Synthesis of an Unnatural Amino Acid Based on Hypervalent Iodine Reagents: Exploring the Potential of Umpolung Reactions

• Autor(a) principal: Negrão, Ana Cláudia Ribeiro
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/132392
• topic: Hypervalent iodine reagent; Umpolung; −amination; Unnatural amino acids; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

The C-N bond is one of the most abundant bonds in organic compounds and has great relevance due to the diverse biological activities displayed by nitrogen-containing compounds. Additionally, there has been an increasing interest by the pharmaceutical industry in drugs and produgs bearing the amino acid moiety. Driven by the broad scope of their biotechnological application, unnatural amino acids have been receiving significant attention in the last decades. Thus, the search for efficient methods for the construction of C-N bonds assumes great importance and is always on demand. Efforts have been made towards the synthesis of unnatural amino acids, however there is still room for improvement, as their preparation often involves limitations such as complex and multi-step reactions and poor enantio- and stereoselectivity. Taking advantage of the umpolung reactivity of hypervalent iodine compounds, 4 benziodoxolone-derived iodine(III) reagents containing a transferable primary amine have been developed. These novel reagents have been employed in electrophilic a-amination reactions of suitable carbon nucleophiles leading to the desired a-aminated products in up to 83% yield. In order to be used as carbon nucleophiles, indanone-derived-b-keto esters bearing different electron-donating and electron-withdrawing ring-substituents were synthesized. Structural confirmation of the obtained products was based on NMR and IR spectroscopy and mass spectrometry. Furthermore, it was envisioned that this umpolung strategy for a-amination using hypervalent iodine reagents could serve as a promising approach towards the synthesis of unnatural a-amino acids. Thus, one a-aminated product was chosen as model substrate for proof of concept. This product was submitted to a catalytic hydrogenolysis protocol and the resulting amino ester was hydrolysed giving access to the first unnatural amino acid prepared in an umpolung strategy using hypervalent iodine reagents.