This thesis describes two main programmes: the synthesis of a new class of homochiral amines and the synthesis of ketone analogues of 3a-esterified tropane alkaloids. In chapter one, a scaled-up synthesis of (5)-a-(diphenylmethyl)pyrrolidine 1 is described. The key hydrogenation step of the oxazolidinone intermediate 2 was extended to the synthesis of the other chiral amines 70, 73, 76, 79 and 82. Hydrogenation of the oxazolidinones proceeded in good yields (71 - 87 %) and was not susceptible to racemisation. Thus, a convenient route from amino acid ester hydrochlorides (S)-valine 65, (S)-phenylalanine 66, (S)-alanine 67, (S)-isoleucine 68 and (S)-leucine 69 allowed a range of novel chiral amines to be prepared. In chapters two and three, a new route to ketone analogues of tropane esters is described. In chapter two, results of an attempt to prepare ketone 110 are outlined. Ketone 110 is an analogue of the tropane alkaloid littorine 101, where the bridging ester O atom is replaced by a CH2 group. The first approach to ketone 110 involved the Wittig reaction of acetylmethylenephosphorane 118 and the Homer-Wadsworth- Emmons reaction of diethylbenzoylmethanephosphonate 122 with tropinone 116. Tropinone 116 was found to be particularly unreactive in both cases. The second approach to ketone 110 involved the coupling reactions of both N-troc-3a- tosyloxymethyltropane 170 and N-troc-3 a-iodomethyltropane 185 with 2-phenylacetyl- 1,3-dithiane 147 and 1,3-ditihiane 142. These were also unreactive and as a result the synthesis of ketone 110 remains unresolved. In chapter three, the synthesis of other ketone analogues of naturally occurring 3 a- esterified tropane alkaloids is described. A six-step route to the ketones was devised and in this route the Grignard reactions of tropan-3 -ylacetaldehyde 227 emerged as the key to the success of the strategy. Three ketone analogues 218, 219 and 220 of tropate esters were successfully prepared. Ketone 220, the analogue of apoatropine 201, was found to be a muscarinic acetylcholine receptor antagonist (EC(_50) 1.9x10(^-7) M) in guinea-pigileum, showing a 500-fold less activity than atropine 202. However the activity is still within the clinical range.

The high affinity, selective dopamine transporter ligand GBR 12909 has served as a template for the design of two novel classes of dopamine transporter ligands. A series of 3-[2- (diarylmethoxyethyidenyl)]-N-substituted tropane derivatives were synthesized and the binding affinities of these compounds were determined at the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in rat brain tissue preparations. The tropane derivatives were found to exhibit more potent affinity and selectivity for DAT than GBR 12909. From the SAR of the tropane analogues and GBR 12909, a novel series of 3-[2-(diarylmethoxyethylidenyl)]-Nsubstituted azetidine derivatives has been developed.

In an effort to search for potential therapeutic agents for cocaine addiction, a novel class of compounds was synthesized and evaluated for in vitro dopamine and serotonin transporter affinities. These unique 3ƒÀ-aryl-3ƒ¿-arylmethoxytropane analogues incorporated the structure of dopamine selective 2-substituted-3-phenyltropanes and the design of serotonin selective meperidine derivatives. In general, the 3ƒÀ-aryl-3ƒ¿-arylmethoxytropane analogues exhibited greater potency for the serotonin transporter than the dopamine transporter. The most potent compounds of this series were 3ƒÀ-phenyl-3ƒ¿.(3, 4-dichlorophenyl)methoxy-8.azabicyclo [3.2.1]nortropane (Ki = 0.06 nM) and 3ƒÀ-(4Œ-chlorophenyl)-3ƒ¿.(4-chlorophenyl)methoxy-8. azabicyclo[3.2.1]nortropane (Ki = 0.09 nM) at the serotonin transporter and their binding affinities were equipotent with paroxetine and fluoxetine (Prozac). A series of 8-azabicyclo[3.2.1]oct-2-ene derivatives were synthesized from 3-tropinone based on the structure of triple re-uptake inhibitor, DOV 216, 303. The compounds were designed as potential triple re-uptake inhibitors which could exhibit equipotent affinities at the monoamine transporters for dopamine, serotonin and norepinephrine. A short and efficient synthetic methodology was developed for the synthesis of unique compounds which could exhibit potency for both the dopamine and serotonin transporters. The 3ƒÀ-aryl-3ƒ¿-(4Œ, 4-disubstituteddiphenylmethoxy)tropane analogues were designed as hybrid structures of the dopamine transporter selective benztropines and the serotonin transporter selective meperidine derivatives.

