Development of methodologies and synthetic processes employing a new technological platform: micro and meso reactor assisted synthesis of natural products and derivatives with potential pharmacological activity

• Grant number: 14/26378-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: August 01, 2015
• End date: January 31, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Júlio Cezar Pastre
• Grantee: Júlio Cezar Pastre
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated research grant(s): 21/06661-5 - Enabling technologies for the sustainable chemical synthesis of platform molecules, new chemicals and bioactive compounds, AP.BIOEN.JP2; 18/14555-8 - Chemical reactions under continuous flow conditions: chemical and economic aspects of the use of enabling technologies for obtaining low cost medicines, AV.EXT
• Associated scholarship(s): 19/26450-9 - Application of green chemistry in Synhtesis of materials and building blocks employing renewable resources and continuous flow syntesis, BP.DR; 18/25233-1 - Continuous flow synthesis of biomass-derivatives, BP.MS; 18/09861-2 - Synthesis of novel ionic liquids from renewable sources and application on biomass conversion, BP.DR; + associated scholarships 17/24294-4 - Total synthesis and evaluation of the cytotoxicity of cyclic depsipeptides Kohamamides A, B and C, BP.IC; 17/19953-9 - Total synthesis and evaluation of the cytotoxic activity of cacofurans A and B, BP.IC; 15/18572-6 - Continuous flow synthesis of 3-thio-1,2,4-triazoles and biological evaluation, BP.DR - associated scholarships

Abstract

The fine chemicals industry is entirely based on batch processes. Although the performance of batch reactors is well predictable, there are some limitations related to scale-up, reproducibility, safety, etc. The use of continuous processes by the fine chemicals industry is hampered mainly by financial and regulatory issues, however the high competitiveness of the industry and the pressure for a more sustainable manufacturing should boost a change of this paradigm. In this context, the use of continuous micro- and meso-reactors in the early stages of development stands as a promising alternative. Indeed, micro- and meso-reactors technology has been employed in the multi-step synthesis of molecules with high added value, particularly in academia. Micro- and meso-reactors offer significant advantages over traditional batch reactors such as faster and safer reactions, purer products, fast reaction optimization, easer scale up and integration of processes that are usually performed separately such as synthesis, purification and analysis. In this context, this proposal has as the main goal the establishment of a research group in the field of micro-reactor assisted organic synthesis. To achieve this goal, we intend to develop efficient methods for synthesis using micro and meso-reactors, aiming at the preparation of compounds with different properties and applications, such as natural products, drugs and new drug candidates. This proposal is strategically divided into sub projects that envolves (i) the development of new procedures for conjugate addition reactions and copper catalyzed allylic substitution reactions in continuous flow conditions, (ii) the synthesis of carbon nanotube supported organocatalyst aiming at its application to the addition of organozinc reagents to aldehydes and other organocatalyzed reactions, (iii) the development of methodologies for the ketene generation under continuous flow conditions and its application for multi step synthesis and (iv) the synthesis of biologically active natural products, such as goniothalamin, spilanthol, piplartine, cenocladamide and derivatives, using this platform for their preparation, aiming at surpassing limitations associated with the batch mode providing an alternative route. Also, this proposal aims to support further studies for the evaluation of the biological activity of the compounds prepared through the established collaborations with researchers from CPQBA / UNICAMP. (AU)

Scientific publications

(28)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FORNI, JOSE AUGUSTO; TONETO NOVAES, LUIZ FERNANDO; GALAVERNA, RENAN; PASTRE, JULIO C.. Novel polystyrene-immobilized chiral amino alcohols as heterogeneous ligands for the enantioselective arylation of aldehydes in batch and continuous flow regime. CATALYSIS TODAY, v. 308, n. SI, p. 86-93, JUN 15 2018. (14/26093-8, 15/08199-6, 14/25770-6, 14/26378-2)

PASTRE, JULIO C.; MURRAY, PHILIP R. D.; BROWNE, DUNCAN L.; BRANCAGLION, GUILHERME A.; GALAVERNA, RENAN S.; PILLI, RONALDO A.; LEY, V, STEVEN. Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin. ACS OMEGA, v. 5, n. 29, p. 18472-18483, JUL 28 2020. (13/07607-8, 12/05909-4, 14/26378-2)

