Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Ipecacuanha had been used for many years in medical practice before Rogers (1), in 1912, showed that emetine, one of the constituent alkaloids, was a specific agent against dysentery. This discovery, in relation to the toll which the diseases takes in tropical countries, intensified the efforts of chemists to deduce the structure of the alkaloid in the hope of synthesising it. This hope was not finally achieved until 1950. The final stages in selecting the correct structure for emetine were aided by a consideration fo the possible biogenetic route to the alkaloid in the light of current theories of the biogenesis of alkaloids. In consequences of this, a detailed examination of the alkaloidal material present in the root was undertaken in the hope of isolating some compound which might be a biogenetic intermediate. The results of that investigation are described in this thesis. At the same time the opportunity was taken to study the chemistry of the minor alkaloids. The work on the structural formula of emetine had shown the marked specificity of the alkaloid in the treatment of amoebic dysentery. There are four centres of asymmetry in the molecule and inversion of the configuration at the asymmetric centres had to be ascertained. In the latter part of the thesis the initial experiments in the elucidation of the stereochemistry of emetine are described. These results and the subsequent elucidation of the stereochemistry and the stereospecific synthesis of emetine and emetamine have been reported by Dr. Battersby and his associates in a series of papers in the Journal of the Society of Chemistry and Industrial and the Journal of the Chemical Society (80)(56)(57).

The occurrence and syntheses of the pyrrolizidine alkaloids from 1976 to March 1988 is reviewed, and a stereoselective total synthesis of swazinecic acid dilactone was attempted. One approach involved an asymmetric synthesis of the allylic α-hydroxy acid 2-hydroxy-2,3-dimethyl-3-butenoic acid employing oxazolines as chiral auxilaries. The oxazoline, (4S,5S)-2-(1-bromoethyl)-4-methoxymethyl-5-phenyl-2-oxazoline, was obtained by direct halogenation of the 2-ethyl oxazoline analogue. This was condensed with acetone in a Darzens type reaction and the resultant epoxy oxazoline rearranged to an allylic α-hydroxy oxazoline which was then hydrolysed to the chiral hydroxy acid in low enantiomeric excess. The hydroxy acid, as the O-silylated ethyl ester, was elaborated by allylic diethyl malonate to bromination and condensation with diethyl 5-carboethoxy-2-methyl-3- methylene-2-0-tert-butyldimethylsilylhexanedioate. Removal of the silyl protecting group and epoxidation provided an epoxy triester, which on hydrolysis provided a mixture of acids of uncertain structures.

In Part I, hypotheses for the biogenesis of Erythrina alkaloids are discussed. Di-(β-3,4-dihydroxyphenyl)-ethylamine the theoretical precursor predicted by the biogenetic theory, was prepared and ring closure to the erythrinane ring system by oxidative coupling was attempted under various conditions. Consequently, the biogenesis of the Erythrina alkaloids was re-examined and a new proposal is advanced for the biosynthesis of these alkaloids. Synthetic routes to a hypothetical precursor, proposed here for the first time as a potential intermediate, are described. The biogenetic-type synthesis of the spiro-amine ring system present in the Erythrina alkaloids was achieved by oxidative coupling of the blocked diphenolic precursor, as predicted by the proposed biosynthetic scheme. Oxidation of di-(β-3-hydroxy-4-methoxyphenyl)-ethylamine by alkaline potassium ferricyanide afforded 3,15-dimethoxy-16-hydroxy-2-oxo-erythrina-1(6),3-diene in 15% yield. Reduction of the latter by sodium borohydride gave 3,15-dimethoxy-2,16-dihydroxyerythrina-l(6),3-diene. Acetylation of the dienone yielded 3,15-dimethoxy-16-acetoxy-2-oxoerythrina-1(6),3-diene. The total biogenetic-type synthesis of erysodine is therefore but two steps from completion. The results as a whole confirm the hypothesis that Erythrina alkaloids are produced in Nature by oxidative coupling of diphenols. They also demonstrate the directing role of the protective groups in the phenolic precursor. The evidence allows a biosynthetic pathway for the aromatic Erythrina alkaloids to be considered, and the