andrey antonchick group

Carbocycles are a key and widely present structural motif in organic compounds. The construction of structurally intriguing carbocycles, such as highly-strained fused rings, spirocycles or highly-functionalized carbocycles with congested stereocenters, remains challenging in organic chemistry. Cyclopropanes, cyclobutanes and cyclopentanes within such carbocycles can be synthesized through ring contraction. These ring contractions involve re-arrangement of and/or small molecule extrusion from a parental ring, which is either a carbocycle or a heterocycle of larger size. This review provides an overview of synthetic methods for ring contractions to form cyclopropanes, cyclobutanes and cyclopentanes en route to structurally intriguing carbocycles.

The evolution of synthetic design toward the efficient synthesis of cyclobutane natural product (±)-piperarborenine B is demonstrated. Taking the advantages of good functional group compatibility of contractive synthesis of cyclobutanes from pyrrolidines, stereoselective synthesis of unsymmetric highly functionalized cyclobutanes core of (±)-piperarborenine B was realized in one step. Also, an unprecedented carboxylic acid assisted-diastereoselective Kracho decarboxylation/transmethylation features a new strategy for a non-symmetrical cyclobutane core. The synthesis of (±)-piperarborenine B illustrates the advancement of methodology resulting in the improvement in synthetic efficiency.

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented “pseudo-natural products” in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.

The use of conventional nitrenoids and/or metal nitrenes as electrophilic aminating reagents requires a pre-activated nitrogen atom, which makes transfer of an unprotected NH-group a difficult challenge. Iodonitrene, which is generated in situ from phenyliodine(III) diacetate and an ammonia surrogate, represents a new type of reactive electrophilic aminating reagent. The novel reactivity of iodonitrene not only resulted in direct NH-group transfer to nucleophilic atoms such as sulfur and nitrogen, but also led to the development of new reactions such as diazirine synthesis via decarboxylation and contractive synthesis of cyclobutanes via nitrogen extrusion. We highlight the contemporary advances in the application of iodonitrene and discuss the current limitations and future prospects.

We report on the feasibility to harness embryonic development in vitro for the identification of small-molecule cytokine mimetics and signaling activators. Here, a phenotypic, target-agnostic, high-throughput assay is presented that probes bone morphogenetic protein (BMP) signaling during mesodermal patterning of embryonic stem cells. The temporal discrimination of BMP- and transforming growth factor-β (TGFβ)-driven stages of cardiomyogenesis underpins a selective, authentic orchestration of BMP cues that can be recapitulated for the discovery of BMP activator chemotypes. Proof of concept is shown from a chemical screen of 7000 compounds, provides a robust hit validation workflow, and afforded 2,3-disubstituted 4H-chromen-4-ones as potent BMP potentiators with osteogenic efficacy. Mechanistic studies suggest that Chromenone 1 enhances canonical BMP outputs at the expense of TGFβ-Smads in an unprecedented manner. Pharmacophoric features were defined, providing a set of novel chemical probes for various applications in (stem) cell biology, regenerative medicine, and basic research on the BMP pathway.

Derivatives of fused 1,2,4-triazines containing heterocyclic and metallocene fragments were obtained by one-pot oxidative cyclization of heterocyclic hydrazones in the presence of hypervalent iodine(III) reagents. For 1,2,4-triazolo[4,3-a]azines, the ability to activate HSF1 was investigated. The obtained compounds were shown to increase the degree of HSF1 activation. It was shown that the 1,2,4-triazines can be used to induce Hsp70 expression and decrease the extent of mutant HTT aggregate formation.

Here we report a contractive synthesis of multisubstituted cyclobutanes containing multiple stereocenters from readily accessible pyrrolidines using iodonitrene chemistry. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsymmetrical spirocyclobutanes were prepared successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported.

A metal-free protocol for the synthesis of substituted 1,6-dihydropyridines with quaternary stereogenic centers via a cascade aza-Wittig/6 pi-electrocyclization process has been developed. The high functional group compatibility and broad scope of this method were demonstrated by using a wide range of easily available vinyliminophosphoranes and ketones, with yields up to 97%. A modification of the obtained products allowed for an increase in complexity and chemical diversity. Finally, attempts for asymmetric synthesis of 1,6-dihydropyridines are demonstrated.

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent-bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal-complex-catalyzed 1,3-dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo- and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag-catalyzed 1,3-dipolar cycloadditions of azomethine ylides with electron-poor olefins. Time-dependent reversible dynamic covalent-bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents.

