Novel approaches toward sp2-sp3 medicinal chemistry relevant scaffolds

In recent years sp3-sp2 hybrids are emerging as compounds of interest in medicinal chemistry.1–3 In this thesis two different approaches to sp3-sp2 hybrids have been explored. The first chapter describes the development of a dearomative platform for the synthesis of analogs of (amino)cyclitols, a class of compounds characterized by a broad range of biological activities formed by heavily decorated.4 The dearomative chemistry has been used to decrease the sp2 fraction of polyaromatics compounds, obtaining sp3-sp2 adducts between arenes, (hetero)arenes, and (amino)cyclitols This approach gave access to several cyclohexanes decorated and condensed with benzenic, pyridinic, and pyrazinic rings. The second chapter discussed the synthesis of sp2-sp3 hybrids between (hetero)aromatics and bicyclo[2.1.1]hexanes, these structures are emerging as valuable benzene bioisosteres.5 In this case, the sp2 fraction of the saturated bicycles is increased by the synthesis of (hetero)aromatics giving bicyclo[2.1.1]hexanes condensed with imidazoles, pyridazines, and quinoxaline.   Bibliografia: (1) Tomohiro, D.; Hiroki, Y.; Takahiro, N. α, β-UNSATURATED AMIDE COMPOUND, December 27, 2018. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018235926 (accessed 2023-08-12). (2) Janda, K. D.; Dickerson, T. J. Nicotine Immunoconjugates. WO2009120954A2, October 1, 2009. https://patents.google.com/patent/WO2009120954A2/en/en17 (accessed 2023-08-12). (3) Graceffa, R.; Kaller, M.; La, D.; Lopez, P.; Patel, V. F.; Zhong, W. Substituted Pyrano [2,3-b] Pyridinamine Compounds as Beta-Secretase Modulators and Methods of Use. US20100120774A1, May 13, 2010. https://patents.google.com/patent/US20100120774/en (accessed 2023-08-12). (4) Delgado, A. Recent Advances in the Chemistry of Aminocyclitols. Eur. J. Org. Chem. 2008, 2008 (23), 3893–3906. https://doi.org/10.1002/ejoc.200800238. (5) K. Mykhailiuk, P. Saturated Bioisosteres of Benzene: Where to Go Next? Org. Biomol. Chem. 2019, 17 (11), 2839–2849. https://doi.org/10.1039/C8OB02812E.

Recentemente gli ibridi sp3-sp2 sono emersi come composti di interesse in chimica medicinale.1–3 In questa tesi due diversi approcci ad ibridi sp3-sp2 sono stati esplorati. Nel primo capitolo viene descritto lo sviluppo di una piattaforma dearomative per la sintesi di analoghi di (amino)ciclitoli, una classe di composti dalle diverse proprietà biochimiche caratterizzati da una struttura carbociclica a sei membri altamente decorata.4 La chimica dearomative è stata utilizzata per diminuire la frazione sp2 di composti poliaromatici, ottenendo addotti sp3-sp2 tra areni/etero areni e (amino)ciclitoli. Questo approccio ha dato accesso a diversi cicloesani altamente decorati condensati ad anelli benzenici, piridinici e pirazinici. Nel secondo capitolo viene trattata la sintesi di ibridi sp2-sp3 tra etero aromatici e biciclo[2.1.1]esani, delle strutture bicicliche che stanno emergendo come bioisosteri del benzene.5 In questo caso la frazione sp2 dei bicicli saturi viene aumentata attraverso la sintesi di anelli etero aromatici ottenendo biciclo[2.1.1]esani condensati ad imidazoli, piridazine e alla chinossalina.   Bibliografia: (1) Tomohiro, D.; Hiroki, Y.; Takahiro, N. α, β-UNSATURATED AMIDE COMPOUND, December 27, 2018. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018235926 (accessed 2023-08-12). (2) Janda, K. D.; Dickerson, T. J. Nicotine Immunoconjugates. WO2009120954A2, October 1, 2009. https://patents.google.com/patent/WO2009120954A2/en/en17 (accessed 2023-08-12). (3) Graceffa, R.; Kaller, M.; La, D.; Lopez, P.; Patel, V. F.; Zhong, W. Substituted Pyrano [2,3-b] Pyridinamine Compounds as Beta-Secretase Modulators and Methods of Use. US20100120774A1, May 13, 2010. https://patents.google.com/patent/US20100120774/en (accessed 2023-08-12). (4) Delgado, A. Recent Advances in the Chemistry of Aminocyclitols. Eur. J. Org. Chem. 2008, 2008 (23), 3893–3906. https://doi.org/10.1002/ejoc.200800238. (5) K. Mykhailiuk, P. Saturated Bioisosteres of Benzene: Where to Go Next? Org. Biomol. Chem. 2019, 17 (11), 2839–2849. https://doi.org/10.1039/C8OB02812E.