Estudio de la reacción de Mannich organocatalizada de Boc-cetoiminas derivadas de 1h-pirazol-4,5-diona con 1,3-dicetonas

Facultad de Ciencias TRABAJO FIN DE GRADO GRADO EN QUÍMICA ESTUDIO DE LA REACCIÓN DE MANNICH ORGANOCATALIZADA DE BOC-CETOIMINAS DERIVADAS DE 1H-PIRAZOL-4,5-DIONA CON 1,3DICETONAS Autor: Cristopher Niño Rodríguez Tutor: José María Andrés García Co-Tutora: Marta Gil Ordóñez Trabajo Fin de Grado Cristopher Niño Rodriguez Índice 1. Introducción ............................................................................................................... 7 2. Objetivos y plan de trabajo..................................................................................... 17 2.1. Síntesis de N-Boc-cetoiminas derivadas de pirazolonas ............................................... 17 2.2. Estudio del alcance y limitaciones sintéticas de la reacción de Mannich organocatalizada de N-Boc-cetoiminas derivadas de pirazolonas con β-dicetonas ...... 17 2.3. Estudio de la transformación de los aductos obtenidos en nuevos diheterociclos enantioenriquecidos mediante reacción con 1,2-dinucleófilos ..................................... 18 3. Resultados y discusión ............................................................................. 19 3.1. Síntesis de N-Boc cetoiminas derivadas de pirazolonas ......................... 19 3.2. Reacción de Mannich enantioselectiva de N-Boc cetoiminas derivadas de pirazolonas con β-dicetonas ............................................................................................................ 20 3.3. Síntesis de derivados de 4-pirazolil-4-aminopirazolona y de 4-isoxazolil-4aminopirazolona enantioenriquecidos .......................................................................... 24 4. Conclusiones ............................................................................................................. 29 5. Experimental ............................................................................................................ 31 6. Bibliografía ............................................................................................................... 49 7. Supporting information .......................................................................................... 51 7.1. NMR Spectra for New Compounds ............................................................................. 51 7.2. HPLC profiles .............................................................................................................. 74 Trabajo Fin de Grado Cristopher Niño Rodriguez 1 RESUMEN En este trabajo hemos utilizado una serie de N-Boc cetoiminas derivadas de pirazolin-5onas como electrófilos en reacciones de Mannich enantioselectivas con diferentes compuestos 1,3-dicarbonílicos. Este método proporciona una vía directa de acceso a derivados de 4-amino-5-pirazolona con un estereocentro tetrasustituido, que contienen dos motivos estructurales privilegiados, las subestructuras de β-dicetona y de pirazolinona. Los aductos se obtienen con excelentes rendimientos químicos (hasta 90 %) y enantioselectividades (hasta 94:6 er) empleando sólo un 2 mol % de una escuaramida bifuncional derivada de la quinina como organocatalizador para una amplia variedad de sustratos. Además, se ha demostrado la utilidad de los productos obtenidos mediante su transformación en un solo paso en sistemas diheterocíclicos (4-pirazolilpirazolona y 4-isoxazolil-pirazolona) enantioenriquecidos de interés biológico. ABSTRACT A series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in enantioselective Mannich reactions with different 1,3-dicarbonyl compounds. This method provides a direct pathway to access to the 4-amino-5pyrazolone derivatives bearing a tetra-substituted stereocenter and containing two privileged structure motifs, the β-diketone and pyrazolinone substructures. The aducts are obtained in excellent yields (up to 90%) and enantioselectivities (up to 94:6 er) by employing a very low loading of 2 mol % of a quinine-derived bifunctional squaramide as a organocatalyst for a wide range of substrates. In addition, the utility of the obtained products was demonstrated through one step transformations to enantioenriched diheterocyclic systems (4-pyrazolyl-pyrazolone and 4-isoxazolyl-pyrazolone) of biological interest. 2 Trabajo Fin de Grado Cristopher Niño Rodriguez 3 ABREVIATURAS Y ACRÓNIMOS 𝐀𝐍 Adición nucleófila Ar Arilo ATR Reflectancia total atenuada (Attenuated Total Reflection) Boc terc-Butoxicarbonilo (tert-butoxycarbonyl) ◦C Grado(s) centígrado(s) Cat. Catalizador d Día(s) DMSO Dimetil sulfoxido (dimethyl sulfoxide) dr Diastereomeric ratio (Relación de diastereoisómeros) E Eliminación ee Exceso enantiomérico ent Enantiómero equiv Equivalente(s) er Enantiomeric ratio (Relación de enantiómeros) Et Etilo g Gramo(s) GC/MS Cromatografía de gases acoplada a espectrometría de masas h Hora(s) HPLC High Performance Liquid Chromatography (Cromatografía líquida de alta resolución) HRMS High Resolution Mass Spectrometry (Espectrometría de masas de alta resolución) Hz Hertzio(s) iBu Isobutilo iPr Isopropilo IR Infrarrojo (Infrared) Trabajo Fin de Grado Cristopher Niño Rodriguez 4 J Constante de acoplamiento Lit. Literatura 𝛌 Longitud de onda M Molaridad Me Metilo mg Miligramo(s) MHz Megahertzio(s) mL Mililitros(s) mm Milímetros(s) mmol Milimol(es) mol% Tanto por cien molar M.p. Melting point (Punto de fusión) MS 4Å Tamiz molecular 4Å (Molecular Sieves) m/z Relación masa/carga nm Nanómetro(s) NMR/RMN Nuclear Magnetic Resonance (Resonancia magnética nuclear) Ph Fenilo ppm Parte(s) por millón QTOF Cuadruple Time Of Flight (Cuadrupolo de tiempo de vuelo) R Sustituyente Rdto. Rendimiento t Tiempo ta/rt Temperatura ambiente (room temperatura) tBu terc-Butilo THF Tetrahidrofurano (tetrahydrofuran) TLC Cromatografía en capa fina (Thin Layer Chromatography) TMS Tetrametilsililo, tetrametilsilano Trabajo Fin de Grado Cristopher Niño Rodriguez 5 tR Tiempo de retención (Retention time) UV Ultravioleta Trabajo Fin de Grado Cristopher Niño Rodriguez 12 Esquema 5 El grupo de Enders ha estudiado a su vez la reacción dominó asimétrica azaFriedel-Crafts/N,O-acetalización de 2-naftoles con Boc-cetoiminas derivadas de pirazolinona catalizada por sólo un 0.5 mol% de una escuaramida bifuncional quiral derivada de la quinina (Esquema 6). 14 Esquema 6 La reacción proporciona derivados de furanonaftopirazolidinona con dos estereocentros vecinales tetra-sustituidos con excelentes rendimientos (95-98%) y 14 U. Kaya, P. Chauhan, S. Mahajan, K. Deckers, A. Valkonen, K. Rissanen, D. Enders. Angew. Chem. Int. Ed. 2017, 56, 15358. Trabajo Fin de Grado Cristopher Niño Rodriguez 13 estereoselectividades (>99:1 dr y 97–98% ee). Una reactividad diferente se observa en el caso de 1-naftoles y otros fenoles ricos en electrones, que conducen a los aductos azaFriedel-Crafts con un rendimiento del 70-98% y 47-98% ee. Posteriormente, Deng ha descrito la reacción asimétrica aza-Friedel-Crafts de Boc-cetoiminas derivadas de pirazolonas con hidroxiindoles catalizada por una escuaramida bifuncional derivada de la quinina (Esquema 7). 15 Esta reacción funciona también con fenoles ricos en electrones, proporcionando los productos deseados con elevados rendimientos (hasta 99%) y enantioselectividades (91-99% ee). Esquema 7 Du ha estudiado la reacción de Mannich enantioselectiva de N-aril cetoiminas derivadas de pirazolin-4,5-dionas con 3-fluorooxindoles que permite la preparación de derivados de amino-pirazolona-oxindol fluorados con dos estereocentros adyacentes tetrasustituidos (Esquema 8). 