Alfa Chemistry

Petroleum-derived polyolefins exhibit diverse properties and are the most important and largest volume class of plastics. However, polyolefins are difficult to efficiently recycle or break down and are now a persistent global contaminant. Broadly replacing polyolefins with bio-derived and degradable polyethylene-like materials is an important yet challenging endeavour towards sustainable plastics. Here Miyake et al. report a solution for circular bio-based polyethylene-like materials synthesized by acceptorless dehydrogenative polymerization from linear and branched diols and their catalytic closed-loop recycling. The polymerization and depolymerization processes utilize earth-abundant manganese complexes as catalysts. These materials exhibit a wide range of mechanical properties, encompassing thermoplastics to plastomers to elastomers. The branched diols, produced through a thiol–ene click reaction, can be polymerized to plastics with significantly enhanced tensile properties, toughness and adhesive properties. These materials could be depolymerized back to monomers through hydrogenation and were separatable with a monomer recovery of up to 99%, unaffected by the presence of dyes and additives. Overall, this system establishes a route to more sustainable plastics.

The hydrochlorination of unsaturated hydrocarbons is a fundamental reaction in organic synthesis. Traditional acid-mediated approaches proceed with Markovnikov selectivity, but direct access to anti-Markovnikov hydrochlorination products is still a longstanding pursuit. Previous methods are restricted by the need for multiple synthetic steps, stoichiometric chlorine and hydride sources and/or highly oxidative photocatalysis, resulting in limited scope and, in some cases, low regioselectivity. So, the development of redox-neutral hydrochlorination with high anti-Markovnikov regioselectivity compatible with both alkenes and alkynes remains important. Here West et al. report a photocatalytic anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons enabling access to diverse alkyl and alkenyl chlorides regio- and stereoselectively. Broad scope (125 examples), mild conditions and regio- and isotopo-divergent syntheses are demonstrated. Key to this method is the combination use of ligand-to-metal charge transfer photoreactivity of earth-abundant iron and hydrogen atom transfer reactivity of redox-active thiol. This cooperative system offers a powerful strategy for anti-Markovnikov hydrofunctionalization of unsaturated hydrocarbons.

Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, Miller et al. found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), they show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. The results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, they provide evidence that other proton pump inhibitors can be activated in the same way. They conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.

The unique properties of fluorinated organic compounds have received intense interest and have conquered a myriad of applications in the chemical and pharmaceutical sciences. Today, an impressive range of alkyl fluorides are commercially available, and there are many practical methods to make them exist. However, the unmatched stability and inertness of the C–F bond have largely limited its synthetic value, which is very different from the widely accepted utility of alkyl chlorides, bromides, and iodides that serve everyday as “workhorse” building blocks in countless carbon–carbon bond forming reactions. This study demonstrates practical and high-yielding functionalization of the C–F bond under mild conditions, i.e., at temperatures as low as ?78 °C, in short reaction times and with unconventional chemoselectivity. Cryogenic Csp3–F bond cleavage using fluorophilic organoaluminum compounds together with fast nucleophile transfer of intermediate ate complexes forge carbon–carbon bonds with unactivated primary, secondary, and tertiary alkyl fluorides alike. This method, which exploits the stability of the Al–F bond as the thermodynamic driving force, is highly selective toward Csp3–F bond functionalization, whereas many other functional groups including alkyl chloride, bromide, iodide, aryl halide, alkenyl, alkynyl, difluoroalkyl, trifluoromethyl, ether, ester, hydroxyl, acetal, heteroaryl, nitrile, nitro, and amide groups are tolerated, which is an unexpected reversal of long-standing main group organometallic and alkyl halide cross-coupling reactivity and compatibility patterns. As a result, the strongest single bond in organic chemistry can now be selectively targeted in high-yielding arylation, alkylation, alkenylation, and alkynylation reactions and used in late-stage functionalization applications that are complementary to currently available methods.

Benzene reduction by molecular complexes remains an important synthetic challenge, requiring harsh reaction conditions involving group I metals. Reductions of benzene, to date, typically result in a loss of aromaticity, although the benzene tetra-anion, a 10π-electron system, has been calculated to be stable and aromatic. Due to the lack of sufficiently potent reductants, four-electron reduction of benzene usually requires the use of group I metals. Here Anker et al. demonstrate the four-electron reduction of benzene and some of its derivatives using a samarium(ii) alkyl reagent, with no requirement for group I metals. Whereas organosamarium(ii) typically reacts through one-electron processes, the compounds reported here feature a rare two-electron process. Combined experimental and computational results implicate a transient samarium(i) intermediate involved in this reduction process, which ultimately provides the benzene tetra-anion. The remarkably strong reducing power of this samarium(ii) alkyl implies a rich reactivity, providing scope for its application as a reducing agent.

