Natural products of polyketide origin, in particular small-sized lactones often possess a very broad range of impressive biological activities. An efficient way to demonstrate the concise access to six-membered lactones was emphasized as part of a stereodivergent and protecting-group-free synthesis of all three representatives of the helicascolide family. This strategy features an atom-economical and highly diastereoselective rhodium-catalyzed “head-to-tail” lactonization by an intramolecular addition of ω-allenyl-substituted carboxylic acids to terminal allenes, including the selective construction of a new stereocenter in the newly formed core structures. The excellent selectivities with which the helicascolide precursors were obtained are remarkable, thus resulting in an expeditious and highly efficient natural product synthesis.

A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.

Regio- and enantioselective additions of alcohols to either terminal allenes or internal alkynes provides access to allylic ethers by using a Rh^I/diphenyl phosphate catalytic system. This method provides an atom-economic way to obtain chiral aliphatic and aryl allylic ethers in moderate to good yield with good to excellent enantioselectivities.

A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom-economical rhodium-catalyzed coupling of ω-allenyl-substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM-diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β-unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio- and diastereoselectivity.

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with internal and terminal alkynes features an utmost chemo-, regio-, and enantioselective access to enantiopure allylic pyrazoles, readily available for incorporation in small-molecule pharmaceuticals. This methodology is distinguished by a broad substrate scope, resulting in a remarkable compatability with a variety of different functional groups. It furthermore exhibits an intriguing case of regio-, position-, and enantioselectivity in just one step, underscoring the sole synthesis of just one out of up to six possible products in a highly flexible approach to allylated pyrazoles by emanating from various internal and terminal alkynes.

Regio- and enantioselective additions of alcohols to either terminal allenes or internal alkynes provides access to allylic ethers by using a Rh^I/diphenyl phosphate catalytic system. This method provides an atom-economic way to obtain chiral aliphatic and aryl allylic ethers in moderate to good yield with good to excellent enantioselectivities.

Natural products of polyketide origin, in particular small-sized lactones often possess a very broad range of impressive biological activities. An efficient way to demonstrate the concise access to six-membered lactones was emphasized as part of a stereodivergent and protecting-group-free synthesis of all three representatives of the helicascolide family. This strategy features an atom-economical and highly diastereoselective rhodium-catalyzed “head-to-tail” lactonization by an intramolecular addition of ω-allenyl-substituted carboxylic acids to terminal allenes, including the selective construction of a new stereocenter in the newly formed core structures. The excellent selectivities with which the helicascolide precursors were obtained are remarkable, thus resulting in an expeditious and highly efficient natural product synthesis.

Strukturen der O-Glycosyltransferase LanGT2 und der generierten C-Glycosyltransferase LanGT2S8Ac zeigen, dass der Austausch eines kurzen Peptidfragments die Funktionalität eines Enzyms deutlich verändern kann. Eine synthetische TDP-Carbaolivose wurde mit den Enzymen kokristallisiert. Es zeigte sich, dass die Bindung des Carbazuckers zu einer Konformationsänderung des Enzyms führt, die dann eine Bindestelle für ein Aglykonsubstrat erzeugt. Obwohl eine Bindung des Aglykons nicht experimentell nachgewiesen wurde, deuten Docking-Studien auf unterschiedliche Bindungsmodi im Fall von O- bzw. C-Glycosylierung hin.

Die rutheniumkatalysierte reduktive Kupplung von Paraformaldehyd mit Dienen, Alkinen und Allenen ermöglicht den Zugang zu hydrohydroxymethylierten Produkten, welche so unter Hydroformylierungsbedingungen nicht selektiv zugänglich sind. In speziellen Fällen, unter der Verwendung von Ni-Katalysatoren, kann die Regioselektivität dieser C-C-Kupplung umgedreht werden. Ir-Katalysatoren ermöglichen mit Methanol eine redoxneutrale, regioselektive Hydrohydroxymethylierung.

