Periodic Reporting for period 1 - ELECTRORGANO (Constructing chiral molecules merging ELECTRochemistry and ORGANOcatalysis)
Berichtszeitraum: 2021-09-01 bis 2023-08-31
Drug discovery must identify successful lead candidates. As such, the development of new catalytic methods for the production of chiral molecules is extremely valuable. ELECTRORGANO seeks to synergistically combine two powerful modes of molecule activation, namely asymmetric organocatalysis and microfluidic electrochemistry, to provide an attractive new pathway for the formation of demanded chiral molecules. Both organocatalysis and electrochemistry possess extraordinary potential for the sustainable preparation of novel organic molecules, which are required to drive innovation within the pharmaceutical industry. However, the implementation of electrochemical methods for the design of stereoselective processes is still falling short, mostly due to the fleetingness of the radical ions intermediates generated on the electrode surface. ELECTRORGANO asks whether the use of an electrochemical microfluidic setup, coupled with asymmetric organocatalysis, can overcome these intrinsic limitations, rapidly providing chiral building blocks with high stereocontrol. Specifically, ELECTRORGANO aims at accomplishing, through the combination of microfluidic electrochemistry and asymmetric organocatalysis, three specific objectives:
1) The enantioselective α-functionalization of carbonyl compounds through aminocatalysis.
2) The enantioselective β-functionalization of carbonyl compounds through NHC catalysis.
3) Full understanding of the underlying mechanisms of these reactions.
This project is highly interdisciplinary, involving different research areas such as asymmetric organocatalysis, electrochemistry, and microfluidics. As such, it is envisioned that the development of this new platform can generate breakthrough scientific papers, valuable discoveries and/or potential patents. This fellowship brings a two-fold transfer of knowledge: advanced techniques in asymmetric catalysis to the host institution and electrochemical methods and microfluidic flow chemistry to the fellow. Overall, the project’s multidisciplinarity and intersectoral nature will broaden the fellow’s competencies and will place him in a competitive position for his next career move.
1) The enantioselective α-functionalization of carbonyl compounds through aminocatalysis.
2) The enantioselective β-functionalization of carbonyl compounds through NHC catalysis.
3) Full understanding of the underlying mechanisms of these reactions.
This project is highly interdisciplinary, involving different research areas such as asymmetric organocatalysis, electrochemistry, and microfluidics. As such, it is envisioned that the development of this new platform can generate breakthrough scientific papers, valuable discoveries and/or potential patents. This fellowship brings a two-fold transfer of knowledge: advanced techniques in asymmetric catalysis to the host institution and electrochemical methods and microfluidic flow chemistry to the fellow. Overall, the project’s multidisciplinarity and intersectoral nature will broaden the fellow’s competencies and will place him in a competitive position for his next career move.
We have performed intensive studies in both batch and flow conditions. Specifically, we have focused on the enantioselective intermolecular α-arylation of carbonyl compounds through aminocatalysis. Despite our efforts, we were not able to observe the formation of the desired compound by any means.
In light of these results, we fall back on our contingency plan, that included the use of a specialized molecule, already adorned with a radical-trapping moiety, to assess the feasibility of electrochemically activating enamines. By simply placing a pendant olefin on the aldehyde core, we started observing formation of the cyclized product when using pyrrolidine as achiral catalyst for the non-asymmetric reaction. Unfortunately, already at this stage of the project we noticed how the use of flow was not beneficial to the overall yield of the reaction as well as on the rate of the process. We rationalized that, while the electrochemical steps are greatly enhanced by flow chemistry, the organocatalytic steps do not particularly benefit from this type of setup, thus the two modes of activation are outbalanced and results in lower yield of the desired product. In light of this, all the remaining experiments have been carried out in batch.
Next, we focused on the use of a chiral catalyst. We soon realized how the MacMillan Imidazolidinone catalyst was not effective for promoting this reaction since the product was not formed in its presence. On the contrary, the use of the Jorgensen catalyst, a silyl prolinol derivative, delivered the desired cyclized product in 25% yield and 87% enantiometic excess (ee). Intensive optimization of the reaction conditions lead to an increase in the yield to 45% and no change in the enantioinduction (87% ee). However, one thing that puzzled us was the fact that, in the vast majority of the optimization endeavors, the catalyst was always degraded at the end of the reaction. In order to better understand this somewhat suboptimal chemical efficiency, we monitored the conversion of the starting material, the yield of the product and the degradation of the catalyst over time. We noticed that the depletion of the starting material is somehow affecting the degradation of the starting material. We rationalized how, because the formation of the active enamine complex is an equilibrium, the lower the amount of aldehyde starting material, the higher the amount of organocatalyst free in solution, the higher the possibility of its degradation at the anode.
In light of these results, we fall back on our contingency plan, that included the use of a specialized molecule, already adorned with a radical-trapping moiety, to assess the feasibility of electrochemically activating enamines. By simply placing a pendant olefin on the aldehyde core, we started observing formation of the cyclized product when using pyrrolidine as achiral catalyst for the non-asymmetric reaction. Unfortunately, already at this stage of the project we noticed how the use of flow was not beneficial to the overall yield of the reaction as well as on the rate of the process. We rationalized that, while the electrochemical steps are greatly enhanced by flow chemistry, the organocatalytic steps do not particularly benefit from this type of setup, thus the two modes of activation are outbalanced and results in lower yield of the desired product. In light of this, all the remaining experiments have been carried out in batch.
Next, we focused on the use of a chiral catalyst. We soon realized how the MacMillan Imidazolidinone catalyst was not effective for promoting this reaction since the product was not formed in its presence. On the contrary, the use of the Jorgensen catalyst, a silyl prolinol derivative, delivered the desired cyclized product in 25% yield and 87% enantiometic excess (ee). Intensive optimization of the reaction conditions lead to an increase in the yield to 45% and no change in the enantioinduction (87% ee). However, one thing that puzzled us was the fact that, in the vast majority of the optimization endeavors, the catalyst was always degraded at the end of the reaction. In order to better understand this somewhat suboptimal chemical efficiency, we monitored the conversion of the starting material, the yield of the product and the degradation of the catalyst over time. We noticed that the depletion of the starting material is somehow affecting the degradation of the starting material. We rationalized how, because the formation of the active enamine complex is an equilibrium, the lower the amount of aldehyde starting material, the higher the amount of organocatalyst free in solution, the higher the possibility of its degradation at the anode.
This is the first time enamine intermediates are directly activated by electrochemical means. Moreover, these results are quite crucial into understanding how the currently available organocatalysts are suboptimal for electrochemical processes. In light of this, we are going to focus to identify and build a series of organocatalyst stable under electrochemical conditions.