HERRERA, CHRISTIAN LEONARDO; SANTIAGO, JOAO VICTOR; PASTRE, JULIO CEZAR; CORREIA, CARLOS ROQUE DUARTE. In Tandem Auto-Sustainable Enantioselective Heck-Matsuda Reactions Directly from Anilines. ADVANCED SYNTHESIS & CATALYSIS, v. 364, n. 11, p. 10-pg., 2022-04-22. (14/26378-2, 13/07600-3, 14/25770-6)

COSTA, RENNA K. E.; BRANCAGLION, GUILHERME A.; PINHEIRO, MATHEUS P.; ADAMOSKI, DOUGLAS; DA SILVA, BIANCA N.; NEGRAO, CYRO Z. DE V.; GONCALVES, KALIANDRA DE A.; RODRIGUES, CAMILA T.; AMBROSIO, ANDRE L. B.; GUIDO, RAFAEL V. C.; et al. Discovery of aminothiazole derivatives as a chemical scaffold for glutaminase inhibition. RESULTS IN CHEMISTRY, v. 5, p. 17-pg., 2023-02-17. (13/07600-3, 16/09077-4, 21/13736-1, 14/26378-2, 19/16351-3, 20/12904-5, 21/06661-5, 14/15968-3)

SANTOS, CARLA C. F.; PARADELA, LUCIANA S.; NOVAES, LUIZ F. T.; DIAS, SANDRA M. G.; PASTRE, JULIO C.. Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines. MedChemComm, v. 8, n. 4, p. 755-766, APR 1 2017. (15/08199-6, 14/25770-6, 14/26378-2, 14/15968-3)

GOMES, GUSTAVO R.; MATTIOLI, RENAN R.; PASTRE, JULIO CEZAR. Amino Acid-Based Deep Eutectic Solvents in Biomass Processing- Recent Advances. Journal of the Brazilian Chemical Society, v. 33, n. 8, p. 9-pg., 2022-08-01. (14/26378-2, 19/26450-9, 18/09861-2, 14/25770-6, 20/11578-7)

FORNI, JOSE AUGUSTO; TONETO NOVAES, LUIZ FERNANDO; GALAVERNA, RENAN; PASTRE, JULIO C.. Novel polystyrene-immobilized chiral amino alcohols as heterogeneous ligands for the enantioselective arylation of aldehydes in batch and continuous flow regime. CATALYSIS TODAY, v. 308, p. 8-pg., 2018-06-15. (15/08199-6, 14/26378-2, 14/25770-6, 14/26093-8)

DAMIAO, MARIANA C. F. C. B.; GALAVERNA, RENAN; KOZIKOWSKI, ALAN P.; EUBANKS, JAMES; PASTRE, JULIO C.. Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles. REACTION CHEMISTRY & ENGINEERING, v. 2, n. 6, p. 896-907, DEC 2017. (15/18572-6, 14/25770-6, 14/26378-2, 13/07607-8)

GALAVERNA, RENAN; BREITKREITZ, MARCIA C.; PASTRE, JULIO C.. Conversion of D-Fructose to 5-(Hydroxymethyl)furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-Line FTIR Monitoring. ACS SUSTAINABLE CHEMISTRY & ENGINEERING, v. 6, n. 3, p. 4220-4230, MAR 2018. (14/25770-6, 16/05636-9, 06/57897-9, 14/26378-2, 13/07607-8)

NOVAES, LUIZ F. T.; PASTRE, JULIO C.. Formal Total Synthesis of Actinoranone and Asymmetric Synthesis of Labda-7,13-(E)-dien-15-ol. ORGANIC LETTERS, v. 19, n. 12, p. 3163-3166, JUN 16 2017. (15/08199-6, 14/25770-6, 14/26378-2)