Natural products of polyketide origin with a high level of symmetry, in particular C₂-symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important structural motif was developed as part of a concise and highly convergent synthesis of clavosolide A. This strategy features an atom-economic “head-to-tail” dimerization by the stereoselective rhodium-catalyzed addition of carboxylic acids to terminal allenes with the simultaneous construction of two new stereocenters. The excellent efficiency and selectivity with which the C₂-symmetric core structures were obtained are remarkable considering the outcome under classical dimerization conditions. Furthermore, this approach facilitates late-stage modification and provides ready access to potential new lead structures.

A Z-selective rhodium-catalyzed hydrothiolation of 1,3-disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate 1,4-bis(diphenylphosphino)butane (dppb) ligand, Z/E-selectivities up to >99:1 were obtained. The highly atom-economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3-disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)-Me-DuPhos as the chiral ligand. The desired Z-allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee.

A highly regio- and enantioselective hydrothiolation of terminal allenes, a reaction which fulfills the criteria of atom economy, is reported. Applying two chiral rhodium catalyst systems, a wide variety of thiols and allenes could be coupled. Oxidation gave access to the corresponding allylic sulfones in essentially enantiomerically pure form. The reaction tolerates a variety of functional groups and labeling experiments gave first insights into the reaction mechanism of this new methodology.

A Z-selective rhodium-catalyzed hydrothiolation of 1,3-disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate 1,4-bis(diphenylphosphino)butane (dppb) ligand, Z/E-selectivities up to >99:1 were obtained. The highly atom-economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3-disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)-Me-DuPhos as the chiral ligand. The desired Z-allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee.

Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer-cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o-DPPB-directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs.

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.

A rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes is reported. Using a Rh^I/6-DPPon catalyst system, one can obtain β,γ-unsaturated aldehydes in high regio- and chemoselectivity. The Z-configured product is formed with up to >95 % selectivity when unsymmetrically 1,1-disubstituted allenes are submitted to the reaction conditions. This is the first time that these interesting building blocks are accessible by hydroformylation of allenes. The utility of this methodology is demonstrated by further transformations of one of the obtained products.

A highly regio- and enantioselective hydrothiolation of terminal allenes, a reaction which fulfills the criteria of atom economy, is reported. Applying two chiral rhodium catalyst systems, a wide variety of thiols and allenes could be coupled. Oxidation gave access to the corresponding allylic sulfones in essentially enantiomerically pure form. The reaction tolerates a variety of functional groups and labeling experiments gave first insights into the reaction mechanism of this new methodology.

Natural products of polyketide origin with a high level of symmetry, in particular C₂-symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important structural motif was developed as part of a concise and highly convergent synthesis of clavosolide A. This strategy features an atom-economic “head-to-tail” dimerization by the stereoselective rhodium-catalyzed addition of carboxylic acids to terminal allenes with the simultaneous construction of two new stereocenters. The excellent efficiency and selectivity with which the C₂-symmetric core structures were obtained are remarkable considering the outcome under classical dimerization conditions. Furthermore, this approach facilitates late-stage modification and provides ready access to potential new lead structures.

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.

A rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes is reported. Using a Rh^I/6-DPPon catalyst system, one can obtain β,γ-unsaturated aldehydes in high regio- and chemoselectivity. The Z-configured product is formed with up to >95 % selectivity when unsymmetrically 1,1-disubstituted allenes are submitted to the reaction conditions. This is the first time that these interesting building blocks are accessible by hydroformylation of allenes. The utility of this methodology is demonstrated by further transformations of one of the obtained products.

Ruthenium-catalyzed reductive couplings of paraformaldehyde with dienes, alkynes, and allenes provide access to products of hydrohydroxymethylation that cannot be formed selectively under the conditions of hydroformylation. In certain cases, the regioselectivity of the CC coupling can be inverted by using nickel catalysts. With iridium catalysts, methanol engages in redox-neutral regioselective hydrohydroxymethylations.

