Yeni pirolizin türevlerinin baz-katalizli karbohalkalaşma yoluyla sentezi

Pyrrolizines have been considered of great importance due to their various biological activities like anticancer, antitumor, antimalarial, anti-inflammatory, etc. They have been extensively studied in the application and synthesis of many bio-active compounds since they exhibit substantial pharmaceutical activities. Recent researches have revealed that integration of aryl or alkyl unit with structural features of pyrrolizine can be effective in the formation of new products with enriched or/and surprising biochemical effect since a number of pyrrolizines have already been proven to be active against several disorders. Within the scope of the present work, the nucleophilic cyclizations of N-alkynyl substituted proline moieties have been investigated to afford the new aryl or alkyl substituted pyrrolizine derivatives. First, the requisite N-alkynyl proline derivatives were synthesized by either the reactions of proline esters with propargyl bromide followed by the Sonogashira coupling for derivatization or via one pot A3 coupling of pyrrolidine-2-carboxylates, formaldehyde, together with a series of acetylenes yielding the precursors for cyclization products in good to moderate yield. In the following step, the nucleophilic cyclizations or more specifically the nucleophilic carbocyclizations of the N-alkynyl substituted prolines were investigated by treating them with lithium bis(trimethylsilyl)amide as a non-nucleophilic steric strong base. By employing these carbocyclization reactions, a novel series of 7-phenyl-2,3,5,7a-tetrahydro-1H-pyrrolizine carboxylates and 7-butyl-2,3,5,7a-tetrahydro-1H-pyrrolizine carboxylates have been synthesized in good to excellent yields. Summarily, a small and new library of pyrrolizines has been obtained by a simple and efficient three-steps methodology including different coupling reactions and besides, it's understood that this smooth conversion of N-alkynyl compounds into pyrrolizines have been controlled by an endo-dig cyclisation mechanism in the final step.