LABES, RICARDO; PASTRE, JULIO C.; INGHAM, RICHARD J.; BATTILOCCHIO, CLAUDIO; MARCON, HENRIQUE M.; DAMIAO, MARIANA C. F. C. B.; TRAN, DUC N.; LEY, STEVEN V.. Automated multistep synthesis of 2-pyrazolines in continuous flow. REACTION CHEMISTRY & ENGINEERING, v. 9, n. 3, p. 8-pg., 2023-11-09. (14/25770-6, 15/18572-6, 14/26378-2, 20/11578-7, 18/25233-1)

DE SOUZA, JULIANA M.; GALAVERNA, RENAN; DE SOUZA, ALINE A. N.; BROCKSOM, TIMOTHY J.; PASTRE, JULIO C.; DE SOUZA, RODRIGO O. M. A.; DE OLIVEIRA, KLEBER T.. Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients. Anais da Academia Brasileira de Ciências, v. 90, n. 2, p. 1131-1174, 2018. (11/13993-2, 13/07276-1, 14/25770-6, 14/26378-2)

GUSTAVO R. GOMES; RENAN R. MATTIOLI; JULIO CEZAR PASTRE. Amino Acid-Based Deep Eutectic Solvents in Biomass Processing - Recent Advances. Journal of the Brazilian Chemical Society, v. 33, n. 8, p. 815-823, 2022-06-15. (18/09861-2, 19/26450-9, 14/25770-6, 14/26378-2, 20/11578-7)

ALONSO, ISABELLA G.; YAMANE, LAIS T.; DE FREITAS-BLANCO, VERONICA S.; NOVAES, LUIZ F. T.; FRANZ-MONTAN, MICHELLE; DE PAULA, ENEIDA; RODRIGUES, MARILI V. N.; RODRIGUES, RODNEY A. F.; PASTRE, JULIO C.. A new approach for the total synthesis of spilanthol and analogue with improved anesthetic activity. Tetrahedron, v. 74, n. 38, p. 5192-5199, SEP 20 2018. (15/08199-6, 14/06461-2, 14/25770-6, 14/16186-9, 14/26378-2)

GALAVERNA, RENAN; RIBESSI, RAFAEL L.; ROHWEDDER, JARBAS J. R.; PASTRE, JULIO C.. Coupling Continuous Flow Microreactors to MicroNIR Spectroscopy: Ultracompact Device for Facile In-Line Reaction Monitoring. ORGANIC PROCESS RESEARCH & DEVELOPMENT, v. 22, n. 7, p. 780-788, JUL 2018. (14/50951-4, 14/26378-2, 14/25770-6, 13/07607-8)

NOVAES, LUIZ F. T.; GONCALVES, KALIANDRA DE ALMEIDA; TRIVELLA, DANIELA B. B.; PASTRE, JULIO C.. Formal Total Synthesis of Actinoranone: Synthesis Approaches and Cytotoxic Studies. Journal of Organic Chemistry, v. 83, n. 9, p. 5160-5176, MAY 4 2018. (15/08199-6, 14/25770-6, 14/26378-2)

GALAVERNA, RENAN; FERNANDES, LUCAS P.; BROWNE, DUNCAN L.; PASTRE, JULIO C.. Continuous flow processing as a tool for the generation of terpene-derived monomer libraries. REACTION CHEMISTRY & ENGINEERING, v. 4, n. 2, p. 362-367, FEB 1 2019. (14/25770-6, 14/26378-2)

GALAVERNA, RENAN; MCBRIDE, TOM; PASTRE, JULIO C.; BROWNE, DUNCAN L.. Exploring the generation and use of acylketenes with continuous flow processes. REACTION CHEMISTRY & ENGINEERING, v. 4, n. 9, p. 1559-1564, SEP 1 2019. (14/25770-6, 14/26378-2)

SIVO, ALESSANDRA; GALAVERNA, RENAN DE SOUZA; GOMES, GUSTAVO RODRIGUES; PASTRE, JULIO CEZAR; VILE, GIANVITO. From circular synthesis to material manufacturing: advances, challenges, and future steps for using flow chemistry in novel application area. REACTION CHEMISTRY & ENGINEERING, v. 6, n. 5, p. 756-786, MAY 1 2021. (14/25770-6, 14/26378-2, 18/09861-2)