The structures of the O-glycosyltransferase LanGT2 and the engineered, CC bond-forming variant LanGT2S8Ac show how the replacement of a single loop can change the functionality of the enzyme. Crystal structures of the enzymes in complex with a nonhydrolyzable nucleotide-sugar analogue revealed that there is a conformational transition to create the binding sites for the aglycon substrate. This induced-fit transition was explored by molecular docking experiments with various aglycon substrates.

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium-catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)- and (18R)-stereoisomers in high stereoselectivity under ligand control.

A rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction was initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2-pyridones.

The rhodium-catalyzed, highly N²- and N¹-selective coupling of benzotriazoles with allenes is reported. The exceptionally high N² and N¹ selectivities were achieved by using a rhodium(I)/DPEphos and rhodium(I)/JoSPOphos catalyst, respectively. This method permits the atom-economic synthesis of valuable branched N²- and N¹-allylated benzotriazole derivatives and allows for preliminary studies of their reactivity.

New Rh- and Pd-catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with mono-substituted allenes are herein reported. Using a Rh^I/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a Pd^II/dppf system gave linear products with high regioselectivities and high E/Z selectivities. This method permits the atom economic synthesis of valuable branched and linear allylic imidazole derivatives.

The rhodium-catalyzed, highly N²- and N¹-selective coupling of benzotriazoles with allenes is reported. The exceptionally high N² and N¹ selectivities were achieved by using a rhodium(I)/DPEphos and rhodium(I)/JoSPOphos catalyst, respectively. This method permits the atom-economic synthesis of valuable branched N²- and N¹-allylated benzotriazole derivatives and allows for preliminary studies of their reactivity.

New Rh- and Pd-catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with mono-substituted allenes are herein reported. Using a Rh^I/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a Pd^II/dppf system gave linear products with high regioselectivities and high E/Z selectivities. This method permits the atom economic synthesis of valuable branched and linear allylic imidazole derivatives.

A rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction was initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2-pyridones.

To develop more active catalysts for the rhodium-catalyzed addition of carboxylic acids to terminal alkynes furnishing anti-Markovnikov Z enol esters, a thorough study of the rhodium complexes involved was performed. A number of rhodium complexes were characterized by NMR, ESI-MS, and X-ray analysis and applied as catalysts for the title reaction. The systematic investigations revealed that the presence of chloride ions decreased the catalyst activity. Conversely, generating and applying a mixture of two rhodium species, namely, [Rh(DPPMP)₂][H(benzoate)₂] (DPPMP=diphenylphosphinomethylpyridine) and [{Rh(COD)(μ₂-benzoate)}₂], provided a significantly more active catalyst. Furthermore, the addition of a catalytic amount of base (Cs₂CO₃) had an additional accelerating effect. This higher catalyst activity allowed the reaction time to be reduced from 16 to 1–4 h while maintaining high selectivity. Studies on the substrate scope revealed that the new catalysts have greater functional-group compatibility.

The increasing prevalence of multidrug-resistant strains of the malarial parasite Plasmodium falciparum requires the urgent development of new therapeutic agents with novel modes of action. The vacuolar malarial aspartic proteases plasmepsin (PM) I, II, and IV are involved in hemoglobin degradation and play a central role in the growth and maturation of the parasite in the human host. We report the structure-based design, synthesis, and in vitro evaluation of a new generation of PM inhibitors featuring a highly decorated 7-azabicyclo[2.2.1]heptane core. While this protonated central core addresses the catalytic Asp dyad, three substituents bind to the flap, the S1/S3, and the S1′ pockets of the enzymes. A hydroformylation reaction is the key synthetic step for the introduction of the new vector reaching into the S1′ pocket. The configuration of the racemic ligands was confirmed by extensive NMR and X-ray crystallographic analysis. In vitro biological assays revealed high potency of the new inhibitors against the three plasmepsins (IC₅₀ values down to 6 nM) and good selectivity towards the closely related human cathepsins D and E. The occupancy of the S1′ pocket makes an essential contribution to the gain in binding affinity and selectivity, which is particularly large in the case of the PM IV enzyme. Designing non-peptidic ligands for PM II is a valid route to generate compounds that inhibit the entire family of vacuolar plasmepsins.