mechanism for the ring closure process is discussed. The isotopically labelled precursor 3-hydroxy-4-methoxy-N-(3-hydroxy-4-methoxyphen[1-¹⁴C]ethyl)-phenethylamine was prepared to test the biosynthetic hypothesis in the plant. Feeding experiments are in progress. In Part II, the biogenesis of cholesterol and methods for functionalising inert methyl groups are reviewed, and a new theoretical approach to removal of the 14α-methyl group from lanosterol is described. The removal of this methyl group in vitro could not be achieved, but a series of interesting compounds was obtained. Evidence for the structures of these compounds is presented. Thus, photosensitized oxygenation of dihydrolanosteryl acetate in the presence of para-nitrobenzenesulphonyl chloride yielded 3β-acetoxylanosta-7,9(ll)-diene, 3β-acetoxylanost-8-ene-7-one and 3β-acetoxylanost-8-ene-7a-hydroperoxide. In addition a compound having an ambiguous structure and designated as IP1 was obtained. The dibromo-derivative of the latter is 33-acetoxy-7a,lla-dibromolanostane-8 a,9α-epoxide, the structure of which was determined by X-ray crystallographic study. A working structure for compound IP1 based on the physical and chemical evidence is discussed. / Science, Faculty of / Chemistry, Department of / Graduate

Part I of the thesis describes four investigations of some of the neutral components of bark extractives. The petroleum ether extract of grand fir [Abies grandis (Dougl.) Lindl.] was found to contain two triterpene lactones. The first compound, cyclo-grandisolide, was shown by chemical and spectroscopic considerations and confirmed by X-ray analysis to be (2 3R)-3a-methoxy-9,19-cyclo-9β-lanost-24-ene-26 ,23-lactone (38) . The second component, epi-cyclograndisolide, was isomeric with the first and was assigned as (23S)-3α-methoxy-9,19-cyclo-9 β- lanost-24-ene-26,23-lactone (43). In the second investigation, three triterpenes of the chloroform extract of Pacific silver fir [A. amabilis (Dougl.) Forbes] were examined. The main component, abieslactone, was known and had been assigned as (23R)-3α-methoxylanosta-9(11),24—diene-26,23-lactone (30). Chemical and spectroscopic evidence is considered which indicates that assignment to be incorrect and abieslactone is tentatively re-assigned as (23R)-3a-methoxy-9β-lanosta-7,24-diene-26,23-lactone (81). A minor component, AA₃ was assigned on the basis of methylation studies as 3-desmethylabieslactone or (23R)-3α-hydroxy-9β-lanosta-7,24-diene-26,23-lactone (83). Oxidation of AA₃ gave a ketone identical to the second minor component, AA₂, which is then (23R)-3-oxo-9β-lanosta-7,24-diene-26,23-lactone (82). The third investigation concerns the structure of W₄, a triterpene ketone from the petroleum ether extract of Western white spruce [Picea glauca (Moench) Voss. var. albertiana (S. Brown) Sarg.]. The structure tentatively assigned on the basis of spectroscopic evidence is 3β-methoxy-8α-serrat-13-en-21-one (91). The fourth investigation was a chemosystematic study of the petroleum ether extract of Engelmann spruce [P. engelmannii Parry]. The presence of methoxyserratene derivatives known to be present in other members of the same genus were not detected in the present investigation. Part II of the thesis describes synthetic endeavors leading to possible bio-intermediates of indole alkaloids and the biosynthetic evaluation of one synthetic compound. Condensation of 3-ethylpyridine with 2-carboethoxy-3(β-chloroethyl)indole (60) followed by reduction gave N-[β{3(2-hydroxymethylindolyl)}ethyl]-3-ethy1-1,2,5,6-tetrahydropyridine (64). The benzoxymethyl derivative 65 of compound 64 was treated with potassium cyanide to give the cyanomethyl derivative 66 which could be hydroxyzed to N-[β{3(2-carbomethoxymethylindolyl)}ethyl]-3-ethyl-1,2,5,6-tetrahydropyridine (67). Alkylation of the compound with methyl formate followed by reduction of the resulating enol, gave 16,17-dihydrosecodin-17-ol (69). This compound was shown to be not, or very slightly, incorporated into the alkaloids of Vinca rosea L. plants. Attempts to oxidize the tetrahydropyridine 64 with mercuric acetate under various conditions failed to give detectable amounts of the corresponding pyridinium salt. In another synthetic sequence, condensation of the tryptophyl derivative 60 with 3-acetylpyridine ethylene ketal followed by the same sequence of reduction and