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

The work in this thesis describes investigations into the development of a tandem radicallDiels-Alder reaction strategy for the construction of indole alkaloids. The synthesis of a key precursor, 2-[(4-methylphenyl)sulfonyl]indole, was investigated and involved two main· strategies: functionalisation of the indole ring using lithiation procedures and assembling the indole as a key step (chapter 2). A method based on the former strategy was deemed to be the most practical and delivered the desired product in moderate yields (35 - 45%). The viability of the first step of the proposed tandem radicallDiels-Alder strategy was investigated by examining the intramolecular addition of vinyl and aryl radicals to a sulfone substituted indole (chapter 3). These studies showed that the addition of sp2 centred radicals to substituted indoles was feasible (20 - 40%). A study using an acetylenic precursor also provided useful information about the relative rates of desulfonylation and radical addition to acetyleneS; de-sulfonylation is a competing process. An alternative tandem palladiumlDiels-Alder reaction was briefly examined, but was thwarted by capricious palladium catalysed cross coupling reactions. Further studies were carried out to extend the scope of the novel ipso substitution reaction (chapter 4). It was found that alkyl radical cyclisations proceed efficiently to give a new ~ethod for the synthesis of fused[1,2-a]indoles (30 - 84%). The feasibility of a related ipso substitution using phenylthio and phenylsulfinyl substituted indoles was also examined. It was found that these reactions are also successful, but proceed in reduced yields compared with the sulfones (24 - 51 %). These results could be attributed to the more favoured reaction of the electron rich carbon centred radical with the more electrophilic 1t bond. The thesis is concluded by a brief discussion of the mechanism of these cyclisations with the available experimental evidence supporting an addition! elimination pathway.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

No description available.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further attempted synthetic approaches to calixindoles using new leaving groups led to uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane- 2,2'-dicarbaldehydes gives potential for further ligand design and metal complex formation. In addition, 4,6-dimethoxyindole-7- carbaldehydes have been effectively converted to a range of 6-methoxyindole-4,7-diones by Dakin oxidation. Various electrophilic substitution reactions have been performed on the 4,6-dimethoxybenzimidazoles. Formylation, acylation, acid catalyzed addition of formaldehyde and nitration revealed that the activated benzimidazoles are less reactive at the specified C-7 position compared to the analogous indoles. The key starting material for a potential calixbenzimidazole was synthesized by the selenium dioxide oxidation of 2-methyl-7-formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy- 2-styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless, attempted preparation of calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy benzimidazole led to formation of a dibenzimidazolyl ether. The synthesis of some novel activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were incorporated into new ligand systems which have led to a wide range of acyclic quadridentate neutral metal complexes. Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a radical cation followed by multielectron oxidations. On the other hand, the nickelII and cobaltII benzimidazole metal complexes investigated showed one electron ligand centered reversible reduction. Irreversible radical cation oxidation followed by multielectron oxidation of the metal complexes further demonstrates the rich electrochemical nature of the 4,6-dimethoxybenzimidazoles. Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one and triflic anhydride and an alternate procedure afforded 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles from activated indoles and 2-benzimidazolinone. Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles were synthesized via Jacobson cyclization. The two strategically placed electron donating methoxy groups activate these benzothiazoles to undergo various electrophilic substitutions at the 4- and 7- positions respectively.

