Hydrazones as C-Nucleophiles in Asymmetric Organocatalysis

• Autores: Esteban Matador Martínez
• Directores de la Tesis: Rosario Fernández Fernández (dir. tes.), José María Lassaletta Simón (dir. tes.)
• Lectura: En la Universidad de Sevilla ( España ) en 2021
• Idioma: español
• Número de páginas: 454
• Enlaces
  • Tesis en acceso abierto en: Idus
• Resumen

  • In this PhD Thesis, novel catalytic processes and methodologies for the asymmetric functionalization of prochiral substrates (neutral or ionic) employing hydrazones as versatile umpolung reagents have been developed. In general, double H-bond donors organocatalysts based on unnatural amino acids provided good reactivities and suitable chiral environments for that purpose, affording valuable building blocks and appealing structures for multiple applications in Organic Synthesis (M. G. Retamosa, E. Matador, D. Monge, J. M. Lassaletta, R. Fernández, Chem. Eur. J. 2016, 22, 13430-13455; E. Matador, M. G. Retamosa, D. Monge, R. Fernández, J. M. Lassaletta, Chem. Commun. 2020, 56, 9256-9267). In this context, the present dissertation is structured as follow: Along Chapter I, the contextualization of the developed work are first shown, starting from the activation modes in Asymmetric Organocatalysis to the state of the art of the different strategies developed which employ hydrazones as C-nucleophiles in that field. In Chapter II and III, the specific objectives and a brief summary of the results accomplished are displayed, respectively. A deep discussion of the results obtained is presented along Chapter IV in four different sections: In Section IV.1, the nucleophilic 1,2-addition of formaldehyde N-tert-butylhydrazone to simple aldehydes is described. This strategy could be performed with both excellent reactivity and enantioselectivity by virtue of the dual H-bonding activation exerted by amide-squaramide derived organocatalysts (up to 96% ee). The resulting hydroxydiazenes were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent high-yielding and racemization-free derivatizations led to valuable β-amino alcohols and derivatives thereof (E. Matador, M. G. Retamosa, D. Monge, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta, Chem. Eur. J. 2018, 24, 6854-6860). Along Section IV.2, the formal diaza-ene reactivity of formaldehyde N-tert-butylhydrazone was extended to the use of more challenging fluorinated ketones for the synthesis of densely functionalized fluorine-containing tertiary alcohols. H-Bonding thiourea/squaramide organocatalysts enabled an enantioselective approach for a variety of di- and tri-fluoromethyl ketones and afforded diazenes (N-oxides) in good-to-excellent yields and moderate-to-good enantioselectivities (up to 90% ee). The synthesis of valuable building blocks was also highlighted by virtue of the marked versatility of the diazenyl group (E. Matador, M. G. Retamosa, A. Jiménez-Sánchez, D. Monge, R. Fernández, J. M. Lassaletta, Eur. J. Org. Chem. 2019, 130-138). Ensuing the high intrinsic reactivity observed for the reactions between formaldehyde N-tert-butylhydrazone and trifluoromethyl ketones, a green key step of a nucleophilic formylation strategy is depicted in Section IV.3. The unprecedented reaction of this hydrazone with trifluoromethyl ketones under solvent-free conditions afforded analytically pure diazenes in short reaction times without the need of any purification process (>99% yield in all cases). Subsequent unmasking of the formyl group in one pot fashion afforded valuable α-hydroxy α-trifluoromethyl aldehydes as key intermediates for the construction of relevant building blocks for target-oriented synthesis (E. Matador, D. Monge, R. Fernández, J. M. Lassaletta, Green Chem. 2016, 18, 4042-4050). In Section IV.4, a highly stereoselective, and scalable thiourea-organocatalyzed dearomatization of isoquinolines with N-tert-butylhydrazones is described. This multicomponent reaction afforded diazenes in excellent enantio- and diastereomeric ratios (up to >99% ee, dr >20/1 in all cases). The proposed activation model relies on a simultaneous binding of the thiourea and the hydrazone nucleophile to the chloride anion with preferential positioning of the isoquinolinium cation, thereby inducing excellent stereocontrol in the formation of two contiguous stereogenic centers. Subsequent simple derivatizations of primary adducts under mild conditions gave enantioenriched valuable building blocks with appealing structures for Organic Synthesis (E. Matador, J. Iglesias-Sigüenza, D. Monge, P. Merino, R. Fernández, J. M. Lassaletta, Angew. Chem. Int. Ed. 2020, early view 10.1002/anie.202012861). Finally, the conclusions of the present PhD Thesis are shown in Chapter V, and the original articles and their corresponding supplementary materials are provided in Appendix II. All the reactivities and strategies developed during this PhD thesis, supported by experimental and computational methods, have contributed to the advance of the previously contextualized field, and provided efficient alternatives to solve problems of great interest in fundamental chemical research.