homologation as employed before gave N-[β{3(2-carbomethoxy-methylindolyl)}ethyl]-3-acetyl-l,2,5,6-tetrahydropyridine (82). Attempts to oxidize 82 with mercurous acetate followed by hydrogenation failed to give the desired N-[β{3(2-carbomethoxymethylindolyl)}ethyl]-3-acetyl-l,4,5,6-tetrahydropyridine (83). In a second attempt to synthesize 83, the pyridinium chloride salt 84 from the condensation of 3-acetylpyridine with the tryptophyl derivative 60, was hydrogenated to N-[β{3(2-carboethoxyindolyl) }ethyl]-3-acetyl-l,4,5, 6-tetrahydropyridine (85). Reduction of 85 under a variety of conditions gave major amounts of N-[β{3(2-hydroxymethylindolyl)}ethyl]-3-acetylpiperi-dine (86) with only trace amounts of N-[β{3(2-hydroxymethylindoiy 1)}ethy1]-3-acety1-1,4,5,6-tetrahydropyridine (87) containing the necessary vinylogous amide chromophore. In a third approach to the synthesis of 83, methyl indole-2-carboxylate (88) was reduced and homologated as before to give methyl indole-2-acetate (92). Treatment of 92 with ethylene oxide and stannic.chloride gave methyl 3(β.-hydroxyethyl)indole-2-acetate (93). Treatment of the tryptophyl bromide derivative 94, produced by the action of phosphorous tribromide on hydrogenated to the vinylogous amide 83. More conveniently, treatment of 93 in 3-acetylpyridine with phosphorous tribromide and immediate hydrogenation gave 83 in better yield. / Science, Faculty of / Chemistry, Department of / Graduate

The first part of this thesis describes a sequence which provides a total synthesis of cleavamine (23) and catharanthine (12). Dihydrocatharanthinol (76) obtained by lithium aluminum hydride reduction of dihydrocatharanthine (34) was converted to its tosylate derivative. The latter intermediate upon heating in benzene containing two equivalents of triethylamine underwent an interesting fragmentation reaction to provide a seco-diene (78) containing the cleavamine ring system. Reaction of this diene with osmium tetroxide provided a tetrol (96) which could be converted to cleavamine on the one hand and the C₄-functionalized cleavamine derivatives on the other. Thus treatment of the tetrol with sodium borohydride allowed the hydrogenolysis of the carbinol amine function and provided a triol (97). The vicinal diol present in 97 was cleaved by means of periodate and the resultant 2-acylindole chromophore was further converted by borohydride to a 4,18-dihydroxy dihydrocleavamine derivative (99). Reductive removal of the C₁₈ hydroxyl function by means of lithium aluminum hydride provided isovelbanamine (100). Acid catalyzed dehydration of the latter yielded cleavamine (23) while isomerization under aqueous acidic conditions provided velbanamine (22). To complete the total synthesis of catharanthine (12), cleavamine was reacted with t-butyl hypochlorite and the resultant chloroindolenine was then subjected to nucleophilic attack by cyanide ion to provide 18ϐ-cyanocleavamine. Basic hydrolysis of the nitrile function followed by esterification provided 18ϐ-carbomethoxycleavamine (60). This compound upon reaction with mercuric acetate was cyclized to catharanthine. The second part of this thesis establishes the utility of both the chloroindolenine and the C₁₈-hydroxy analogues of the cleavamine systems to the synthesis of dimeric compounds structurally similar to the natural dimeric alkaloids. Treatment of either of these analogues with vindoline under mild acidic conditions yielded the appropriate dimers containing the indole and dihydroindole units present in vincaleukoblastine. The dimerization reaction was shown to be stereospecific and led in each case to the same stereochemistry at C₁₈, of the resulting dimers / Science, Faculty of / Chemistry, Department of / Graduate