A transition-metal-free direct electrolytic C-H amination involving an electrochemically generated nitrenium ion intermediate has been developed. The electrosynthesis takes place in the absence of any organoiodine catalysts and is enabled by an in situ generated electrolyte. A novel, efficient intramolecular and intermolecular C-H amination has been demonstrated using a simple reaction setup.

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space. Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

Cyclopropylamines are characteristic structural motifs found in a variety of natural products and pharmaceuticals and therefore engaging targets for the development of new methods for their synthesis. Herein the synthesis of enantioenriched cyclopropylamines through catalytic enantioselective C-H functionalization using a chiral RhJasCp complex is reported. The reaction proceeds under mild conditions with high enantiocontrol. This reaction enables access to cyclopropylamines with three contiguous stereocenters originating from the corresponding cyclopropenes.

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C-H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.

A metal-free, regioselective C–H functionalization of heteroaromatic N-oxides has been developed. The method enables the synthesis of various benzylated and alkynylated N-heterocycles in a transition-metal-free manner employing organosilanes as coupling partners. The unanticipated reactivity has been exploited for the synthesis of a number of symmetrical disubstituted acetylenes from ethynyltrimethylsilane via carbon–silicon bond metathesis.

Small-molecule chemotypes with unexpected bioactivity may be identified by combining strategies built on the biological relevance of, e.g., natural products (NPs), such as biology-oriented synthesis, with principles that enable efficient coverage of chemical space, such as fragment-based compound design. Evaluation in target-agnostic phenotypic assays and target identification may link biologically relevant chemotypes to unexpected and unknown targets. We describe the phenotypic identification of an unprecedented kinase inhibitor chemotype obtained by synthetic combination of two biosynthetically unrelated NP fragment types. Target identification and biological characterization revealed that the inhibitor, termed Myokinasib, impairs cytokinesis, induces formation of multinucleated cells, and reduces phosphorylated myosin II light chain abundance on stress fibers by selective inhibition of myosin light chain kinase 1.

Nitrosonium ions are versatile and mild oxidants, which were successfully employed in organic transformations. The applications cover different fields, such as the functionalization of carbon-carbon and carbon-heteroatom bonds, functionalization of unsaturated bonds and the oxidative coupling of arenes, catalyzed by nitrosonium ions. Due to the ability of nitrosonium ions to modify various types of bonds with different modes of action, a variety of applications has been established, which addresses current challenges in organic chemistry research. By considering additional points, such as safety of reagents, by-product formation, employed solvents and energy consumption, several aspects of green and sustainable chemistry can be addressed. Within this review, synthetic applications of nitrosonium ions under transition metal-free reaction conditions are summarized.

Catalytic cross-dehydrogenative coupling of heteroarenes with thiophenols and phenothiazines has been developed under mild and environmentally benign reaction conditions. For the first time, NO_x⁺ was applied for catalytic C–S and C–N bond formation. A comprehensive scope for the C–H/S–H and C–H/N–H cross-dehydrogenative coupling was demonstrated with >60 examples. The sustainable cross-coupling conditions utilize ambient oxygen as the terminal oxidant, while water is the sole by-product.

Herein we report the first enantioselective annulation of α‐arylidene pyrazolones through a formal C(sp3)‐H activation under mild conditions enabled by highly variable Rh(III)‐Cpx catalysts. The method has wide substrate scope proceeds with good to excellent yields and enantioselectivity. Its synthetic utility was demonstrated by late‐stage functionalization of drugs and natural products as well as preparation of enantioenriched [3]‐dendralenes. Preliminary biological investigation also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.

Sweet chemistry. A catalytic transfer hydrogenation using biomass‐derived carbohydrates as reagent is developed. Stereoselective and chemoselective hydrogenation of alkynes, alkenes, and carbonyl compounds is demonstrated. This work provides an operationally simple method for transfer hydrogenation and represents a new concept for the application of renewable biomass.

Axially chiral 4‐arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. However, enantioselective synthesis of axially chiral 4‐arylisoquinolones by means of C‐H activation has not been reported to date. We describe rhodium (III)‐catalyzed C‐H bond activation and annulation for the atroposelective synthesis of axially chiral 4‐arylisoquinolones. The method employs chiral cyclopentadienyl ligands embodying a piperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity. Biological relevance of the 4‐arylisoquinolones was demonstrated by their investigation in different cellular assays, leading to the discovery of novel non‐SMO binding Hedgehog pathway inhibitors.

Novel complexes of 1,2-P,N-bidentate ferrocenyl ligands with AgOAc or with [RuCl₂(PPh₃)₃] as catalysts have been studied in asymmetric synthesis. The catalytic activity of these systems have been studied in [3+2]-cycloaddition of azomethine ylides with olefins and the asymmetric transfer hydrogenation of ketones.

