With thousands of natural products containing halogen-bearing stereogenic centers, a wealth of methods have been developed for their stereocontrolled introduction in the context of total synthesis. This Review highlights the creative ways in which organic chemists have dealt with the challenges of stereochemically rich, halogenated natural products.

The exceptional reactivity of hypervalent iodine compounds make them privileged reagents in organic synthesis. Of them, cyclic derivatives stand apart because of their enhanced stability. The use of benziodoxol(on)es for trifluoromethylation (Togni's reagents) is now well recognized, but other transformations have also attracted strong interest recently. The progress in the area since 2011 is presented in this Review. Q=8-aminoquinoline.

Three of a kind: The biologically important tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B (see scheme) were constructed by an efficient strategy involving an intramolecular [2+2] cyclization, a regio- and diastereoselective semipinacol rearrangement, and an intramolecular aldol cyclization as key steps. The synthesis also enabled the correction of the absolute configuration of naturally occurring conidiogenone B.

Throw away the crystal ball: Three-dimensional human-artery models allowed in vitro prediction of the in vivo behavior of drug-delivery nanoparticles. In vivo experiments with atherosclerotic mice suggested strong biological characteristics and potential treatment effects of nanoparticles optimized in vitro (see picture). This approach is a promising alternative to animal experiments for the optimization of nanomaterials.

Magnetic attraction: β-Ag₃RuO₄ was synthesized using hydrothermal conditions. The crystal structure is based on a hexagonal close packing of oxygen, and displays tetrameric polyoxoanions [Ru₄O₁₆]¹²⁻ embedded in a 2D trigonal environment. The Ru₄ diamonds are separated by silver, which suppress the frustrated antiferromagnetic exchange common to trigonal lattices. Strong interanionic antiferromagnetic interactions dominate instead. Key: Ag gray, Ru cyan, O red.

In-bead screening: A one bead–one compound screening format was developed. A combinatorial library of 55 800 hydroxamic acids were synthesized and readily screened inside polymer beads, which led to the discovery of potent HDAC inhibitors with IC₅₀ values in the nanomolar range.

In the porous metal oxide capsule [{Mo^VI₆O₂₁(H₂O)₆}₁₂{(Mo^V₂O₄)₃₀(L)₂₉ (H₂O)₂}]⁴¹⁻ (L=propionate), the ethyl tails of the endohedrally coordinated ligands form a spherical, hydrophobic shell, while their methyl end groups generate a hydrophobic cavity at the center of the capsule. Whereas C₇ to C₃ alkanes are tightly intercalated between the ethyl tails, two or three rapidly rotating ethane molecules reside in the central cavity.

Weight and see: A matrix-free mass spectrometry imaging technique uses nanophotonic ionization based on laser desorption ionization from a highly uniform silicon nanopost array. In mouse-brain and kidney tissue sections, the distributions of over 80 molecular species could be determined with 40 μm spatial resolution.

Bendy batteries: A flexible, fiber-shaped lithium–air battery was developed from a gel polymer electrolyte and an aligned carbon nanotube sheet air electrode. It delivered a high specific capacity of 12 470 mAh g⁻¹ and could work for 100 cycles in air. Its electrochemical performance was maintained during and after bending and it could be woven into textiles to power electronic devices.

Trigger happy: Transition-metal-free couplings of iodoarenes with arenes are triggered by the use of alkali metal alkoxides in the presence of an organic additive. Recently 1 was shown to extend the reaction to aryl bromides. Evidence is reported for the dianion (2), derived from 1, which serves as an electron donor to initiate the reaction. Routes by which electron-poor benzoyl derivatives can be transformed into electron donors to initiate these reactions are also proposed.

Stay on the right side: Co-reconstitution of the cytP450–cytb₅ complex into a lipid membrane environment is achieved using peptide-based nanodiscs containing a planar lipid bilayer, completely obviating the need to use denaturing detergents. NMR experiments revealed effective interactions between the two proteins to form productive complexes where the proteins are properly oriented with respect to each other and to the lipid bilayer.

