Research Synopsis

The major goals of our research are the development and application of new synthetic methods in organic chemistry. The focus is on catalytic methods, which enable previously unknown transformations employing both photochemical and conventional techniques. Our research is curiosity-driven and does not strive for immediate industrial application. However, entrepreneurial opportunities will be considered where applicable.

Natural product synthesis

The selection of natural product targets in our group is based on aspects of structural uniqueness, suitable new methodology and biological activity. In our work we have been able to substantiate the constitution and configuration of several natural products by accomplishing their first total syntheses. Examples include the syntheses of wailupemycin B, punctaporonin C, lactiflorin, and pinolinone.

New synthetic methods, which were developed in our group, have been successfully applied to the synthesis of natural products. The synthesis of meloscine for example was the first synthesis, employing an enantioselective photochemical key step in natural product synthesis. A C-H activation protocol, which we developed for addressing the C2 position of the indole core, was applied to the synthesis of the aspidosperma alkaloids aspidospermidine and goniomitine. Our interest in diastereoselective reactions of carbenium ions led to a concise synthesis of podophyllotoxin.

Biological activity is a further motivation to approach a synthetic target. In this regard, our research has been devoted to the synthesis of anticancer and antiinfective compounds. To highlight an example, the syntheses of the GE-factors and the amythiamicins are mentioned here, which address the bacterial elongation factor EF-Tu. Several of these studies have been and are performed in collaborations. We successfully elucidated the mode of action of some modified EF-Tu inhibitors (ChemMedChem 2013, 8, 1954-1962) and we contributed to the elucidation of the vioprolide biosynthesis pathway (Angew. Chem. Int. Ed. 2018, 57, 8754-8759). In addition to our efforts towards the synthesis of natural products, there is a focus on the preparation of new scaffolds for medicinal chemistry (e.g. Angew. Chem. Int. Ed. 2012, 51, 10169-10172) and on the development of new probes for biological studies (e.g. J. Am. Chem. Soc. 2018, 140, 2718-2721). These studies are mostly performed in collaboration with other academic and industrial institutions.

 

Catalytic Methods

Our interest in the synthesis of heterocycles has led to the development of regioselective cross-coupling reactions, which in turn have found widespread applications (Tetrahedron 2005, 61, 2245-2267). In recent years, interest has shifted towards the direct C-C bond formation on heterocyclic cores by C-H activation reactions. Examples include the alkylation of indoles and pyrroles and the arylation of thiophenes.

The facial diastereoselectivity in the intermolecular reaction of free carbenium ions was first addressed by our group. It was shown that the reaction of benzylic cations proceeds with high diastereoselectivity and that the outcome depends on the steric size of the respective substituents at the stereogenic center in a-position of the cation. Catalytic versions of these transformations were developed employing FeCl3, AuCl3 or Bi(OTf)3 as catalysts. The study has been further extended to allyllic and propargylic cations.

Initial work in the area of hydrogen-bonded catalysis was dedicated towards finding enantioselective catalysts for photochemical reactions (see below). Our interest in this topic has further expanded towards enantio- and regioselective transition metal catalysis. Therefore, we designed templates, which bear a site for substrate binding via hydrogen bonds and which also enable the attachment of catalytically active transition metals, such as Mn, Ru or Rh. Proof of principle studies were performed using a Ru-based oxidation catalyst and quinolone-based olefins for selective epoxidation reactions. It was demonstrated with high confidence that hydrogen bonding is responsible for both regio- and enantioselectivity. Rh catalysis allowed us to address the issue of enantioselective amination and aziridination.

The latest development relates to Mn-based catalysts which allow for site- and highly enantioselective oxygenation reactions (Angew. Chem. Int. Ed. 2018, 57, 2953-2957).

 

Given that our goal is to develop synthetic methods for practical applications, we strive to show for of our methods their immediate relevance for total synthesis. Recent examples include a convenient C-H amination reaction (Adv. Synth. Catal. 2016, 358, 2083-2087) or a new pyrrole synthesis (J. Org. Chem. 2016, 81, 6149-6156) which were both applied to the synthesis of heterocyclic alkaloids. 

