DESIGN AND SYNTHESIS OF ALPHA-AMINO ACID AND MORPHOLINO `CHIMERA' BUILDING-BLOCKS

SCUOLA DI DOTTORATO IN SCIENZE E TECNOLOGIE CHIMICHE AA 2009/2010 XXIII CICLO Chimica Industriale Dottorando: Foschi Francesca Matr.R07809 Tutor: Prof. Dario Landini Co-Tutor: Dr. Michele Penso Design and synthesis of -amino acid and morpholino ‘chimera’ building-blocks Non-natural quaternary α-aryl-α-amino acids are of great interest for their potential intrinsic bioactivity.1 here we reported the stereoselective conversion of a series of N-aryl-sulphonyl-α-amino acid t-butyl esters into the corresponding N-alkyl-α-aryl-α-amino esters. These α-quaternary compounds are obtained with good enantioselectivities (ee up to 98%) and high yields. This methodology has been applied to the transposition of both cyclic tertiary sulfonamide esters2 (i.e. proline derivatives) and open chain secondary compounds.3 These latter, in the first step, are N-alkylated and then rearrange to the target products. This protocol has also been applied to the degradative rearrangement of a series of arylsulfonamido esters bearing on the aromatic ring different electron withdrawing groups. The high enantioselectivity reached in this process, indicates that the stereochemical information is transferred from the N-alkylated sulfonamide A to the final rearranged product 2 via a chiral non-racemic enolate B. 4,5,6 This intermediate, through a Re-face attack, evolves into a chiral spiro-Meisenheimer complex that, in turn, undergoes the stereoselective S-Cα migration of the aryl group, with loss of sulphur dioxide. As a second part of this PhD work, we improved a synthesis of 2,6-disubstituted morpholines by the double and consecutive oxirane ring-opening under SL-PTC, followed by regioselective conversion of only one hydroxy group into a leaving group. Our background in the synthesis of 2,6-disobstituted morpholines, made us focus our attention on improving a chemical synthesis of morpholino monomer alternative to the Summerton approach, who is the sole known synthesis.