Micro-RAFTing: By using the enzyme glucose oxidase to effectively remove oxygen, highly controlled polymers are prepared in low volumes under ambient conditions on 384 well plates. This method enables the combinatorial synthesis of polymer libraries for high-throughput screening applications. RAFT=reversible addition–fragmentation chain transfer.

A cyclic octapeptide has been shown to fold into a “V-shaped” conformation that allows the selective recognition of anions such as chloride, nitrate, and carbonate. The selective anion recognition process involves the simultaneous assembly of six cyclic peptide subunits and four anions to give a supramolecular cluster that efficiently facilitates transmembrane transport of the anions.

Colloidal anisotropies: Bicompartmentalized Janus microparticles were synthesized using seeded polymerization. Selectively patching the silica nanoparticles onto one of the bulb surfaces allowed the Janus particles to assemble at the oil–water interface with a designated level of adhesion, thus producing structurally stable Pickering emulsions.

Tunable H₂S supply: Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described (see example). By modifying the ester group and thus its susceptibility to esterase H₂S release rates can be tuned. The anti-inflammatory effects of one candidate were examined by studying its ability to inhibit TNF-α production in RAW 264.7 cells.

It's all about topology: Upon complexation with silver(I) the tripeptide ligand (Pro-Gly-Pro) simultaneously folds into an Ω-looped conformation and self-assembles into a discrete peptide [4]catenane with the crossing number of 12. Within the [4]catenane each of the four equivalent M₃L₃ macrocycles is interlocked with the other three rings with tetrahedral symmetry.

SOFly, SOFly: Two supramolecular organic frameworks (SOFs) based on C-pentylpyrogallol[4]arene (PgC₅) with spacer molecules, such as 4,4′-bipyridine, are prepared. Their highly optimized and symmetric intermolecular hydrogen-bonding interactions give robust extended frameworks. One of the evacuated frameworks shows excellent affinity for carbon dioxide over other gases.

Wing it: The title reaction has been achieved for the first time with a Rh/(R,R,R,R)-WingPhos catalyst, providing a range of chiral diaryl alkyl carbinols with excellent ee values and yields. The method was applied for a concise synthesis of the antidepressant drug escitalopram. MTBE=tert-butyl methyl ether.

Molecular magnet: A single-molecule metal compound of 1 a encapsulated in a silica nanosphere (1 a=[Gd₅₂Ni₅₆(IDA)₄₈(OH)₁₅₄(H₂O)₃₈]¹⁸⁺) was prepared through a facile one-pot microemulsion method (see picture). The single-molecule high-nuclearity lanthanide–transition-metal compound showed experimentally and theoretically magnetic interactions.

Biomedical sensor: A highly controllable strategy has been developed for synthesizing Au nanotubes with a large aspect ratio. The nanotubes were used to construct an effective stretchable electrochemical sensor and to realize real-time monitoring of mechanically sensitive cells and tissues.

Strictly structured: The biomolecule l-arginine triggered CeO₂ crystal growth and self-assembly on Pd nanoparticles. Following the initial formation of cerium–l-arginine precursors on the Pd surface, heat treatment led to the production of high-quality Pd/CeO₂ nanostructures (see picture). By controlling the synthetic conditions, it was possible to tune the core size and shape, nanostructure, and sheath thickness of the resulting nanospheres.

Powerful electrophiles: properly substituted keteniminium ions, simply generated by acidic treatment of the corresponding ynamides, can induce a remarkably efficient [1,5]-hydride shift from unactivated C−H bonds. This triggers a cationic cyclization which gives, within minutes, highly functionalized tetrahydropyridine and piperidine derivatives.

End of the tether: The first catalytic and highly enantioselective synthesis of tribenzothiepin derivatives was achieved. Two types of intermolecular cycloadditions, either using diphenyl-sulfide-tethered diynes or 2-phenyl sulfanylbenzene tethered diynes with a monoalkyne, led to chiral multisubstituted tribenzothiepins in good to excellent ee values under mild reaction conditions. The present protocol was used to prepare a chiral tribenzoselenepin.

