Periodic Reporting for period 1 - ESO (Early-Stage Organocatalysis)
Reporting period: 2022-06-01 to 2024-11-30
Most manufactured fine and speciality chemicals that are necessary for the production of pharmaceuticals, polymers, food additives like vitamins, and cosmetics originate from fossil materials such as coal, natural gas, and crude oil. The current societal move toward decarbonization will probably neither significantly change this situation in the short term, nor would there be a strong need to doing so. Because chemistry, in contrast to simply burning refined fossil-based hydrocarbons, producing gigatons of carbon dioxide, uses them instead to produce the valuable molecules and materials that surround us and are needed in daily life – but only on a megaton-scale and not necessarily producing carbon dioxide emissions. Nonetheless, it is also clear that until a truly sustainable chemistry will have been developed, which starts rather than ends with carbon dioxide, fossil materials should be used as sparingly as possible.
The project Early-Stage Organocatalysis (ESO) contributes to this goal by shortcutting the process of fine chemical manufacturing. When starting from coal, gas and crude oil, these fossil materials first need to be refined to so-called petrochemicals consisting of hydrocarbons such as arenes, olefins, and alkanes that are contained for instance in petrol. Traditionally, this is followed by large-scale refinement processes such as carbonylations, oxidations or halogenations to bulk chemicals. These cheap raw materials produced in huge quantities are subsequently converted to fine chemicals in further refinement steps, e.g. asymmetric catalysis, aminations, cross-couplings. By designing organocatalysts and processes that operate highly selectively on early-stage hydrocarbon feedstock, traditional refinement processes normally preceding further refinements, may be avoided, saving valuable resources and energy. Accordingly, this research program aims at converting early-stage hydrocarbons such as arenes, olefins, and alkanes, directly with high enantioselectivity to valuable fine chemicals that traditionally only appear after another layer of refinement (Scheme 1).
This ambitious program will be made possible by the design and use of a new generation of highly sophisticated, though readily available organocatalysts, comprising very strong and enzyme-like acids. Within the last few years, the Principal Investigator and his group have developed a powerful class of highly reactive, structurally confined chiral organic acids. These catalysts are characterized by an enzyme-like pocket and feature structural tunability, but also the possibility to install the desired acid strength by properly choosing modifications around the inner core. As a result, an entire family of imidodiphosphoryl-type catalysts (IDP, iIDP, IDPi) has been designed, displaying a broad range of reactivity and acid strength (in acetonitrile, see Scheme 2).
The project Early-Stage Organocatalysis (ESO) contributes to this goal by shortcutting the process of fine chemical manufacturing. When starting from coal, gas and crude oil, these fossil materials first need to be refined to so-called petrochemicals consisting of hydrocarbons such as arenes, olefins, and alkanes that are contained for instance in petrol. Traditionally, this is followed by large-scale refinement processes such as carbonylations, oxidations or halogenations to bulk chemicals. These cheap raw materials produced in huge quantities are subsequently converted to fine chemicals in further refinement steps, e.g. asymmetric catalysis, aminations, cross-couplings. By designing organocatalysts and processes that operate highly selectively on early-stage hydrocarbon feedstock, traditional refinement processes normally preceding further refinements, may be avoided, saving valuable resources and energy. Accordingly, this research program aims at converting early-stage hydrocarbons such as arenes, olefins, and alkanes, directly with high enantioselectivity to valuable fine chemicals that traditionally only appear after another layer of refinement (Scheme 1).
This ambitious program will be made possible by the design and use of a new generation of highly sophisticated, though readily available organocatalysts, comprising very strong and enzyme-like acids. Within the last few years, the Principal Investigator and his group have developed a powerful class of highly reactive, structurally confined chiral organic acids. These catalysts are characterized by an enzyme-like pocket and feature structural tunability, but also the possibility to install the desired acid strength by properly choosing modifications around the inner core. As a result, an entire family of imidodiphosphoryl-type catalysts (IDP, iIDP, IDPi) has been designed, displaying a broad range of reactivity and acid strength (in acetonitrile, see Scheme 2).
Towards the utilization of all three targeted compound classes, arenes, olefins, and alkanes, in Early-Stage Organocatalysis, novel reaction processes and the required catalysts are being developed. For each compound class, the Principal Investigator and his team could develop the first successful examples which will be explained in the following.
Arenes could be transformed very elegantly in the first asymmetric catalytic Friedel-Crafts reaction of simple alkylbenzenes to the valuable arylglycine esters that can be used as building blocks for biologically active compounds (published in JACS 2023, 145, 15708). A reaction like this with unactivated substrates like the purely hydrocarbon alkylbenzenes used here had so far not been discovered.
Another so far unprecedented reaction showed that the second compound class, olefins, can also be activated by an acidic IDPi catalyst, here both starting material and product are purely aliphatic hydrocarbons. Alkenyl cycloalkanes could be reacted in the so-called Wagner-Meerwein rearrangement to cycloalkenes - rearrangements such as this are important for natural product synthesis, so ultimately for the production of pharmaceuticals (published in Nature 2024, 625, 287).
The Principal Investigator and his group even succeeded in the activation of alkanes, the primary feedstock of the global economy and the main component in petrol. Cyclopropanes could be activated by very strong acid catalysts and yielded the corresponding alkenes, a transformation that constitutes a longstanding and grand challenge for chemistry. The manuscript about this discovery has been submitted to Science.
Since the organocatalysts developed for this project are all extremely strong acids, measurements to determine the acid strength were successfully implemented as a novel methodology in the team of the Principal Investigator so that the acid strength of novel catalysts can now be benchmarked.
Arenes could be transformed very elegantly in the first asymmetric catalytic Friedel-Crafts reaction of simple alkylbenzenes to the valuable arylglycine esters that can be used as building blocks for biologically active compounds (published in JACS 2023, 145, 15708). A reaction like this with unactivated substrates like the purely hydrocarbon alkylbenzenes used here had so far not been discovered.
Another so far unprecedented reaction showed that the second compound class, olefins, can also be activated by an acidic IDPi catalyst, here both starting material and product are purely aliphatic hydrocarbons. Alkenyl cycloalkanes could be reacted in the so-called Wagner-Meerwein rearrangement to cycloalkenes - rearrangements such as this are important for natural product synthesis, so ultimately for the production of pharmaceuticals (published in Nature 2024, 625, 287).
The Principal Investigator and his group even succeeded in the activation of alkanes, the primary feedstock of the global economy and the main component in petrol. Cyclopropanes could be activated by very strong acid catalysts and yielded the corresponding alkenes, a transformation that constitutes a longstanding and grand challenge for chemistry. The manuscript about this discovery has been submitted to Science.
Since the organocatalysts developed for this project are all extremely strong acids, measurements to determine the acid strength were successfully implemented as a novel methodology in the team of the Principal Investigator so that the acid strength of novel catalysts can now be benchmarked.
All of the significant achievements mentioned here can be seen as a proof of principle for the Early-Stage Organocatalysis program envisioned above and show that the research project will be very successful. Each of the described discoveries advances the field of organocatalysis and with it that of organic synthesis beyond the state-of-the-art, all of them can thus be considered as massive breakthroughs for the field of organocatalysis as a whole.