Allylalkohole sind eine wichtige und überaus nützliche Klasse chiraler Bausteine für die organische Synthese. Dieser Aufsatz fasst die Vielzahl an Methoden zur katalytischen asymmetrischen Synthese von enantiomerenangereicherten Allylalkoholen zusammen. Diese umfassen die dynamische kinetische Racematspaltung (DKR/DYKAT), 1,2-Additionen von Nucleophilen an Carbonylgruppen, allylische Substitutionen, Oxidationen von C-H-Bindungen, die Addition von O-Nucleophilen an π-Systeme, die Reduktion von ungesättigten Carbonylverbindungen und eine alternative Syntheseroute ausgehend von enantiomerenangereicherten Propargylalkoholen. Darüber hinaus wird der präparative Nutzen dieser katalytischen asymmetrischen Transformationen jeweils am Beispiel ihrer Anwendung in der Synthese komplexer Moleküle wie z. B. Naturstoffen oder potenzieller Therapeutika gezeigt.

The hydroformylation of terminal alkenes is one of the most important homogeneously catalyzed processes in industry, and the atomistic understanding of this reaction has attracted enormous interest in the past. Herein, the whole catalytic cycle for rhodium-catalyzed hydroformylation with the 6-diphenylphosphinopyridine-(2H)-1-one (6-DPPon) ligand 1 was studied. This catalytic transformation is challenging to describe computationally, since two requirements must be met: 1) changes in the hydrogen-bond network must be modeled accurately and 2) bond-formation/bond-breaking processes in the coordination sphere of the rhodium center must be calculated accurately. Depending on the functionals used (BP86, B3LYP), the results were found to differ strongly. Therefore, the complete cycle was calculated by using highly accurate CCSD(T) computations for a PH₃ model ligand. By applying an integrated molecular orbital plus molecular orbital (IMOMO) method consisting of CCSD(T) as high level and DFT as low-level method, excellent agreement between the two functionals was achieved. To further test the reliability of the calculations, the energetic-span model was used to compare experimentally derived and computed activation barriers. The accuracy of the new IMOMO method apparently makes it possible to predict the catalytic potential of real-world systems.

Allylic alcohols represent an important and highly versatile class of chiral building blocks for organic synthesis. This Review summarizes the plethora of methods developed for the catalytic asymmetric synthesis of enantioenriched allylic alcohols. These include: dynamic kinetic resolution (DKR/DKAT), nucleophilic 1,2-addition to carbonyl groups, allylic substitution, oxidation of CH bonds, the addition of O nucleophiles to π systems, reduction of unsaturated carbonyl compounds, and an alternative route from enantioenriched propargylic alcohols. Furthermore, these catalytic asymmetric processes are exemplified by their applications in the syntheses of complex molecules such as natural products and potential therapeutic agents.

The determination of the relative configuration of 1,3-dimethyl-substituted alkyl chains is possible by interpretation of ¹H NMR shift differences. Additionally, assignments are feasible in a variety of deuterated solvents, because the corresponding shift differences are not significantly influenced by the solvent. The trends for Δδ values depending on functional groups adjacent to the stereogenic centers are shown. Based on a thorough comparison with literature data, the relative configuration of natural products can be predicted. For this purpose, we derived an empirical rule for the ranges in which Δδ values usually occur. Furthermore, we were able to proof the validity of our method by the successful prediction of the relative configuration for the polyketide natural product xylarinic acid A, which was confirmed by the asymmetric total synthesis of its enantiomer. Based on the proposed simple analysis of published ¹H NMR data and the determination of the relevant chemical-shift differences, we predicted the relative configurations of several previously unassigned natural products.

Iron nanoparticles (Fe-NP) supported on chemically-derived graphene (CDG) were prepared and identified as an effective catalyst for the hydrogenation of alkenes and alkynes. The catalyst can easily be separated by magnetic decantation.