MARCON, HENRIQUE MAGRI; PASTRE, JULIO CEZAR. Continuous flow Meerwein-Ponndorf-Verley reduction of HMF and furfural using basic zirconium carbonate. RSC ADVANCES, v. 12, n. 13, p. 10-pg., 2022-03-08. (14/26378-2, 18/25233-1, 14/25770-6, 20/11578-7)

GOMES, GUSTAVO R.; SCOPEL, EUPIDIO; BREITKREITZ, MARCIA C.; REZENDE, CAMILA A.; PASTRE, JULIO C.. Valorization of sugarcane bagasse C5-fraction by furfural production mediated by renewable glycine-based ionic liquid. INDUSTRIAL CROPS AND PRODUCTS, v. 191, p. 11-pg., 2023-01-01. (18/09861-2, 18/23769-1, 14/26378-2, 21/06661-5, 20/11578-7, 19/19360-3, 14/25770-6)

GOMES, GUSTAVO RODRIGUES; PASTRE, JULIO CEZAR. Microwave-assisted HMF production from water-soluble sugars using betaine-based natural deep eutectic solvents (NADES). SUSTAINABLE ENERGY & FUELS, v. 4, n. 4, p. 1891-1898, APR 1 2020. (18/09861-2, 14/25770-6, 14/26378-2)

DAMIAO, MARIANA C. F. C. B.; MARCON, HENRIQUE M.; PASTRE, JULIO CEZAR. Continuous flow synthesis of the URAT1 inhibitor lesinurad. REACTION CHEMISTRY & ENGINEERING, v. 5, n. 5, p. 865-872, MAY 1 2020. (14/25770-6, 14/26378-2, 15/18572-6, 13/07607-8, 18/25233-1)

GOMES, GUSTAVO R.; SCOPEL, EUPIDIO; ROCHA, NICOLA L.; BREITKREITZ, MARCIA C.; CORMANICH, RODRIGO A.; REZENDE, CAMILA A.; PASTRE, JULIO C.. Direct Ethyl Levulinate Production from Raw Lignocellulosic Biomass Mediated by a Novel Taurine-Based Imidazolium Ionic Liquid. ACS SUSTAINABLE CHEMISTRY & ENGINEERING, v. N/A, p. 13-pg., 2022-11-21. (18/23769-1, 18/09861-2, 14/26378-2, 18/03910-1, 21/06661-5, 19/19360-3, 14/25770-6, 20/11578-7)

GALAVERNA, RENAN S.; FERNANDES, LUCAS P.; DA SILVA, VITOR H. MENEZES; DE SIERVO, ABNER; PASTRE, JULIO C.. Humins-Like Solid Support for Palladium Immobilization: Highly Efficient and Recyclable Catalyst for Cross-Coupling Reactions. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, v. 2022, n. 24, p. 11-pg., 2022-06-27. (14/26378-2, 14/25770-6, 20/11578-7)

GOMES, GUSTAVO RODRIGUES; BREITKREITZ, MARCIA CRISTINA; PASTRE, JULIO CEZAR. Ash Influence on the Ethyl Levulinate Production from Sugarcane Molasses Mediated by Taurine Hydrogen Sulfate. ACS SUSTAINABLE CHEMISTRY & ENGINEERING, v. 9, n. 40, p. 13438-13449, OCT 11 2021. (14/25770-6, 20/11578-7, 18/09861-2, 14/26378-2)

DE SOUZA, JULIANA M.; GALAVERNA, RENAN; DE SOUZA, ALINE A. N.; BROCKSOM, TIMOTHY J.; PASTRE, JULIO C.; DE SOUZA, RODRIGO O. M. A.; DE OLIVEIRA, KLEBER T.. Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients. Anais da Academia Brasileira de Ciências, v. 90, p. 44-pg., 2018-01-01. (14/25770-6, 14/26378-2, 13/07276-1, 11/13993-2)

LUIZ F. T. NOVAES; JULIO C. PASTRE. AVANÇOS RECENTES NA HIDROAMINAÇÃO DE COMPOSTOS INSATURADOS. Química Nova, v. 40, n. 8, p. 932-945, 2017-09-00. (14/26378-2, 15/08199-6, 14/25770-6)

Filed patent(s) as a result of this research project