Ring contraction in synthesis of functionalized carbocycles.

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.

Concise synthesis of piperarborenine B.

A concise synthesis of piperarborenine B is reported. Organocatalytic electrophilic amination of pyrrolidines, stereospecific oxidative ring contraction and an original diastereoselective Krapcho dealkoxycarbonylation/transmethylation contribute to a novel synthetic strategy to the preparation of a non-symmetrical cyclobutane core. Being transition-metal-free, directing-group-free and protecting-group-free, a five-step synthesis of piperarborenine B was accomplished.

The Pseudo-Natural Product Rhonin Targets RHOGDI.

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.

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines.

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.

Electrochemical Dehydrogenative C(sp2 )-H Amination.

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.

Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions.

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.

Enantioselective Formal C(sp3 )-H Bond Activation in the Synthesis of Bioactive Spiropyrazolone Derivatives.

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 RhIII -Cpx catalysts. The method has a wide substrate scope and proceeds with good to excellent yields and enantioselectivities. Its synthetic utility was demonstrated by the late-stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Preliminary biological investigations also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.

Catalytic Enantioselective Synthesis of a Pyrrolizidine-Alkaloid-Inspired Compound Collection with Antiplasmodial Activity.

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.

Enantiomerically Enriched 1,2-P,N-Bidentate Ferrocenyl Ligands for 1,3-Dipolar Cycloaddition and Transfer Hydrogenation Reactions.

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.

Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis.

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 α-diazo ketones was developed for the intramolecular generation of transient azomethine ylides catalyzed by an achiral RhII complex and a subsequent intermolecular 1,3-dipolar cycloaddition catalyzed by a chiral N,N'-dioxide NdIII 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.

C-H Bond Activation for the Synthesis of Heterocyclic Atropisomers Yields Hedgehog Pathway Inhibitors.

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. Described here is a 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 (SMO= smoothened) binding Hedgehog pathway inhibitors.

Enantioselective Organocatalytic Synthesis of a Secoyohimbane-Inspired Compound Collection with Neuritogenic Activity.

Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a 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 by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections 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.

Sustainable, Oxidative, and Metal-Free Annulation.

Annulation has received steadily growing interest in the interplay with the increasing emphasis towards selective C-H bond functionalization reactions. Metal-free oxidative annulation through functionalization of inert and abundant C-H bonds offers great improvements in terms of atom- and step-economics as well as reduced waste production under mild reaction conditions. Annulation is considered to be a highly efficient strategy for the construction of cyclic molecules because at least two new bonds are formed within a single reaction step. The combination of annulation and direct C-H bond functionalization allows the efficient and straightforward synthesis of carbo- and heterocyclic molecules using simple and non-prefunctionalized precursors. This Concept highlights novel strategies and recent breakthroughs for metal-free annulation through C-H bond functionalization giving access to a variety of important structural motifs.

A Metal-Free Oxidative Dehydrogenative Diels-Alder Reaction for Selective Functionalization of Alkylbenzenes.

Functionalization of C(sp3 )-H bonds under metal-free reaction conditions is a great challenge due to poor bond reactivity. A novel metal-free oxidative dehydrogenative Diels-Alder reaction of alkylbenzene derivatives with alkenes through 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 by selective C(sp3 )-H bond functionalization has been demonstrated.

Highly Enantioselective Catalytic Vinylogous Propargylation of Coumarins Yields a Class of Autophagy Inhibitors.

A highly enantioselective copper-catalyzed vinylogous propargylic substitution has been developed. Aromatic and aliphatic propargylic esters react smoothly with substituted coumarins under mild reaction conditions to give the desired products with excellent yields and enantioselectivities. Subsequent single-step transformations enable the synthesis of a wide range of multifunctional and diverse compounds, and allow the efficient combination of different natural product fragments. Investigation of the obtained compound collection in cell-based assays monitoring changes in phenotype led to the discovery of a novel class of autophagy inhibitors.

General Enantioselective C-H Activation with Efficiently Tunable Cyclopentadienyl Ligands.

Cyclopentadienyl (Cp) ligands enable efficient steering of various transition-metal-catalyzed transformations, in particular enantioselective C-H activation. Currently only few chiral Cp ligands are available. Therefore, a conceptually general approach to chiral Cp ligand discovery would be invaluable as it would enable the discovery of applicable Cp ligands and to efficiently and rapidly vary and tune their structures. Herein, we describe the three-step gram-scale synthesis of a structurally diverse and widely applicable chiral Cp ligand collection (JasCp ligands) with highly variable and adjustable structures. Their modular nature and their amenability to rapid structure variation enabled the efficient discovery of ligands for three enantioselective RhIII -catalyzed C-H activation reactions, including one unprecedented transformation. This novel approach should enable the discovery of efficient chiral Cp ligands for various further enantioselective transformations.

Oxidative Heterocycle Formation Using Hypervalent Iodine(III) Reagents.

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.

Iridium(iii)-catalyzed regioselective C7-sulfonamidation of indoles.

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.

Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection.

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.

[1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes.

The synthesis of small rings by functionalization of C(sp(3) )-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(sp(3) )-H bonds. The cascade of sixfold C(sp(3) )-H bond functionalization allows the synthesis of cyclopropanes in a highly stereoselective approach.