Carbon–hydrogen (C–H) bonds are the foundation of essentially every organic molecule, making them an ideal place to do chemical synthesis. The key challenge is achieving selectivity for one particular C(sp3)?H bond. In recent years, metalloenzymes have been found to perform C(sp3)?H bond functionalization. Despite substantial progress in the past two decades, enzymatic halogenation and pseudohalogenation of unactivated C(sp3)?H—providing a functional handle for further modification—have been achieved with only non-haem iron/α-ketoglutarate-dependent halogenases, and are therefore limited by the chemistry possible with these enzymes. Here Tang et al. report the discovery and characterization of a previously unknown halogenase ApnU, part of a protein family containing domain of unknown function 3328. ApnU uses copper in its active site to catalyse iterative chlorinations on multiple unactivated C(sp3)?H bonds. By taking advantage of the softer copper centre, they demonstrate that ApnU can catalyse unprecedented enzymatic C(sp3)?H bond functionalization such as iodination and thiocyanation. Using biochemical characterization and proteomics analysis, they identified the functional oligomeric state of ApnU as a covalently linked homodimer, which contains three essential pairs—one interchain and two intrachain—of disulfide bonds. The metal-coordination active site in ApnU consists of binuclear type II copper centres, as revealed by electron paramagnetic resonance spectroscopy. This discovery expands the enzymatic capability of C(sp3)?H halogenases and provides a foundational understanding of this family of binuclear copper-dependent oxidative enzymes.

The automated synthesis of small organic molecules from modular building blocks has the potential to transform the capacity to create medicines and materials. Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed. Here Blair et al. report a streamlined approach for the rapid, quantitative analysis of chemical reactions by mass spectrometry. The intrinsic fragmentation features of chemical building blocks generalize the analyses of chemical reactions, allowing sub-second readouts of reaction outcomes. Central to this advance was identifying that starting material fragmentation patterns function as universal barcodes for downstream product analysis by mass spectrometry. Combining these features with acoustic droplet ejection mass spectrometry could eliminate slow chromatographic steps and continuously evaluate chemical reactions in multiplexed formats. This enabled the assignment of reaction conditions to molecules derived from ultrahigh-throughput chemical synthesis experiments. More generally, these results indicate that fragmentation features inherent to chemical synthesis can empower rapid, data-rich experimentation.

Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs. Here Baker et al. used deep learning methods to de novo design proteins to bind short-chain and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, the researchers obtained protein designs with remarkable thermal stability, high binding affinity and near-atomic-level agreement with the computational models. The designed proteins effectively neutralized all three 3FTx subfamilies in vitro and protected mice from a lethal neurotoxin challenge. Such potent, stable and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective and widely accessible next-generation antivenom therapeutics. Beyond snakebite, results highlight how computational design could help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for the development of therapies for neglected tropical diseases.

Enzyme-like enantiopure supramolecular hosts leverage non-covalent and electrostatic interactions to engage substrates in a chiral environment without direct coordination. Elucidating the mechanistic underpinnings of enantioinduction in these systems is critical to the success of this nascent field. Toste et al. report herein an enantiopure Ga4L612? host-catalyzed asymmetric reduction of aromatic, heteroaromatic, and aliphatic oximes to hydroxylamines, without N–O bond cleavage, using pyridine borane as a reductant cofactor. The reaction scope and mechanistic study, in combination with data science analysis, showcase that guest recognition and enantioinduction are highly sensitive to both steric and electronic effects. Optimization of interactions between the host, oxime, and reductant within the host cavity enabled highly enantioselective reactivity (>99% ee) for even previously unreported pyridine oximes.

A concise synthesis of the complex diterpene azorellolide, inspired by speculations on biosynthetic cationic cascades, is presented. The approach, guided by computation, relies on the intramolecular interception of a cyclopropylcarbinyl cation by an appended carboxylate. The successful execution of this strategy was achieved through acid-catalyzed isomerization of a β-lactone in competition with a type I dyotropic rearrangement.