The development of oxidative heteroatom–heteroatom bond‐forming reactions based on the use of hypervalent iodine reagents is summarized, with emphasis on metal‐free and transition‐metal‐catalyzed reactions. The most important approaches are located in the field of nitrogen–heteroatom and sulfur–heteroatom bond formation, but also chemical transformations including rather rarely used elements are discussed. Increasing interest in the field of heteroatom–heteroatom bond formation in the past decades led to some notable discoveries, which are discussed within this chapter.

Selective oxidative homo- and cross-coupling of electron-rich phenols and anilides was developed using nitrosonium tetrafluoroborate as a catalyst. Oxidative coupling of phenols revealed unusual selectivities, which translated into the unprecedented synthesis of inverse Pummerer-type ketones. Mechanistic studies suggest that oxidative coupling of phenols and anilides shares a common pathway via homolytical heteroatom–hydrogen bond cleavage. Nitrosonium salt catalysis was applied for cross-dehydrogenative coupling initiated by generation of heteroatom-centered radicals.

A catalytic, metal-free intramolecular rearrangement of benzyl phenyl ethers using nitrosonium salt as a catalyst is described. The optimized reaction conditions enabled a catalytic and metal-free Friedel–Crafts alkylation reaction with benzylic alcohols, producing water as the stoichiometric byproduct. A comprehensive scope (>50 examples) for both approaches and application in drug synthesis were demonstrated. Mechanistic studies suggest a Lewis acid-based mechanism for the metal-free Friedel–Crafts reaction.

The nitrosonium ion-catalyzed dehydrogenative coupling of heteroarenes under mild reaction conditions is reported. The developed method utilizes ambient molecular oxygen as a terminal oxidant, and only water is produced as byproduct. Dehydrogenative coupling of heteroarenes translated into the rapid discovery of novel hedgehog signaling pathway inhibitors, emphasizing the importance of the developed methodology.

Recent years have witnessed a significant advancement in the field of radical oxidative coupling of ketones towards the synthesis of highly useful synthetic building blocks, such as 1,4-dicarbonyl compounds, and biologically important heterocyclic and carbocyclic compounds. Besides oxidative homo- and cross-coupling of enolates, other powerful methods involving direct C(sp³)–H functionalizations of ketones­ have emerged towards the synthesis of 1,4-dicarbonyl compounds. Moreover, direct α-C–H functionalization of ketones has also allowed an efficient access to carbocycles and heterocycles. This review summarizes all these developments made since 2008 in the field of metal-catalyzed/promoted radical-mediated functionalization of ketones at the α-position.

A combination of readily available and bench stable CF₃SO₂Na and t-BuOOH was efficiently used for hydrotrifluoromethylation of alkynes. An excellent trans-selectivity was demonstrated in the synthesis of alkenes. The developed mild reaction conditions allow to suppress the competing Meyer-Schuster type rearrangement.

Spirotropanyl oxindole alkaloids like alstonisine and chitosenine show a wide range of bioactivites. We report the first enantioselective synthesis of the spirotropanyl oxindole scaffold by means of a bimetallic relay catalysis strategy. A new class of E-oximino a-diazo ketones was developed for the intramolecular generation of transient azomethine ylides catalyzed by an achiral Rh^II complex and a subsequent intermolecular 1,3‐dipolar cycloaddition catalyzed by a chiral N,N'-dioxide Nd^III Lewis acid complex. The enantioselectively catalyzed transformation has broad scope and yields the desired spirotropanyl oxindole cycloadducts in high yields and with very high enantio‐ and diastereoselectivity.

A novel enantioselective approach to the synthesis of a compound collection inspired by natural pyrrolizidine alkaloids was developed, employing an enantioselectively catalyzed 1,3-dipolar cycloaddition as the key step. The cycloadducts were obtained with excellent enantio- and diastereoselectivity. Biological evaluation of the resulting compound collection revealed that the compound class has multiple bioactivities, including activity against Plasmodium falciparum 3D7 and inhibition of Hedgehog signaling.

Functionalization of heterocycles through free radical intermediates has been widely employed in a diverse array of synthetic transformations. This chapter focuses on the recent developments in the light-assisted as well as traditional free radical generation methodology and the subsequent utilization in functionalization of various heterocycles.

