L’obtenció de lligands quirals eficients i de fàcil accés segueix essent un dels objectius principals en catàlisi. Les fosfines estereogèniques voluminoses han mostrat ser molt eficients en un ampli ventall de reaccions catalítiques. No obstant, la seva síntesis de forma enantiomèricament pura és molt sovint complicada. Podem considerar que els mètodes més efectius per a la construcció de fòsfor estereogènic són els desenvolupats per Jugé i Evans basats en l’obertura d’oxazafosfolidines enantiopures i la desprotonació enantioselectiva de fosfino-borans, respectivament. Aquests mètodes, tanmateix, presenten limitacions i desavantatges. Aquest fet confereix atractiu al desenvolupament de nous processos per a la síntesi de fòsfor estereogènic. En la present tesi doctoral, es va estudiar la condensació de fenil i tert-butilfosfines amb el (cis)-1-amino-2-indanol. Aquestes ens conduí a les corresponents oxazafosfolidines amb bon rendiment i diastereoselectivitats de fins a 18 : 1. La condensació amb aquest aminoalcohol ens proporcionà oxazafosfolidines amb funció NH lliure. Justament aquesta nova funcionalitat s’ha revelat clau en la química d’obertura d’anells d’oxazafosfolidines. Pel que fa l’obertura d’anell de la 2-feniloxazafosfolidina amb organolítics, aquestes transcorregueren amb inversió o retenció depenent de la substitució sobre l’àtom de nitrogen. Quan tenim un grup NH, l’obertura transcorre amb inversió mentre que quan el nitrogen està substituït amb un metil s’observa retenció tal i com havia descrit Jugé i col•laboradors. En la mateixa línia, l’obertura d’anell de la 2-tert-butiloxazafosfolidina amb el grup NH lliure amb organomagnesians té lloc de forma totalment estereoselectiva a temperatures elevades amb inversió. També s’ha desenvolupat una obertura reductiva de la 2-tert-butiloxazafosfolidina mitjançant l’ús combinat d’una font d’hidrur i un magnesià. Aquesta obertura també és totalment estereoselectiva i no té precedents en la literatura. Els productes d’obertura de la 2-feniloxazafosfolidina es van hidrolitzar segons la metòdica descrita per Jugé a les corresponents metoxifosfines amb bons rendiments i elevats ee. Els productes d’obertura de la 2-tert-butiloxazafosfolidina amb grups alquil es van poder trencar de l’auxiliar quiral amb Li/NH3(liq.) obtenint-se les aminofosfines amb ee>99%. Alternativament, es va desenvolupar una seqüència d’eliminació i posterior hidròlisis que permet alliberar les aril-tert-butilaminofosfines amb bons rendiments i ee>99%. Aquests es va derivatitzar la tert-butilaminofosfina en diferents compostos. Finalment també es va descriure una nova família de lligands basats en fosfinosulfonamides. Es van descriure nous complexos de Rh-fosfinosulfonamida els quals es van aplicar a la reacció de cicloaddició [2+2+2] intramolecular de manera exitosa. Aquests complexos ens van permetre superar amb escreix els resultats descrits prèviament. Finalment, es va dissenyar una nova família de lligands que hem anomenat ThaxPHOS. Es van emprar aquests en la reacció de Pauson-Khand intermolecular catalítica enantioselectiva. La desprotecció i complexació amb dicobalt dóna molt bon resultats i bones diastereoselectivitats gràcies a equilibracions tèrmiques. Inicialment, es va dissenyar una estratègia estequiomètrica enantioselectiva per a l’obtenció de l’adducte de Pauson-Khand amb acetilè lliure sense emprar l’acetilè en forma de gas. L’aplicació d’aquests complexos en la reacció catalítica han donat els millors resultats mai descrits en aquest camp. S’ha plantejat un nou mecanisme catalític per justificar els resultats obtinguts. / The synthesis of efficient and easily affordable chiral ligands are one of the main goals in catalysis. Bulky stereogenic phosphine have demonstrated to be excellent ligands in a broad range of catalytic reactions. Furthermore, their synthesis in an optically pure form is usually difficult. We can consider that the method developed independently by Jugé and Evans are the most effective in this field. Nevertheless, these methods have some drawbacks. These downsides need to be improved and new synthetic methodologies need to be developed to obtain stereogenic phosphorus compounds. In this doctoral thesis we studied the condensation of phenyl- and tert-butylphosphines with (cis)-1-amino-2-indanol. These allowed us to obtain the corresponding oxazaphospholidines with excellent yields and diastereoselectivities (up to 18 : 1). These condensations allowed us to get a free NH functionality. We saw as this secondary amine was the key for our ring-opening strategy. Taking advantage of this group, we performed the ring-opening reaction allowing us to obtain the corresponding ring-opened product with inversion of configuration on the phosphorus atom. This reaction was carried out with total diastereoselectivity, and the ring-opened products obtained from 2-phenyloxazaphospholidine were hydrolyzed following the Jugé procedure described in literature. We obtained the corresponding methoxyphosphine with excellent yields and high ee. The ring-opened products obtained from 2-tert-butyloxazaphospholidine with alkyl groups were reductively cleaved with Li/NH3(l) affording the corresponding aminophosphine with ee>99%. Alternatively, we developed a new strategy based on elimination-hydrolysis to free the corresponding aryl-tert-butylaminophosphines with excellent results and optically pure. Subsequently, we described a new ligand family based on phosphinosulfonamide. We described new complexes of Rh-phosphinosulfonamide and we tested them in the intramolecular cycloaddition [2+2+2] significantly improving on the previous results described. Finally, we designed a new family of PnP* ligands called ThaxPHOS. These ligands were used in the enantioselective catalytic intermolecular Pauson-Khand reaction. The deprotection and successive coordination gave excellent yields and diastereoselectivities due to thermal equilibration. We used ThaxPHOS ligands in this reaction and we described the best results ever obtained in this field and we described a new catalytic mechanism to explain our results.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA. / Fundação Para a Ciência e a Tecnologia (FCT)

The aim of my Thesis was to develop a general synthetic methodology for the preparation of long helicenes equipped with suitable functional groups that control their solubility or serve as anchoring groups for attachment to metallic surfaces, especially gold. The well-established transition metal catalyzed [2+2+2] cyclotrimerization of triynes was selected as the key scaffold-forming transformation in the synthesis of long helicenes because of its high regioselectivity, atom efficiency, functional group tolerance and general robustness. A modular approach was used for the preparation of the starting oligoynes, thus enabling a high level of their structural diversity. Individual resorcinol- based aromatic building blocks were interconnected by Sonogashira cross-coupling reactions, providing complex cyclization precursors encompassing up to twelve alkyne units pre-arranged for the multiple [2+2+2] cycloisomerization to produce three six- membered rings from each set of three neighboring alkyne units. Thus, a small series of long helicenes with up to 19 rings constituting the helical scaffold was synthesized. The quadruple cyclization leading to the longest oxahelicene prepared to date was performed in a high-temperature-high-pressure flow reactor at 250 řC in the presence of CpCo(CO)2. The set of...