Metabólitos secundários de organismos vivos constituem uma fonte promissora para a descoberta de compostos biologicamente ativos, em particular para o tratamento de doenças como câncer, malária e doenças infecciosas. O capítulo 1 desta tese descreve a síntese e a avaliação da relação estrutura versus atividade de análogos da pseudoceratidina. A pseudoceratidina e sete de seus análogos apresentaram boa atividade contra P. falciparum, cepa 3D7, sensível à cloroquina. Os análogos apresentaram alto índice de seletividade, sugerindo que pequenas modificações estruturais exercem influência na redução da citotoxicidade. A pseudoceratidina também apresentou atividade antiplasmodial contra linhagens resistentes de P. falciparum, cepa K1 (IC50 = 1,1 0,1 μM), com um mecanismo de ação rápido. Outro metabólito secundário de destaque é o alcaloide citotóxico, agelastatina A. No capítulo 2 é descrita a síntese racêmica do esqueleto central ABC da 7-hidroxi agelastatina A. O sistema tricíclico de 5, 6 e 5 membros foi obtido em 4 etapas e com rendimento global de 8% a partir de reagentes comerciais. O capítulo 3 descreve o isolamento de peptaibóis produzidos pelo fungo Hypocrea sp., oriundo da Antártica. Foram isolados seis peptaibóis: a trichogina GA IV, os isômeros AT1M3I-4 e AT1M3I-5, a AT1M3I-3, de esqueleto semelhante à trikoningina KB, a trichokonina VI e a trichokonina VIII. Foram realizados estudos estruturais completos destes peptídeos de massa moecular maior do que 800 Da, inclusive estudos conformacionais por dicroísmo circular. A trichokonina VI e a trichokonina VIII foram ativas contra bactérias Gram-positivas, linhagens de células cancerígenas (MCF-7, MCF-10A, ACP01, HELA e A549) e contra o parasita P. falciparum, cepa 3D7, com IC50 de 0,61 ± 0,17 e 0,53 ± 0,19 μM, respectivamente. / Secondary metabolites of living organisms constitute a promising source for the discovery of biologically active compounds, in particular for the treatment of diseases such as cancer, malaria and infectious diseases. Chapter 1 of this thesis describes the synthesis and the evaluation of the structure versus activity relationship of pseudoceratidine analogs. Pseudoceratidine and seven of its analogues showed good activity against P. falciparum, strain 3D7, sensitive to chloroquine. Synthetic analogues showed a high selectivity index, suggesting that small structural modifications influence the reduction of cytotoxicity. Pseudoceratidine also showed antiplasmodial activity against resistant strains of P. falciparum, strain K1 (IC50 = 1.1 ± 0.1 μM), with a fast-acting mechanism. Another important secondary metabolite is the cytotoxic alkaloid, agelastatin A. In Chapter 2 the racemic synthesis of the central ABC core of 7-hydroxy agelastatin A is reported. The tricyclic ring system of 5, 6 and 5 membered was obtained in 4 steps and with an overall yield of 8% from commercial reagents. Chapter 3 describes the isolation of peptaibols produced by the fungus Hypocrea sp., from Antarctica. Six peptaibols have been isolated: trichogin GA IV, isomers AT1M3I-4 and AT1M3I-5, AT1M3I-3, with a similar skeleton to trikoningin KB, trichokonin VI and trichokonin VIII. A complete structural investigation of these peptides has been performed, including conformational analyses by circular dichroism spectroscopy. These peptides have a molecular weight higher than 800 Da. Trichokonin VI and trichokonin VIII were active against Gram-positive bacteria, cancer cells lines (MCF-7, MCF-10A, ACP01, HELA and A549) and against P. falciparum, strain 3D7, with an IC50 of 0.61 ± 0, 17 and 0.53 ± 0.19 μM, respectively.

The objective of this research was to development new methodologies for the asymmetric syntheses of amine and natural products from enantiopure sulfinimines (N-sulfinyl imines). In this context, new methods was devised for the asymmetric synthesis of 2,5-cis and trans-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates, prepared by an intramolecular metal carbenoid N-H insertion from a sulfinimine derived delta-amino-alpha-diazo- beta-ketophosphonate. Horner-Wadsworth-Emmos reaction of the 3-oxo pyrrolidine 2-phosphonates and aldehydes provided pyrrolidine enones. Hydrogenation (Pd/H2) of the pyrrolidine enones gave cis-2,5-disubstituted pyrrolidines. Luche reduction the pyrrolidine enones followed by a TFA-NaBH3CN mediated hydroxy directed reduction provided the 2,5-trans products. (+)-Preussin, a potent antiviral and antitumor agent was prepared in 9 steps in 28% overall yield from the sulfinimine. An acid catalyzed intramolecular Mannich cyclization of a sulfinimine-derived N-sulfinyl syn-alpha-methyl-beta-amino ketones was employed for the asymmetric synthesis of 2,3,5,6-tetrasubstituted piperidinones. The beta-amino ketones were prepare by treatment of prochiral lithium Weinreb amide enolates with enantiopure (E)-N-(4-(benzyloxy)butylidene)-2,4,6-triisopropylbenzenesulfinamide. This new methodology was highlighted in the first asymmetric synthesis of the poison frog alkaloid (-)-indolizidine 221T. By manipulation of water concentration in tetrahydrofuran, syn- and anti-2,3-diamino esters were prepared by treatment of the lithium enolate of N-(diphenylmethylene) glycine ethyl ester with sulfinimines. Anhydrous THF afforded enantiopure syn-2,3-diamino esters with a syn/anti selectivity of better than 25:1. In a THF-H2O the anti-2,3-diamino esters were formed. The mechanism involves the generation of H2O-LDA species in the formation of enolate which inhibited the retro-Mannich fragmentation in the diamino ester species. (SR,2S,3R)-(-)-Ethyl-2-(N,N-dibenzylamino)-3-N-(p-toluenesulfinyl)amino-pent-4-enoate was employed in an improved total synthesis of the anti-tumor antibiotic (-)-agelastatin A. A series of N-sulfinyl aza-Morita-Baylis-Hillman products were prepared by addition of vinylaluminum and N-methylmorpholine-N-oxide reagents to enantiopure N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the these acrylates with a rhodium(I) catalyst afforded anti-alpha-substituted-beta-amino esters with a anti/syn selectivity of better than 17:1. This new methodology is useful for the asymmetric synthesis of anti-alpha-alkyl-beta-amino esters, which are valuable chiral building blocks for the preparation of biologically active nitrogen-containing natural products. / Chemistry