Regioselective functionalization of chloroquinolines to synthesize compounds of medicinal interest

Author(s)

Valter Eduardo Murie

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2020-03-09

Examining board members

Giuliano Cesar Clososki; Paulo Marcos Donate; Diogo Montes Vidal

• Advisor: Giuliano Cesar Clososki; Ian Richard Baxendale

Abstract

Quinoline is one of the most investigated heterocycles of azanaphthalene type since it is present in some prominent biologic compounds such as antimalarial, anticancer, antileishmanial, antibiotic and others. In this context, this work is focused on the functionalization of chloroquinolines to synthesize compounds of medicinal interest. The regioselective metallation of 4,7-dichloroquinoline at C3 and C8 positions was found to be controlled by base type. Deproto-metallation using LDA took place at C3 position while C8 was preferentially accounted for either mixed lithium-magnesium amide (TMPMgCl.LiCl) or mixed lithium-zinc amide (TMPZnCl.LiCl). The selectivity of the bases can be associated with hydrogen acidities and metal coordination capability of the quinolinic nitrogen by DFT calculations and experimental results. A library of functionalized chloroquinolines at C3 and C8 positions was synthesized by trapping the organometallic intermediate with different electrophiles. To demonstrate the relevance of this results, a chloroquine analog has already reported in the literature was synthesized using a microwave reactor in agreement with green chemistry. The functionalization of C8 position was investigated under flow conditions using coil reactors and TMPMgCl.LiCl. The reaction time in such mode was shorter with high yields than in a batch setting. According to the literature, 4-anilinoquinoline and 4-aminoquinazoline are key scaffolds as epidermal growth factor receptor inhibitors (EGFR). Thus, from molecular docking studies of antitumoral activity using erlotinib and gefitinib as reference standards, we proposed the synthesis of quinoline-4-carbinol derivative envisaging the bioisosteric replacement of R1R2NH group for CHR1R2OH. The iodo/magnesium exchange between 7-chloro-4-iodoquinoline and Turbo-Grignard was used as synthetic strategy to prepare compounds in a fast way, at smoothly temperature conditions and high yield. A library of 4-substituted quinolines was synthesized and the antiproliferative activity in tumor cell lines of carbinol derivatives is under investigation. The ketone derivatives were submitted to enantioselective hydrogenation to prepare asymmetric alcohol in the presence of ruthenium catalyst. The compounds prepared under Negishi conditions were tested in direct remote metallation reaction. Finally, the search for a starting material of low cost gave us the opportunity to explore the metallation of the quinoline N-oxide, which is going to be investigated after this composition. (AU)

• FAPESP's process: 15/21364-6 - Applicantion of Organometallic Reagents in the Directed Functionalization of Quinolines Aimming the Synthesis of Medicinal Interest Compounds
• Grantee: Valter Eduardo Murie
• Support Opportunities: Scholarships in Brazil - Doctorate