Diastereoselective synthesis of a new dissubstitued cyclopentenones series with potential anti-inflammatory activity

Author(s)

Mariane Valéria Roldão

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2019-08-07

Examining board members

Fernando Antonio Santos Coelho; Luiz Alberto Beraldo de Moraes; Júlio Cezar Pastre

• Advisor: Fernando Antonio Santos Coelho; Wanda Pereira Almeida

Abstract

Recently, our research group synthesized some disubstituted cyclopentenones that showed anti-inflammatory activity, through the inhibition of cyclooxygenase isoform 2 (COX-2). In this work, we revisit the preparation strategy for these cyclopentenones, having the goal of making it more direct and increasing its scope. The synthetic route consisted on the conjugated addition of a boronic acid to a Morita-Baylis-Hillman adduct, the product of that reaction being converted into an alkylating agent for a malonate. The resulting di-ester was subjected to a decarboxylation step, using the Krapcho reaction, followed by hydrolysis in basic medium. Finally, the resulting g,d-unsaturated acid was subjected to an intramolecular cyclization reaction to form the cyclopentenone. To optimize the synthetic route, we made two modifications: the boronic acid was replaced by the corresponding trifluorophenylboronate, and the decarboxylation and hydrolysis steps were performed in acid medium one-pot reaction. Thus, we obtained the cyclopentenones with one step less, and there was an overall yield increase, which jumped from 10-30% to 29- 43%. Considering the anti-inflammatory activity of cyclopentenones, observed in a previous study, we performed a planning for new cyclopentenones with potential anti-inflammatory activity. Analyzing analogues of Celecoxib, a commercially available anti-inflammatory drug with potent inhibitory effect in vitro of COX-2, and also guided by the prediction of pharmacokinetic parameters of these analogues, we proposed six new cyclopentenones, which were obtained by the modified route. These samples will be forwarded for evaluation of their anti-inflammatory effect and investigation of the action mechanism (AU)

• FAPESP's process: 17/08229-8 - New synthetic approach for the preparation of non-steroidal anti-inflammatory drugs, selective COX-2 inhibitors: study of mechanisms of anti-inflammatory action
• Grantee: Mariane Valéria Roldão
• Support Opportunities: Scholarships in Brazil - Master