• amine
• chemoenzymatic
• cnjugate addition
• enzyme

The topic of this thesis is the diastereoselective synthesis of 4,4’- diarylbutan-2-amines combining metallic and enzyme catalysis in a chemo-enzymatic sequential stereo-divergent approach.
In the introduction of the thesis, examples of biologically active molecules containing the 3,3’- diarylpropylamine motif are reported. Then, the sequential stereo-divergent approach for the achievement of all possible stereoisomer of a compound presenting multiple stereogenic centers is described followed by the aim of the thesis.
The section containing the results and discussion is divided into three chapters:
In chapter 1, the Rh-catalyzed enantioselective conjugate addition (ECA) of boronic acids to enones is briefly discussed. Next, the use of monodentate ligands is discussed, reporting literature examples. Particular attention is given to bile acid-based phosphite ligands and the preparation of the phosphite ligand used during the internship is thoroughly described. Lastly, the results obtained in the Rh-catalyzed ECA of boronic acids to the selected enone substrates are discussed.
In chapter 2, the use of biocatalysts in organic synthesis is introduced. Next, enzymatic methods for the synthesis of enantioenriched primary amines are presented. Particular emphasis is put on methods involving lipase enzymes, discussing some examples reported in the literature. Next, the procedure for the non-selective synthesis of 4,4’-diarylbutan-2-amines from the respective 4,4’-diarylbutan-2-one by reductive amination promoted by Ti(OiPr)4 is described in details. Finally, the results obtained in the kinetic resolution of 4,4’-diarylbutan-2-amines are discussed. Further considerations on the stereochemistry of the kinetic resolution are reported.
In chapter 3, the dynamic kinetic resolution strategy to obtain enantioenriched amines is introduced and examples of heterogeneous Pd-based racemization catalyst from the literature are presented. Next, the synthesis of Pd/ALO(OH) nanoparticle catalysts is described in details followed by the discussion of the results obtained in the Pd-catalyzed dynamic kinetic resolution of 4,4’-diarylbutan-2-amines. Afterward, examples of the use of homogeneous racemization catalysts for the dynamic kinetic resolution of amines are reported. Particular attention is dedicated to Ruthenium-based Shvo-like catalysts, with details on their mechanism and properties. The synthesis of a Shvo-like catalyst is thoroughly described and lastly, the results obtained in the Ru-catalyzed dynamic kinetic resolution and racemization experiments on 4,4’-diarylbutan-2-amines are discussed.
Finally, general conclusions are drawn followed by the experimental section.