Part I: Pyrrolidine derivatives were attached a methoxy group on a-C position of pyrrolidine-ring via anodic oxidation. Followed with alkylation and series of transformation under Lewis acids to obtain tropane alkaloids. Part II: Application of intramolecular radical cyclization toward the synthesis of aporphine alkaloids. Tributyltinhydride and AIBN were used to generate aryl radicals. Trapping of aryl radicals with unsaturated alkenes led to products.

No description available.

The cultured tissues and organs of Duboisia myoporoides, an endemic medicinal plant of Australia, were investigated with the aim of establishing a relationship between organogenesis, differentiation and alkaloid localization. Histological analyses explained the relationship between cell arrangement in the cultured tissues and organs and the cytokinin/auxin combinations used at the callus induction stage. The cultured tissues and organs were analysed histochemically to localize alkaloids in different types of cells by using selected alkaloid colour reagents i.e., platinic chloride (5%) and iodoplatinate. The presence or absence of nicotine, hyoscyamine and scopolamine in the cultured tissues and organs was then confirmed by GC-MS analysis. This is the first work to show that tropane alkaloid formation in the separated cultured organs is related to xylem differentiation and tropane alkaloid formation in the calli cultured in suspension may allow commercial tropane alkaloid production without regenerating the organs. The roots of the D. myoporoides field-grown trees were colonized by the AM fungi and the mycorrhizal infection was ranged from 0-30% which indicates that the secondary metabolite atropine and scopolamine did not prevent AM fungal colonization. / Doctor of Philosophy (PhD)

