Amino alcohols are vital in natural products, pharmaceuticals and agrochemicals, and as key building blocks for various applications. Traditional synthesis methods often rely on polar bond retrosynthetic analysis, requiring extensive protecting group manipulations that complicate direct access. Here we show a streamlined approach using a serine-derived chiral carboxylic acid in stereoselective electrocatalytic decarboxylative transformations, enabling efficient access to enantiopure amino alcohols. Unlike conventional strategies, this radical method is both modular and general, offering stereoselective and chemoselective synthesis of diverse substituted amino alcohols. For example, aryl, alkenyl, alkyl and acyl fragments can be coupled efficiently with the serine-derived chiral acid under electrocatalytic decarboxylative conditions. We demonstrate its utility through the rapid synthesis of medicinally important compounds, as well as useful building blocks, highlighting its ability to simplify complex synthetic pathways through entirely different bond disconnections. This electrocatalytic method is robust and scalable, as demonstrated in a 72-gram-scale flow reaction. Amino alcohols are essential in pharmaceuticals, agrochemicals and other applications. Now, using a serine-derived chiral carboxylic acid, an electrocatalytic decarboxylative transformation enables efficient and stereoselective access to diverse amino alcohols. This method is scalable, modular and could offer rapid synthesis of medicinal compounds and key building blocks.

Strained, multicyclic hydrocarbons are increasingly important structural motifs for drug discovery. In particular, substituted bicyclo[1.1.1]pentanes (BCPs) have risen to prominence as bioisosteres for the ubiquitous benzene ring. Despite their favorable pharmacokinetic properties, synthetic strategies toward BCPs suffer from significant drawbacks-namely an overreliance on [1.1.1]propellane, an operationally challenging to utilize starting material which complicates scale-up and hampers widespread adoption of these motifs. In this work, the synthesis of 2,2-dibromo BCPs is described, presenting a class of versatile substituted BCPs and circumventing the need for [1.1.1]propellane-based precursors. Scalable access to these compounds is demonstrated in a simple and inexpensive process, and their applicability for medicinal chemistry campaigns is highlighted through the synthesis of a diverse range of valuable building blocks-including highly sought-after bridge heteroarylated BCP derivatives which are prepared via an electrocatalytic cross-coupling procedure.

Electrochemical, fully stereoselective P(V)-radical hydrophosphorylation of olefins and carbonyl compounds using a P(V) reagent is disclosed. By strategically selecting the anode material, radical reactivity is accessible for alkene hydrophosphorylation whereas a polar pathway operates for ketone hydrophosphorylation. The mechanistic intricacies of these chemoselective transformations were explored in-depth.

Tertiary nitroalkanes, as well as their reduced products, α-tertiary amines, play an essential role in drug discovery as either key synthetic precursors or final motifs in targeted molecules. Existing methods to prepare tertiary nitro compounds generally rely on polar-bond disconnections, in which strong bases or highly active electrophiles are needed. Here we report the development of an anomeric nitroamide-based reagent that enables selective metal-hydride hydrogen atom transfer-based Co-catalysed alkene hydronitration for the preparation of valuable tertiary nitro compounds. This mild, scalable reaction shows broad functional group tolerance. Its synthetic application is demonstrated via late-stage nitration of complex alkenes derived from drugs and natural products, and simplifying the synthesis of a rare naturally occurring nitro sugar. Simple access to isotopically labelled 15N-containing nitro compounds is also disclosed. The anomeric nitroamide reagent was deemed safe by energetic measurements and its reactivity rationalized based on X-ray crystallographic analysis. Synthetic methods to generate tertiary nitroalkanes are scarce. Now the cobalt-catalysed synthesis of tertiary nitro-containing compounds under mild conditions from easily available olefins is enabled by a nitro-transfer reagent containing an anomeric amide.

Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 1957 (ref. 1), offers immense pharmaceutical potential owing to its interaction with voltage-gated sodium channels2, which are ubiquitously present in all excitable cells of the central and peripheral nervous system3. Hundreds of studies towards its synthesis have been disclosed so far, yet a fully modular and scalable approach to the family remains elusive4-12. Here we show how a tactical combination of radical retrosynthesis, biocatalysis and C-H functionalization logic can be used to solve this problem, resulting in a scalable approach to the STX family in fewer than ten steps, including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analogue previously under clinical investigation13. The modular nature of the synthesis enables access to diverse analogues that were previously inaccessible and have now been evaluated through electrophysiological assays for biological activity.

Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds ('stereoprobes') offers a versatile way to discover covalent ligands for proteins in native biological systems. Here we report the synthesis and chemical proteomic characterization of stereoprobes bearing a P(V)-oxathiaphospholane (OTP) reactive group. ABPP experiments identified numerous proteins in human cancer cells that showed stereoselective reactivity with OTP stereoprobes, and we confirmed several of these liganding events with recombinant proteins. OTP stereoprobes engaging the poorly characterized transmembrane protein TLCD1 impaired the incorporation of monounsaturated fatty acids into phosphatidylethanolamine lipids in cells, a lipidomic phenotype that mirrored genetic disruption of this protein. Using AlphaFold2, we found that TLCD1 structurally resembles the ceramide synthase and fatty acid elongase families of coenzyme Adependent lipid processing enzymes. This structural similarity included conservation of catalytic histidine residues, the mutation of which blocked the OTP stereoprobe reactivity and lipid remodeling activity of recombinant TLCD1. Taken together, these data indicate that TLCD1 acts as a lipid acyltransferase in cells, and that OTP stereoprobes function as inhibitors of this enzymatic activity. Our findings thus illuminate how the chemical proteomic analysis of electrophilic compounds can facilitate the functional annotation and chemical inhibition of a key lipid metabolic enzyme in human cells.

ENPP-1 is a transmembrane enzyme involved in nucleotide metabolism, and its overexpression is associated with various cancers, making it a potential therapeutic target and biomarker for early tumor diagnosis. Current detection methods for ENPP-1 utilize a colorimetric probe, TMP- p NP, which has significant limitations in sensitivity. Here, we present probe CL-ENPP-1, the first nucleic acid-based chemiluminescent probe designed for rapid and highly sensitive detection of ENPP-1 activity. The design of probe CL-ENPP-1 features a phenoxy-adamantyl-1,2-dioxetane luminophore linked to thymidine via a phosphodiesteric bond. Upon cleavage of the enzymatic substrate by ENPP-1, the probe undergoes an efficient chemiexcitation process to emit a green photon. Probe CL-ENPP-1 demonstrates an exceptional signal-to-noise ratio of 15000 and a limit of detection value approximately 4500-fold lower than the widely used colorimetric probe TMP- p NP. A comparison of TMP- p NP activation by ENPP-1 versus alkaline phosphatase (ALP) reveals a complete lack of selectivity. Removal of the self-immolative spacer from probe CL-ENPP-1 resulted in a new chemiluminescent probe, CL-ENPP-2, with an 18.4-fold increase in selectivity for ENPP-1 over ALP. The ability of probe CL-ENPP-2 to detect ENPP-1 activity in mammalian cells was assessed using the human breast cancer cell line MDA-MB-231. This probe demonstrated a 19.5-fold improvement in the signal-to-noise ratio, highlighting its superior ability to detect ENPP-1 activity in a biological sample. As far as we know, to date, CL-ENPP-1 and CL-ENPP-2 are the most sensitive probes for the detection of ENPP-1 catalytic activity. We anticipate that our new chemiluminescent probes will be valuable for various applications requiring ENPP-1 detection, including enzyme inhibitor-based drug discovery assays. The insights gained from our probe design principles could advance the development of more selective probes for ENPP-1 and contribute to future innovations in chemiluminescence research.

