Synthesis of bicyclic N-heterocycles via photochemical formal cycloadditions of cyclopropyl ketones and strained amines

• Grant number: 24/14260-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: November 30, 2024
• End date: November 29, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Arlene Gonçalves Corrêa
• Grantee: Lucas Giani Furniel
• Supervisor: Till Opatz
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Institution abroad: Johannes Gutenberg University Mainz (JGU), Germany
• Associated to the scholarship: 23/11454-4 - Photocatalytic synthesis of 1-pyrrolines under continuous flow conditions and synthesis of pyrrolo[2,1-a]isoquinolines for antiplasmodial evaluation, BP.PD

Abstract

With the resurgence of organic photochemistry, mainly due to the new applications of visible-light photocatalysis, there has been a growing interest in the development of new methodologies for photocatalyzed or photochemical formal cycloadditions, which are efficient in synthesizing fully saturated cyclic compounds. The search for new saturated bicyclic structures has been on the rise for the last 15 years, propelled by the growing medicinal chemistry interest in saturated bioisosteres for aromatic rings, which reportedly show an improved pharmacokinetic profile. However, the development of photochemical methodologies for the synthesis of N-substituted bicyclic structures has been far less developed, making it necessary to search and design new strategies. In this context, cyclopropanes are an interesting class of strained starting materials, having been used in several light-induced formal photocycloaddition reactions. The Opatz group has extensive experience in the development of strain-release formal cycloadditions with vinyl cyclopropanes and cyclopropyl ketones, as well as in the development of new organic photocatalysts. Therefore, this project aims to develop a methodology to promote the photochemical or photocatalytic cycloaddition between cyclopropyl ketones or vinyl cyclopropanes and 1-azabicyclo[3.1.1]butanes derivatives, in collaboration with the Opatz group. This strategy combines a alternative source of energy (light) with a high atom economy design. During the optimization study, the use of green solvents and organic photocatalysts will be emphasized, in the effort to combine effectiveness with sustainable chemistry principles. After optimizing the reaction conditions for the model substrates, different structural modifications will be carried out to obtain greater structural complexity and to study the scope and limitations of the methodology. This protocol would allow access to multisubstituted bicyclic N-heterocycles.