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C-H Acids for Organic Synthesis

Periodic Reporting for period 3 - CHAOS (C-H Acids for Organic Synthesis)

Reporting period: 2019-10-01 to 2021-03-31

Utilising acids as catalysts is the most universal catalysis strategy as a plethora of industrial processes are catalysed by acids on a multi-million ton scale. In sharp contrast to this, almost no Lewis or Brønsted acids are used as catalysts in enantioselective synthesis. Our research program is designed to overcome this gap between acid-catalysed large-scale industrial processes and so far not acid-catalysed enantioselective syntheses. Here is a gigantic potential for the development of novel energy-saving and ecologically friendly catalytic methods.

Enantioselective Brønsted and Lewis acid organocatalysis has the potential to revolutionize asymmetric synthesis. However, a common feature of the so far known asymmetric organocatalytic processes is that they require relatively high catalyst loadings of typically 10 to even 20 mol% which hampers their wider use in the chemical and pharmaceutical industries.

We established very acidic and highly active C-H acids (Science 2016) which form the basis for this research program for the development and investigation of novel catalysts. Here, a research program with three major goals is currently investigated: 1) broadly conceived synthetic studies are undertaken, which have given access to C–H acids and related catalysts with a wide range of acidity and steric confinement. 2) The newly developed catalysts are applied to address one of the most general limitations currently encountered in organocatalysis: The enantioselective conversion of small and unbiased substrates. 3) The newly developed catalysts, which enable unprecedented acidities and catalytic activities, will be employed in the activation of increasingly less reactive electrophiles, for example aliphatic aldehydes but also esters and olefins, for which enantioselective organocatalytic reactions are currently very limited or even unknown. Overall, this research program aims at the design, synthesis and application of C–H acids and related catalysts as a platform for solving several long standing challenges in asymmetric organocatalysis. The introduction of C–H acids and other highly acidic and confined catalysts for organic synthesis is expected to enrich the toolbox of synthetic chemists in both academic and industrial laboratories.
After establishing chiral binaphthyl-allyl-tetrasulfone C–H acid motifs as highly enantioselective and reactive catalysts for the asymmetric Diels–Alder reaction, we sought to further increase the acidity of these motifs and thus performed broadly conceived synthetic studies. Substituting the binaphthyl moiety with bistriflylmethane led to the design of 1,1,3,3-tetratriflylpropene (TTP) which is even more acidic. The acidity of TTP was demonstrated through its remarkable activity in non-enantioselective Brønsted and Lewis acid catalyzed reactions and through acidity measurements, among which an exceptionally low, experimental pKa value for the strength of the acid was determined. The lithium salt of TTP (LiTTP) was characterized for a potential application in lithium ion batteries in which it showed a promising Li cation conductivity. The incorporation of N-triflyl groups instead of the oxo groups into the imidodiphosphate catalysts originally developed in our group, using the so-called Yagupolskii trick, also enabled the synthesis of imidodiphosphorimidates (IDPi), an entirely new catalyst motif which outperformed all expectations and is by far the most interesting and most active catalyst class this laboratory has ever worked with. The triflyl group is significantly more electron-withdrawing and polarizable and, as a result, acids incorporating such groups are much more acidic than their unsubstituted counterparts. The newly developed IDPis hence show a 10 millionfold increased acidity and have proven to be the most versatile and enantioselective catalysts developed in this lab. This catalyst class solved many of the reactions described in the research program regarding the enantioselective conversion of small and unbiased substrates and the activation of increasingly less reactive electrophiles as they feature a “pocket” like enzymes into which the substrate binds. IDPi catalysts enabled us to tackle catalytic asymmetric Mukaiyama aldol reactions using ketones as electrophile with enantioselectivities >90% and catalyst loadings below 1 ppm. To reach sub-ppm levels of catalyst loading is a milestone in asymmetric organocatalysis. A very exciting discovery is an asymmetric intramolecular hydroalkoxylation reaction of unbiased olefins in excellent yields and enantioselectivities suitable for a broad substrate scope. Here preliminary studies revealed that the developed method can be further applied to an asymmetric intermolecular hydroalkoxylation. This is the first time steam-cracker products could be activated by a highly acidic organocatalyst. This advancement opens new pathways for the synthesis of pharmaceutical compounds, crop protection agents and fragrance ingredients. Furthermore, IDPi catalysts allowed for a highly enantioselective Mukaiyama aldol reaction with simple enolates of acetaldehyde and various aldehydes, a real breakthrough as this reaction would normally lead to oligomers or polymers due to the similarity of starting material and product. The newly formed product would usually just act in the same way as the starting material and react on which is prevented in our methodology. We could successfully direct this reaction towards the formation of an anti-depressive agent.

IDPi catalysts also allow for the enantiocontrol of reactions proceeding via simple aliphatic oxocarbenium ions, a direct diene aldehyde cycloaddition reaction, the utilization of the non-classical 2-norbonyl cation in asymmetric catalysis, Diels–Alder and Mukaiyama–Michael reaction of methyl cinnamates and a regio- and enantioselective catalytic method which affords highly substituted tetrahydrofurans and tetrahydropyrans.
All results mentioned above represent progress beyond the state-of-the-art.

Until the end of the project we intend to advance our investigations on further hydrofunctionalisations of olefins towards chiral drugs, crop protection agents as well as fragrances etc. and to work in particular on the intermolecular versions. We expect to expand the scope of applications of our acid catalysts and of the reactions catalysed by them. As 80% of all small-molecule drugs contain nitrogen, a special focus will be on nitrogen-containing substances, which have previously proved to be challenging in the context of the approaches developed here.