Aproximacions sintètiques per a la preparació estereoselectiva de noves quinolil i pirazolilglicines i per a la preparació en fase sòlida de llibreries de benzotiazoles, 1,2,4-triazines i benzimidazoles

Abstract

El treball experimental que ha permès redactar la present Tesi Doctoral ha estat dividit en dues parts. A la primera part es presenten els resultats referents a la síntesi estereocontrolada de noves heteroarilglicines (quinolil i pirazolilglicines) a partir de cetones acetilèniques, substrats quirals que permeten accedir a l'esquelet de diferents heterocicles (quinolines i pirazoles), la posterior obtenció dels corresponents quinolil i pirazolil--aminoalcohols i les diferents metodologies d'oxidació per tal d'accedir a les corresponents quinolil i priazolilglicines objectiu. A la segona part d'aquesta memòria s'ha estudiat, en dissolució, l'habilitat del grup alquilsulfona com a grup sortint eficaç en reaccions d'ipso-substitució nucleofilica. El desenvolupament d'aquesta reacció ha servit de punt de partida per a la creació de llibreries d'heterocicles amb alta diversitat molecular i potencial interès biològic sobre fase sòlida.

These work have been divided in two sections. In the first section, a new and efficient methodology towards the stereocontrolled synthesis of novel -acetylenic ketones containing a masked -amino acid functionality in enantiomerically pure form has been developed. This new chiral building block is the starting material for the synthesis of enantiomerically pure quinolyl and pyrazolylglycines, important structures with potential biological activity and very useful for the synthesis of peptidomimetics. The methods begins from the Garner's aldehyde and takes place through an alkyne derivative via a carbonyl-alkyne homologation reaction. Condensation of the lithium acetylide at low temperatures with different aldehydes yielded the corresponding propargyllic alcohol derivatives in good yields, which under mild oxidative conditions gave the corresponding acetylenic ketones algmost quantitatively.In the second part of this work, the ability of alkylsulfonyl groups as efficient leaving groups in heteroaromatic mucleophilic ipso-substitution reactions has been studied. The rational behind this study has been the possibility of transferring the developed methodology to the solid support and thus to synthesize in a parallel fashion a small library of molecularly diverse heterocycles with potential biological interest. An in solution optimised methodology has been successfully transferred to the solid support and a small library of molecularly diverse benzothiazoles (-excedent heterocylces) was prepared in a parallel fashion in good overall yields and purities of the final products.