Class act: In the copper-catalyzed title reaction, aromatic and aliphatic propargylic esters react with substituted coumarins to give the desired products in excellent yields and enantioselectivities. Single-step transformations enabled the synthesis of several compounds. Biological investigation of the compound collection led to the discovery of a novel class of autophagy inhibitors.

The combination of annulation strategies and direct C–H bond functionalization reactions allow the efficient synthesis of cyclic molecules using readily available and non-prefunctionalized precursors. Metal-free oxidative coupling via C–H bond functionalization is a green and sustainable approach due to its environmental benign and step- and atom-economic advantages. This concept highlights novel strategies and recent breakthroughs for metal-free annulation via C–H bond functionalization giving access to a variety of important structural motifs.

Functionalization of C(sp3)-H bonds under metal-free reaction conditions is a great challenge due to low bond reactivity. A novel metal-free oxidative dehydrogenative Diels-Alder reaction of alkylbenzene derivatives with alkenes via C(sp3)-H bond functionalization is described. The developed oxidative method provides a straightforward approach to biologically relevant 1,4-phenanthraquinone and isoindole derivatives from readily available starting materials. Furthermore, the synthesis of nitrostyrenes from enylbenzene derivatives via selective C(sp3)-H bond functionalization has been demonstrated.

Natural products provide evolutionary validated core structures inspiring the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species which has been used to treat neurological diseases in Chinese traditional medicine. According to the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide the tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded decorating the periphery of the basic scaffold with additional substituents to increase the diversity and the number of the library members. Evaluation of the different sub-collections of secoyohimbanes for modulation of neurite outgrowth in the SH-SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth.

The discovery of chiral Cp ligands that unite the advantages of previously developed ligand classes is enabled by a novel approach. They can be readily synthesized on gram scale, and both their structures and configurations can be efficiently adjusted by means of flexible enantioselective [6+3] cycloaddition reactions. With these ligands, three rhodium(III)-catalyzed C−H activation reactions were rendered highly enantioselective.

Transition-metal-free cis-dihydroxylation of saturated hydrocarbons under ambient reaction conditions has been developed. The described approach allows direct and selective synthesis of vicinal diols. The new reaction proceeds thereby via radical iodination and a sequence of oxidation steps. A broad scope of one-pot dual C(sp³)-H bond functionalization for the selective synthesis of vicinal syn-diols was demonstrated.

A biology-oriented synthesis of 3,3-spiro(2-tetrahydrofuranyl)oxindole derivatives is realized through the rhodium(II)-catalyzed three-component reaction of diazoamides, aldehydes and β-nitrostyrenes. The reactions are conducted under mild conditions and the products are obtained in moderate to good yields with excellent regio- and diastereoselectivity.

The potential of deuterated pharmaceuticals is being widely demonstrated. Here we describe the first trideuteromethylation under radical reaction conditions using deuterated dimethyl sulfoxide as reagent for the synthesis of labelled heterocycles and trideuteromethylated compounds. A broad scope of developed method for the synthesis of various scaffolds was demonstrated.

Two for one offer: An efficient method based on copper(I)-catalyzed [3+2] cycloadditions has been developed for the enantiodivergent combination of natural product derived tropane and pyrrolidine scaffolds. The strategy enables the synthesis of two enantiopure products in a one-pot reaction with one chiral catalyst in high diastereo- and enantioselectivity.

Iridium(III)-catalyzed direct C7-sulfonamidation of indoles with sulfonyl azides is described. The developed method has good compatibility with diverse functional groups, providing various 7-amino-substituted indoles with good to excellent yields in a short time under mild reaction conditions. The key feature of the developed method is the regioselective functionalization at the C7-position of 2,3-unsubstituted indoles. Biologically active compounds can be obtained using this protocol. The application of the iridium(III) catalyst and directing group plays a crucial role in the regioselectivity of the developed reaction.

A practical synthesis of polycyclic heterocycles by radical annulation of tertiary arylamine derivatives is described. Radical annulation occurs via formation of α-aminoalkyl radicals. The reaction is initiated by tetrabutylammonium iodide using tert-butyl hydroperoxide as oxidant. The developed method allows functionalization of diverse tertiary alkylanilines with different alkenes.

The synthesis of small rings by functionalization of C(sp³)−H bonds remains a great challenge. We report for the first time a copper-catalyzed [1+1+1] cyclotrimerization of acetophenone derivatives under mild reaction conditions. The reaction has a broad scope for the stereoselective synthesis of cyclopropanes by trimerization of acetophenone. The developed transformation is based on an extraordinary copper-catalyzed cascade process that allows saturated carbocycles to be obtained for the first time by cyclotrimerization through functionalization of C(sp³)−H bonds. The cascade of sixfold C(sp³)−H bond functionalization allows the synthesis of cyclopropanes in a highly stereoselective approach.

Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B.

A novel, mild, and practical method of amination of simple nonfunctionalized arenes under metal free conditions has been developed. The approach allows coupling of electron-rich arenes with amino derivatives of electron-deficient heterocycles providing rapid access to scaffolds of bioactive compounds and is based on the application of the hypervalent iodine(III) reagent as an oxidant. Regioselective functionalization of C–H bonds of arenes by the formation of C–N bonds under organocatalytic conditions was demonstrated.

A synthesis of multisubstituted furans from readily available acetophenones and electron-deficient alkynes via direct C(sp3)−H bond functionalization under radical reaction conditions is described. The developed transformation is catalyzed by copper(I) salts using di-tert-butyl peroxide as an external oxidant. This method offers an efficient access to biologically important scaffolds from simple compounds.

Who needs metals anyway? This Minireview covers the rapidly growing area of metal-free oxidative C-C bond formation through direct C-H bond functionalization. A selection of recent important developments in this area is presented along with discussions of their reaction mechanisms.

Hypervalent iodine(III) reagents have been widely exploited in a diverse array of synthetic transformations. This chapter focuses on the general application of hypervalent iodine(III) reagents in the de novo synthesis and in the late stage functionalization of heterocyclic compounds.

A novel and operationally simple one-step C–H bond functionalization of quinoline N-oxides to 2-substituted quinolines was developed. This approach enables the regioselective functionalization under external oxidant- and metal-free conditions. The developed transformation represents the first application of the Petasis reaction in functionalization of heterocycles.

A practical synthesis of azabicyclo[3.1.0]hexane derivatives by direct oxidative coupling of arylmethyl ketones and maleimides was developed. The dehydrogenative annulation involves a double C-H bond functionalization at the α-position of the ketone using a copper(II) complex as the catalyst and di-tert-butyl peroxide as the oxidant.

Direct methods of novel bond formation through functionalization of nonreactive carbon–hydrogen bonds represent an efficient synthetic approach. Cross-dehydrogenative coupling has emerged as an area of huge potential and importance for novel bond formation. The application of hypervalent iodine(III) reagents in direct carbon–hydrogen bond functionalization reactions is of immense interest because the functionalization of the nonreactive carbon–hydrogen bonds proceeds under metal-free reaction conditions. This account covers recent developments in the area of hypervalent iodine(III) mediated direct carbon–hydrogen bond functionalization.

Decisive dipoles: In the rhodium(II)-catalyzed asymmetric 1,3-dipolar cycloaddition of tropone with carbonyl ylides, a programmable chemoselective reaction with the keto group or the 6 π system of tropone was controlled by the substrate (see scheme). The developed method enables the synthesis of complex products in highly enantiomerically enriched form.

A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows a broad substrate scope.

We have developed a novel method for the regioselective annulation of 2-nitrosopyridines with variably substituted alkynes under mild reaction conditions. This approach allows the annulation of alkynes with 2-nitrosopyridines under reagent- and catalyst-free reaction conditions. The developed method shows excellent functional group tolerance and provides easy access to N-oxide-imidazo[1,2-a]pyridines.

A new cascade reaction for the synthesis of complex products with eight stereocenters was developed. The reaction cascade proceeds with excellent diastereo- and enantioselectivity from simple starting chemicals such as aromatic aldehydes, amino acid esters, cyclopentadiene and molecular oxygen.

An operationally simple, transition metal-free, oxidative, regioselective cross-coupling between non-functionalized azoles and chromones was developed using iodine. The C2- position of chromone can be selectively coupled with nitrogen containing heterocycles. A broad scope of reaction with respect to coupling partners and further transformation of obtained products was demonstrated. The biological evaluation of obtained products revealed a novel class of hedgehog signaling pathway inhibitors.

A phosphine-catalyzed dearomatizing [3+2] annulation of isoquinolinium methylides with allenoates or allenones yields highly functionalized pyrroloisoquinolines with high regioselectivity and in viable yields.

Fischer-man’s friend: A regioselective multicomponent route to indole synthesis by functionalization of simple alkenes has been developed and has a broad scope. The novel application of alkene trifluoromethylation provides entry into Fischer indole synthesis, and various trifluoromethylated nitrogen heterocycles can be conveniently obtained.

Disappearing Me: A novel selective annulation between 2-aminopyridine derivatives and arenes under metal-free conditions provides the important pyrido[1,2-a]benzimidazole scaffold under mild reaction conditions. In this intermolecular reaction the methyl group of methylbenzenes serves as a traceless, non-chelating, and highly regioselective directing group.