Made available in DSpace on 2015-05-14T12:59:34Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 3371563 bytes, checksum: 0f72f1a088caa63b4cd2bf4057752d08 (MD5) Previous issue date: 2012-02-03 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work describes the results of phytochemical studies from three species of the Erythroxylum genus: Erythroxylum caatingae Plowman, Erythroxylum subrotundum A. St.-Hil and Erythroxylum revolutum Mart, which were identified by the botany sector of the Laboratory of Pharmaceutical Technology, UFPB. The species were submitted to extraction process, followed by partition with hexane, chloroform and ethyl acetate, resulting in their respective phases. Four Tropane alkaloids were isolated by chromatography methods from the chloroformic phase of Erythroxylum caatingae, in which two were already isolated [3α, 6β dibenzoyloxytropane and 3α-(3 ,4 ,5 - trimethoxybenzoiloxi)-6β-benzoyloxytropane (Catuabine B)] and the other two were reported for the first time in the literature [3-(3 ,4 -dimethoxy)-6-hydroxytropane and 3α-(trans-3 ,4 ,5 trimethoxycinnamoyloxy)-6β-benzoyloxytropane]. From the ethyl acetate phase of Erythroxylum subrotundum, two flavonoids were isolated: Quercetin-3-O-α-L-rhamnoside and 5,7,4 -trihydroxyflavone-3-O-α-L-rhamnoside. The study of the Erythroxylum revolutum hexanic phase resulted in the isolation of six diterpenes: ent-kauran-16-ene, 13-hydroxy-8(17),14-labdadien (Manool), ent-kaur-16- en-3β-ol, 3-oxo-13-hydroxi-8(17),14-labdadien, 3,13,19-trihydroxy-8(17),14-labdadien and ent-kauran-16β, 17-diol. All the species had their chemical constituents identified through data analysis obtained from spectroscopic methods such as Infrared and Nuclear Magnetic Resonance of 1H and 13C with uni-bidimensional techniques, besides comparison with literature data. Therefore, the given results of this work contributed to the chemical study of the species from Erythroxylaceae family. / Este trabalho descreve os resultados dos estudos fitoquímicos de três espécies do gênero Erythroxylum: Erythroxylum caatingae Plowman, Erythroxylum subrotundum A. St.- Hil e Erythroxylum revolutum Mart, identificadas pelo setor de botânica do Laboratório de Tecnologia Farmacêutica da UFPB. As espécies foram submetidas a processos de extração e posterior particionamento de seus extratos resultando nas fases hexânica, clorofórmica e acetato de etila. Do estudo da fase clorofórmica de Erythroxylum caatingae foram isolados, através de métodos cromatográficos, quatro alcaloides tropânicos, sendo dois destes alcaloides [3α,6β dibenzoiloxitropano e 3α-(3 ,4 ,5 - trimetoxibenzoiloxi)-6β-benzoiloxitropano (Catuabina B)], já isolados anteriormente e dois alcalóides inéditos na literatura [3-(3 ,4 -dimetoxi)-6-hidroxitropano e 3α- (trans-3 ,4 ,5 trimetoxicinamoiloxi)-6β-benzoiloxitropano]. Da fase acetato de etila de Erythroxylum subrotundum foram isolados dois flavonoides: a Quercetina-3-O-α-Lraminosídeo e 5,7,4 -trihidroxiflavona-3-O-α-L-raminosídeo. Do estudo da fase hexânica de Erythroxylum revolutum foram isolados seis diterpenos: ent-cauran-16-eno, 13-hidroxi-8(17),14-labdadieno (Manool), ent-caur-16-en-3β-ol, 3-oxo-13-hidroxi- 8(17),14-labdadieno, 3,13,19-trihidroxi-8(17),14-labdadieno e ent-cauran-16β, 17-diol. As espécies tiveram seus constituintes químicos identificados através da análise de dados obtidos por métodos espectroscópicos como Infravermelho e Ressonância Magnética Nuclear de 1H e 13C uni-bidimensional, além de comparação com dados obtidos na literatura. Assim, os resultados obtidos neste trabalho contribuíram para o estudo químico de espécies da família Erythroxylaceae.

240f. / Submitted by Ana Hilda Fonseca (anahilda@ufba.br) on 2013-04-01T16:40:21Z No. of bitstreams: 1 teseErikaVersaoFinal.pdf: 196222025 bytes, checksum: 392c4cd58c8a5d154afc1f1036d99967 (MD5) / Approved for entry into archive by Ana Hilda Fonseca(anahilda@ufba.br) on 2013-04-24T17:20:14Z (GMT) No. of bitstreams: 1 teseErikaVersaoFinal.pdf: 196222025 bytes, checksum: 392c4cd58c8a5d154afc1f1036d99967 (MD5) / Made available in DSpace on 2013-04-24T17:20:14Z (GMT). No. of bitstreams: 1 teseErikaVersaoFinal.pdf: 196222025 bytes, checksum: 392c4cd58c8a5d154afc1f1036d99967 (MD5) Previous issue date: 2011 / CNPq / Este trabalho descreve o estudo fitoquímico das fases hexânica, clorofórmica e acetato de etila obtidas do extrato metanólico de Erythroxylum rimosum, além da realização de testes de atividade biológicas (atividade antioxidante e o teste da letalidade da Artemia salina) com essas três fases. Descreve também o estudo fitoquímico com a fase clorofórmica obtida do extrato metanólico de E. betulaceum. A partir das folhas de E. rimosum foram isolados e identificados flavonóides tais como, quercetina, kaempferol-3-O-α-L-arabinofuranosídeo, catequina, epicatequina, quercetina-3-O-α-arabinofuranosídeo, quercetina-3-O-α-arabinopiranosídeo, quercetina-3-O-β-arabinopiranosídeo, quercetina-3β-glucopiranosídeo, kaempferol e quercetina-3-O-β-galactopiranosídeo. Foram ainda isolados e identificados nas folhas de E. rimosum, um alcalóide tropânico inédito (2β-acetoxi-3β,6α-dibenzoiloxitropano) e os ésteres de α-amirina e β-amirina, α-amirina, β- amirina e β-sitosterol. A partir do caule de E. betulaceum foram isolados 3-oxo (-)-manool, 3β-hidroxi (-)-manool e ent-2β,19- diidroxibeyer-15-en-1-one, bem como a vanilina. Estas substâncias foram isoladas através de métodos cromatográficos e a identificação estrutural foi realizada através da análise dos dados espectrométricos de RMN de 1H e de 13C uni- e bidimensional (DEPT, gHMQC, gHMBC, gCOSY 1H-1H, gTOCSY 1D, gNOESY 1D, HOMODEC), EM e IV, propriedades físicas (pf. e [α]D), e pela comparação desses dados com aqueles disponibilizados na literatura. / Salvador

