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C-H Acids for Organic Synthesis

Periodic Reporting for period 4 - CHAOS (C-H Acids for Organic Synthesis)

Reporting period: 2021-04-01 to 2021-09-30

Utilizing acids as catalysts is the most universal catalysis strategy as illustrated with a plethora of industrial processes catalyzed by acids on a multi-million ton scale. In sharp contrast to this, Lewis or Brønsted acids are hardly used as industrial catalysts in enantioselective synthesis. Our research program was designed to overcome this gap between acid-catalyzed large-scale industrial processes and so far not acid-catalyzed enantioselective syntheses. Here is a gigantic potential for the development of novel energy-saving and ecologically friendly catalytic methods as we could show.
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 was 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 formed the basis for this research program for the development and investigation of novel catalysts. Here, a research program with three major goals was investigated: 1) broadly conceived synthetic studies were 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 were 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, were 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 aimed 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 most 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-type 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. Imidodiphosphorimidate catalysts also enabled the synthesis of (+)-2-epi-ziza-6(13)en-3-one, a molecule that could be proved to be the active smelling principle of vetiver oil, an efficient and highly enantioselective asymmetric intramolecular hydroarylation of aliphatic and aromatic olefins with indoles and a scalable, catalytic one-pot approach to enantiopure and unmodified β²-amino acids.
All results mentioned above represent progress beyond the state-of-the-art and the entire project can be considered highly successful with many breakthrough discoveries in the field of organocatalysis. Before long, this work is expected to result in processes that are highly attractive for industrial purposes, featuring low to very low catalyst loadings, catalyst recyclability, high yields and enantioselectivities and a broad substrate scope.
Overview of newly developed reactions with IDPis
Synthesis methodology for highly acidic and confined acids