Orientador: Carlos Roque Duarte Correia / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T13:56:31Z (GMT). No. of bitstreams: 1 Santos_MarceloRodriguesdos_M.pdf: 3262231 bytes, checksum: bb662dc4c97ef3d912795cf1e9624aad (MD5) Previous issue date: 2008 / Resumo: Produtos naturais são uma rica fonte de compostos de valor medicinal, e também têm inspirado a confecção de agentes não-naturais de grande importância farmacêutica. A relação da estrutura com a atividade biológica do produto natural pode servir como inspiração para o cientista. Nesse sentido, a (-)-isoaltolactona serviu de modelo para a síntese da (-)-aza-isoaltolactona, seu aza-análogo. Em nossa estratégia sintética, a reação de arilação de Heck é a etapa chave, na qual ocorre o acoplamento do tetrafluoroborato de benzenodiazônio com um enecarbamato endocíclico rico eletronicamente. O enecarbamato endocíclico foi eficientemente obtido a partir do ácido L-piroglutâmico em quatro etapas, com rendimento de 58%. A arilação de Heck mostrou ser dependente das características eletrônicas da olefina bem como do sal de arildiazônio. Essa dependência é refletida também na seletividade observada. Neste trabalho, a primeira síntese total da (-)-aza-isoaltolactona foi realizada em 13 etapas com rendimento global de 7% a partir do ácido L-piroglutâmico. / Abstract: Natural products are a rich source of medicinal compounds, and have also inspired the design of non-natural product of relevant pharmaceutical importance. The structure-activity relationship in natural product are an interesting area for research. In this work, we describe the synthesis of (-)-aza-isoaltholactone, an analogous of the (-)-isoaltolactone. The synthetical strategy, uses a Heck arylation reaction was the key step, involving the coupling the benzenediazonium tetrafluorborate salt with an electron rich endocyclic enecarbamate. The endocyclic enecarbamate was eficiently obtained fron L-pyroglutamic acid in four steps, with 58% overall yield. The Heck reaction showed dependence on the olefin electronic characteristics as well as on the arenediazonium salt. This dependence is also reflected on the observed selectivity. In this work, the first total synthesis of (-)-aza-isoaltholactone was accomplished in 13 steps with 7% overall yield from L-pyroglutamic acid. / Mestrado / Quimica Organica / Mestre em Química

The thesis entitled “Enantiospecific synthesis of bio-active stryllactones” comprise an introduction about stryllactone and two chapters describes the synthesis of stryllactones. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven as folkloric medicine. Stryryllactones were found to exhibit moderate to significant biological activity including antitumour, antifungal as well as antibiotic properties. Because of their unique and intriguing structures and the activity associated much effort has been centered on the development of methodology for the synthesis of these compounds. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis and by mass spectroscopic techniques. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. Figure 1:features styryllactone the genus In this thesis, enantioselective total synthesis of styryllactones ()-9-deoxygoniopypyrone 1, ()-goniopypyrone 2, ()-7-epi-goniofufurone 3, ()-7-epigoniodiol 4 and the putative structure of ()-etharvendiol 5 is presented. a) Total synthesis of ()-9-deoxygoniopypyrone, ()-goniopypyrone, ()-7-epigoniofufurone and ()-7-epi-goniodiol: Synthesis of the styrylalctones is relied on elaboration of the trihydroxy ester 11 derived from tartaric acid. Appropriate protection of the hydroxy groups and further modifications of the ester functionality (which can be transformed into the corresponding alcohol or aldehyde) is planned for the synthesis of the styryllactones 1-5. Accordingly, the bis-dimethylamide 9 derived from D-()-tartaric acid, was transformed to the -hydroxy amide 10 using a combination of Grignard reagent addition followed by reduction of the resultant ketone. Acid mediated deprotection of the acetonide with concomitant hydrolysis of the amide to the ester is accomplished in one pot by treating 10 with p-TSA in benzene/MeOH mixture Treatment of the trihydroxy ester with 2,2-dimethoxy propane in presence of p-TSA afforded the hydroxy ester 12 which was elaborated to the styrylalctones 9deoxygoniopypyrone, 7-epi-goniodiol, 7-epi-goniofufurone and goniopypyrone (Scheme-2). (Part of this work is published: Prasad, K. R.; Dhaware, M.G. Synlett. 