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

Direct Enantioselective Michael Reactions of Ketones and Aldehydes with Nitroalkenes under Brønsted Base/H-Bonding Catalysis

467 p.promover la a-funcionalización directa y enantioselectiva de cetonas y aldehídos con ciertascaracterísticas estructurales. Específicamente, en esta Tesis Doctoral se ha estudiado la reacción deMichael enantioselectiva de cetonas y aldehídos con nitroolefinas promovida por bases de Brønstedbifuncionales, lo que conduce a los correspondientes aductos con muy buen estereocontrol. En estasreacciones se han empleado a-hidroxicetonas saturadas e insaturadas, bencil alquinil cetonas yarilacetaldehídos como dadores de Michael eficientes.La posterior elaboración de los correspondientes aductos ha proporcionado a) mediante escisiónoxidativa de la función aciloínica en el caso de las a-hidroxicetonas, ácidos carboxílicos y aldehídos a-funcionalizados enantiopuros, b) mediante reducción de las bencil alquinil cetonas a-funcionalizadas,cetonas dialquílicas no simétricas a-sustituidas enantiopuras, c) mediante ciclación ipso intramolecularde los correspondientes aductos de las bencil alquinil cetonas, espirociclos y estructuras molecularestricíclicas.Para el estudio de la citada reacción con aldehídos una nueva familia de catalizadores de basesde Brønsted que contienen un amino ácido y el grupo escuaramida ha sido sintetizada para obtener loscorrespondientes aductos con elevada estereoselectividad.Finalmente, durante una breve estancia en la Unviersidad de Toronto en los Lash MillerChemical Laboratories, bajo la supervisión del Prof. Robert Batey, se ha llevado a cabo el estudio y lavalidación de una metodología para la síntesis de 5-aminotetrazoles 1-sustituidos obteniéndose conbuenos rendimientos

Direct Enantioselective Michael Reactions of Ketones and Aldehydes with Nitroalkenes under Brønsted Base/H-Bonding Catalysis

467 p.promover la a-funcionalización directa y enantioselectiva de cetonas y aldehídos con ciertascaracterísticas estructurales. Específicamente, en esta Tesis Doctoral se ha estudiado la reacción deMichael enantioselectiva de cetonas y aldehídos con nitroolefinas promovida por bases de Brønstedbifuncionales, lo que conduce a los correspondientes aductos con muy buen estereocontrol. En estasreacciones se han empleado a-hidroxicetonas saturadas e insaturadas, bencil alquinil cetonas yarilacetaldehídos como dadores de Michael eficientes.La posterior elaboración de los correspondientes aductos ha proporcionado a) mediante escisiónoxidativa de la función aciloínica en el caso de las a-hidroxicetonas, ácidos carboxílicos y aldehídos a-funcionalizados enantiopuros, b) mediante reducción de las bencil alquinil cetonas a-funcionalizadas,cetonas dialquílicas no simétricas a-sustituidas enantiopuras, c) mediante ciclación ipso intramolecularde los correspondientes aductos de las bencil alquinil cetonas, espirociclos y estructuras molecularestricíclicas.Para el estudio de la citada reacción con aldehídos una nueva familia de catalizadores de basesde Brønsted que contienen un amino ácido y el grupo escuaramida ha sido sintetizada para obtener loscorrespondientes aductos con elevada estereoselectividad.Finalmente, durante una breve estancia en la Unviersidad de Toronto en los Lash MillerChemical Laboratories, bajo la supervisión del Prof. Robert Batey, se ha llevado a cabo el estudio y lavalidación de una metodología para la síntesis de 5-aminotetrazoles 1-sustituidos obteniéndose conbuenos rendimientos

Ruthenium-catalyzed azide alkyne cycloaddition reaction: scope, mechanism and applications

The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.This research was funded by the National Natural Science Foundation of China (No. 21761132021), and IKERBASQUE, Basque Foundation for Science. The financial support from the University of the Basque Country UPV/EHU (UFIQOSYC11/22), Basque Government (GVgrant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GBC21) for. A.L. are also acknowledged

Enantioselective α-Aminophosphonate Functionalization of Indole Ring through an Organocatalyzed Friedel-Crafts Reaction

Chiral phosphoric acids efficiently catalyze the asymmetric Friedel−Crafts reaction of several indoles with α-iminophosphonates to afford enantioenriched hybrid α-aminophosphonate functionalized indole derivatives.Financial support from the Ministerio de Economía, Industria y Competitividad (MINECO, CTQ-2015-67871R), and by Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. We also thank SGIker (UPV/EHU) for technical support for NMR spectra (MINECO, GV/EJ, and European Social Found)

