Heinz Falk

The Diels-Alder reaction, first described in 1928, is one of the most celebrated and versatile transformations in organic chemistry. This reaction enables the efficient construction of six-membered rings with remarkable regio- and stereocontrol, making it indispensable for synthesizing complex natural products and pharmaceuticals. Over the decades, methodological advancements such as asymmetric catalysis, organocatalysis, and inverse electron demand variants have expanded its scope, allowing the synthesis of highly functionalized and stereochemically dense frameworks. Biomimetic applications have further bridged the gap between chemical synthesis and natural product biogenesis, while the discovery of Diels-Alderases has unveiled the ability of Nature to catalyze pericyclic reactions with exceptional efficiency and stereocontrol. The reaction has been pivotal in addressing synthesis challenges posed by intricate natural products, such as vinigrol, scabrolide, and the manzamine alkaloids, and continues to evolve with emerging applications in sustainable chemistry, photochemical activation, and enzyme engineering. This volume highlights the historical significance, methodological innovations, biomimetic strategies, enzymatic catalysis, and future directions of the Diels-Alder reaction, underscoring its enduring relevance as a cornerstone of chemical innovation.

The natural products synthesized by organisms that were living a long time ago gave rise to their molecular fossils. These can consist of either the original unchanged compounds or they may undergo peripheral transformations in which their skeletons remain intact. In cases when molecular fossils can be traced to their organismic source, they are termed “geological biomarkers”. This contribution describes apolar and polar molecular fossils and, in particular biomarkers, along the lines usually followed in organic chemistry textbooks, and points to their bioprecursors when available. Thus, the apolar compounds are divided in linear and branched alkanes followed by alicyclic compounds and aromatic and heterocyclic molecules, and, in particular, the geoporphyrins. The polar molecular fossils contain as functional groups or constituent units ethers, alcohols, phenols, carbonyl groups, flavonoids, quinones, and acids, or are polymers like kerogen, amber, melanin, proteins, or nucleic acids. The final sections discuss the methodology used and the fundamental processes encountered by the biomolecules described, including diagenesis, catagenesis, and metagenesis.

Complete structural elucidation of natural products is often challenging due to structural complexity and limited availability. This is true for present-day secondary metabolites, but even more for exceptionally preserved secondary metabolites of ancient organisms that potentially provide insights into the evolutionary history of natural products. Here, we report the full structure and absolute configuration of the borolithochromes, enigmatic boron-containing pigments from a Jurassic putative red alga, from samples of less than 50 μg using microcryoprobe NMR, circular dichroism spectroscopy, and density functional theory calculations and reveal their polyketide origin. The pigments are identified as spiroborates with two pentacyclic sec-butyl-trihydroxy-methyl-benzo[gh]tetraphen-one ligands and less-substituted derivatives. The configuration of the sec-butyl group is found to be (S). Because the exceptional benzo[gh]tetraphene scaffold is otherwise only observed in the recently discovered polyketide clost...

The syntheses are described for centrally expanded bilirubin analogs: b-homorubins with propionic and butyric acid groups in the positions corresponding to the propionic acids of bilirubin. Their syntheses were accomplished by coupling two equivalents of a reactive monopyrrole (5-(bromomethylene)pyrrolin-2-one) to a dipyrrylethane. The corresponding b-homoverdins and dehydro-b-homoverdins were prepared by dehydrogenating the rubins or their dimethyl esters using DDQ. As supported by NMR measurements and molecular mechanics calculations, the homorubins are found to engage in conformation-determining intramolecular hydrogen bonding between the dipyrrinone and carboxylic acid moieties. Likewise, the homoverdins are believed to favor intramolecularly hydrogen-bonded conformations. Graphical Abstract

Its outstanding ability to generate singlet oxygen or reactive oxygen species upon irradiation with light makes hypericin one of the most powerful photosensitizers to be found in Nature. The most important fields of application of hypericin seem presently to be its use as a photosensitizing antiviral agent to destroy virus particles in blood preparations, to sensitize the destruction of superficial tumors, and its use as a diagnostic tool for fluorescence detection of malignant tissue. Despite all of its benefits and its strong photosensitizing ability, the application of hypericin in photodynamic therapy (PDT) suffers from three main disadvantages: cost intensive isolation from natural sources, limited solubility under physiological conditions, and long wavelength absorption maximum outside the optimum wavelength range for a PDT photosensitizer. Thus, over the last years several efforts have been undertaken to synthesize new hypericin derivatives with increased solubility, a bathochromically shifted long wavelength absorption band, enhanced photosensitizing potential, and applicability to a more widespread field (second generation hypericin based photosensitizers). The objective of this review is to discuss the investigations undertaken in the development of second generation hypericin based photosensitizers. The focus will be on the synthesis of such derivatives as well as on their photochemical properties, their advantages, and disadvantages. Several of these novel synthetic hypericin derivatives have already been tested in vitro and/or in vivo. Accordingly, a summary of the corresponding results will be presented.

Organic biomolecules that have retained their basic chemical structures over geological periods (molecular fossils) occur in a wide range of geological samples and provide valuable paleobiological, paleoenvironmental, and geochemical information not attainable from other sources. In rare cases, such compounds are even preserved with their specific functional groups and still occur within the organisms that produced them, providing direct information on the biochemical inventory of extinct organisms and their possible evolutionary relationships. Here we report the discovery of an exceptional group of boron-containing compounds, the borolithochromes, causing the distinct pink coloration of well-preserved specimens of the Jurassic red alga Solenopora jurassica . The borolithochromes are characterized as complicated spiroborates (boric acid esters) with two phenolic moieties as boron ligands, representing a unique class of fossil organic pigments. The chiroptical properties of the pigments unequivocally demonstrate a biogenic origin, at least of their ligands. However, although the borolithochromes originated from a fossil red alga, no analogy with hitherto known present-day red algal pigments was found. The occurrence of the borolithochromes or their possible diagenetic products in the fossil record may provide additional information on the classification and phylogeny of fossil calcareous algae.

The present communication describes for the first time the synthesis and preliminary testing of two cationic hypericin derivatives. Uncharged hypericin derivatives with ω,ω’‐attached C₂‐linkers leading to a pyridyl or a 4‐dimethylaminophenyl residue were prepared and subsequently quaternized by means of iodomethane. Photobactericidal activity was assessed using Propionibacterium acnes. The quaternary N,N,N‐trimethyl‐anilinium derivative displayed a pronounced photodynamic inactivation of the bacteria at low incubation concentrations (−2), whereas the photobactericidal efficacy of the N‐methyl‐pyridinium derivative was negligible under identical experimental conditions.