2007, 11121114.; Prasad, K.R.; Dhaware, M.G. Synthesis 2007, 3697) b) Stereoselective synthesis of the putative structure of (+)-etharvendiol: In 1997, Bermejo et al isolated the styryl pyrone etharvendiol 5 from the ethanolic extract of stem bark from Goniothalamus arvensis. Hitherto, no synthesis of etharvendiol is reported in the literature. In this section, approach towards the synthesis of putative structure of etharvendiol will be discussed. Synthesis of etharvendiol 5 is anticipated by the elaboration of masked tetrol 15, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 15, and subsequent elaboration to 7. Bis-dimethylamide 9, derived from D-()-tartaric acid was identified as the suitable precursor for the synthesis of 15. Synthesis of masked tetrol 15 is accomplished from 9 involving a combination of selective Grignard additions and stereoselective reduction (Scheme 3). (For structural formula pl see the pdf file)

The thesis titled “Stereoselective synthesis of bio-active styryllactones” comprises an introduction about styryllactones and three sections delineating the results and discussion about the synthesis of styryllactones and experimental section. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven use in folk medicine. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. It was proposed by Shing et al. that the bio-synthesis of styryllactones 1-7 occur via the shikimic acid pathway. This proceeds through the formation of cinnamic acid from phenylalanine, followed by the incorporation of two acetate–malonate units activated as co-enzyme A, generating the styryl-pyrone, goniothalamin 9 a key styryllactone, which on further hydroxylation/oxidation leads to the formation of other styryllactones Section 1: Stereoselective synthesis of styryllactones containing furanofurone, pyrano-pyrone and styryl-pyrone structural units. In this section of the thesis, stereoselective total synthesis of furano-furone, pyrano-pyrone and styryl-pyrone type styryllactones (+)-7-epi-goniofufurone 1, (+)-goniofufurone 2, (+)goniopypyrone 3, (+)-goniotriol 4, (+)-9-deoxygoniopypyrone 5 and (+)-goniodiol 6 is discussed. It is anticipated that the masked tetrol 13, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration would serve as the intermediate for the synthesis of styryllactones 1-6. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 13, and subsequent elaboration to styryllactones 1-6. Bis-dimethylamide 10, derived from D-(−)-tartaric acid was identified as the suitable precursor for the synthesis of 13. Synthesis of masked tetrol 13 is accomplished from 10 involving a combination of selective Grignard additions and a stereoselective reduction (Scheme 2). Section 2: Stereoselective synthesis of styryllactones containing tetrahydrofuran and furano-pyrone structural units This section deals with stereoselective synthesis of natural antitumor tetrahydrofuran containing natural product (+)-goniothalesdiol 8. Key features of the synthesis include a FeCl3 mediated formation of THF 15 with very high selectivity (Scheme 3). THF 15 is further elaborated into the furano-pyrone type styryllactones (+)-altholactone 7 and (−)-etharvensin 16 in good yields (Scheme 3). Section 3: Stereoselective total synthesis of (+)-cardiobutanolide Recently, a new styryllactone cardiobutanolide 20 was isolated from the stem bark of Goniothalamus cardiopetalus, together with four known styryllactones by Hisham et al. Stereoselective total synthesis of this natural product from D-(−)-tartaric acid is described in this section. Key features of the synthesis include the elaboration of the γ-hydroxy butyramide 17 obtained from the bis-dimethylamide 10, involving a combination of the addition of 1,3-dithian-2-yllithium and stereoselective reduction (Scheme 4). (For structural formula pl see the pdf file)