16 De todos los organocatalizadores utilizados, la escuaramida derivada de la hidroquinina fue la que proporcionó mayores rendimientos químicos (hasta 98%) y diastereoy enantioselectividad (>20:1 dr y >99% ee). 15 Z.-T. Yang, W.-L. Yang, L. Chen, H. Sun, W. i-P. Deng. Adv. Synth. Catal. 2018, 360, 2049. 16 Q.-D. Zhang, B.-L. Zhao, B.-Y. Li, D.-M. Du. Org. Biomol. Chem. 2019, 17, 7182. Trabajo Fin de Grado Cristopher Niño Rodriguez 14 Esquema 8 No obstante, la reacción no es extrapolable a las N-Boc cetoiminas derivadas de pirazolona. En las condiciones optimizadas de reacción, el rendimiento químico y la estereoselectividad conseguidas con estos sustratos no fueron satisfactorios (Esquema 9). Esquema 9 Shao 17 ha descrito una reacción de Mannich de Boc-iminas derivadas de pirazolonas con propionaldehido, catalizada por aminas secundarias acíclicas quirales, que proporciona los correspondientes aductos de manera enantiodivergente con excelentes diastereoselectividades y buenas relaciones enantioméricas (Esquema 11). La simple pero estratégica modificación del sustituyente nitrogenado de la amina secundaria del catalizador (de N-i-Bu en Ia al grupo N-Me en Ib), manteniendo la misma configuración del estereocentro, condujo a la inversión de la enantioselectividad a través de la modulación de la conformación del catalizador. 17 J. Dai, Z. Wang, Y. Deng, L. Zhu, F. Peng, Y. Lan, Z. Shao. Nat. Commun. 2019, 10, 5182. Trabajo Fin de Grado Cristopher Niño Rodriguez 15 Esquema 10 En la literatura no existe ningún antecedente de adición enantioselectiva organocatalizada de compuestos 1,3-dicarbonílicos a Boc-cetoiminas derivadas de pirazolonas. Esta reacción es de gran interés por la posibilidad de transformar los aductos obtenidos en nuevos diheterociclos (pirazolil-pirazolonas, isoxazolilpirazolonas), con propiedades biológicas potencialmente interesantes, mediante su reacción con diferentes 1,2-dinucleófilos (hidracinas diferentemente sustituidas, hidrocloruro de hidroxilamina) (Esquema 11). Esquema 11 En un trabajo previo realizado en el grupo de investigación en el que he realizado este TFG, han estudiado la adición enantioselectiva de acetilacetona a la NBoc cetoimina 1 promovida por organocatalizadores bifuncionales quirales en diferentes condiciones experimentales (disolvente, temperatura, estequiometría, % de catalizador). Las condiciones optimizadas de reacción se corresponden con la utilización de tolueno como disolvente, temperatura ambiente, 1.1 equiv de dicetona y un 2% de la escuaramida bifuncional I, derivada de la quinina (Esquema 12). Trabajo Fin de Grado Cristopher Niño Rodriguez 16 Esquema 12 Como continuación de este trabajo, en este TFG nos planteamos el estudio del alcance de esta reacción, utilizando para ello pirazolonas y β-dicetonas diferentemente sustituidas, y la transformación de los aductos obtenidos en nuevos derivados de pirazolil-pirazolona e isoxazolil-pirazolona enantioenriquecidos. Trabajo Fin de Grado Cristopher Niño Rodriguez 17 2.OBJETIVOS Y PLAN DE TRABAJO 2.1. Síntesis de N-Boc-cetoiminas derivadas de pirazolonas. En primer lugar, prepararemos las N-Boc cetoiminas derivadas de pirazolonas, diferentemente sustituídas, mediante un procedimiento en dos etapas: transformación de las pirazolin-5-onas en las correspondientes pirazolin-4,5-dionas, seguida de reacción aza-Wittig con N-Boc-trifeniliminofosforano (Esquema 1). Esquema 1 2.2. Estudio del alcance y limitaciones sintéticas de la reacción de Mannich organocatalizada de N-Boc cetoiminas derivadas de pirazolonas con β-dicetonas. Inicialmente, estudiaremos la reacción de N-Boc cetoiminas derivadas de pirazolona (1) diferentemente sustituidas con acetilacetona promovida por la escuaramida bifuncional I derivada de la quinina, para extender posteriormente el estudio a otras β-dicetonas (Esquema 2). Esquema 2 Trabajo Fin de Grado Cristopher Niño Rodriguez 18 Estudiaremos la influencia de la naturaleza de los sustituyentes R y Ar de la pirazolona y R1 y R2 de la dicetona en la velocidad de reacción, en el rendimiento químico y en la enantioselectividad de los aductos obtenidos. 2.3. Estudio de la transformación de los aductos obtenidos en nuevos diheterociclos enantienriquecidos mediante reacción con 1,2dinucleófilos. Finalmente, en este tercer apartado estudiaremos la transformación de los aductos 2, obtenidos en el apartado anterior, en nuevos derivados de 4-pirazolil-4aminopirazolona (3) y 4-isoxazolil-4-aminopirazolona (4) enantioenriquecidos mediante su reacción respectiva con hidrato de hidracina o hidrocloruro de 4-clorfenilhidracina e hidrocloruro de hidroxilamina (Esquema 3). Comprobaremos en todos los casos que dichas transformaciones transcurren sin erosión alguna de la enantioselectividad. Esquema 3 Paralelamente, habrá que realizar la síntesis de los racematos de todos los compuestos preparados para su resolución posterior mediante HPLC quiral. Trabajo Fin de Grado Cristopher Niño Rodriguez 19 3. RESULTADOS Y DISCUSIÓN 3.1. Síntesis de N-Boc cetoiminas derivadas de pirazolonas. La síntesis de las 1H-pirazol-4,5-dionas (1a-g) se realiza mediante la condensación de las pirazolonas de partida con nitrosobenceno en metanol a reflujo catalizada por K2CO3, seguida de la hidrólisis ácida de las feniliminas intermediarias (Esquema 1). Éstas se convierten posteriormente en las N-Boc cetoiminas 2a-g mediante la reacción aza-Wittig con N-Boc-trifeniliminofosforano en 1,4-dioxano a reflujo, según el procedimiento descrito por Enders.10 Esquema 1. Reactivos y condiciones: (i) 1. PhNO, K2CO3 (20 mol%), MeOH, reflujo. 2. 2N HCl, THF, ta. (ii) BocN=PPh3, 1,4-dioxano, reflujo. La mayoría de las Boc-iminas de partida habían sido sintetizadas previamente en el grupo. Por ese motivo sólo tuve que realizar la síntesis de las iminas 2a (R = Me) y 2g (R = Ph), las más utilizadas en las transformaciones estudiadas, y cuyos rendimientos son los únicos que figuran en el Esquema 1. El mecanismo de la reacción de condensación de la pirazolona con nitrosobenceno es referible al de la condensación aldólica (Esquema 2). En la primera etapa, el carbonato potásico sustrae el hidrógeno en α de la pirazolona para generar un enolato (I) que se adiciona al nitrosobenceno para formar el intermedio II. Éste se transforma en el nitrosoenolato III, mediante un equilibrio tautomérico catalizado por base, que conduce a la fenilimina final mediante una eliminación E1CB. Trabajo Fin de Grado Cristopher Niño Rodriguez 20 Esquema 2 En el Esquema 3 se muestra el mecanismo de la reacción de la reacción azaWittig de las pirazolin-4,5-dionas con N-Boc-trifeniliminofosforano. Las reacciones de Aza-Wittig son similares a las reacciones de Wittig y consisten en la reacción de un iluro de fosfonio, en este caso un iminofosforano, con el grupo carbonilo de la pirazolin-4,5-diona para formar el doble enlace carbono-nitrógeno de la Boc-imina junto con el óxido de trifenilfosfina como subproducto. Esquema 3 3.2. Reacción de Mannich enantioselectiva de N-Boc cetoiminas derivadas de pirazolonas con β-dicetonas. En este apartado estudiamos inicialmente el alcance de la reacción haciendo reaccionar Boc-cetoiminas 2a-g diferentemente sustituidas con acetilacetona en presencia de la escuaramida I (Tabla 1). Para ello realizamos diferentes ensayos en las condiciones de reacción optimizadas: 2% de catalizador, 1.1 equivalentes de dicetona, tolueno como disolvente y temperatura ambiente. Trabajo Fin de Grado Cristopher Niño Rodriguez 21 Tabla 1. Alcance de la reacción con diferentes Boc-iminas.a Entrada R Ar t (h) Producto (%)b erc 1 Me Ph 2.5 3a (90) 85:15 (95:5)e 2 Me C6H4Cl (p) 1 3b (81) 87:13 (96:4)e 3 Me C6H4Me (p) 2 3c (68) 89:11 4 Et Ph 3 3d (67) 84:16 5 iPr Ph 24 3e (71) 88:12 6 tBu Ph >7d 3f (0) - 7d Ph Ph 48 3g (68) 94:6 aReacción llevada a cabo con 0.1 mmol de imina, acetilacetona (0.11 mmol, 1.1 equiv) y catalizador I (0.002 mmol, 0.02 equiv) en 1 mL de PhMe a temperatura ambiente. bRendimiento aislado. cDeterminado mediante HPLC quiral. dReacción realizada en presencia de un 5% del catalizador. eAguas madres. La reacción de la imina 2a con acetilacetona condujo al aducto 3a con excelente rendimiento químico y una relación enantiomérica de 85:15 (entrada 1). Las iminas 2bc con grupos electroaceptores (-Cl) o electrodonadores (-Me) en la posición para del fenilo en N-1 reaccionaron en las mismas condiciones con la acetilacetona, proporcionando los productos deseados 3b-c con buenos rendimientos y una mayor enantioselectividad, siendo este aumento más acusado para el caso del grupo p-tolilo (comparar entradas 1 y 2-3). 