Periodic Reporting for period 5 - single-C (Automatized Catalysis and Single-Carbon Insertion)
Reporting period: 2022-07-01 to 2023-08-31
The synthesis of candidate organic molecules is crucial in the development of medicines, materials, devices, and more. Each of these candidates require the discrete design and execution of synthetic routes that consume time and human resources. As such, at the moment the synthesis of compound libraries require specific materials and methods for each member that is targeted. On the contrary, the strategic unification of the synthesis of organic molecules could significantly accelerate R&D campaigns. The synthesis routes based on late-stage functionalization are particularly attractive as they enable access to diverse compounds by recycling the same synthetic intermediates. As such, and given the ubiquitous nature of carbon stereocenters in organic molecules, the development of unified approaches to stereogenic carbon units can significantly reduce the time of development of the new products to be introduced the market.
Towards this end, it is required to develop chiral carbon atom precursors that can be predictably functionalized in stereo controlled fashion. However, the carbon-atom reagents with various reactive leaving groups are inherently unstable, and their manipulation in enantioselctive way is complicated. In this project, several possible designs for such precursors are to be explored and the technologies required for their manipulation are to be developed. The implementation of these new synthesis logics in various families of important compounds is aimed at testing the utility of the new reagents and methods, and to illustrate the advantages of this conceptual approach to carbon stereogenic elements to popularise its adoption.
Towards this end, it is required to develop chiral carbon atom precursors that can be predictably functionalized in stereo controlled fashion. However, the carbon-atom reagents with various reactive leaving groups are inherently unstable, and their manipulation in enantioselctive way is complicated. In this project, several possible designs for such precursors are to be explored and the technologies required for their manipulation are to be developed. The implementation of these new synthesis logics in various families of important compounds is aimed at testing the utility of the new reagents and methods, and to illustrate the advantages of this conceptual approach to carbon stereogenic elements to popularise its adoption.
The new homogeneous catalysts that are required to tame the reactivity of single-carbon reagents, and particularly the need to assemble these catalysts in a fast and modular fashion have inspired the discovery of a new class of organometallic amide reagents (Angew. Chem. Int. Ed. 2017, 12962; Angew. Chem. Int. Ed. 2017, 16042; Synlett 2018, 1329). These have demonstrated to enable new Pummerer (Angew. Chem. Int. Ed. 2017, 16042) and carboxylate addition reactions (Org. Lett. 2019, 7908; Chem. Eur. J. 2022, e202104053) without a precedent in organic chemistry. These reagents are advantageous because their reactivity and selectivity are clearly superior to current carbon nucleophiles, and they are conveniently prepared in situ from commercial components. We have also explained the exotic mechanism of action of these reagents (Chem. Eur. J. 2020, 2767).
After initial scouting of iterative coupling on sulphides (Angew. Chem. Int. Ed. 2017, 16042; Synlett 2018, 1329), we have identified redox-active carbenes as ideal single-carbon precursors due to the superior reactivity of carbene intermediates and the versatility of the redox-active ester manifold. In fact, we have found that the presence of the latter enhances the reactivity and selectivity of geminal carbene intermediates (Angew. Chem. Int. Ed. 2019, 5930 - journal cover). We have illustrated these findings in the context of cyclopropanation reactions due to their challenging synthesis and their importance in medicinal chemistry. Redox-active carbenes have demonstrated to be instrumental in the enantioselective cyclopropanation of aliphatic olefins, which are traditionally unreactive and poorly selective in this context. We have developed several adapted methods to transform the resulting enantiopure redox-active cyclopropanes into various classes of compounds through stereoselective decarboxylative coupling reactions. Further, we have proven that the same carbene precursor can also lead to more congested quaternary stereocenters with high enantioselectivity using simple rhodium catalysts (ACS Catal. 2019, 7870) and explored the mechanistic details behind the unusual performance of redox-active carbenes through high level calculations and kinetic studies (ACS Catalysis 2021, 10950).
These results have inspired unforeseen breakthroughs discovered during the diversification of the redox-active carbene insertion products, including a photo ligation using visible light and NADH (J. Am. Chem. Soc. 2020, 20143), a stereoselective decarboxylative reduction mediated by visible light and benzothiazolines (ACS Catalysis 2021, 13312), and a new scalable decarboxylative borylation that will be published soon.
