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Faculty of Science; School of Chemistry; PhD Thesis / The synthesis of nitrogen containing ring systems has been one of the interests of this research group at the University of the Witwatersrand for a long time. These systems form part of a group of compounds called alkaloids, whose structural diversity is rivalled only by their distribution in nature. A small sub-set of the alkaloids is the fused 5 and 6 membered bicyclic frames with nitrogen at one bridgehead. Having developed a unique method of synthesising these indolizidine alkaloids, we examined various aspects of this methodology and there remained one crucial question – what is the best way to control the stereochemical outcome of the ring-forming steps? This project looks at this question from the view of a model natural product, the indolizidine alkaloids (+)- and (–)-tashiromine. The synthesis of tashiromine and related compounds was examined using chiral auxiliaries such as the Oppolzer sultam and the Evans oxazolidinone, as well as the use of chirally modified reductants. The efficacies of the chiral auxiliaries were studied using molecular modelling techniques, and certain modifications were suggested from these results.

A phytochemical survey to detect alkaloids was performed on extracts of 339 discrete plants parts from a total of 77 species from five genera of Elaeocarpaceae, including 30 species from Queensland, 38 from PNG, and nine from China. An alkaloid detecting reagent, bismuth (III) tetraiodide (Dragendorff's reagent) was used in a preliminary test for alkaloids, with positive ESIMS used to confirm the presence of alkaloids. A total of 35 extracts of various plant parts produced positive results with Dragendorff's reagent. Positive ESIMS detected alkaloids in only 13 of these extracts. Bismuth (III) tetraiodide was demonstrated to produce false positive results with the new non-alkaloidal poly-oxygenated compounds 112 and 113, which were purified from the extract of Sloanea tieghemii. Two new alkaloid producing species, Elaeocarpus habbeniensis, and E. fuscoides were detected from the survey. These species were chemically investigated for the first time. Two other previously investigated species, E. grandis and Peripentadenia mearsii, were also studied. A total of 16 alkaloids, 11 of which are new, were purified from the extracts of these four species. The novel pyrrolidine alkaloids habbenine (114) and peripentonine (123), were isolated from the leaves of E. habbeniensis and Peripentadenia mearsii, respectively. Both of these compounds were purified as inseparable mixtures of diastereomers. The new pyrrolidine alkaloid mearsamine 1 (124), and the novel amino alkaloid mearsamine 2 (125), were also purified from the leaves of P. mearsii. The known pyrrolidine alkaloid peripentadenine (81), was purified from the bark of P. mearsii. Peripentonine (123) was reduced to peripentadenine (81) upon reaction with Pd/C. Four aromatic indolizidine alkaloids were isolated from the extract of the leaves of E. fuscoides. One new compound, elaeocarpenine (122), was isolated from this New Guinean plant. Three known Elaeocarpus alkaloids, isoelaeocarpicine (62), elaeocarpine (60) and isoelaeocarpine (61) were also purified from E. fuscoides. Elaeocarpenine (122) was demonstrated to produce the epimeric compounds elaeocarpine and isoelaeocarpine via reaction with ammonia. The chemical investigation of the Queensland plant E. grandis by two separate purification procedures was performed. An SCX/C18 isolation protocol was used to purify the new indolizidine alkaloids grandisine C (127), D (126), and E (128), in conjunction with the known tetracyclic indolizidine isoelaeocarpiline (63). The second purification of E. grandis was achieved with the use of ammonia in an acid/base partitioning protocol. Grandisine F (129) and G (130), and compounds 131a and b were purified by this procedure, as were 63, 126 and 127. Grandisine F and G were proposed to be ammonia adducts of grandisine D (126). Compound 131a and b were isolated as a mixture of diastereomers. The reduction of grandisine D (126) with Pd/C yielded a mixture of isoelaeocarpine (61) and elaeocarpine (60), whereas the reduction of isoelaeocarpiline (63) produced isoelaeocarpine (61). All of the alkaloids isolated from the Elaeocarpaceae, except grandisine E (128) and 131a and b, were evaluated for binding affinity against the human ? opioid receptor. Every compound except mearsamine 2 (125) possessed a binding affinity of less than 100 ?M. The most active compounds were grandisine F (129), D (126), C (127), elaeocarpenine (122), isoelaeocarpine (61), isoelaeocarpiline (63) and peripentadenine (81). The IC50 values for these compounds were 1.55, 1.65, 14.6, 2.74, 13.6, 9.86 and 11.4 ?M, respectively. The SAR of the active compounds was compared. These observations indicated that the indolizidine alkaloids were more active than the pyrrolidine alkaloids, and a phenol or ketone at position C-12 of the indolizidine alkaloids produced better binding affinity. All of these alkaloids, except 