28 Trabajo Fin de Grado Cristopher Niño Rodriguez 29 CONCLUSIONES 1. La reacción de N-Boc cetoiminas derivadas de pirazolona con acetilacetona en presencia de un 2 mol% de la escuaramida bifuncional I, derivada de la quinina, proporciona los correspondientes derivados de 4-aminopirazolona con un estereocentro cuaternario con buenos rendimientos químicos y enantioselectividades que dependen de los sustituyentes en el nitrógeno y en la posición C-3 de la imina de partida. Las mejores relaciones enantioméricas se han conseguido con las Boc-cetoiminas 2c, N-p-tolilsustituida, (er 89:11) y 2g, sustituida en C-3 por un grupo fenilo (er 94:6). 2. La reacción se puede extender a otras dicetonas dialquílicas o diarílicas, obteniendo los aductos correspondientes con buenos rendimientos y análogas enantioselectividades en tiempos de reacción mayores. Por ese motivo con las iminas menos reactivas (R = Ph) es necesario utilizar un 10% de catalizador. 3. La reacción de los aductos 3a-g,j con hidrato de hidracina en metanol a temperatura ambiente conduce a los pirazoles 4a-j con buenos rendimientos químicos y enantioselectividades análogas a las de los aductos de partida. La reacción no funciona con el aducto 3i, sustituido por un grupo dibenzoilmetilo, que conduce al producto de deacilación 5i. La correlación de su rotación específica con la descrita en la literatura nos ha permitido confirmar la estereoquímica absoluta (S) propuesta inicialmente para los aductos 3a-l. 4. La utilidad sintética de los productos obtenidos se ha demostrado además a través de su transformación en una etapa en otros derivados heterocíclicos, (pirazoles N-4-clorofenilsustituidos e isoxazoles) de previsible interés biológico, mediante su reacción con los hidrocloruros de 4-clorofenilhidracina e hidroxilamina, sin erosión alguna de su pureza enantiomerica. 30 Trabajo Fin de Grado Cristopher Niño Rodriguez 31 EXPERIMENTAL 1H NMR (500 MHz, 400 MHz) and 13C NMR (126 MHz, 101 MHz) spectra were recorded in CDCl3 or DMSO-d6 as solvent (Laboratory of Instrumental Techniques, University of Valladolid). Chemical shifts for protons are reported in ppm from TMS with the residual CHCl3 resonance as internal reference. Chemical shifts for carbons are reported in ppm from TMS and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, sext = sextuplet, sept = septuplet, m = multiplet, br s = broad signal), coupling constants in Hertz, and integration. Specific rotations were measured on a Perkin-Elmer 341 digital polarimeter using a 5-mL cell with a 1-dm path length, and a sodium lamp, and concentration is given in g per 100 mL. Infrared spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer and are reported in frequency of absorption (only the structurally most important peaks are given). Melting points were obtained with a micro melting point Leica Gallen III apparatus and are uncorrected. Flash chromatography was carried out using silica gel (230-240 mesh). Chemical yields refer to pure isolated substances. TLC analysis was performed on glass-backed plates coated with silica gel 60 and an F254 indicator, and visualized by either UV irradiation or by staining with phosphomolybdic acid solution. Chiral HPLC analysis was performed on a JASPO HPLC system (JASCO PU-2089 pump and UV-2075 UV/Vis detector) equipped with a quaternary pump, using a Chiralpak AD-H, Chiralpak IA, LuxAmylose-2 and Lux-i-Amylose-3 analytical columns (250 x 4.6 mm). UV detection was monitored at 254 nm. ESI mass spectra were obtained on an Agilent 5973 inert GC/MS system. Commercially available organic and inorganic compounds were used without further purification. Solvents were dried and stored over microwave-activated 4 Å molecular sieves. N-Boc-triphenyliminophosphorane, 20 pyrazolones, 21 and squaramide I 22 were prepared according to literature procedures. Racemic mixtures were synthesized 20 P. Calí, M. Begtrup. Synthesis. 2002, 63. 21 (a) X. Li, F.-Y. Chen, J.-W. Kang, J. Zhou, C. Peng, W. Huang, M.-K. Zhou, G. He, B. H. J. Org. Chem. 2019, 84, 9138. (b) P. Yadav, A. Awasthi, S. Gokulnath, D. K. Tiwari. J. Org. Chem. 2021, 86, 2658. 22 S. Del Pozo, S. Vera, M. Oiarbide, C. Palomo. J. Am. Chem. Soc. 2017, 139, 15308. Trabajo Fin de Grado Cristopher Niño Rodriguez 32 according to general procedure using an aquiral bifunctional thiourea derived from N1,N1-dimethylethane-1,2-diamine 23 (0.01 mmol) as catalyst. General Procedure for the Synthesis of Pyrazolone-Derived Ketones 1a-g. Nitrosobenzene (25.0 mmol, 1.0 equiv) and K2CO3 (0.2 equiv) were added to a solution of pyrazolone derivative (25.0 mmol, 1.0 equiv) in MeOH (0.6 M) at room temperature. The reaction mixture was then refluxed for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed three times with water and once with brine and then dried over anhydrous MgSO4. After evaporation of ethyl acetate under reduced pressure, the crude product was purified by flash column chromatography (hexane/ethyl acetate, 20:1) to afford pyrazolone-derived phenyl ketimine. Phenyl-ketimine (10 mmol) was dissolved in THF (0.13 M), and an aqueous HCl (2 M) solution (25 mL) was added to it at room temperature. The progress of the reaction was monitored via TLC. After completion of the reaction, the mixture was diluted with water. The organic layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed under reduced pressure. ▪ 3-Methyl-1-phenyl-1H-pyrazole-4,5-dione (1a).10 Compound 1a was prepared from 5-methyl-2-phenyl-2,4-dihydro-3Hpyrazol-3-one (2.0 g, 11.5 mmol) as described in general procedure. The crude product was directly purified by flash column chromatography (Hexane/EtOAc = 4:1) to afford the desired product 1a as a red solid: 0.90 g (4.8 mmol, 42% yield). The 1H-NMR spectrum of the product was matched with reported.10 ▪ 1,3-Diphenyl-1H-pyrazole-4,5-dione (1g).10 Compound 1g was prepared from 2,5-diphenyl-2,4-dihydro-3H-pyrazol3-one (2.07 g, 8.76 mmol) as described in general procedure. The crude product was directly purified by flash column chromatography (Hexane/EtOAc = 3:1) to afford the desired product 1g as a red solid: 1.03 g (4.12 mmol, 47% yield). The 1H-NMR spectrum of the product was matched with reported.10 23 S. M. Opalka, J. L. Steinbacher, B. A. Lambiris, D. Tyler, McQuade. J. Org. Chem., 2011, 76, 6503. Trabajo Fin de Grado Cristopher Niño Rodriguez 33 General Procedure for the Synthesis of Pyrazolone-Derived N-Boc Ketimines 2a-g. tert-Butyl(triphenylphosphoranylidene)acetate (2.2 mmol, 1.1 equiv) was added to a solution of the pyrazolone-derived ketone 1 (2 mmol) in 1,4-dioxane (0.2 M) at room temperature, and the mixture was refluxed. After the completion of the reaction (TLC), the solvent was removed under reduced pressure and the residue was purified by flash chromatography. ▪ tert-Butyl (Z)-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene) carbamate (2a).10 Compound 2a was prepared from 1a (1.13 g, 6.0 mmol) as described in general procedure and the crude product was purified by flash column chromatography (n-Hexane/EtOAc = 15:1) to afford the desired N-Boc ketimine 2a as a red solid: 1.50 g (5.22 mmol, 87% yield). 