Annulation without hesitation: N-alkoxybenzamides convert into isoquinolones smoothly and rapidly under organocatalytic conditions. The annulation of unsymmetrical diarylacetylenes proceeds with a high regioselectivity. The transformation is based on the hypervalent-iodine mediated generation of nitrenium ions.

This Account highlights examples, mostly from our work, of the application of 1,3-dipolar cycloaddition reactions of azomethine ylides for the catalytic enantioselective synthesis of complex products. We successfully applied the 1,3-dipolar cycloaddition in the synthesis of spiro-compounds such as spirooxindoles, for kinetic resolution of racemic compounds in the synthesis of an iridoid inspired compound collection and in the synthesis of a nitrogen-bridged bicyclic tropane scaffold by application of 1,3-fused azomethine ylides. Furthermore, we performed the synthesis of complex molecules with eight stereocenters using tandem cycloadditions. In a programmable sequential double cycloaddition, we demonstrated the synthesis of both enantiomers of complex products by simple changes in the order of addition of chemicals. Complex products were obtained using enantioselective higher order [6 + 3] cycloaddition of azomethine ylides with fulvenes followed by Diels–Alder reaction. The bioactivity of these compound collections is also discussed.

C-C bond formation is the most fundamental way for the chain propagation in organic molecules. This achievement through tandem oxidation of two different C-H bonds represents the state of the art in organic synthesis. Selective functionalization of the ubiquitous aliphatic C-H bonds offers an attractive option for this oxidative cross-coupling methodology. To develop such a methodology under mild and “metal-free” conditions remains challenging. Herein, we report hypervalent iodine-mediated selective oxidative functionalization of aliphatic C-H bonds of alkanes with chromones and (thio)chromones. A wide range of alkanes, both cyclic and acyclic, has been found to react selectively and predictably in good yields. The developed methodology is also the first report of a direct oxidative functionalization of the C-2 position of (thio)chromones with alkanes to access bioactive compounds.

A novel method for the oxidative radical azidation of alkenes relies on an azide in combination with a hypervalent iodine reagent. A cascade of C-N and C-C bond-forming reactions yields 2-oxindoles under metal-free conditions with high reaction rates at ambient temperature and provides access to complex products (see scheme; TMS=trimethylsilyl).

The development of new bond formation methods through coupling of simple compounds by direct functionalization of non-reactive C–H bonds is an important area of modern organic synthesis. The current status in the development of synthetic methodologies for carbon-heteroatom bond-forming reactions under metal-free conditions is highlighted.

Natural products endowed with neuromodulatory activity and their underlying structural scaffolds may inspire the synthesis of novel neurotrophic compound classes. The spirocyclic secoyohimbane alkaloid rhynchophylline is the major component of the extracts of Uncaria species used in Chinese traditional medicine for treatment of disorders of the central nervous system. Based on the structure of rhynchophylline, a highly enantioselective and efficient organocatalyzed synthesis method was developed that gives access to the tetracyclic secoyohimbane scaffold, embodying a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence. Investigation of a collection of the secoyohimbanes in primary rat hippocampal neurons and embryonal stem cell-derived motor neurons led to discovery of compounds that promote neurite outgrowth and influence the complexity of neuronal network formation.

A dream reaction: An efficient and practical method for the oxidative cross-coupling of heteroaromatic compounds and simple alkanes has been developed. The desired products are smoothly and regioselectively formed under mild reaction conditions at ambient temperature in a hypervalent-iodine-mediated transformation. The method allows for preferential transformation of stronger C(sp³)-H bonds in the presence of weaker C(sp³)-H bonds under metal-free conditions.

A range of heterocyclic compounds were synthesized by a novel, metal-free cross-dehydrogenative coupling between heterocycles and aldehydes under mild reaction conditions that are not sensitive to moisture. The products are formed smoothly and regioselectively at room temperature by a hypervalent iodine mediated transformation. This method has a broad substrate scope and was used in the highly efficient, one-step synthesis of natural products.

An atom-economical, Rh(III)-catalyzed, direct oxidative cross-coupling at the C5 position of chromones and flavones with a broad range of alkenes was developed. The products were formed in a highly regioselective manner in good to excellent yields. The developed method was applied in the cross-coupling of natural products for the synthesis of hybrid molecules.

New atom-economical, environmental friendly, direct oxidative intermolecular processes of amination and hydrazination of nonprefunctionalized arenes were developed. The products were formed in a good regioselective manner under organocatalytic conditions at ambient temperature.