Made available in DSpace on 2014-08-20T13:42:06Z (GMT). No. of bitstreams: 1 Dissertacao_Gabrie_Olle_ Dalmazo.pdf: 526235 bytes, checksum: 5e78165179f8f9e3164e0269bd617ab9 (MD5) Previous issue date: 2011-02-28 / The tropane alkaloids (TA) pathway has a branch-point controlled by the enzymes tropinone reductase 1 and 2 (TR1 and TR2). Tropinone is the common substrate for these enzymes and is reduced either by TR1 to form tropine, hyoscyamine and scopolamine or by TR2 to form pseudotropine and calystegines. Hyoscyamine and scopolamine are largely used in medicine as anticholinergic, antiemetic, parasympatholytic and anaesthetic. Calystegines mimic different sugars and are potent and specific inhibitors of glucosidases. The function of hyoscyamine, scopolamine and calystegines in the plants is not fully understood. Recent studies suggest that they are involved in the plant defense against pathogens. Regulation of TA biosynthesis in planta has attracted interest not only in view of its applications in the pharmaceutical industry, but also in respect to human nutrition and plant physiology. In the present study a virus-based transgenic approach devised to induce PTGS of tr1 and tr2 in whole transformed Hyoscyamus muticus plants is evaluated. It was observed that a significant reduction in transcript accumulation for tr2 caused a tremendous increase in transcript accumulation for tr1. / Um ponto de bifurcação na rota metabólica de tropano alcalóides (TA) é controlado pelas enzimas tropinona redutase 1 e 2 (TR1 e TR2). Tropinona, o substrato comum para estas enzimas, é reduzido por TR1 para formar tropina, hiosciamina e escopolamina ou por TR2 para formar pseudotropine e calisteginas. Hiosciamina e escopolamina são largamente utilizadas em medicina como anticolinérgicos, antieméticos, parassimpatolíticos e anestésicos. Calisteginas têm estrutura molecular semelhante a açúcares e são potentes inibidores específicos de glucosidases. A função dos alcalóides hiosciamina, escopolamina e calisteginas em plantas não é completamente entendida. Estudos recentes sugerem o envolvimento destes alcalóides na defesa da planta contra patógenos. A regulação da biossíntese de TA na planta tem atraído interesse não apenas quanto à aplicação na indústria farmacêutica, mas também com respeito à nutrição humana e fisiologia de plantas. No presente estudo avaliou-se uma estratégia transgênica, baseada em vírus, para induzir o silenciamento gênico pós-transcricional de tr1 e tr2 em plantas de Hyoscyamus muticus L. Observou-se que reduções significativas no acúmulo de transcritos para tr2 causaram um tremendo aumento no acúmulo de transcritos para tr1.

Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular S_N2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.