Synthesis and application of symmetric organocatalysts, stability studies of atropisomeric hydrazides by dynamic-HPLC and off-column HPLC experiments

This Ph.D. research program in Molecular Design and Characterization for the Promotion of Health and Well-being: From Drug to Food (XXXVII Cycle) at the Department of Chemistry and Drug Technologies at the University of Roma "Sapienza", under the supervision of Prof. Alessia Ciogli, aimed different topics whose the common unit is chirality. We studied the preparation of Symmetric Chiral Organocatalysts and their applications in the synthesis of enantioriched molecules together with the investigation of the Stereochemical Stability of Atropoisomeric Hydrazides by dynamic-HPLC and Off-Column HPLC experiments. The Ph.D. research and obtained results were collected in three distinct chapters. Part-A has been focused on the asymmetric synthesis of warfarin and analogues catalyzed by C2-symmetric amido and C3-symmetric amino-organocatalysts. The use of small chiral organic molecules as catalysts for stereoselective reactions has captured great attention and shown impressive advancement for the past two decades to attain enantiopure molecules mainly intermediates of pharmaceutical products with green chemistry principles and without purification. Today, organocatalysts are established as the third fundamental pillar in asymmetric catalysis, next to enzymes and metal-based catalysts. As concern the topic of my thesis, despite the advances of organocatalysts, applications in the synthesis of enantioenriched warfarin and its analogues still a significant synthetic challenge remained. We developed, in high yield, C2-symmetric amido and C3-symmetric amino-organocatalysts with easy synthetic procedures. The asymmetric Michael addition of 4-hydroxycoumarin to α, β-unsaturated ketones promoted by C2-symmetric amido-organocatalysts have shown good performance in yield and enantioselectivity than C3-symmetric amide prepared by installation of 1,3,5-benzenetricarbonyl trichloride onto a (2-Amino-1,2-diphenyl-ethyl)-carbamic acid tert-butyl ester. For C3-symmetric amino-organocatalysts, we have evaluated the chiral 1,2-diphenylethylendiamine (DPEDA) as scaffold where the core was the 1,3,5-benzoltricarbonyltrichloride. A small library of 4-hydroxycoumarin and 4-hydroxyquinoline derivatives was provided through a Michael addition. In addition, this novel C3-symmetric amino catalyst was used in gram-scale synthesis and transformation of product was well deserved. The second chapter (Part B) shows the results concerning the stereo stability studies of the atropoisomeric hydrazides by dynamic HPLC and off-column-HPLC experiments. The synthesis and analysis of the energy barrier needed for the racemization process of the studied molecules using a computational approach were done by collaborating with Prof. Giorgio Bencivenni at the University of Bologna. In this section, our aim focuses on the experimental determination of energy barriers through chromatographic approaches. Compounds that can exhibit optical properties due to the presence of axial chirality are widely studied and well-developed, while hydrazides represent a new class of atropisomers to be investigated. The knowledge of the rotational stability of such molecules is crucial for designing and developing newly important pharmaceutical drugs as well as gives the highest contribution in the separation of desired active enantiomer. Mainly, we focused on dynamic-HPLC and off-column HPLC experimental studies of these chiral molecules capable of interconverting their enantiomers upon rotation of the σ bonds. Experimental data were then used to extract the kinetic parameters and the free energy barrier of hindered rotation. Specifically for the dynamic-HPLC experiments, kinetic data were obtained by using the simulation software, Auto-D-HPLC-Y2K. The study of the symmetric amido-thiourea organocatalysts for the synthesis of α-aminonitriles (Part-C) was carried out at the Institute of Organic Chemistry in the research group of Prof. Olga Garcia, University of Munster (Germany). In this part, our goal is to develop C2-symmetric thiourea-organocatalysts using a spacer containing pyridine structure where hydrogen-bonding catalysis, anion-binding and Lewis-base have become the prime focus. The performance of the prepared catalysts was evaluated in the enantioselective Strecker reaction. Unfortunately, despite the very high product yields, the catalysts are not able of inducing stereoselection. To understand this trend, the analysis of anion binding abilities of dual hydrogen bond donor symmetric amido-thiourea (for the selected Cat-2) has been performed by titration experiments. Finally, these 3-years gave me a well-rounded view of different working environment and groups that prepare me for the next endeavors.