Illustrious ylides: 4-Bromo-1,2-dihydroisoquinolines were obtained conveniently from 4-(2-(bromomethyl)phenyl)-1-sulfonyl-1,2,3-triazoles 1 through the formation of bromonium ylides from α-imino rhodium carbene intermediates and subsequent rearrangement (see scheme). The versatile products participated as intermediates in a series of one-pot reactions and were converted into valuable polycyclic systems.

The choice is yours: [Mo(CO)₆] is demonstrated to be an efficient catalyst for the chemoselective reduction of tertiary amides in the presence of a large number of reducible groups, including imines and aldehydes. The reaction is tunable by variation of the temperature, and either an amine or an aldehyde can be obtained as the major product from the corresponding amide. TMDS=1,1,3,3-tetramethyldisiloxane.

Double the eFFect: A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α-silyldifluoroamides is reported. The reaction forms α,α-difluoro-α-aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be further transformed to provide access to a diverse array of difluoroalkylarenes. TMS=trimethylsilyl.

Aryl sulfides, although typically poisonous to transition-metal catalysts, serve as aryl electrophiles in the catalytic α-arylation of ketimines. Low catalyst loadings (down to 0.5 mol %) of a Pd–NHC complex are sufficient for efficient arylation. α-Arylated ketimine products were used to synthesize various azaarenes including 2,3-diarylpyrroles.

Flexible friend: The quantum efficiency of flexible photovoltaic devices in the near-infrared spectral region has been improved by integrating Si nanowire arrays with plasmonic Ag nanoplates. The Ag nanoplates can directly harvest and convert NIR light into plasmonic hot electrons for injection into Si, while the Si nanowire arrays allow light trapping. The flexible devices show excellent durability over 50 flexing cycles.

Cancer therapy: An inorganic layered double hydroxide (LDH) nanovector with a folic acid (FA) conjugated surface showed siRNA-based cancer therapeutic efficacy in vivo through receptor-mediated active targeting (see picture). A 1.2-fold higher accumulation of the drug was achieved in tumor tissue, resulting in 3.0-fold higher suppression of tumor volume.

Converging on a moving target: The first enantioconvergent palladium-catalyzed Fukuyama cross-coupling of racemic benzylic organozinc reagents with thioesters has been developed. The reaction furnishes acyclic α,α-disubstituted ketone products in good yields and high enantioselectivities, under mild reaction conditions which prevent racemization of the potentially labile tertiary stereocenter.

Click and lock: By twisting the OH groups in ethylene glycol, the molecule is prepared for a symmetric four-fold hydrogen-bond lock with its transient enantiomer, resulting in an outstandingly stable dimer which has so far been elusive in both theory and experiment.

Take two: Two-electron reduction of 1,1′-bis(o-carborane) and subsequent metalation with {Ru(mes)}²⁺ results in a 4,1,8-RuC₂B₁₀ species. A further two-electron reduction allows a direct electrophilic insertion reaction promoted by the carborane substituent for the addition of a second metal fragment and the formation of 1,13,2,9-Ru₂C₂B₁₀. A mechanism is proposed to rationalize the observed fluxionality of the products.

Gamma style: While γ-functionalization is well established in the setting of aldol, Mannich, and Michael reactions, γ-reactivity is scarce in other reaction classes. By using the newly developed vinylogous reactivity involving the release of ring strain in the rhodium-catalyzed asymmetric ring opening (ARO) the privileged coumarin motif was incorporated into the hydronaphthalene scaffold enantioselectively.

Singlet oxygen is able to transform unprotected primary furylalkylamines into the important pyrrolizidine and indolizidine scaffolds. The outcome of the one-pot sequences can be readily tailored to need by varying the choice of sensitizer. The synthetic utility of this method was demonstrated in the rapid synthesis of five natural products. PS: Photosensitizer. RB: rose Bengal. MB: Methylene blue.