1H-NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.6 Hz, 2H, Har), 7.42 (m, 2H, Har), 7.23 (m, 1H, Har), 2.30 (s, 3H, CH3), 1.64 (s, 9H, C(CH3)3) ppm. ▪ tert-Butyl (Z)-(5-oxo-1,3-diphenyl-1,5-dihydro-4H-pyrazol-4-ylidene)carbamate (2g).10 Compound 2g was prepared from 1g (0.50 g, 2.0 mmol) as described in general procedure and the crude product was purified by flash column chromatography (n-Hexane/EtOAc = 8:1) to afford the desired N-Boc ketimine 2g as a red solid: 0.49 g (1.4 mmol, 70% yield). 1H-NMR (500 MHz, CDCl3): δ 8.23 (m, 2H, Har), 7.95 (dd, J = 8.8, 1.1 Hz, 2H, Har), 7.48 (m, 5H, Har), 7.28 (m, 1H, Har), 1.67 (s, 9H, C(CH3)3) ppm. General procedure for the synthesis of Mannich products 3a-l by enantioselective Mannich reaction of N-Boc ketimines with β-diketones. To a mixture of N-Boc ketimine 2 (0.1 mmol), catalyst I (0.002 mmol, 0.02 equiv) in 1.0 mL of toluene, β-diketone (0.11 mmol, 1.1 equiv) was added at room temperature and the reaction mixture was stirred in a Wheaton vial. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash column chromatography to afford the corresponding product 3a-l. The diastereomeric Trabajo Fin de Grado Cristopher Niño Rodriguez 34 excess was determined by 1H-NMR. The enantiomeric excess was determined by chiralphase HPLC analysis using mixtures of hexane/isopropanol as eluent. Synthesis of (±)-Mannich products. Racemic mixture of the enantiomers was synthesized according to general procedure, using an aquiral bifunctional thiourea derived from N1,N1-dimethylethane-1,2-diamine (0.01 mmol, 0.1 equiv) as catalyst. ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (3a). Product 3a was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (1.3 mg, 0.002 mmol, 0.02 equiv). Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 3a as a colorless solid (35 mg, 0.09 mmol, 90% yield). M.p. 140-141 ºC (hexane-ethyl acetate). [α]D25 = +18.9 (c = 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 8.6, 1.2 Hz, 2H, Har), 7.39 (dd, J = 8.6, 7.4 Hz, 2H, Har), 7.19 (tt, J = 7.4, 1.3 Hz, 1H, Har), 6.38 (br s, 1H, NH), 4.08 (s, 1H, CH), 2.31 (s, 3H, CH3CO), 2.30 (s, 3H, CH3CO), 2.08 (s, 3H, CH3), 1.36 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 200.4 (CO), 169.9 (CON), 137.7 (Car), 128.9 (CHar), 125.4 (CHar), 118.9 (CHar), 77.3 (C(CH3)3), 66.9 (CH), 66.7 (CNHBoc), 32.1 (CH3CO), 31.9 (CH3CO), 28.1 (C(CH3)3), 14.8 (CH3) ppm. IR (ATR): 3403, 3356, 2974, 2931, 1707, 1596, 1496, 1375, 1254, 1154, 758, 688 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C20H26N3O5 388.1867; Found 388.1868. HPLC: Chiralpak AD-H column, hexane/i-PrOH 85:15, 0.7 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 11.5 min, minor enantiomer (R) tr = 26.1 min. (er: 85:15). A sample of 3a (er: 85:15) was recrystallized from MeOH to afford 3a as white crystals (quasi-racemic mixture, er 58:42) and almost enantiomerically pure 3a from the mother liquors (er 95:5). This last fraction was then used to prepare compound 4a. Trabajo Fin de Grado Cristopher Niño Rodriguez 35 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-4,5dihydro-1H-pyrazol-4-yl)carbamate (3b). Product 3b was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (1.3 mg, 0.002 mmol, 0.02 equiv). Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 3b as a colorless solid (34 mg, 0.081 mmol, 81% yield). M.p. 166167 ºC (hexane-ethyl acetate). [α]D25 = +17.9 (c = 0.6, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.9 Hz, 2H, Har), 7.34 (d, J = 8.9 Hz, 2H, Har), 6.36 (br s, 1H, NH), 4.05 (s, 1H, CH), 2.30 (s, 3H, CH3CO), 2.29 (s, 3H, CH3CO), 2.07 (s, 3H, CH3), 1.35 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 200.4 (CO), 169.9 (CON), 136.3 (Car), 130.5 (Car), 128.9 (CHar), 120.0 (CHar), 77.3 (C(CH3)3), 66.9 (CH), 66.6 (CNHBoc), 32.1 (CH3CO), 31.9 (CH3CO), 28.1 (C(CH3)3), 14.7 (CH3) ppm. IR (ATR): 3419, 2975, 2905, 1714, 1494, 1461, 1365, 1251, 1152, 836, 810 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. ForC20H25ClN3O5 422.1477; Found 422.1487. HPLC: Chiralpak AD-H column, hexane/i-PrOH 85:15, 0.7 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 10.2 min, minor enantiomer (R) tr = 33.6 min. (er: 87:13). A sample of 3b (er: 85:15) was recrystallized from hexane-ethyl acetate to afford 3b as white crystals (quasi-racemic mixture, er 59:41) and almost enantiomerically pure 3a from the mother liquors (er 96:4). ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-1-(p-tolyl)-4,5-dihydro1H-pyrazol-4-yl)carbamate (3c). Product 3c was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (1.3 mg, 0.002 mmol, 0.02 equiv). Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 3c as a colorless solid (27 mg, 0.068 mmol, 68% yield). M.p. 150-151 ºC (hexane-ethyl acetate). [α]D25 = +19.0 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz, 2H, Har), 7.18 (d, J = 8.4 Hz, 2H, Har), 6.35 (br s, 1H, NH), 4.07 (s, 1H, CH), 2.33 (s, 3H, CH3C6H4), 2.30 (s, 3H, CH3CO), 2.29 (s, 3H, CH3CO), 2.07 (s, 3H, CH3), 1.35 (s, Trabajo Fin de Grado Cristopher Niño Rodriguez 36 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 200.4 (CO), 169.7 (CON), 135.3 (Car), 135.1 (Car), 129.4 (CHar), 119.0 (CHar), 77.3 (C(CH3)3), 67.0 (CH), 66.7 (CNHBoc), 32.1 (CH3CO), 31.9 (CH3CO), 28.1 (C(CH3)3), 21.0 (CH3C6H4), 14.8 (CH3) ppm. IR (ATR): 3423, 2978, 2923, 1714, 1703, 1512, 1472, 1369, 1255, 1156, 1056, 814 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C21H28N3O5 402.2023; Found 402.2043. HPLC: Chiralpak AD-H column, hexane/i-PrOH 85:15, 0.7 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 11.5 min, minor enantiomer (R) tr = 44.7 min. (er: 89:11). ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-ethyl-5-oxo-1-phenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (3d). Product 3d was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (1.3 mg, 0.002 mmol, 0.02 equiv). Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 3d as a colorless solid (27 mg, 0.067 mmol, 67% yield). [α]D25 = +10.7 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.89 (dd, J = 8.7, 1.2 Hz, 2H, Har), 7.38 (dd, J = 8.7, 7.4 Hz, 2H, Har), 7.18 (tt, J = 7.4, 1.2 Hz, 1H, Har), 6.40 (br s, 1H, NH), 4.05 (s, 1H, CH), 2.41 (m, 1H, CHHCH3), 2.34 (m, 1H, CHHCH3), 2.30 (s, 3H, CH3CO), 2.29 (s, 3H, CH3CO), 1.34 (s, 9H, C(CH3)3), 1.27 (t, J = 7.3 Hz, 3H, CH3CH2) ppm. 13C NMR (126 MHz, CDCl3): δ 200.7 (CO), 170.1 (CON), 137.9 (Car), 128.8 (CHar), 125.3 (CHar), 118.9 (CHar), 77.3 (C(CH3)3), 67.1 (CH), 66.9 (CNHBoc), 32.1 (CH3CO), 31.9 (CH3CO), 28.1 (C(CH3)3), 22.2 (CH2CH3), 9.6 (CH3CH2) ppm. IR (ATR): 3388, 2985, 2942, 1707, 1596, 1493, 1453, 1351, 1279, 1152, 1054, 761, 692 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C21H28N3O5 402.2023; Found 402.2029. HPLC: Chiralpak AD-H column, hexane/i-PrOH 85:15, 0.7 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 10.0 min, minor enantiomer (R) tr = 20.0 min. (er: 84:16). Trabajo Fin de Grado Cristopher Niño Rodriguez 37 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-isopropyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (3e). Product 3e was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (1.3 mg, 0.002 mmol, 0.02 equiv). Chromatography on a silica gel using hexane/EtOAc = 4:1 as eluent afforded compound 3e as a colorless solid (30 mg, 0.071 mmol, 71% yield). [α]D25 = +42.5 (c = 0.8, MeOH). 