Janthitrems are believed to be involved in the observed sporadic cases of AR37- infected perennial ryegrass staggers. Investigations into the role of janthitrems in perennial ryegrass staggers are difficult as isolation of the compounds from the ryegrass is hindered by the inherent instability of these compounds. Therefore attempts were made to isolate janthitrems from an alternative source, allowing these janthitrem analogues to be used as surrogates for endophyte produced janthitrems. Analysis of a series of Penicillium janthinellum cultures revealed the presence of janthitrems in a number of strains, including janthitrem B, janthitrem C and two novel janthitrem compounds. Detailed one- and two-dimensional NMR and mass spectral techniques identified the two novel compounds as 11,12- epoxyjanthitrems B and C, which were subsequently given the trivial names janthitrems A and D, respectively. Janthitrems B and C were isolated and identified by NMR and revisions of some previously reported chemical shift assignments were proposed. In addition to the janthitrems, penitrems were also identified in two strains of P. janthinellum. The isolated janthitrem B was utilised for the development of efficient extraction procedures, and for the determination of ideal storage conditions for janthitrem compounds. A method for the extraction and isolation of janthitrem B from a P. janthinellum culture was developed and optimised to yield 6 mg of janthitrem B from 900 mL of fungal culture in two days. Stability studies of janthitrem B indicated the ideal storage condition which minimised degradation was dry at −80 C where only 7% sample loss was observed over 300 days. Bioactivity studies of janthitrems A and B found these compounds to be tremorgenic to mice, with janthitrem A (an epoxyjanthitrem) inducing more severe tremors than janthitrem B. Insect testing also showed that both janthitrems A and B displayed anti-insect activity to porina larvae. Since the epoxyjanthitrems, which are associated with AR37 endophyte-infected ryegrass, were also shown to be tremorgenic and to display anti-insect activity, the insect resistance and the sporadic cases of ryegrass staggers displayed by AR37 may be related to the presence of epoxyjanthitrem compounds. LC-UV-MS analysis of janthitrems A-D, penitrems A-F, lolitrem B, paspalinine, paxilline and terpendole C found these indole-diterpenoids to be more sensitive by analysis using an APCI source as opposed to an ESI source. APCI negative ion LC-UV-MS required source induced dissociation in combination with increased collision energy to suppress an acetate adduct peak, sourced from the acetic acid buffer. Negative ion MS2 and MS3 data produced more informative fragments compared to the conventional positive ion MS2 and MS3 data. The availability of both positive and negative ion LC-UV-MS methodologies will allow future endophyte products to be more thoroughly screened for different classes of secondary metabolites. Extracts of mouldy walnuts were analysed for the presence of tremorgenic mycotoxins after a dog was found to exhibit symptoms characteristic of tremorgenic mycotoxicosis. LC-UV-MS analysis of the mouldy walnuts identified the tremorgenic mycotoxins penitrems A-F, thus confirming the veterinarian's tentative diagnosis of canine tremorgenic mycotoxicosis the first reported case in New Zealand.

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

A new protocol for direct amination of N-Methyl-2-phenylindole catalyzed by copper(II) trifluoromethanesulfonate was presented. Both of (E)-N-(1,1'-Dimethyl-2,2' -diphenyl-2,3'-biindolin-3-ylidene)-4-methylbenzenesulfonamide¡]4¡^and 4-methyl -N-(1-methyl-2-phenyl-1H-indol-3-yl)benzenesulfonamide¡]2¡^were obtained under the optimal reaction conditions (2.5 mol% Cu(OTf)2, 1.2 equiv PhI=O, 0.7 equiv PhI=NTs heated at 25 ¢J in acetonitrile for 1 hour) in 78 % and 11 % yields, respectively. In addition, (E)-N-(2-hydroxy-1-methyl-2-phenylindolin-3-ylidene)-4-methylbenzene sulfonamide ¡]6¡^and (E)-N-(1,1'-dimethyl-2,2'-diphenyl-2,3'-biindolin-3-ylidene) -4-methylbenzenesulfonamide ¡]4¡^were synthesized in 47 % and 24 % yields, respectively, by using 5 mol% Cu(OTf)2, 2 equiv PhI=O, 1.2 equiv PhI=NTs at ambient temperature in acetonitrile for 1 hour. Finally, 4-methyl-N-(1-methyl-2-oxo-3-phenyl indolin-3-yl)benzenesulfonamide ¡]3¡^and 1,1'-dimethyl-2,2'-diphenyl-2,3'-biindolin -3-one ¡]7¡^can be formed under the following reaction condition, 5 mol% Cu(OTf)2, 2 equiv PhI=O, 1.2 equiv PhI=NTs and 3 equiv Ag2CO3 heated at 100 ¢J in acetonitrile for 1 hour, in 41% and 22% yields, respectively.