Enantioselective Prototropy as a Powerful Synthetic Tool

• Applicant: Lilla Koser
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2023 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528507886

Chiral molecules are omnipresent in nature. Many modern pharmaceuticals are also chiral and their development is of great importance. Drugs interact with chiral entities, like the active site of an enzyme pocket, and depending on whether they have a matched or a mismatched pair interaction, they either show the desired biological activity, no activity or even an undesired effect. The enantioselective 1,3-prototropic shift, comprised of deprotonation and enantioselective reprotonation, represents a straightforward opportunity to synthesize such chiral molecules from prochiral substrates. Previously, bifunctional urea-based catalysts have been used to achieve such enantioselective 1,3-prototropic shifts. However, the weakly basic amine functionality of these catalysts often only facilitates the deprotonation of acidic substrates. By introducing a superbasic functionality to the bifunctional catalyst, also less acidic positions are deprotonated leading to an enantioselective 1,3-prototropic shift. In the first part of the project, it is proposed to establish an enantioselective 1,3-prototropic shift with a bifunctional iminophosphorane (BIMP) catalyst in combination with different driving forces (higher conjugation in the product, release of 1,3-allylic strain, or the release of ring strain) to access chiral molecules, which are otherwise difficult to synthesize. With the described reactivity, it is proposed to access α,β-unsaturated lactones and lactams, 1,3-disubstituted cyclobutanes, and acyclic β,γ-unsaturated amids/esters/ketones and sulfones. Additionally, the desymmetrization reaction of achiral substrates will be investigated. The second part will focus on the BIMP-catalysed transamination of non-activated ketones to chiral secondary amines, which has not been achieved with high enantioselectivity so far. In nature, a 1,3-prototropic shift is applied to synthesize chiral amino acids from activated ketoacids. However, it was previously not possible to establish a transamination protocol with high enantioselectivity for non-activated ketones, such as double alkyl-substituted ketones. Since the imine intermediates are only weakly acidic, they are hard to deprotonate and the transamination process cannot be initiated with a weakly basic amine functionality. Thus, it is proposed to establish the enantioselective transamination of non-activated ketones with a superbasic BIMP-catalyst, which would allow deprotonation and subsequent transamination to the secondary amine. The established methodologies will then be applied in total syntheses of biological active compounds.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Dr. Darren J. Dixon