Under control: Highly functionalized chiral annulated piperidines with eight stereocenters are efficiently obtained by means of a highly enantioselective onepot [6+3]/[4+2] sequence. This sequence included the first enantioselective [6+3] cycloaddition of azomethine ylides with fulvenes.

An efficient novel protocol for the construction of an hyellazole-inspired compound collection is described. Starting from 2,6-diarylacetanilides, the desired products were obtained using hypervalent iodine promoted electrocyclization. The mechanism of product formation was investigated through intramolecular competition experiments.

We developed an enantioselectively catalyzed tandem synthesis of structurally and stereochemically complex molecules that forms four carbon-carbon bonds and sets eight stereocenters with high regio-, diastereo- and enantioselectivity. It can be programmed to yield different stereoisomers by varying only the order of combination of a common set of reagents and catalysts. We report what is to our knowledge the first synthesis of both enantiomers of a chiral compound using the same chiral catalyst

A new atom-economical process of direct oxidative intermolecular functionalization of aniline derivatives by simple arenes was developed. The products were formed in a highly regioselective manner under metal-free conditions at ambient temperature

Direct oxidative methods of C-H bond functionalization represent efficient straightforward approaches in formation of new bonds. Those transformations allow coupling of nonprefunctionalized building blocks and engaged growing attention from academic and industrial communities. Recent results on development of environmentally benign oxidative aminations of C-H bonds are highlighted.

The twinkling of an I: In a new atom-economical and environmentally friendly organocatalytic method for intramolecular C-H amination, the C-N bond forms at ambient temperature by abstraction of two atoms of hydrogen; only acetic acid and water are formed as by-products. The method has also been extended to the unprecedented metal-free cross-amination of nonactivated arenes.

Alkaloids are an important class of natural products that are widely distributed in nature and produced by a large variety of organisms. They have a wide spectrum of biological activity and for many years were used in folk medicine. These days, alkaloids also have numerous applications in medicine as therapeutic agents. The importance of these natural products in inspiring drug discovery programs is proven and, therefore, their continued synthesis is of significant interest. The condensation discovered by Pictet and Spengler is the most important method for the synthesis of alkaloid scaffolds. The power of this synthesis method has been convincingly proven in the construction of stereochemicaly and structurally complex alkaloids.

S=O shows where to go: A novel double C-H activation of aromatic compounds with a sulfoxide as a directing group results in the highly regioselective synthesis of polysubstituted dibenzothiophenes (see scheme). The reaction cascade consists of palladium-catalyzed double C-H activation and a Pummerer rearrangement followed by palladium-catalyzed C-S bond formation.

The underlying stereochemically complex and densely functionalized scaffold of the B-seco limonoids was synthesized employing an Ireland–Claisen rearrangement as key transformation.

The pentacyclic spirotryprostatin scaffold embodies an oxindole with an all-carbon quaternary stereocenter. The scaffold can efficiently be accessed in a one-pot reaction sequence consisting of a highly enantioselective 1,3-dipolar cycloaddition, N-acylation of the resulting stereochemically complex 3,3′-pyrrolidinyl-spirooxindole core with Fmoc-proline and spontaneous ring closure upon N-deprotection.

A convenient protocol for the enantioselective synthesis of 4-substituted tetrahydroquinolines has been developed. Chiral BINOL phosphoric acids promote the reduction of a wide range of 4-substituted quinolines with Hantzsch esters with good to high levels of enantioselectivity.

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3'-pyrrolidinyl spirooxindoles - which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1–3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF₆(CH₃CN)₄. Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.

A highly enantioselective metal-free reduction of 3H-indoles has been developed. This Brønsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source constitutes an efficient method for the synthesis of various optically active indolines with high enantioselectivities.

Protein phosphatases (PPs) constitute a large family of enzymes, which are crucial modulators of cellular phosphorylation events. Malfunction in PP activity has been associated with human diseases, including diabetes, obesity, cancer, and neurodegenerative and autoimmune disorders, and makes this class of enzymes attractive targets for chemical biology and medicinal chemistry research. A number of strategies are currently explored for the identification and development of various classes of PP modulators and have resulted in a plethora of chemically distinct inhibitors. Limited selectivity and adverse pharmacological properties of PP inhibitors are still major bottlenecks for further clinical development and resulted in only a few molecular entities currently in clinical trials

Surprisingly straightforward: A metal-free, highly enantioselective Brønsted acid catalyzed condensation/addition reaction has been developed for the construction of 2,3-dihydroquinazolinones starting from 2-aminobenzamide and aldehydes (see scheme). This efficient approach provides 2,3-dihydroquinazolinones with a strong preference for the S-enantiomers, which have higher biological activities than the R-enantiomers.