129, were proposed to interact with two of the three binding domains of the ? opioid receptor. Grandisine F (129) was proposed to have a different mode of action than the other alkaloids in the series. Synthetic modifications to isoelaeocarpine (61) and peripentadenine (81) were investigated in an attempt to incorporate an extra aromatic group into these molecules. An extra aromatic group was proposed to provide increased binding affinity to the ? opioid receptor by interaction with the third binding domain of the receptor. Two different aromatic amines were successfully attached to peripentadenine (81) by a reductive amination reaction using NaBH(OAc)3 and a titanium catalyst. The reductive amination of the ketone in isoelaecarpine (61) with various amines and NaBH(OAc)3 or NaBH4 proved unsuccessful.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

O presente trabalho descreve 3 abordagens divergentes para obtenção do esqueleto bicíclico presente nos alcaloides indolizidínicos. A primeira abordagem consiste no desenvolvimento de um novo método de preparação de diazocetonas α,β-insaturadas a partir da reação de Horner-Wadsworth-Emmons (HWE) entre diazofosfonato e aldeídos. As dizocetonas α,β-insaturadas obtidas foram utilizadas como bloco de construção do esqueleto cabocíclico indolizidínico, onde o intermediário chave foi obtido através do rearranjo de Wolff. A segunda estratégia consiste no desenvolvimento do acoplamento redutivo entre derivados α-aminocarbonílicos e acrilato de metila mediado por SmI2, onde em apenas duas etapas foram obtidos os intermediários avançados da síntese da (-)-pumiliotoxina 251D e da (+/-)-epiquinamida. A terceira estratégia utiliza como etapa chave a reação de Wittig/HWE intramolecular para preparação do intermediário bicíclico contendo o sistema α,β-insaturado que pode ser utilizado na síntese divergente dessas substâncias. / Herein were described three diverted oriented approaches for the construction of the bicyclic scaffold of indolizidines alkaloids, that figures between one of the most important classes of natural products. In the first approach, a new method to prepare α,β - unsaturated diazoketones was described using the Horner-Wadsworth-Emmons (HWE) reaction between diazophosphonate and aldehydes. The unsaturated diazoketones were used as powerful plataforms to construct the indolizidine carbocyclic scaffold, enploying the Wolff rearrangement as the key step. The second approach was the development of a reductive coupling between α-aminocarbonyl derivatives and methyl acrylate, mediate by SmI2, from this approach, the well-known advanced intermediate for the synthesis of (-)-pumiliotoxin 251D e of the (+/-)-epiquinamide was obtained in only two steps. The third approach uses the intermolecular Wittig/HWE reaction as the key step in the construction of a bicyclic intermediate containing an α,β -unsaturated moiety that could be used for a diverted oriented approach in the indolizidine alkaloids synthesis.

O presente trabalho descreve 3 abordagens divergentes para obtenção do esqueleto bicíclico presente nos alcaloides indolizidínicos. A primeira abordagem consiste no desenvolvimento de um novo método de preparação de diazocetonas α,β-insaturadas a partir da reação de Horner-Wadsworth-Emmons (HWE) entre diazofosfonato e aldeídos. As dizocetonas α,β-insaturadas obtidas foram utilizadas como bloco de construção do esqueleto cabocíclico indolizidínico, onde o intermediário chave foi obtido através do rearranjo de Wolff. A segunda estratégia consiste no desenvolvimento do acoplamento redutivo entre derivados α-aminocarbonílicos e acrilato de metila mediado por SmI2, onde em apenas duas etapas foram obtidos os intermediários avançados da síntese da (-)-pumiliotoxina 251D e da (+/-)-epiquinamida. A terceira estratégia utiliza como etapa chave a reação de Wittig/HWE intramolecular para preparação do intermediário bicíclico contendo o sistema α,β-insaturado que pode ser utilizado na síntese divergente dessas substâncias. / Herein were described three diverted oriented approaches for the construction of the bicyclic scaffold of indolizidines alkaloids, that figures between one of the most important classes of natural products. In the first approach, a new method to prepare α,β - unsaturated diazoketones was described using the Horner-Wadsworth-Emmons (HWE) reaction between diazophosphonate and aldehydes. The unsaturated diazoketones were used as powerful plataforms to construct the indolizidine carbocyclic scaffold, enploying the Wolff rearrangement as the key step. The second approach was the development of a reductive coupling between α-aminocarbonyl derivatives and methyl acrylate, mediate by SmI2, from this approach, the well-known advanced intermediate for the synthesis of (-)-pumiliotoxin 251D e of the (+/-)-epiquinamide was obtained in only two steps. The third approach uses the intermolecular Wittig/HWE reaction as the key step in the construction of a bicyclic intermediate containing an α,β -unsaturated moiety that could be used for a diverted oriented approach in the indolizidine alkaloids synthesis.

