Asymmetric Synthesis of Highly Functionalized alpha-Amino Acids via Radical Intermediates

Enantiopure α-amino acids (α-AA) play a key role in nature being building blocks for the construction of a broad range of peptides and proteins. At the moment the scientific community pays attention to the non-proteinogenic (or unnatural) AAs due to their wide use in the modification of the structure of peptides and proteins in order to improve their bioactivity and stability. Furthermore, unnatural AAs provide a unique opportunity for modulation of artificial enzymes with novel biological activities.

Non-proteinogenic AAs are often inspired by the natural structure and can be synthesized either by enzymatic conversion or organic synthetic methods. On the other hand, enantiopure unnatural AAs are broadly applied in asymmetric catalysis as organocatalysts and as ligands for transition-metal catalysis. However, due to the lack of synthetic methodologies, their structural diversity is strongly limited. For example, the introduction of new functional groups at the α- or β-carbon of AA could lead not only to the creation of synthetically new unnatural AAs, but also opens up a wealth of opportunities for its application in both biology and organic synthesis. Among them perfluoroalkyl (Rf)-containing α-AAs are great of interest because perfluoroalkyl groups can improve their stability, increase the lipophilicity of target molecules, and can act as “labels” in protein structure studies. However, the methods of asymmetric synthesis of such AAs are scarce and, in most cases, restricted by the introduction of the trifluoromethyl (CF3) group only. From the point of view of synthetic organic chemistry, there remains a great need for new methods that can expand the availability and diversity of unnatural AAs.

Given this hurdle, the collaborative work aims to develop novel catalytic concepts for the synthesis of unnatural perfluoroalkyl-containing AAs through the post-functionalization of the chiral nickel(II) complexes of Schiff bases bearing AA fragments with unsaturated motifs (double and triple C-C bonds). It is proposed to modify the AA residue using the various in situ generated radical intermediates from the hypervalent-iodine-based reagents under catalytic manner including transition-metal catalysis, photocatalysis, and electrochemical synthesis. Further, functionalized enantiopure AAs that are important for pharmaceutical studies or synthesis of bioactive compounds, will be isolated from the nickel complexes through one-step chemical decomposition under an acidic media, while the chiral auxiliary will be recovered from the reaction mixture, and reused to obtain the starting nickel complexes. This method will allow to obtain enantiopure unnatural AAs that cannot be synthesized using classical methods including Michael or Mannich additions, and etc. Besides the introduction of the fluorinated motifs, successful catalytic methodologies will also be used for the incorporation of other vital functional groups into the structure of AAs including nitro (NO2), azido (N3), alkoxy (OR), and cyano (CN) groups.

It was demonstrated that the chiral nickel(II) complexes are perspective synthetic tools for the development of efficient methodologies to generate enantiomerically pure AAs and they already applied in industrial processes. Therefore, we are convinced that successful methodologies developed within this research collaborative platform will be extensively used by chemists both in the laboratory and in industry.

Participants:

University of Fribourg:

A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences (INEOS RAS):