A condensation–rearrangement sequence forms the basis of a high-yielding route to chiral homoallylic amines from readily accessible aldehydes (see scheme). This transformation is both the first enantioselective Brønsted acid catalyzed sigmatropic rearrangement and the first example of a catalytic asymmetric aza-Cope rearrangement.

One cat. is enough! A highly enantioselective reaction has been developed for the three-component reaction of an enamine with a vinyl ketone and a Hantszsch ester in which each of the six reaction steps is catalyzed by the same chiral Brønsted acid (see scheme). This reaction offers efficient access to tetrahydropyridines and azadecalinones from simple and readily available starting materials.

A direct asymmetric organocatalytic aza-Henry reaction has been developed in which a new bifuctional Brønsted-acid-catalyzed activation of nitroalkanes provides an efficient access to α,β-diamino acids with high dia- and enantioselectivities under mild and base-free reaction conditions.

Low catalyst loadings, high enantioselectivities, mild conditions, and fast reaction times are the important features of the first enantioselective organocatalytic electrocyclic reaction: a Nazarov cyclization leading to the synthesis of substituted five-membered rings with a chiral Brønsted acid as a catalyst. A further advantage of this method is the possible entry to all four diastereomers of the product.

The first metal-free Brønsted acid catalyzed hydrogenation of quinolines using Hantzsch dihydropyridine as the hydrogen source has been developed. This, so far unprecedented organocatalytic reduction of heteroaromatic compounds provides a variety of differently substituted 1,2,3,4-tetrahydroquinolines in excellent yields under mild reaction conditions using a remarkably low amount of Brønsted acid catalyst.

A number of hexadeuterated brassinosteroids (BS) containing a hydroxy group at C-22 or a 22R,23R-diol function were prepared starting from 23,24-bisnorcholenic acid methyl ester for biosynthetic studies. Synthesis of the cyclic part was accomplished via the initial hydroboration–oxidation of Δ⁵-double bond. The key step in the synthesis of the side chain involved addition of (2S)-[3,4-²H₆]2,3-dimethylbutylphenyl sulfone to the corresponding C-22 aldehydes

Two new brassinosteroids, (22R,23R,24S)-22,23-dihydroxy-24-methyl-5α-cholest- 2-en-6-one (secasterol) and (22R,23R,24S)-22,23-dihydroxy-2α,3α-epoxy-24- methyl-5α-cholest-6-one (2,3-diepisecasterone) have been identified together with a known 2,3-epoxybrassinosteroid, secasterone, in seedlings of Secale cereale. Deuterated secasterol, teasterone, and typhasterol, upon administration to rye seedlings, were incorporated into secasterone and 2,3-diepisecasterone, indicating a biosynthetic route via teasterone/typhasterol to secasterol to 2,3-epoxybrassinosteroids.

Two hexadeuterated brassinosteroids (BS) ([26,27-²H₆]-23-dehydroxycastasterone and [26,27-²H₆]-cathasterone) containing a hydroxy group at C₂₂ instead of the 22R,23R-diol function characteristic for most compounds of this class were prepared for biochemical studies. The corresponding non-deuterated compounds are considered intermediates in brassinolide biosynthesis. The carbon skeleton of the side chain with proper stereochemistry at C₂₄ was prepared from commercially available (2R)-3-hydroxy-2-methylpropanoate. This low molecular fragment was coupled to the tetracyclic steroidal fragment through the reaction of the appropriate sulfone with C₂₂ aldehyde. Formation of the necessary configuration of the 22-hydroxy group was achieved by hydride reduction of the corresponding ketone. Deuterium atoms at C₂₆ and C₂₇ originated from [²H₃]methyl iodide used for alkylation of the intermediate sulfone.

A number of [26-²H₃]brassinosteroids were prepared for biochemical studies. The parent, nondeuterated compounds were considered to be biosynthetic intermediates in brassinosteroid biosynthesis. Claisen rearrangement was used to construct the steroidal side chain. Deuterium was introduced by reducing the corresponding intermediates with lithium aluminium deuteride.

In the course of investigations on brassinosteroid (BS) biosynthetic and metabolic pathways in plants, an approach using HPLC/APCI-MS analysis of underivatized BS for their identification in plant material has been developed. Its application to root-callus suspension cultures of Arabidopsis thaliana led to the first identification of 3-epibrassinolide as natural brassinosteroid.