Photochemical amino acid decarboxylative borylation: “Lighting” the way towards new proteasome inhibitors


Rodríguez González, Laura


Boron-containing amino acids and peptidomimetics represent privileged structures in the development of new anti-cancer drugs, especially in the field of proteasome inhibition. Most of the currently existing methods for the preparation of these molecules are based on their stepwise construction. A direct transformation of conventional amino acids into the corresponding amino boronic acids by means of a decarboxylative borylation would be a very useful tool in this respect. Towards this goal, two strategies are proposed for the activation and subsequent radical decarboxylation of the carboxylic group of α, b, and g model amino acids.
Firstly, based on the group's previous experience in the synthesis and reactivity of hypervalent iodine compounds, radical generation through the transient formation of an oxygen-iodine(III) bond is considered. For this purpose, it is necessary to form the key intermediates PhI(O2CR)2, being the -O2CR group an anion of amino acid, in order to subsequently perform the photolytic cleavage of the O-I bond. Secondly, coupling with N-hydroxyphthalimide is proposed to generate ester-type derivatives capable of forming radicals under the application of light. In both strategies, the trapping of the radicals with boronic species is proposed.
Among the achievements to be highlighted in this methodological study is the optimization of a method to generate λ3-iodane derivatives by means of a ligand exchange process applying high temperatures and reduced pressure. Likewise, it is worth mentioning the optimization of the parameters that affect the photolytic process, which has made it possible to achieve high efficiency for the decarboxylative borylation process of N-hydroxyphthalimide esters derived from amino acids. Among the substrates included in the study is the g-aminobutyric acid, GABA, the main inhibitory neurotransmitter in the central nervous system as well as some of its key analogues including the drugs Gabapentin and Pregabalin.



Cuenca González, Ana Belén 
Shafir, Alexandr


IQS SM - Master’s Degree in Pharmaceutical Chemistry