Terminal alkynes (RCCH) are homologated by a sequence of ruthenium-catalyzed anti-Markovnikov hydration of alkyne to aldehyde (RCH₂CHO), followed by Bestmann–Ohira alkynylation of aldehyde to chain-elongated alkyne (RCH₂CCH). Inverting the sequence by starting from aldehyde brings about the reciprocal homologation of aldehydes instead. The use of ¹³C-labeled Bestmann–Ohira reagent (dimethyl ((1-¹³C)-1-diazo-2-oxopropyl)phosphonate) for alkynylation provides straightforward access to singly or, through additional homologation, multiply ¹³C-labeled alkynes. The labeled alkynes serve as synthetic platform for accessing a multitude of specifically ¹³C-labeled products. Terminal alkynes with one or two ¹³C-labels in the alkyne unit have been submitted to alkyne–azide click reactions; the copper-catalyzed version (CuAAC) was found to display a regioselectivity of >50 000:1 for the 1,4- over the 1,5-triazine isomer, as shown analytically by ¹³C NMR spectroscopy.

Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The Fe^II/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl-induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring-loads the 6,7-bicyclic skeleton for non-enzymatic rearrangement into the 6,6-bicyclic scaffold of the quinolone alkaloid 4′-methoxyviridicatin. Herein, we report different crystal structures of the protein in the absence and presence of synthesized substrates, surrogates, and intermediates that mimic the various stages of the reaction cycle of this exceptional dioxygenase.

Für die Biosynthese von Naturstoffen sind Multi-Enzymkaskaden verantwortlich, die generell eine Inspirationsquelle für Synthesechemiker darstellen. Die Fe^II/α-Ketoglutarat-abhängige Dioxygenase AsqJ aus Aspergillus nidulans ist außergewöhnlich, da sie stereoselektiv sowohl eine Desaturierung als auch Epoxidierung eines Benzodiazepindions katalysiert. Interessanterweise löst das enzymatisch gebildete, gespannte Spiro-Epoxid die enzymunabhängige Umlagerung des 6,7-Bicyclus zum 6,6-Chinolongerüst des Alkaloids 4′-Methoxyviridicatin aus. Verschiedene Kristallstrukturen des Proteins in Ab- und Anwesenheit synthetisierter Substrate, Substratanaloga und Zwischenprodukte erlaubten uns, die einzelnen Stufen der Reaktionssequenz dieser einzigartigen Dioxygenase nachzuahmen und zu hinterleuchten.

The asymmetric catalytic addition of alcohols (phenols) to non-activated alkenes has been realized through the cycloisomerization of 2-allylphenols to 2-methyl-2,3-dihydrobenzofurans (2-methylcoumarans). The reaction was catalyzed by a chiral titanium–carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)-1-(2-methoxy-1-naphthyl)-2-naphthoic acid or its derivatives, and a co-catalytic amount of water in a ratio of 1:1:1 (5 mol % each). This homogeneous thermal catalysis (HOT-CAT) gave various (S)-2-methylcoumarans with yields of up to 90 % and in up to 85 % ee at 240 °C, and in 87 % ee at 220 °C.

The asymmetric catalytic addition of alcohols (phenols) to non-activated alkenes has been realized through the cycloisomerization of 2-allylphenols to 2-methyl-2,3-dihydrobenzofurans (2-methylcoumarans). The reaction was catalyzed by a chiral titanium–carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)-1-(2-methoxy-1-naphthyl)-2-naphthoic acid or its derivatives, and a co-catalytic amount of water in a ratio of 1:1:1 (5 mol % each). This homogeneous thermal catalysis (HOT-CAT) gave various (S)-2-methylcoumarans with yields of up to 90 % and in up to 85 % ee at 240 °C, and in 87 % ee at 220 °C.

A two-step synthesis of 2-arylpyrimidine-5-carbaldehydes, which are of relevance as substrates for Soai's asymmetric autocatalysis, was realized by exploiting a hidden threefold symmetry in the target core structure. Condensation of Arnold's C₃-symmetric vinamidinium cation with S-methylisothiouronium sulfate provides 2-methylsulfanyl-pyrimidine-5-carbaldehyde; introduction of aryl groups at C-2 of the latter was accomplished by a Liebeskind–Srogl palladium-catalyzed desulfurative (de-methylsulfanylative) coupling with aryl boronic acids to obtain the target compounds 1 (14 examples, 60–95 % yield).