1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 8.1 Hz, 2H, Har), 7.38 (dd, J = 8.7, 7.4 Hz, 2H, Har), 7.17 (tt, J = 7.4, 1.2 Hz, 1H, Har), 6.49 (br s, 1H, NH), 4.04 (s, 1H, CH), 2.65 (sept, J = 6.9 Hz, 1H, CH(CH3)2), 2.29 (s, 3H, CH3CO), 2.28 (s, 3H, CH3CO), 1.37 (s, 9H, C(CH3)3), 1.27 (d, J = 6.8 Hz, 6H, (CH3)2CH) 1.24 (d, J = 7.0 Hz, 6H, (CH3)2CH) ppm. 13C NMR (126 MHz, CDCl3): δ 201.1 (CO), 169.8 (CON), 138.0 (Car), 128.8 (CHar), 125.2 (CHar), 119.1 (CHar), 77.3 (C(CH3)3), 67.4 (CH(COCH3)2), 67.0 (CNHBoc), 32.1 (CH3CO), 31.7 (CH3CO), 28.8 (CH(CH3)2), 28.1 (C(CH3)3), 20.3 ((CH3)2CH) ppm. IR (ATR): 3413, 2975, 2935, 1710, 1598, 1493, 1457, 1359, 1283, 1156, 1083, 1054, 754, 688 cm-1. HRMS (ESIQTOF) m/z: [M+Na]+ Calcd. For C22H29N3NaO5 438.1999; Found 438.1999. HPLC: Chiralpak AD-H column, hexane/i-PrOH 95:5, 0.7 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 18.6 min, minor enantiomer (R) tr = 27.0 min. (er: 88:12). ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-5-oxo-1,3-diphenyl-4,5-dihydro-1Hpyrazol-4-yl)carbamate (3g). Product 3g was obtained according to general procedure using pentane-2,4-dione (11 µL, 0.11 mmol, 1.1 equiv) as β-diketone and catalyst I (3.2 mg, 0.005 mmol, 0.05 equiv). Chromatography on a silica gel using hexane/EtOAc = 4:1 as eluent afforded compound 3g as a colorless solid (31 mg, 0.068 mmol, 68% yield). [α]D25 = +56.3 (c = 0.6, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.98 (dd, J = 8.4, 1.2 Hz, 2H, Har), 7.90 (dd, J = 7.8, 2.0 Hz, 2H, Har), 7.43 (m, 5H, Har), 7.23 (tt, J = 7.4, 1.0 Hz, 1H, Har), 6.82 (br s, 1H, NH), 3.97 (s, 1H, CH), 2.11 (s, 3H, CH3CO), 2.03 (s, 3H, CH3CO), 1.31 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 202.2 (CO), 200.5 (CO), 170.0 (CON), 137.9 (Car), 130.8 (CHar), 129.0 (CHar), 128.9 Trabajo Fin de Grado Cristopher Niño Rodriguez 44 ▪ tert-Butyl (S)-(3'-isopropyl-3,5-dimethyl-5'-oxo-1'-phenyl-1',5'-dihydro1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (4e). Product 4e was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 2:1 as an eluent afforded compound 4e as a colorless solid (32 mg, 0.078 mmol, 78% yield). [α]D25 = +139.8 (c = 0.46, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.99 (d, J = 7.1 Hz, 2H, Har), 7.40 (dd, J = 8.5, 7.4 Hz, 2H, Har), 7.18 (t, J = 7.4 Hz, 1H, Har), 6.22 (br s, 1H, NH), 2.66 (sept, J = 6.8 Hz, 1H, CH(CH3)2), 2.23 (s, 6H, CH3), 1.36 (s, 9H, C(CH3)3), 1.32 (d, J = 7.0 Hz, 3H, CH3CH), 1.07 (d, J = 6.8 Hz, 3H, CH3CH) ppm. 13C NMR (126 MHz, CDCl3): 172.3 (CON), 167.0 (CO2tBu), 154.4 (CiPr), 141.9 (CCH3), 138.1 (Car), 128.8 (CHar), 125.0 (CHar), 118.6 (CHar), 107.8 (C4pyrazole), 77.2 (C(CH3)3), 66.2 (CNHBoc), 28.2 (CH(CH3)2), 28.1 (C(CH3)3), 21.1 (CH3CH), 20.8 (CH3CH), 12.8 (CH3) ppm. IR (ATR): 3290, 2975, 2931, 1708, 1597, 1494, 1367, 1159, 759, 737, 693 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd. For C22H29N5NaO3 434.2163; Found 434.2162. HPLC: Lux Amylose-2 column, hexane/i-PrOH 90:10, 1 mL/min, λ = 254 nm, minor enantiomer (R) tr = 17.5 min, mayor enantiomer (S) tr = 23.5 min. (er: 90:10). ▪ tert-Butyl (S)-(3,5-dimethyl-5'-oxo-1',3’-diphenyl-1',5'-dihydro-1H,4'H-[4,4'- bipyrazol]-4'-yl)carbamate (4g). Product 4g was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 1:1 as eluent afforded compound 4g as a colorless solid (36 mg, 0.082 mmol, 82% yield). [α]D25 = -190.0 (c = 0.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H, NH), 7.99 (dd, J = 8.7, 1.2 Hz, 2H, Har), 7.85 (d, J = 7.1 Hz, 2H, Har), 7.39 (m, 5H, Har), 7.19 (tt, J = 7.4, 1.2 Hz, 1H, Har), 2.30 (s, 6H, CH3), 1.19 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 171.5 (CON), 167.0 (CO2tBu), 153.7 (CPh), 143.1 (CCH3), 138.3 (Car), 138.2 (Car), 128.9 (CHar), 128.8 (CHar), 126.4 (CHar), 125.1 (CHar), 118.7 (CHar), 108.7 (C4pyrazole), 77.2 (C(CH3)3), 64.1 (CNHBoc), 27.9 (C(CH3)3), 12.8 (CH3) ppm. IR (ATR): 3237, 3123, 3060, 2978, 2931, 1730, 1708, 1594, 1500, 1367, 1159, 759, 737, 689 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C25H28N5O3 446.2187; Found Trabajo Fin de Grado Cristopher Niño Rodriguez 45 446.2205. HPLC: Lux i-Amylose-3 column, hexane/i-PrOH 90:10, 1 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 12.8 min, minor enantiomer (R) tr = 32.5 min. (er: 94:6). ▪ tert-Butyl (S)-(3,5-diethyl-5'-oxo-1',3'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'- bipyrazol]-4'-yl)carbamate (4j). Product 4j was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 2:1 as eluent afforded compound 4j as a colorless solid (19 mg, 0.040 mmol, 40% yield). [α]D25 = -134.3 (c = 0.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.97 (dd, J = 8.6, 1.2 Hz, 2H, Har), 7.82 (d, J = 7.6 Hz, 2H, Har), 7.42 (m, 5H, Har), 7.21 (tt, J = 7.4, 1.2 Hz, 1H, Har), 2.98 (m, 2H, CHHCH3), 2.86 (dq, J = 15.5, 7.6 Hz, CHHCH3), 1.24 (t, J = 7.5, 6H), 1.20 (s, 9H, C(CH3)3 ppm. 13C NMR (126 MHz, CDCl3): δ 166.1 (CON), 148.5 (CPh), 144.0 (CEt), 133.4 (Car), 124.3 (CHar), 124.2 (CHar), 121.7 (CHar), 120.6 (CHar), 114.1 (CHar), 104.4 (C4pyrazole), 72.3 (C(CH3)3), 23.2 (C(CH3)3), 15.1 (CH3CH2), 8.7 (CH3CH2), 7.3 (CH3CH2) ppm. IR (ATR): 3250, 2975, 2928, 1701, 1594, 1490, 1368, 1159, 756, 693 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C27H32N5O3 474.2500; Found 474.2486. HPLC: Chiralpak IA, hexane/i-PrOH 95:5, 1 mL/min, λ = 254 nm, minor enantiomer (R) tr = 20.158 min, major enantiomer (S) tr = 25.042 min. (er: 95:5). ▪ tert-Butyl (S)-(3-methyl-5-oxo-4-(2-oxo-2-phenylethyl)-1-phenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (5i).12 Product 5i was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 5i as a colorless solid (21 mg, 0.052 mmol, 52% yield). [α]D25 = -17.5 (c = 0.3, CH2Cl2). [Lit.12 [α]D20 = -20.2 (c = 1, CH2Cl2, er 94:6 for (S) enantiomer)]. 1H NMR (400 MHz, DMSO-d6): δ 7.90 (br s, 1H, Har), 7.83 (m, 2H, Har), 7.74 (d, J = 7.8 Hz, 2H, Har), 7.62 (tt, J = 7.4, 1.3 Hz, 1H, Har), 7.49 (t, J= 7.8 Hz, 2H, Har), 7.38 (dd, J = 8.7, 7.4 Hz, 2H, Har), 7.14 (tt, J = 7.4, 1.3 Hz, 1H, Har), 3.74 (d, J = 17.2 Hz, 1H, CHHCOPh), 3.62 (d, J = 17.2 Hz, 1H, CHHCOPh), 1.99 (s, 3H, CH3), 1.31 (s, 9H, C(CH3)3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 195 (CO), 172.3 (CON), 158.8 (CO2tBu), 153.8 (CCH3), 138.7 (Car), 136.2 (Car), 134.2 (CHar), 129.3 (CHar), 129.2 (CHar), 128.4 (CHar), 124.7 (CHar), 118.1 (CHar), 80.0 (C(CH3)3), 63.6 (CNHBoc), 42.6 (CH2), 28.4 (C(CH3)3), Trabajo Fin de Grado Cristopher Niño Rodriguez 46 13.5 (CH3) ppm. IR (ATR): 2856, 1714, 1594, 1500, 1364, 1251, 1159, 753, 693 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd. For C35H25N3NaO4 430.1737; Found 430.1759. HPLC: Chiralpak IA column, hexane/i-PrOH 80:20, 1 mL/min, λ = 254 nm, minor enantiomer (R) tr = 6.9 min, major enantiomer (S) tr = 32.4 min. (er 77:23). General procedure for the synthesis of pyrazole derivatives 6. A solution of 3 (0.1 mmol),4-chlorophenylhydrazine hydrochloride (19 mg, 0.11 mmol, 1.1 equiv) and and K2CO3 (8 mg, 0.055 mmol, 0.55 equiv) in ethanol (1 mL) was heated to 80 °C for 2-3 h. After that, the solvent of reaction mixture was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel to afford product 6. ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-3,3',5-trimethyl-5'-oxo-1'-phenyl-1',5'- dihydro-1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (6a). Product 6a was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 4:1 as an eluent afforded compound 6a as a colorless solid (37 mg, 0.075 mmol, 75% yield). M.p. 166-167 ºC (hexane-ethyl acetate). M.p. 196-197 ºC. [α]D25 = +59.9 (c = 0.7, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.94 (dd, J = 8.7, 1.2 Hz, 2H, Har), 7.40 (m, 4H, Har), 7.28 (d, J = 8.5 Hz, 2H, Har), 7.18 (tt, J = 7.4, 1.2 Hz, 1H, Har), 5.41 (br s, 1H, NH), 2.40 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.19 (s, 3H, CH3), 1.39 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 171.5 (CON), 159.8 (CO2tBu), 153.7 (CCH3), 146.6 (CCH3), 138.0 (Car), 137.1 (Car), 134.4 (Car), 129.4 (CHar), 128.9 (CHar), 127.1 (CHar), 125.1 (CHar), 118.6 (CHar), 110.0 (C4pyrazole), 79.7 (C(CH3)3), 65.4 (CNHBoc), 28.1 (C(CH3)3), 14.5 (CH3), 14.1 (CH3), 12.3 (CH3) ppm. IR (ATR): 3269, 2982, 2928, 1711, 1598, 1500, 1393, 1364, 1295, 1254, 1163, 1093, 1014, 838, 759, 690, 645 cm-1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd. For C26H29ClN5O3 494.1953; Found 494.1931. HPLC: Chiralpak AD-H column, hexane/iPrOH 90:10, 1 mL/min, λ = 254 nm, major enantiomer (S) tr = 45.0 min, minor enantiomer (R) tr = 74.2 min. (er 84:16). Trabajo Fin de Grado Cristopher Niño Rodriguez 47 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-3,5-dimethyl-5'-oxo-1',3'-diphenyl-1',5'- dihydro-1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (6g). Product 6g was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 4:1 as eluent afforded compound 6g as a colorless solid (22 mg, 0.040 mmol, 40% yield). [α]D25 = -155.0 (c = 0.4, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.01 (dd, J = 8.8, 1.1 Hz, 2H, Har), 7.91 (d, J = 6.5 Hz, 2H, Har), 7.44 (m, 5H, Har), 7.42 (d, J = 8.7 Hz, 2H, Har), 7.29 (d, J = 8.7 Hz, 2H, Har), 7.20 (tt, J = 7.4, 1.2 Hz, 1H, Har), 5.54 (br s, 1H, NH), 2.41 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.22 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 171.7 (CON), 153.6 (CCH3), 146.9 (CPh), 138.4 (Car), 137.5 (Car), 134.1 (Car), 130.7 (CCH3), 130.3 (Car), 129.3 (CHar), 128.9 (CHar), 126.9 (CHar), 126.5 (CHar), 125.1 (CHar), 118.9 (CHar), 110.5 (C4pyrazole), 79.7 (C(CH3)3), 64.4 (CNHBoc), 27.9 (C(CH3)3), 14.2 (CH3), 12.6 (CH3) ppm. IR (ATR): 3245, 2975, 2854, 1727, 1701, 1596, 1500, 1362, 1260, 1158, 1092, 1016, 829, 756, 735, 691 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd. For C31H30N5ClNaO3 578.1929; Found 578.1943. HPLC: Chiralpak AD-H column, hexane/i-PrOH 90:10, 1 mL/min, λ = 254 nm, mayor enantiomer (S) tr = 10.1 min, minor enantiomer (R) tr = 63.7 min. (er 96:4). General Procedure for the synthesis of isoxazole derivatives 7. A solution of 3a (0.1 mmol), hydroxylamine hydrochloride (8 mg, 0.11 mmol, 1.1 equiv) and K2CO3 (8 mg, 0.055 mmol, 0.55 equiv) in ethanol (1 mL) was heated to 80 °C for 2-3 h. After that, the solvent of reaction mixture was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel to afford product 7. ▪ tert-Butyl (S)-(4-(3,5-dimethylisoxazol-4-yl)-3-methyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (7a). Product 7a was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 3:1 as an eluent afforded compound 7a as a colorless solid (17 mg, 0.044 mmol, 44% yield). [α]D25 = +45.2 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.91 (dd, J = 8.8, 1.1 Hz, 2H, Har), 7.41 (dd, J = 8.7, 7.4 Hz, 2H, Har), Trabajo Fin de Grado Cristopher Niño Rodriguez 48 7.20 (tt, J = 7.4, 1.2 Hz, 1H, Har), 5.35 (br s, 1H, NH), 2.47 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.15 (s, 3H, CH3), 1.38 (s, 9H, C(CH3)3) ppm. 13C NMR (126 MHz, CDCl3): δ 170.6 (CON), 167.3 (CCH3), 157.8 (CO2tBu), 153.8 (CCH3), 137.8 (Car), 129.0 (CHar), 125.33 (CHar), 118.5 (CHar), 107.2 (C4isoxazole), 77.3 (C(CH3)3), 63.9 (CNHBoc), 28.1 (C(CH3)3), 14.3 (CH3), 12.9 (CH3), 11.8 (CH3) ppm. IR (ATR): 3270, 2982, 2931, 2249, 1705, 1596, 1497, 1362, 1253, 1158, 1063, 1023, 906, 756, 727, 691, 643 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd. For C20H24N4NaO4 407.1690; Found 407.1693. HPLC: Chiralpak AD-H column, hexane/i-PrOH 90:10, 1 mL/min, λ = 254 nm, major enantiomer (S) tr = 10.6 min, minor enantiomer (R) tr = 19.5 min. (er 83:17). ▪ tert-Butyl (S)-(4-(3,5-dimethylisoxazol-4-yl)-5-oxo-1,3-diphenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (7g). Product 7g was obtained according to general procedure. Chromatography on a silica gel using hexane/EtOAc = 3:1 as eluent afforded compound 7g as a colorless solid (36 mg, 0.080 mmol, 80% yield). [α]D25 = -151.4 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.98 (dd, J = 8.7, 1.3 Hz, 2H, Har), 7.83 (m, 2H, Har), 7.43 (m, 4H, Har), 7.34 (br s, 2H, Har and NH), 7.22 (tt, J = 7.4, 1.2 Hz, 1H, Har), 2.38 (s, 6H, CH3), 1.20 (s, 9H, C(CH3)3) ppm. 13C NMR (100 MHz, CDCl3): δ 170.7 (CON), 167.8 (CCH3), 158.2 (CO2tBu), 153.8 (CPh), 138.1 (Car), 131.0 (CHar), 129.0 (CHar), 128.9 (CHar), 126.2 (CHar), 125.4 (CHar), 118.7 (CHar), 107.7 (C4isoxazole), 77.2 (C(CH3)3), 62.7 (CNHBoc), 27.9 (C(CH3)3), 13.0 (CH3), 11.9 (CH3) ppm. IR (ATR): 3245, 3128, 2978, 2927, 1731, 1705, 1599, 1490, 1380, 1366, 1256, 1150, 1052, 1026, 906, 756, 735, 687 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd. For C25H26N4NaO4 469.1846; Found 469.1858. HPLC: Chiralpak AD-H column, hexane/iPrOH 90:10, 1 mL/min, λ = 254 nm, minor enantiomer (R) tr = 10.1 min, major enantiomer (S) tr = 14.6 min. (er 93:7). Trabajo Fin de Grado Cristopher Niño Rodriguez 49 BIBLIOGRAFÍA 1. (a) P. T. Anastas, J. C. Warner. Green Chemistry: Theory and Practice, Oxford University Press, 2000. (b) P. Anastas, N. Eghbali. Chem. Soc. Rev. 2010, 39, 301. 2. M. C. Nunez, M. E. Garcia-Rubino, A. Conejo-Garcia, O. Cruz-López, M. Kimatrai, M. A. Gallo, A. Espinosa, J. M. Campos. Curr. Med. Chem. 2009, 16, 2064. 3. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive Asymmetric Catalysis. Supplement, Springer, Berlin; New York, 2004. 4. Reviews recientes: (a) B. List, K. Maruoka, (Eds.), Science of Synthesis: Asymmetric Organocatalysis, Vols. 1 and 2, Georg Thieme Verlag, Stuttgart, 2012. (b) M. Rueping, D. Parmar, E. Sugiono, Asymmetric Brønsted Acid Catalysis, Wiley-VCH, Weinheim, 2016. (c) J. Alemán, S. Cabrera. Chem. Soc. Rev. 2013, 42, 774. (d) M. R. Volla, I. Atodiresei, M. Rueping. Chem. Rev. 2014, 114, 2390. (e) P. Chauhan, U. Kaya, D. Enders. Adv. Synth. Catal. 2017, 359, 888. (f) J. Liu, L. Wang. Synthesis 2017, 49, 960. 5. (a) L.-QLu, X.-L. An, J.-R. Chen, W.-J. Xiao. Synlett 2012, 490. (b) M. J. Ajitha, K.-W. Huang. Synthesis 2016, 48, 3449. 6. (a) F. Giacalone, M. Gruttadauria, P. Agrigento, R. Noto. Chem. Soc. Rev. 2012, 41, 2406. (b) D. Parmar, E. Sugiono, S. Raja and M. Rueping. Chem. Rev. 2014, 114, 9047. 7. (a) R. I. Storer, C. Aciroa, L. H. Jones. Chem. Soc. Rev. 2011, 40, 2330 (b) J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen. Chem. Eur. J. 2011, 17, 6890. (c) P. Chauhan, S. Mahajan, U. Kaya, D. Hack, D. Enders. Adv. Synth. Catal. 2015, 357, 253. (d) B.-L. Zhao, J.-H. Li, D.-M. Du. Chem. Rec. 2017, 17, 1. 8. (a) W.-Y. Siau, J. Wang. Catal. Sci. Technol. 2011, 1, 1298. (b) O. V. Serdyuk, C. M. Heckel, S. B. Tsogoeva. Org. Biomol. Chem. 2013, 11, 7051. (c) X. Fanga, C.-J. Wang. Chem. Commun. 2015, 51, 1185. 9. Reviews: (a) X. Xie, L. Xiang, C. Peng, B. Han. Chem. Rec. 2019, 19, 2209. (b) P. Chauhan, S. Mahajan D. Enders. Chem. Commun. 2015, 51, 12890. (c) S. Liu, X. Bao, B. Wang. Chem. Commun. 2018, 54, 11515. 10. P. Chauhan, S, Mahajan, U. Kaya, A. Peuronen, K. Rissanen, D. Enders. J. Org. Chem. 2017, 82, 7050. 