Asymmetric Ligands Derived from Carbohydrates

This thesis describes the incorporation of carbohydrate groups in thiourea, 1, or iminophosphorane, 2, ligands. Several carbohydrate acyl thioureas, 3, were synthesised from the reaction of protected and unprotected D‐glucosamine with acyl isothiocyanates, RCONCS. Internal hydrogen‐bonding forms a planar six‐membered ring, which locks the thiourea into an Z,E,Z‐anti conformation as shown by 1H NMR spectroscopy and confirmed by X‐ray structure determination of two examples. As neutral ligands to Rh(III), Rh(I), Ru(II), Pd(II), Pt(II) and Au(I) they bond through the sulfur atom with retention of the six‐membered ring and the Z,E,Z‐anti conformation. This was confirmed by two X‐ray structure determinations on Rh(III) and Pd(II) examples which also showed the new hydrogen‐bond formed by HN2 to a halide on the metal. Deprotonation of the ligands 3 with NaOAc gave anionic species which formed bidentate chelating complexes with metals. When attached to Rh(III), Ru(II) or with two thiourea bonding to Pd(II) it forms a four‐membered ring through the S and N2 atoms which retains the hydrogen‐bond. If Rh(I) or (C,Ndimethylbenzylamine‐ Pd) is used a six‐membered ring is formed through the S and O atoms which disrupts the hydrogen‐bond. This disruption of the hydrogenbond is apparent from the chemical shift of HN1. For examples where coordination led to a chiral metal complex (e.g. for Cp*RhCl(N,S‐thiourea)) NMR measurements showed that the natural chirality of the ligand did not provide any selectivity with equal proportions of the two diastereoisomers formed. Iminophosphoranes were produced by the reaction of protected sugar azides with phosphines via the Staudinger reaction. Cyclometalated complexes, 4, could not be formed directly which an X‐ray structure determination suggested was because of steric crowding of the nitrogen. An indirect transmetalation route was developed where the sugar azides were reacted with the mercurated diphosphine, Hg(2‐C₆H₄PPh₂)₂, and the resulting iminophosphoranes transmetalated with [NMe₄][AuCl₄] to produce cyclometalated Au(III) dichloride complexes. Two X‐ray structure determinations showed that the five‐membered metalocyclic ring was in an envelope conformation. The chlorides were labile and able to be displaced by PPh3 and thiosalicylic acid. A series of N‐sugar and N‐phenyl iminophosphorane Au(III) complexes were shown to catalyse the addition of 2‐methyl furan to methyl vinyl ketone

Chemically Modified Cyclofructans for Sub/supercritical Fluid Chromatography and Hydrophilic Interaction Liquid Chromatography

Given the importance of supercritical fluid chromatography, several works focused on the application use different SFC stationary phases. In this work, two new derivatized cyclofructan bonded phases with superficially porous particles are introduced in SFC. Sulfonic acid and benzoic acid groups were covalently linked to the cyclofructan molecule to make them polar and hydrophilic. These derivatives were then bonded to superficially porous particles for high-efficiency separations. This work also shows the effect of adding a small amount of water to the modified mobile phases in SFC. Traces of water in the co-solvent enhances the peak symmetry and efficiency of these new column chemistries. Moreover, we also illustrate the advantages of employing tetramethylammonium acetate for fast SFC. The new columns effectively separate polar and hydrophilic compounds, including acidic compounds, β blockers, and basic compounds of pharmaceutical and biological interest. HPLC using chiral stationary phases (CSPs) has proven to be the most widely employed method to separate enantiomers. This work presents HPLC method developments based on the existing CSPs for several chiral analytes. Chiral analytes were separated into six columns containing different chiral stationary phases (CSPs). The CSPs included with superficially porous particles bonded with two macrocyclic glycopeptides (Vancomycin, NicoShell), a cyclodextrin derivative (CD Shell-RSP: (hydroxypropyl-β-CD), a cyclofructan derivative (Isopropyl-derivatized CF6). And a cellulose derivative (IC: tris (3, 5-dichlorophenylcarbamate), and derivatized amylose (IG: tris (3-chloro-5 methyl phenyl carbamate), both bonded to fully porous particles were evaluated. The effects of various chiral selector structures, mobile phase compositions, and analyte structures have been studied

Design, synthesis and evaluation of organocatalysts in 1,4-conjugate additions to nitroolefins and alkylidene malonates

A family of cinchona-based and thiourea pyrrolidine-based organocatalysts were synthesised and fully characterised. Their catalytic activity and selectivity in 1,4-conjugate additions involving the Michael acceptor, nitrostyrene, was evaluated. Thiourea catalysts based upon the cinchona alkaloid framework were found to exhibit excellent activity and enantioselectivity (up to 95% yield and 97% ee) at loadings of 10 mol% when 1,3-diketones were employed as the pronucleophile. This result demonstrated that a thiourea cinchona catalyst was much more efficient at catalysing this Michael addition than previously reported. The same thiourea organocatalysts were employed in the first successful Michael addition of the sterically challenging dipivaloylmethane to β-nitrostyrene. Thiourea catalysts based upon the pyrrolidine motif were also employed in the Michael addition of cyclohexanone to nitrostyrene, furnishing up to 97% yield and 48% ee . The organocatalysed conjugate addition reactions involving less activated Michael acceptors, such as ,-unsaturated diesters, ketones and acrylate esters was also investigated. Although these acceptors are challenging substrates and are considerably less reactive than nitrostyrene, we herein report the first organocatalytic Michael addition to an ,-unsaturated diester using a H-bonding bifunctional catalyst. These thiourea catalysts were excellent promoters of the Michael addition of acetylacetone to dimethyl ethylidenemalonate and the yields were high (up to 99%) for all of the catalysts tested. Other Michael donors, such as nitromethane and malononitrile, were also successfully employed as nucleophiles in Michael additions to ,-unsaturated diesters, with yields and enantioselectivities of up to 88% and 48% respectively. Additionally, a family of -substituted aminoacrylates were synthesised. Ethyl-3-(dimethylamino)acrylate proved to be a good Michael acceptor in the 1,4-conjugate addition of phenyllithium (64% yield). Variable temperature NMR spectroscopy was used to analyse the restricted rotation about the C-N bond in these aminoacrylates. The barrier to rotation about the C-N bond was calculated for a series of compounds. The effect of the steric bulk associated with the various N-substitutions had on the barrier to rotation was evaluated using Charton values