrosecodin-17-ol (90) was dehydrated to secodine (107). Feeding of [ar- ³H]-secondine (107) into Vinca minor L. showed low but positive incorporation into vincamine (72) and minovine (73). "Blank" experiments revealed that after the maximum period required for the plant to absorb a solution of the labelled compound, 61% remained as monomer (107) while 32% had been converted to the dimers (presecamine and secamine). In conclusion this study while providing some preliminary information on the later stages of indole alkaloid biosynthesis has also created an entry into more sophisticated biosynthetic experiments. This situation will hopefully lead to a better understanding of the manner in which this large family of natural products is synthesized in the living plant. In Part B of the thesis some preliminary studies leading to the biosynthesis of vincamine (ebumamine family) are described. The intermediacy of a tetracyclic pyruvic ester (12) was invoked by Wenkert several years ago to rationalise the rearrangement of Aspido-sperma skeleton to vincamine (2) . To confirm this speculation a short synthesis of a close relative (i.e., 24) of the postulated precursor was contemplated. In the synthetic sequence reaction of tryptophyl bromide (18), produced by the action of phosphorus tribromide on tryptophol (17), with 3-acetylpyridine ethylene ketal (16) gave N-[β-(3-indolyl)-ethyl]-3'-acetylpyridinium ethylene ketal bromide (19). The pyridinium bromide (19) on catalytic reduction and acid hydrolysis furnished N-[β-(3-indolyl)-ethyl]-3'-acetylpiperidine (21). Alkylation of the ketone (21) using trityl sodium and allyl bromide gave N-[β-(3-indolyl)-ethyl]-3'-allyl-3'-acetylpiperidine (22). Osmylation of the allylic double bond in (22) did not give the desired diol (23). Tentative assignment is given in structure (34) to the polar compound obtained in this manner. / 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