After initial scouting of iterative coupling on sulphides (Angew. Chem. Int. Ed. 2017, 16042; Synlett 2018, 1329), we have identified redox-active carbenes as ideal single-carbon precursors due to the superior reactivity of carbene intermediates and the versatility of the redox-active ester manifold. In fact, we have found that the presence of the latter enhances the reactivity and selectivity of geminal carbene intermediates (Angew. Chem. Int. Ed. 2019, 5930 - journal cover). We have illustrated these findings in the context of cyclopropanation reactions due to their challenging synthesis and their importance in medicinal chemistry. Redox-active carbenes have demonstrated to be instrumental in the enantioselective cyclopropanation of aliphatic olefins, which are traditionally unreactive and poorly selective in this context. We have developed several adapted methods to transform the resulting enantiopure redox-active cyclopropanes into various classes of compounds through stereoselective decarboxylative coupling reactions. Further, we have proven that the same carbene precursor can also lead to more congested quaternary stereocenters with high enantioselectivity using simple rhodium catalysts (ACS Catal. 2019, 7870) and explored the mechanistic details behind the unusual performance of redox-active carbenes through high level calculations and kinetic studies (ACS Catalysis 2021, 10950).
These results have inspired unforeseen breakthroughs discovered during the diversification of the redox-active carbene insertion products, including a photo ligation using visible light and NADH (J. Am. Chem. Soc. 2020, 20143), a stereoselective decarboxylative reduction mediated by visible light and benzothiazolines (ACS Catalysis 2021, 13312), and a new scalable decarboxylative borylation that will be published soon.
Grignard reagents are one of the most common organometallics used in organic synthesis due to their stability and tolerance to common functionality. However, they are known to be limited nucleophiles when reacted with poorly electrophilic substrates such as sulfoxides and carboxylate anions. However, we have found that upon mixing with a simple Hauser base additive these limitations can be overcome. This discovery enables streamlined access to important compounds by integrating the extensive knowledge accumulated in the parent Grignard reagents into completely new areas of application.
Carbenes are central intermediates in organic chemistry with extreme reactivity. Due to their instability, these intermediates have been deemed incompatible with leaving groups and certainly unsuitable for asymmetric catalysis. The redox-active leaving group that we have developed clearly goes beyond the state of the art in this area, allowing for a more versatile carbene to be transferred to unreactive substrates. Further, it has been found that this redox-active handle enhances the reactivity of the carbene and facilitates asymmetric induction in enantioselective processes. The versatility of redox-active handles as acyl donors and radical precursors is key to the final functionality that is accessible in the final products without developing specific methods and reagents. Moreover, redox-active carbenes have demonstrated to behave as equivalents of the challenging boryl-, alkyl-, amino-, hydroxy- or selenyl-methylidenes which are known to be extremely unstable and thus unsuitable for organic synthesis.
We have expanded the synthetic capacity of redox-active carbenes in various important substrate classes, including indoles and silanes, and expect to address further challenges in the functionalization of alkane feedstocks to streamline access to functionalized derivatives using single carbon ligations.
Carbenes are central intermediates in organic chemistry with extreme reactivity. Due to their instability, these intermediates have been deemed incompatible with leaving groups and certainly unsuitable for asymmetric catalysis. The redox-active leaving group that we have developed clearly goes beyond the state of the art in this area, allowing for a more versatile carbene to be transferred to unreactive substrates. Further, it has been found that this redox-active handle enhances the reactivity of the carbene and facilitates asymmetric induction in enantioselective processes. The versatility of redox-active handles as acyl donors and radical precursors is key to the final functionality that is accessible in the final products without developing specific methods and reagents. Moreover, redox-active carbenes have demonstrated to behave as equivalents of the challenging boryl-, alkyl-, amino-, hydroxy- or selenyl-methylidenes which are known to be extremely unstable and thus unsuitable for organic synthesis.
We have expanded the synthetic capacity of redox-active carbenes in various important substrate classes, including indoles and silanes, and expect to address further challenges in the functionalization of alkane feedstocks to streamline access to functionalized derivatives using single carbon ligations.