Part I of this thesis describes the structural elucidation of eleven triterpenes isolated from the benzene extract of Western white pine (Pinus monticbla Dougl.) bark. Chemical and detailed spectroscopic investigations revealed the presence of a common tetracyclic A9(ll)-lanostene skeleton in all of the investigated materials. Structural variations were found at the C3 position and in the side chain at C17. The following assignments have been made: compound I, 33~methoxy-5a-lanost-9(ll)-en-24S,25-diol (43); compound II, the corresponding 33-hydroxy derivative (51); compound III, 33-methoxy-5a-lanost-9(11)-en-24-one (59); compound IV, 33-methoxy-5a-lanost-9(11),25-dien-24S-ol (65); compound V, 3a-hydroxy-5a-lanost-9(ll),25-dien-24-ol (66); compound VI, 33-methoxy-5a-lanost-9(ll)-en-22,25-diol (70); compound VII, 33-methoxy-26,27-bis nor-5a-lanost-9(ll)-en-24-one (71). Compound VIII was shown to be the ethylidene derivative of 33-methoxy-5a-lanost-9(ll)-en-24S,25-diol (76) and compounds IX and X were assigned to structures (78) and (80), respectively. A novel dimeric steroidal structure (83) has been proposed for compound XI. Part II describes synthetic investigations which lead to the development of a sequence providing a synthon [(193) and (194)] for the synthesis of vobasine (78)- and sarpagine (77)-type alkaloids. 2-Amino-3-indolyl(3a)-propanol (121), obtained by lithium aluminum hydride reduction of L-tryptophan (106), was converted to its ditosylate (150). Treatment of the latter with cyanide ion provided 3-(N~tosylamino)-4-indolyl(3a)-butanonitrile (151) which was transformed to 3-(N-tosylamino)-4-indolyl(3a)-butanoic acid (152) by means of 30% sodium hydroxide solution. 3-Amino-4-indolyl(3a)-butanoi.c acid methyl ester (155) was obtained through reductive cleavage of (152), followed by Fischer esterification. Compound (155) could then be converted to 3-CN-.formylami.no)-4- (N-benzyl-indolyl)(3a)-butanoic acid methyl ester (163) by treatment with a mixture of formic acid and acetic anhydride followed by sodium hydride and benzyl bromide. Reaction with trifluoroacetic acid converted compound (163) to the tricyclic 3-carbomethoxymethyl-N -benzyl-3,4-dihydrocarboline (173) which upon condensation with 3-methylene-pentan-2-one (126) afforded the tetracyclic 2-oxo-3-ethyl-6-carbomethoxymethyl-l,2,3,4,6,7,12,12b-octahydro-(N-benzylindolo)(2,3-a)-quinolizine (175). The ethylene ketal (177) of the latter material was treated with diisopropyllithium amide and methyl chloroformate to provide 2-oxo-3-ethyl-6-dicarbomethoxymethyl-l,2,3,4,6,7, 12,12b-octahydro-(N-benzylindolo)(2,3-a)-quinolizine ethylene ketal (178), which possesses a highly activated acidic proton (C6a) in the side chain. A suitable leaving group at the C2 position, necessary for subsequent transannular cyclisation, was available through conversion of the tetracyclic ketone (175) to the corresponding C2cx-alcohol (181) and further transformation of the latter into various derivatives such as the acetate (182), the mesylate (183) and the p-nitrobenzoate (185). In order to allow generation of an exocyclic olefin at C3, the C2-olefin, 3-ethyl-6-carbomethoxymethyl-l,4,6,7,12,12b-hexahydro-(N-benzylindolo)(2,3-a)quinolizine (184), obtained via dehydration of the alcohol (181), was converted to 2,3-a-dihydroxy-3-ethyl-6-carbomethoxymethyl-l,2,3,4,6,7,12,12b-octahydro-(N-benzylindolo) (2,3-a)-quinolizine (186) by osmium tetroxide oxidation. Treatment of (186) with acetic anhydride or p-nitrobenzoyl chloride provided the diacetate (187) or the C2 mono p-nitrobenzoate (188), respectively. The 10-membered ring system, present in the vobasine skeleton, became availahle through reductive cleavage of the C/D ring junction in the tetracyclic alcohol (181), thus, affording 2a-hydroxy-3a-ethyl-N^-methyl-6-carhomethoxymethyl-l,2,3,4,6,7,12,12b,12b-nonahydro-(N-benzyl-indolo)(2,3-a)-12b,N^-seco-quinolizine (190). Acetic anhydride treatment of the ethylene ketal (177) provided two isomeric components, 2-oxo-3-ethyl-Nb-acetyl-6-carbomethoxymethyl-1,2,3,4,6,7,12,12b-octahydro-12b-acetoxy-(N-benzylindolo)(2,3-a)-12b,Nb-seco-quinolizine ethylene ketal (191a and b), also possessing the 10-membered ring skeleton. Furthermore, the latter materials enable an entry into the family of 2-acylindole alkaloids as well as members of the dimeric alkaloids such as voacamine (75). / Science, Faculty of / Chemistry, Department of / Graduate