 

Photochemistry

Based on the 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonane-2-one scaffold, which is readily derived from Kemp’s triacid, we have developed a chiral template for photochemical and radical reactions, which has proven its versatility over the last ten years.

Interestingly, the template showed some enantioselective catalytic activity in radical reactions. In recent years, it has been successfully employed for enantioselective intra- and intermolecular [2+2] photocycloaddition reactions of isoquinolones.

Upon modification of the oxazole backbone, it was possible to develop the template into enantioselective catalysts, which work either by electron transfer or by energy transfer. A ketone served as catalyst in the enantioselective photoredox cyclization of an aminoethyl quinolone. 

A xanthone was employed for the enantioselective sensitization of [2+2] photocycloaddition reactions with catalyst loadings as low as 2.5 mol%.

The latest development in this area relates to thioxanthone sensitization which can be performed very efficiently with artificial visible light sources or with sunlight. It was found that a chiral thioxanthone enables inter- and intramolecular [2+2] photocycloaddition reactions of quinolones and, most remarkably, the deracemization of allenes. 

The latter reaction allows for a thermally impossible process, i.e. the formation of single enantiomer from a racemic mixture, and holds great promise for further applications. Its mode of action relies on a complex interplay of several parameters including catalyst association, sensitization efficiency and intermediate decay.

Lewis acid catalysis was identified as a method to achieve enantioselective photochemical reactions in 2010 as demonstrated for the intramolecular [2+2] photocycloaddition of coumarins. In 2013, it was shown that enantioselective Lewis acid catalysis is not restricted to the coumarin [2+2] photocycloaddition but can – unexpectedly – also be applied to enone [2+2] photocycloaddition reactions. 

The high enantioselectivity is unexpected because enones – unlike coumarins - undergo uncatalyzed [2+2] photocycloaddition reactions at l = 366 nm. The mode of action in the enone case is clearly different from the coumarin case. Enantioselective Lewis acid catalysis of enone [2+2] photocycloaddition seems to be relatively general and was applied not only to dihydropyridones but more recently also to 2-cyclohexenone substrates.

It has been shown that the disadvantage of high catalyst loading can be overcome if a substrate that is unbound to the Lewis acid and its Lewis acid complex show no overlap in the long-wavelength region of the UV/Vis spectrum. If this requirement is fulfilled there is no racemic background reaction and the enantioselectivity remains high even at low catalyst loading. The visible light-mediated, intermolecular ortho photocycloaddition to phenanthrene-9-carboxaldehyde serves as an example.

 

The latter example illustrates how a chromophore can be activated towards a selective reaction at long wavelength and studies along these lines continue in our laboratory (Angew. Chem. Int. Ed. 2018, 57, 14338-14349). After the discovery of a Brønsted acid-catalyzed [2+2] photocycloaddition (Angew. Chem. Int. Ed. 2017, 56, 4337-4341) it was shown that the generation of iminium ions facilitates a triplet-sensitized process and that the intermolecular [2+2] photocycloaddition of iminium ions can be performed enantioselectively. In photochemistry, we combine synthetic experiments with photophysical studies which are partially performed in our laboratory and partially in collaboration with other groups.

Funding

Our research will be supported until December 2020 by the European Research Council in the framework of the Horizon 2020 research and innovation programme (grant agreement No 665951 – ELICOS). Additional institutions which support us or have supported us over the years include the Deutsche Forschungsgemeinschaft (DFG), the Fonds der Chemischen Industrie, the Alexander von Humboldt Foundation, the German Academic Exchange Service (DAAD), the Elitenetzwerk Bayern, the Federal Ministry of Education and Research and the Studienstiftung des Deutschen Volkes. We trustfully collaborate and have collaborated with many companies on joint research projects, inter alia with (in alphabetical order): AstraZeneca, BASF, Bayer, Bicoll, Evonik, Medigene, Novartis, Roche, Sanofi, and Wacker