The chemistry of firefly bioluminescence is important for numerous applications in biochemistry and analytical chemistry. The emitter of this bioluminescent system, firefly oxyluciferin, is difficult to handle. The cause of its lability was clarified while its synthesis was reinvestigated. A side product was identified and characterized by NMR spectroscopy and X-ray crystallography. The reason for the lability of oxyluciferin is now ascribed to autodimerization of the coexisting enol and keto forms in a Mannich-type reaction.

An aluminum-catalyzed intramolecular hydroalkoxylation of nonactivated alkenes is presented as a powerful synthetic tool for the preparation of oxygen heterocycles, which are of major interest for the preparation of biological and pharmaceutical active compounds. The aluminum isopropoxide catalyzed (5 mol %) cyclization of 2-allylphenols at elevated temperatures (250 °C, 20 min) provides 2-methylcoumarans (2-methyl-2,3-dihydrobenzofuran) in an exceptionally fast, simple, and economic manner. Moreover, heating of allyl aryl ethers with aluminum isopropoxide (5 mol %) gives 2-methylcoumarans by a tandem Claisen rearrangement–hydroalkoxylation reaction. For either reaction, the catalyst tolerates a broad scope of substrates with various functional groups. By using the weakly electrophilic aluminum alkoxide as the catalyst, occurrence of “hidden Brønsted acid” catalysis can be excluded under the present reaction conditions.

Cinchona alkaloids catalyze the oxa-Michael cyclization of 4-(2-hydroxyphenyl)-2-butenoates to benzo-2,3-dihydrofuran-2-yl acetates and related substrates in up to 99 % yield and 91 % ee (ee=enantiomeric excess). Catalyst and substrate variation studies reveal an important role of the alkaloid hydroxy group in the reaction mechanism, but not in the sense of a hydrogen-bonding activation of the carbonyl group of the substrate as assumed by the Hiemstra–Wynberg mechanism of bifunctional catalysis. Deuterium labeling at C-2 of the substrate shows that addition of ROH to the alkenoate occurs with syn diastereoselectivity of ≥99:1, suggesting a mechanism-based specificity. A concerted hydrogen-bond network mechanism is proposed, in which the alkaloid hydroxy group acts as a general acid in the protonation of the α-carbanionic center of the product enolate. The importance of concerted hydrogen-bond network mechanisms in organocatalytic reactions is discussed. The relative stereochemistry of protonation is proposed as analytical tool for detecting concerted addition mechanisms, as opposed to ionic 1,4-additions.

The asymmetric catalytic cyclization of the simple 2′-hydroxychalcone (1) to flavanone (2), a model for the chalcone isomerase reaction, has been realized as a catalytic asymmetric ion-pairing process with chiral quaternary ammonium salts (e.g., 9-anthracenylmethlycinchoninium chloride; 9-Am-CN-Cl) and NaH as small-molecule co-catalyst. In toluene/CHCl₃ solution, the process reaches an intrinsic enantioselectivity of up to S = 14.4 (er = 93.5:6.5). The reversible reaction proceeds in two steps: A fast initial reaction approaches a quasi-equilibrium with K_R/S = 4.5, followed by a second, slow racemization phase approaching K_rac = 9. A simple mechanistic model featuring a living ion-pairing catalysis with full reversibility is proposed. Deuterium transfer from co-solvent CDCl₃ to product 2 and isolation of a Michael conjugate formed from 2 and 1 demonstrate the intermediacy of flavanone enolate ion pairs. A kinetic model shows good agreement with the experimentally observed, peculiar, time-dependent evolution of the species concentrations and the enantiomeric excess of 2. The reaction is a chemical model of the chalcone isomerase enzymatic reaction. Furthermore, it is an ideal model for studying the characteristic behavior of reversible asymmetric catalyses close to their equilibria.

The nickel-catalyzed coupling of thiophene with aryl Grignard reagents (Wenkert reaction) is accelerated by N-heterocyclic carbene or trialkylphosphane ligands, providing a general, scalable direct synthesis of symmetrical 1,4-diarylbutadienes.