A estrutura básica dos alcaloides indolizidínicos é formada por anéis bicíclicos de cinco e seis membros contendo um átomo de nitrogênio compartilhado na posição 4. Esse sistema de anéis possui grande destaque dentre os alcaloides, pois está presente em um grande número de compostos e apresenta um interessante perfil biológico. A ipalbidina, por exemplo, é um alcaloide indolizidínico com propriedades analgésicas e antioxidantes. Este composto possui estrutura química relativamente simples, entretanto, poucas são as rotas que apresentam sínteses curtas e divergentes, sendo apenas quatro delas enantiosseletivas. Assim, este trabalho de dissertação visa o estudo de uma nova estratégia sintética que permite a preparação da (+)-ipalbidina, bem como de outros alcaloides que possuem o sistema 4-azabiciclo[4.3.0]-non-3-eno com um substituinte fenólico na posição 3. Uma rota promitente para a síntese desses alcaloides (objetivo deste trabalho) é a obtenção do esqueleto indolizidínico a partir da reação de ciclização de uma α-clorocetona funcionalizada derivada do (S)-prolinal protegido (Boc e Cbz). As etapas chaves dessa estratégia são: uma reação de olefinação (Wittig), a preparação de α-clorocetonas, adição do grupo aril a α-clorocetona e a conversão destas no esqueleto indolizidínico por uma reação de ciclização. A α-clorocetona pode ser preparada com rendimentos globais de 56% (Cbz) e 81% (Boc) a partir do (S)-prolinal protegido em apenas 3 etapas: reação de olefinação, seguida de uma reação de redução da olefina obtida e a preparação da α-cloroacetona a partir do éster. A adição do grupo aril a α-clorocetona foi obtida tanto para o grupo Boc (40%) quanto para o grupo Cbz (42%). O α-cloroálcool protegido com Boc foi convertido no esqueleto indolizidínico por meio de uma reação \"one-pot\" de desproteção seguida de ciclização (80%). O produto de ciclização, por sua vez, foi convertido ao análogo inédito da (+)-ipalbidina, a (S)-desoxiipalbidina (30%). Essa estratégia levou a síntese da (S)-desoxiipalbidina em 6 etapas e com rendimento global de 8%. Cabe ressaltar que este tipo de abordagem utilizando α-clorocetonas nunca foi empregado na síntese de alcaloides indolizidínicos, sendo que esta estratégia também poderá ser aplicada a síntese total da (+)-ipalbidina e de outros alcaloides indolizidínicos tais como as fenantroindolizidinas. / The basic structure of indolizidine alkaloids is formed by a five and sixmembered bicyclic ring containing one nitrogen atom shared at the 4 position. This ring system has great prominence among the alkaloids, it is present in a large number of compounds and possess interesting biological profiles. Ipalbidine, for example, is an indolizidine alkaloid with analgesic and anti-oxidant properties. Although this compound has a relatively simple chemical structure, only four enantioselective synthesis are described for this compound. Thus, this dissertation aims to study a new synthetic strategy that allows the preparation of (+)-ipalbidine, as well as other alkaloids having the system 4- azabicyclo[4.3.0]non-3-ene with a phenolic substituent in position 3. A possible interesting route for the synthesis of these alkaloids is to obtain the indolizidine skeleton from a cyclization reaction using a functionalized α-chloroketone (derivative of protected (S)-prolinal (Boc and Cbz)). The key steps of this strategy are: an olefination reaction (Wittig), the preparation of α-chloroketones, addition of aryl group to the α-chloroketones and converting them into the indolizidine skeleton by a cyclization reaction. The α-chloroketones were prepared with overall yields varying from 56 % (Cbz) to 81% (Boc) starting from protected (S)-prolinal in just three steps: olefination reaction , followed by a reduction reaction of the obtained olefin and preparation of the α-chloroketone from an ester . The addition step of the aryl group to α-chloroketone was obtained for both Boc (40%) and Cbz (42%) groups. The Boc-protected α-chloroalcohol was converted to indolizidine skeleton through an \"one-pot\" deprotection reaction, followed by a cyclization reaction (80 %). The cyclization product, in turn, was converted to the novel (+)-ipalbidine analog, (S)-desoxyipalbidine (30 %). This strategy led to the synthesis of (S)-desoxyipalbidine in 6 steps and overall yield of 8 %. It is noteworthy that this type of approach using α-chloroketones was never employed in the synthesis of indolizidine alkaloids, and that strategy can be applied also to the total synthesis of (+)-ipalbidine and other indolizidine alkaloids such as phenanthroindolizidine.