Directing groups have been widely used in recent years to achieve control over all aspects of reaction selectivity in a wide range of transformations involving transition-metal catalysis and organometallic reagents. In cases when the existing functional group within a substrate is unsuited to achieve efficient intramolecular delivery of a reagent or catalyst, the specific introduction of an appropriately designed removable reagent-directing group can be a solution to this problem. In this Review we give an overview of the state of the art in this area, including the stoichiometric and catalytic use of directing groups.

New methodology for the stereoselective synthesis of trisubstituted olefins is presented. The use of ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing leaving group for copper-mediated allylic substitution with Grignard reagents allowed for the stereoselective construction of a wide range of E olefins, without the need for an adjacent electron-withdrawing group. Our modular three-step approach toward trisubstituted alkenes commenced with geminal α-methylene aldehydes. Addition of an organometallic reagent and introduction of the o-DPPB group by esterification was followed by the o-DPPB-directed copper-mediated allylic substitution with a Grignard reagent to furnish stereodefined trisubstituted olefins. Additionally, incorporation of a stereocenter from the chiral pool allowed the preparation of an enantiomerically pure olefin that bore three alkyl substituents in high E/Z selectivity.

Stereoselective and diversity-oriented synthesis of trisubstituted olefins was achieved by using ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing group for allylic substitution. The starting point of this methodology was a set of α-methylene aldehydes derived from Baylis–Hillman adducts. Subsequent addition of different organometallic reagents led to a variety of allylic alcohol substrates. After introduction of the reagent-directing o-DPPB group, copper-mediated allylic substitution with a wide range of Grignard reagents enabled the stereoselective construction of a large number of E-configured trisubstituted allylic alcohols and amines in excellent yields and stereoselectivities. Remarkable is the synthetic flexibility, which allows a wide range of permutations starting from an aldehyde followed by successive introduction of the substituents R² and R³ from organometallic Grignard based reagents. Thus, starting from only a few precursors, a diversity-oriented synthesis of stereodefined trisubstituted allylic alcohols and amines becomes possible.

Dirigierende Gruppen haben in den vergangenen Jahren breite Anwendung gefunden, um Reaktionsselektivitäten in einem breiten Spektrum an übergangsmetallkatalysierten Reaktionen und Reaktionen metallorganischer Reagentien zu steuern. In Fällen, in denen die im Substrat vorhandenen funktionellen Gruppen nicht geeignet sind, um eine effiziente intramolekulare Reagens- oder Katalysator-Steuerung zu ermöglichen, kann das gezielte Einbringen von maßgeschneiderten und wieder entfernbaren reagensdirigierenden Gruppen eine Lösung für dieses Problem bieten. In diesem Aufsatz geben wir eine Überblick zum Stand der Forschung auf diesem Gebiet und schließen dabei sowohl den stöchiometrischen wie den katalytischen Einsatz dirigierender Gruppen ein.

S_N2′ sequences have been employed for the synthesis of β-branched α-amino acids using 1,2-diastereocontrol for forming C–C bonds. An oxazolidine fragment derived from Garner's aldehyde provides the handle for facial discrimination and acts as a masked amino acid functionality. This study encompasses directed and non-directed allylic substitution reactions. The stereocontrol of the oxazolidine appendage during terminal olefin hydroformylation was also studied. Efforts to understand the diastereochemical outcome of the reactions as well as synthetic applications are disclosed.

A combination of regioselective room-temperature/ambient-pressure hydroformylation (transition-metal catalysis) and decarboxylative Knoevenagel reactions (organocatalysis) allowed for the development of an efficient, one-pot C3 homologation of terminal alkenes to (E)-α,β-unsaturated acids and esters, (E)-β,γ-unsaturated acids, (E)-α-cyano acrylic acids, and α,β-unsaturated nitriles. All reactions proceed under mild conditions, tolerate a variety of functional groups, and furnish unsaturated carbonyl compounds in good yields and with excellent regio- and stereocontrol. Further, an iterative C2 homologation of (E)-α,β-unsaturated carboxylic acids is possible through a combination of decarboxylative hydroformylation employing a supramolecular catalyst followed by decarboxylative Knoevenagel condensation with an organocatalyst.