The work presented in this thesis is aimed at the total synthesis of 14,21-dehydrosecodine (1). This substance is an indole derivative with reactive substituents at position 2 (an acrylic ester segment) and 3 (a 1,6-dihydropyridine system). The stabilization of the latter involved the generation of chromium carbonyl complexes employing trisacetonitriletricarbonylchromium (0) as the reagent with appropriate synthetic indole derivatives. In order to develop the required methodology for the preparation of the above complexes, the initial experiments employed simple dihydropyridine systems. Thus, when N-methyl-3-ethyl pyridinium iodide (4_1) was treated with NaBH^ in a two-phase system (ether - water), N-methyl-3-ethyl-1,2-dihydropyridine (46_) was obtained. When this compound was treated with the above complexing agent a mixture (ratio 1:2) of (N-methyl-3-ethyl-l,2-dihydropyridine) tricarbonylchromium (0) (4_3) and (N-methyl-3-ethyl-l, 6-dihydropyridine) tricarbonylchromium (0) (4_4) was obtained. Thermal isomerization of this mixture in refluxing cyclo-hexane afforded a 1 : 1 ratio of (4_3) and (4_4) . Liberation of the organic ligand could be achieved by stirring (43) and/or (4_4) with pyridine. The above strategy was applied to the indole intermediate, N-(2-carbomethoxymethyltryptophyl)-3-ethylpyridinium per-chlorate (_36) but only a low yield (2%) of the desired chromium complexes was obtained. These results prompted a change in the original synthetic strategy and a new approach was initiated by other coworkers in this laboratory. Some studies with the novel system (4_6) were conducted as they relate to position of alkylation. It was shown that (46) undergoes reaction with benzyl bromide to afford the 5-substituted derivative. / Science, Faculty of / Chemistry, Department of / Graduate

In Part I, a modified synthesis of radio-labelled secodine (68) and its incorporation into vindoline (7) is described. In a model study, for the synthesis of side-chain labelled 3-ethylpyridine (74), [2-² H]-(3'-pyridyl)-ethane was achieved from the correspondingly labelled 3-acetylpyridine by desulphurization of the intermediate thioketal (93). In a second study, [1- ³H]-(3'-pyridyl)- ethane was synthesized by treating 3-acetylpyridine with sodium borohydride-³H. The resulting alcohol (95) was acetylated, and hydrogenolysis achieved the desired product. The ester alcohol (74) was coupled to [1- ³H]-(3'-pyridyl)-ethane and the resulting pyridinum salt (90) was reduced to the corresponding piperdeine ester (80) in a "one-pot" synthesis. The conversion of (80) to [19-³H]-secodine was achieved by a known procedure. In two experiments, [19-³H, ¹⁴C0₂CH₃]-secodine (68)(³H/¹³C ratios = 3.00 and 1.54) was administered to Catharanthus roseus plants. The vindoline (7) which was isolated was shown to have been biosynthesized from the entire secodine molecule (³H/¹³C = 3.31 and 1.35 respectively). In Part II, a degradation scheme designed to achieve the isolation of the N-methyl group of uleine (1) is described as well as preliminary results from an investigation into the biosynthesis of uleine (1) and olivacine (4). Variously radio-labelled forms of tryptophan (15), anthranilic acid and secodine (18) were administered to Aspidosperma pyricollum root segments and whole plants. The uleine (1) which was isolated was found to be inactive in all experiments. Variously radio-labelled forms of tryptophan (15), anthranilic acid and secodine (18) as well as ¹⁴CH₃-methionine (30) was administered to Aspidosperma australe plants. Uleine (1) and olivacine (4) was isolated. The only incorporation that could be demonstrated was that of ¹⁴CH₃ methionine (30) into uleine (1) to the extent of 0.168% and 0.147%. The isolation of the N-methyl group from (1) showed that it contained 97% and 98% of the activity. In Part III, the attempted synthesis of compounds of the preakuammicine- and stemmadenine-series is described. A new method for the C-18 deoxygenation of curan derivatives using Birch reduction conditions was achieved. Also, a modification of the Oppenauer oxidation of the curenol (36) to achieve improved yields of the aldehyde (37) and nor-fluorocurarine (39) was developed. The introduction of a carbomethoxy group into the C-16 position of the curan aldehyde derivatives (44) and (50) using a base and methylchloroformate was unsuccessful. Also, the introduction of cyanide into position C-16 of the indole alcohol (52) or indole acetate (57) via the corresponding chloroindolenines was unsuccessful. The synthesis of product (60), which is believed to be identical with preakuammicine aldehyde (7), was achieved. This material could not be converted into akuammicine (5) or stemmadenine (4). Only the dehydrated indolenine (72) could be obtained. The ring-opening reaction of the corresponding thioacetal derivative (73) yielded the decarboxylated indole thioacetals (75) and (76). / Science, Faculty of / Chemistry, Department of / Graduate