| Summary: | Natural products from terrestrial plants and microorganisms have long been a traditional source of drugs. For centuries humans have been looking on their environment for medicines to treat illnesses. But unlike terrestrial sources, marine habitat has not been so extensively studied; this field awaited refinements in technologies to collect the source organisms, and development of more advanced analytic techniques to better understand the more complex isolated compounds. Since 1950s this field has suffered an exponential push; considering that water covers around a 70% of the earth’s surface, and 32 of the 33 animal phyla are represented in aquatic media, marine habitat represents an extensive source of new bioactive molecules.
Synthesis represents a powerful tool to use on our behalf for structure determination and supply of material for clinical tests on the development of new bioactive drugs. This thesis is focused on the synthesis and structure determination of bioactive compounds isolated from marine habitat: barmumycin and phormidolides B-D. Our strategy lied on the identification of the target by comparison of the available data from the natural product with data of our synthetic compounds.
Barmumycin was isolated from an extract of a marine actinomycete and found to be cytotoxic against various human tumor cell lines. Macrolactone 1 was assigned on the basis of 1H and 13C NMR spectroscopy. Compound 1 was synthesized by two different routes. The main goal of both our synthesis is the alkylation of a weak nucleophilic aniline by this two different methods, which are based on a reductive amination and on a nucleophilic substitution.
However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure. New structure 2, based on a pyrrolidine with an exocyclic double bond linked to an aromatic ring by an amide bond, was proposed. On the basis of the enantioselective synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of 2.
Polyketide macrolides are a class of secondary metabolites with interesting biological activities and complex structure and stereochemistry. A general overview of THF-containing macrolactones has been compiled, a class of compounds with high potential as drug candidates. Described are isolation, structure determination and the described synthesis up to 2012.
Phormidolides B-D are polyketide macrolides related to oscillariolide and phormidolide A. These compounds were isolated from an active organic extract of a sponge of the Petrosiidae family and presented antitumor activity. The planar structure of Phormidolides B-D was determined on the basis of comparison of the spectra of the natural product with oscillariolide and phormidolide A and with the study of NMR spectra of isolated compounds. The relative stereochemistry of the macrocyclic core was only determined for 4 out of the 6 stereocenters of the macrocycle. The next target of this thesis is the enantioselective synthesis of the macrocyclic core of phormidolides B-D.
The best synthetic pathway to the synthesis of the macrolide core of phormidolides B-D was selected with a not-stereoselective synthetic study. A strategy based on an olefin metathesis was discarded. On the other hand a strategy based on a Julia-Kocienski olefination completed the preparation of the macrocycle as a mixture of diasteromers.
A robust and efficient methodology for the enantioselective synthesis of the macrolide core of phormidolides B-D was developed from the Julia-Kocienski olefination route. The strategy is versatile and can be used for the synthesis of the different diastereomers of the macrocycle making the appropriate changes in the starting materials and chiral inductors. The selective synthesis of the Z-trisubstituted double bond present on the macrocyclic core of phormidolides B-D was the objective of an optimization process that culminated with the use of a 1-(tert-butyl)tetrazolyl sulfone to succesfully afford the formation of the endocyclic alkene with excellent stereoselectivity.
It is a fact that the discovery of New Molecular Entities (NME) requires innovation, new ideas and processes. Scientists have learned over the years how to overcome the problems often associated with marine derived natural products development and this work is one more example of this scenario. === Els productes naturals extrets de plantes i organismes terrestres han estat durant molts anys font d’inspiració per a la preparació de fàrmacs. Per contra el medi marí no ha rebut tanta atenció, la química dels productes naturals marins ha hagut d’esperar que les tecnologies es modernitzessin per facilitar la recol•lecció de mostres i la determinació estructural dels productes extrets, que presenten molta més complexitat estructural que els productes d’origen terrestre. En els últims 50 anys, aquest camp ha estat objecte de gran interès ja que representa una font de noves molècules bioactives, amb estructures i mecanismes d’acció diferents dels coneguts.
En aquesta tesi s’ha treballat en dos projectes focalitzats en l’estudi de molècules d’origen marí com a fàrmacs, utilitzant la síntesi com a eina en els primers estadis de desenvolupament ja que la quantitat aïllada de les fonts naturals només serveix per fer una primera aproximació a estructura i activitat.
La barmumicina és un producte natural amb activitat biològica del que s’ha confirmat l’estructura gràcies a la síntesi. El compost que es va determinar en la primera assignació s’ha obtingut per síntesi i s’ha comparat amb el producte natural duent a la conclusió que l’estructura no era la correcta. La reassignació i síntesi d’una nova molècula proposada ha confirmat la identitat d’aquest producte natural.
Les formidolides B-D són productes naturals d’alta complexitat estructural. S’ha desenvolupat la síntesi del fragment macrocíclic de les formidolides B-D, abordant dues aproximacions per a la formació de l’alquè trisubstituit; una basada en una metàtesi d’olefines i l’altra en una olefinació de Julia-Kocienski. La segona ruta s’ha seleccionat com a ruta per adaptar a procediments estereoselectius. Adaptant aquesta estratègia, s’ha desenvolupat una metodologia que permet sintetitzar eficaçment i de forma enantioselectiva el macrocicle de les formidolides B-D; l’estratègia és versàtil, ja que canviant els materials de partida o els auxiliars quirals es pot dirigir la síntesi cap al diastereòmer desitjat. El punt clau de la síntesi ha estat la formació del doble enllaç trisubstituitZ amb bon rendiment i selectivitat, pel qual s’ha dut a terme una optimització del procés. S’han sintetitzat tres estereoisòmers i la comparació dels espectres de RMN del producte natural i els sintètics ha permès establir la configuració relativa dels esterocentres que presenta la macrolactona del producte natural.
Els resultats presentats demostren la utilitat de la síntesi en el desenvolupament de productes naturals, ja sigui en la determinació d’estructura, estereoquímica o en la producció en sí.
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