(3aR)-14a-Acetoxy-3aß,4,14,14aa-tetrahydro-6,7,8-trimethoxybenzo[3,4]furo[3',4':6,7]cycloocta[1,2-f][1,3]benzodioxol-3(1H)-one (steganacin), 56, has been a popular synthetic target due to its perceived cytotoxic activity. Our proposed strategy for the construction of the key 8-membered ring embedded within steganacin was via an oxidative phenolic coupling of an appropriate (3R,4R)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-benzyldihydrofuran-2(3H)-one analogue which were shown to be readily available from commercially available piperonal in six linear steps involving chain extension, reduction, trichloroacetylation and cyclisation via a copper-catalysed Atom Transfer Radical Cyclisation (ATRC) reaction. In this way, copper-catalysed ATRC reaction of (E)-6-(benzo[d][7’,9’]dioxol-1’-yl)allyl-1,1,1-trichloroacetate afforded (R)-4-{(R)-benzo[d][1,3]dioxol-5-ylchloromethyl}-3,3-dichlorodihydrofuran-2(3H)-one in good isolated yield as a mixture of diastereosiomers. Regiospecific functionalisation of these trihalides at the benzylic position (via an SN1, solvolysis, pathway), followed by dehalogenatioin and subsequent enolate alkylation afforded the key butyrolactone intermediates whose oxidative cyclisation was the key bond construct in our approach to steganacin. Contrary to our expectations it was observed that these substrates suffer intramolecular Friedel-Crafts alkylation reactions, favouring a 3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (6 member ring) formation, rather than phenolic oxidative coupling reactions that would favour the steganacin-like (3aR,11aR,Z)-3a,4,11,11a-tetrahydrobenzo[4,5]cycloocta[1,2-c]furan-1(3H)-one (8 member ring) formation, when the oxidant has any Lewis acid capacity. Taking these observations into account we believe that by judicious choice of synthetic route the ATRC chemistry developed during the current research could be applied to a highly convergent (9 step) route to the synthesis of deoxypodophylotoxin.This work also describes, in detail, the efforts of this worker to establish and optimise a robust route that potentially can lead to the formation of steganacin via the alternative route of an initial microwave-assisted Pd-mediated biaryl coupling of either bromopiperonal or an halogenated derivative of the described γ-butyrolactones with an appropriate boronic acid derived from commercially available 3,4,5-trimethoxybenzalcohol to afford the biaryl scaffold present in steganacin. The completion of this synthesis was unfortunately left unaccomplished due to time constraints.

Submitted by Verena Bastos (verena@uefs.br) on 2015-10-14T21:06:54Z No. of bitstreams: 1 Paloma_R._Meira-disserta??o_2013.pdf: 1508066 bytes, checksum: cc4d4d39667159152b8407fa887ad2fa (MD5) / Made available in DSpace on 2015-10-14T21:06:54Z (GMT). No. of bitstreams: 1 Paloma_R._Meira-disserta??o_2013.pdf: 1508066 bytes, checksum: cc4d4d39667159152b8407fa887ad2fa (MD5) Previous issue date: 2013-09-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / This paper describes the influence of abiotic and biotic factors in the concentration of secondary metabolites of pharmaceutical interest in medicinal plants, while it aims to answer how these factors influence the concentration of podophyllotoxin and yate?na Leptohyptis macrostachys in vitro, this goal. The specimen Leptohyptis macrostachys was established in vitro from seeds collected in the Chapada Diamantina-Ba; studying the rate of germination rate, the germination and mean germination of seeds grown on MS medium with different concentrations of salts constituents of this medium as well as different concentrations of sucrose and gibberellic acid. Was also studied, such as abiotic factors (culture medium, carbon source temperature, photoperiod and gas exchange) and biological (plant growth regulators) influenced the development (number of shoots and leaves and roots presence of friable callus, compact or oxidized) and production of podophyllotoxin and yate?na. To study the influence of these factors in getting these metabolites, plants were steeped at 40 ? C in ethanol to produce the extract. This was partitioned with water and after a specific treatment, injected into the HPLC. We established a protocol for Leptohyptis macrostachys growing from seeds in ? MS medium supplemented with 1.5% sucrose and 11.55 mM of GA3, there was no significant formation of callus in treatments applied and the concentration of podophyllotoxin was favored when L. macrostachys was grown in ? MS medium supplemented with 1.5% sucrose, closed with PVC film and kept in a growth room at 30 ? C. / Este trabalho descreve a influ?ncia de fatores abi?ticos e bi?tico na concentra??o de metab?litos secund?rios de interesse farmacol?gico em plantas medicinais, ao mesmo tempo que se prop?e a responder como esses fatores influenciam na concentra??o de podofilotoxina e yate?na em Leptohyptis macrostachys in vitro, objetivo deste. A esp?cime Leptohyptis macrostachys foi estabelecida in vitro a partir de sementes coletadas na regi?o da Chapada Diamantina-Ba; estudando o ?ndice de velocidade de germina??o, a germinabilidade e o tempo m?dio de germina??o de sementes cultivadas em meio MS com diferentes concentra??es de sais constituintes deste meio, bem como diferentes concentra??es de sacarose e ?cido giber?lico. Foi estudado tamb?m, como fatores abi?ticos (meio de cultivo, fontes de carbono temperatura, fotoper?odo e trocas gasosas)e bi?tico (reguladores vegetais) influenciaram no desenvolvimento (quantidade de brotos folhas e ra?zes e presen?a de calos fri?veis, compactos ou oxidados) e na produ??o de podofilotoxina e yate?na. Para estudar a influ?ncia estes fatores na obten??o destes metab?litos, as plantas foram maceradas ? 40?C em etanol para a produ??o do extrato. Este foi particionado com ?gua e, ap?s tratamento espec?fico, injetado no CLAE. Foi estabelecido um protocolo de cultivo para Leptohyptis macrostachys a partir de sementes em meio MS ? suplementado com 1,5% de sacarose e 11,55?M de GA3; n?o houve forma??o significativa de calos nos tratamentos aplicados e a concentra??o da podofilotoxina foi favorecida quando L. macrostachys foi cultivada em meio MS ? suplementado com 1,5% de sacarose, fechada com filme de PVC e mantida em sala de crescimento a 30?C.