11. (a) Z. Yang, Z. Wang, S. Bai, X. Liu, L. Lin, X. Feng. Org. Lett. 2011, 13, 596. (b) M. Šimek, M. Remeš, J. Veselý, R. Rios. Asian J. Org. Chem. 2013, 2, 64. (c) B. Formánek, V. Šeferna, M. Meazza, R. Rios, M. Patil, J. Veselý. Eur. J. Org. Chem. 2021, 2362. 12. Y. Zhou, Y. You, Z.-H. Wang, X.-M. Zhang, X.-Y. Xu, W.-C. Yuan. Eur. J. Org. Chem. 2019, 3112. 13. S. Mahajan, P. Chauhan, U. Kaya, K. Deckers, K. Rissanen, D. Enders. Chem. Commun. 2017, 53, 6633. Trabajo Fin de Grado Cristopher Niño Rodriguez 50 14. U. Kaya, P. Chauhan, S. Mahajan, K. Deckers, A. Valkonen, K. Rissanen, D. Enders. Angew. Chem. Int. Ed. 2017, 56, 15358. 15. Z.-T. Yang, W.-L. Yang, L. Chen, H. Sun, W. i-P. Deng. Adv. Synth. Catal. 2018, 360, 2049. 16. Q.-D. Zhang, B.-L. Zhao, B.-Y. Li, D.-M. Du. Org. Biomol. Chem. 2019, 17, 7182. 17. J. Dai, Z. Wang, Y. Deng, L. Zhu, F. Peng, Y. Lan, Z. Shao. Nat. Commun. 2019, 10, 5182. 18. V. Kumar, K. Kaur, G.K. Gupta, A.K. Sharma. Eur. J. Med. Chem. 2013, 69, 735. 19. Q. Gao, Y. Zhu, M. Lian, M. Liu, J. Yuan, G. Yin, A. Wu. J. Org. Chem. 2012, 77, 9865. 20. P. Calí, M. Begtrup. Synthesis. 2002, 63. 21. (a) X. Li, F.-Y. Chen, J.-W. Kang, J. Zhou, C. Peng, W. Huang, M.-K. Zhou, G. He, B. H. J. Org. Chem. 2019, 84, 9138. (b) P. Yadav, A. Awasthi, S. Gokulnath, D. K. Tiwari. J. Org. Chem. 2021, 86, 2658. 22. S. Del Pozo, S. Vera, M. Oiarbide, C. Palomo. J. Am. Chem. Soc. 2017, 139, 15308. 23. S. M. Opalka, J. L. Steinbacher, B. A. Lambiris, D. Tyler, McQuade. J. Org. Chem., 2011, 76, 6503. Trabajo Fin de Grado Cristopher Niño Rodriguez 51 SUPPORTING INFORMATION 7.1. NMR Spectra for New Compounds ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (3a). Trabajo Fin de Grado Cristopher Niño Rodriguez 52 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo4,5-dihydro-1H-pyrazol-4-yl)carbamate (3b). Trabajo Fin de Grado Cristopher Niño Rodriguez 53 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-1-(p-tolyl)-4,5dihydro-1H-pyrazol-4-yl)carbamate (3c). Trabajo Fin de Grado Cristopher Niño Rodriguez 60 ▪ tert-Butyl (S)-(4-(1,3-dioxo-1,3-diphenylpropan-2-yl)-5-oxo-1,3-diphenyl4,5-dihydro-1H-pyrazol-4-yl)carbamate (3k). Trabajo Fin de Grado Cristopher Niño Rodriguez 61 ▪ tert-Butyl ((S)-4-((R)-1,3-dioxo-1-phenylbutan-2-yl)-3-methyl-5-oxo-1phenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate (3l). Trabajo Fin de Grado Cristopher Niño Rodriguez 62 ▪ tert-Butyl (S)-(3,3',5-trimethyl-5'-oxo-1'-phenyl-1',5'-dihydro-1H,4'H-[4,4'- bipyrazol]-4'-yl)carbamate (4a). Trabajo Fin de Grado Cristopher Niño Rodriguez 63 ▪ tert-Butyl (S)-(1'-(4-chlorophenyl)-3,3',5-trimethyl-5'-oxo-1',5'-dihydro1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (4b). Trabajo Fin de Grado Cristopher Niño Rodriguez 64 ▪ tert-Butyl (S)-(3,3',5-trimethyl-5'-oxo-1'-(p-tolyl)-1',5'-dihydro-1H,4'H- [4,4'-bipyrazol]-4'-yl)carbamate (4c). Trabajo Fin de Grado Cristopher Niño Rodriguez 65 ▪ tert-Butyl (S)-( 3'-ethyl-3,5-dimethyl-5'-oxo-1'-phenyl-1',5'-dihydro1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (4d). Trabajo Fin de Grado Cristopher Niño Rodriguez 66 ▪ tert-Butyl (S)-( 3'-isopropyl-3,5-dimethyl-5'-oxo-1'-phenyl-1',5'-dihydro1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (4e). Trabajo Fin de Grado Cristopher Niño Rodriguez 67 ▪ tert-Butyl (S)-(3,5-dimethyl-5'-oxo-1',3’-diphenyl-1',5'-dihydro-1H,4'H- [4,4'-bipyrazol]-4'-yl)carbamate (4g). Trabajo Fin de Grado Cristopher Niño Rodriguez 68 ▪ tert-Butyl (S)-(3,5-diethyl-5'-oxo-1',3'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'- bipyrazol]-4'-yl)carbamate (4j). Trabajo Fin de Grado Cristopher Niño Rodriguez 69 ▪ tert-Butyl (S)-(3-methyl-5-oxo-4-(2-oxo-2-phenylethyl)-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (5i). Trabajo Fin de Grado Cristopher Niño Rodriguez 76 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo4,5-dihydro-1H-pyrazol-4-yl)carbamate (3b). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 9.867 5291635 236518 54.969 1.361 2 31.225 4335008 61417 45.031 1.171 HPLC Profile for 3b compound. Table 1, Entry 2, er: 87:13. PeakNumber tR Area Height Area % SymmetryFactor 1 10.233 7232983 311064 86.813 1.279 2 33.608 1098698 15363 13.187 1.120 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 100000 200000 Intensity [µV] CA 17A AD-H_003 - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 55,0 60,0 0 100000 200000 300000 Intensity [µV] CA 45A_002 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 77 PeakNumber tR Area Height Area % SymmetryFactor 1 10.200 14221584 623717 96.180 1.191 2 32.892 564856 9087 3.820 1.044 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 0 200000 400000 600000 Intensity [µV] CN 18A aguas madres_003_44,39min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 78 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-methyl-5-oxo-1-(p-tolyl)-4,5dihydro-1H-pyrazol-4-yl)carbamate (3c). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 11,383 5657641 211401 51,305 79,505 2 44,117 5369868 54496 48,695 20,495 HPLC Profile for 3c compound. Table 1, Entry 3, er: 89:11. PeakNumber tR Area Height Area % SymmetryFactor 1 11.492 5695956 191925 89.075 0.839 2 44.775 698588 7276 10.925 1.120 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 55,0 60,0 65,0 0 100000 200000 Intensity [µV] CA 41A_004 - CH1 1 2 0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 0 100000 200000 Intensity [µV] CA 46A_003 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 79 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-ethyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (3d). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 10.492 3268688 132530 50.530 1.275 2 21.850 3200091 64980 49.470 1.175 HPLC Profile for 3d compound. Table 1, Entry 4, er: 84:16. PeakNumber tR Area Height Area % SymmetryFactor 1 10.025 4156356 206525 83.853 1.260 2 20.033 800333 19632 16.147 1.159 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 0 50000 100000 Intensity [µV] MP 23A pur_003_30,66min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 0 100000 200000 Intensity [µV] CA 42A_003 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 80 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-3-isopropyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (3e). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 17.708 1750023 29389 50.474 0.953 2 25.042 1717121 30883 49.526 1.401 HPLC Profile for 3e compound. Table 1, Entry 5, er: 88:12. Peak Name tR Area Height Area% Symmetry Factor 1 18,600 5241997 112514 88,074 1,437 2 27,017 709806 11458 11,926 1,290 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 10000 20000 30000 Intensity [µV] MP 26A 5% IPA_009_45,49min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 0 50000 100000 Intensity [µV] CN 51A_001_35,25min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 81 ▪ tert-Butyl (S)-(4-(2,4-dioxopentan-3-yl)-5-oxo-1,3-diphenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (3g). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 11.842 4548326 135340 50.294 0.868 2 26.292 4495142 64882 49.706 1.450 HPLC Profile for 3g compound. Table 1, Entry 7, er: 94:6. PeakNumber tR Area Height Area % SymmetryFactor 1 12,683 7750572 278161 93,900 97,052 2 29,083 503455 8450 6,100 2,948 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 55,0 60,0 0 50000 100000 Intensity [µV] MP 27A_001 - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 0 100000 200000 Intensity [µV] CN 62A_006 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 82 ▪ tert-Butyl (S)-(4-(3,5-dioxoheptan-4-yl)-3-methyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (3h). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 9.425 8614606 529030 50.208 1.248 2 25.325 8543387 178745 49.792 1.197 HPLC Profile for 3h compound. Table 2, Entry 1, er: 85:15. PeakNumber tR Area Height Area % SymmetryFactor 1 9.167 5289670 257882 85.194 1.507 2 23.792 919285 18509 14.806 1.196 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 0 200000 400000 Intensity [µV] MP 4A_002_33,81min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 0 100000 200000 Intensity [µV] CA 49A_001 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 83 ▪ tert-Butyl (S)-(4-(1,3-dioxo-1,3-diphenylpropan-2-yl)-3-methyl-5-oxo-1phenyl-4,5-dihydro-1H-pyrazol-4-yl)carbamate (3i). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 15.075 11929079 408849 50.462 1.166 2 40.100 11710796 134520 49.538 1.099 HPLC Profile for 3i compound. Table 1, Entry 2, er: 88:12. PeakNumber tR Area Height Area % SymmetryFactor 1 14.242 12504213 383289 88.315 1.271 2 35.833 1654430 20551 11.685 1.106 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 55,0 0 100000 200000 300000 400000 Intensity [µV] CN 10A_002_57,94min - CH1 1 2 0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 0 100000 200000 300000 400000 Intensity [µV] CA 50A_002 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 84 ▪ tert-Butyl (S)-(4-(3,5-dioxoheptan-4-yl)-5-oxo-1,3-diphenyl-4,5-dihydro1H-pyrazol-4-yl)carbamate (3j). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 8,908 8625302 476025 50,756 1,599 2 21,867 8368363 182162 49,244 1,118 HPLC Profile for 3j compound. Table 1, Entry 3, er: 88:12. PeakNumber tR Area Height Area% SymmetryFactor 1 8,933 8714793 433523 93,270 1,473 2 22,308 628810 13809 6,730 1,093 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 0 200000 400000 Intensity [µV] CN 16C_002_38,71min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 0 100000 200000 300000 400000 Intensity [µV] CN 24A_001_35,12min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 85 ▪ tert-Butyl (S)-(4-(1,3-dioxo-1,3-diphenylpropan-2-yl)-5-oxo-1,3-diphenyl4,5-dihydro-1H-pyrazol-4-yl)carbamate (3k). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 10,517 3074291 105439 52,217 1,020 2 22,317 2813199 44943 47,783 1,060 HPLC Profile for 3k compound. Table 2, Entry 4, er: 88:12. PeakNumber tR Area Height Area% SymmetryFactor 1 10,892 5164528 148763 92,597 1,004 2 23,792 412913 6017 7,403 1,032 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 50000 100000 Intensity [µV] CN 17C 20% IPA_001_47,56min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 0 50000 100000 150000 Intensity [µV] CN 23A_005_34,55min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 92 ▪ tert-Butyl (S)-(3,5-dimethyl-5'-oxo-1',3’-diphenyl-1',5'-dihydro-1H,4'H- [4,4'-bipyrazol]-4'-yl)carbamate (4g). Racemic compound PeakNumber tR Area Height Area % SymmetryFactor 1 12.717 2931594 84826 50.086 1.487 2 31.350 2921501 32808 49.914 1.364 HPLC Profile for 4g compound. Table 3, Entry 6, er: 94:6. PeakNumber tR Area Height Area % SymmetryFactor 1 12.850 4772695 138915 94.217 1.496 2 32.458 292947 3283 5.783 1.184 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 20000 40000 60000 80000 Intensity [µV] CA 56A lux-i-amylose-3_003 - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 0 50000 100000 Intensity [µV] CA 66A_001 - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 93 ▪ tert-Butyl (S)-(3,5-diethyl-5'-oxo-1',3'-diphenyl-1',5'-dihydro-1H,4'H-[4,4'- bipyrazol]-4'-yl)carbamate (4j). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 19,725 276801 61716 51,125 1,299 2 24,550 2646161 52232 48,875 1,205 HPLC Profile for 4j compound. Table 3, Entry 7, er: 95:5. PeakNumbe tR Area Height Area% SymmetryFactor 1 20,158 185714 4311 5,273 1,125 2 25,042 3336290 63586 94,727 1,118 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 20000 40000 60000 Intensity [µV] CN 29A IA 5%IPA_001_45,12min - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 20000 40000 60000 Intensity [µV] CN 30A IA 5%IPA_002_45,16min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 94 ▪ tert-Butyl (S)-(3-methyl-5-oxo-4-(2-oxo-2-phenylethyl)-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (5i). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 7,875 3002905 249516 50,441 1,226 2 33,517 2950438 50333 49,559 1,058 HPLC Profile for 5i compound. Table 3, Entry 8, er: 23:77. PeakNumber tR Area Height Area% SymmetryFactor 1 6,875 1551170 122385 23,092 1,260 2 32,358 5166215 86600 76,908 1,074 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 0 100000 200000 Intensity [µV] CN 37A 20%IPA_002 - CH1 1 2 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 0 50000 100000 Intensity [µV] CN 38A 20%IPA_003_43,56min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 95 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-3,3',5-trimethyl-5'-oxo-1'-phenyl-1',5'- dihydro-1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (6a). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 47,758 2305688 15319 50,132 1,173 2 79,067 2293573 10070 49,868 1,157 HPLC Profile for 6a compound. Scheme 5, er: 84:16. PeakNumber tR Area Height Area% SymmetryFactor 1 44,967 8828181 62101 83,614 1,296 2 74,183 1730125 8461 16,386 1,217 1 2 0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 0 5000 10000 15000 Intensity [µV] CN 45B ADH_002_88,80min - CH1 1 2 0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 90,0 100,0 0 20000 40000 60000 Intensity [µV] CN 54A_001_104,69min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 96 ▪ tert-Butyl (S)-(1-(4-chlorophenyl)-3,5-dimethyl-5'-oxo-1',3'-diphenyl-1',5'- dihydro-1H,4'H-[4,4'-bipyrazol]-4'-yl)carbamate (6g). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 9,275 7170915 261657 50,261 1,120 2 66,267 7096443 30149 49,739 1,008 HPLC Profile for 6g compound. Scheme 5, er: 96:4. PeakNumber tR Area Height Area% SymmetryFactor 1 10,075 4591426 187683 96,419 1,124 2 63,700 170512 1149 3,581 1,007 1 2 0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 90,0 0 100000 200000 Intensity [µV] CN 63A_001_175,30min - CH1 1 2 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 90,0 0 100000 200000 Intensity [µV] CN 64A_001_92,39min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 97 ▪ tert-Butyl (S)-(4-(3,5-dimethylisoxazol-4-yl)-3-methyl-5-oxo-1-phenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (7a). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 10,867 2829567 105132 50,156 1,257 2 20,142 2811934 57245 49,844 1,182 HPLC Profile for 7a compound. Scheme 5, er: 83:17. PeakNumber tR Area Height Area% SymmetryFactor 1 10,608 1618696 63025 83,159 1,271 2 19,475 327817 7360 16,841 1,195 1 2 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 20,0 22,0 24,0 26,0 0 50000 100000 Intensity [µV] CN 47A_002_27,63min - CH1 1 2 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 20,0 0 20000 40000 60000 Intensity [µV] CN 58A_003_21,48min - CH1 Trabajo Fin de Grado Cristopher Niño Rodriguez 98 ▪ tert-Butyl (S)-(4-(3,5-dimethylisoxazol-4-yl)-5-oxo-1,3-diphenyl-4,5dihydro-1H-pyrazol-4-yl)carbamate (7g). Racemic compound PeakNumber tR Area Height Area% SymmetryFactor 1 10,067 3046066 118497 49,751 1,178 2 14,792 3076553 76594 50,249 1,099 HPLC Profile for 7g compound. Scheme 5, er: 7:93. PeakNumber tR Area Height Area% SymmetryFactor 1 10,075 246531 10010 7,067 1,139 2 14,633 3242092 83894 92,933 1,109 1 2 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 20,0 22,0 0 50000 100000 Intensity [µV] CN 70A_002_21,97min - CH1 1 2 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 20,0 22,0 0 20000 40000 60000 80000 Intensity [µV] CN 65A_003_22,09min - CH1 99