A concise, scalable total synthesis of (-)-bipinnatin J is disclosed. Commencing from inexpensive starting materials, this marine diterpenoid was fashioned through a convergent synthesis enabled by Ni-electrocatalytic decarboxylative cross-coupling taking advantage of succinate as an ethylene 2-carbon bridge, a unique halogen dance-Zweifel sequence to access a trisubstituted furan, a Ni-mediated 1,6-conjugate addition, and an asymmetric proton transfer.

A simple, modular, and programmable approach to access complex stereopure azetidines through strain-release functionalization is disclosed. The synthetic methods developed enable the parallel synthesis of stereodefined azetidines that would be otherwise laborious to produce. Given the privileged nature of these structures, a set of stereoprobes for use in activity-based protein profiling was prepared and evaluated, revealing proteins in human cancer cells, which were liganded with clear stereo- and chemo-selectivity.

The construction of stereogenic C(sp³)-C(sp³) bonds through cross-coupling remains a formidable challenge in organic synthesis due to inherent limitations in traditional cross-coupling methods, including β-hydride elimination, homo vs. heterocoupling selectivity, and poor stereocontrol in radical pathways. Herein, we report the first stereoretentive radical-radical cross-coupling (RRCC) of two distinct unstabilized alkyl radicals-derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides-achieved without chiral catalysts, directing groups, or exogenous redox. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, enabling precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. Optimization via highthroughput experimentation yields products with excellent enantiospecificity (typically 80-96% e.s.) and synthetically useful yields (40-90%) across diverse piperidine and pyrrolidine scaffolds with remarkable chemoselectivity, tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies, including radical clock experiments and DFT computations, reveal a caged radical rebound at Ni to preserve chirality, followed by Ni(I)/Ni(III)-mediated radical capture and reductive elimination. The reaction is scalable and can be used to control diastereoselectivity and override innate substrate bias. Synthetic utility is demonstrated through streamlined access to medicinally relevant intermediates and natural products like (S,S)-stenusine, outperforming prior multi-step routes. This paradigm shifts asymmetric synthesis by embedding stereochemistry in radical precursors, opening new retrosynthetic avenues for complex chiral molecules.

Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C-C bond-forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.

The pursuit of increasingly complex, three-dimensional molecules is pushing the boundaries of modern organic synthesis, particularly in drug discovery where rigid, saturated scaffolds such as cyclobutanes, azetidines and oxetanes are in high demand. Here we outline a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of nickel-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have been nearly impossible to access before without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry and related fields. Molecular scaffolds bearing 1,1-diaryl-substituted four-membered rings remain difficult to access using traditional synthesis. Now it has been shown that a modular, nickel-electrocatalytic sequence enables the programmable, scalable and chemoselective synthesis of these high-value motifs, offering broad utility across drug discovery and showcasing strategic applications to patented intermediates.

The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer’s disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as “generally regarded as safe”, indicating diAcCA is suitable for human clinical trials in AD.

Selective C-H bond activation is one of the most critical molecular transformations in synthesizing chemicals, pharmaceuticals, and natural product intermediates with broad applications. Recent efforts have focused on developing electrocatalytic mediators that rapidly and selectively activate specific C-H bonds. These mediated activations offer multiple benefits over direct electrochemical oxidation as they can occur at lower overpotentials, leading to higher faradaic efficiency and selectivity with reduced solvent oxidation. Our previous work described the development of N-alkyl ammonium ylides as a new class of electro-oxidative mediators. Despite its importance, the underlying principles of designing efficient mediators and understanding their site-selectivity are yet to be fully elucidated. The work discussed herein scrutinized mediator design using density functional theory calculations to highlight the critical features of mediators that govern C(sp3)-H activation. The design of newer mediators is guided by scaling relationships between the thermodynamic descriptors associated with the elementary steps involved in C(sp3)-H activation. We subsequently examine the results from detailed transition state calculations to elucidate the site-selectivity for C(sp3)-H activation for various substrates with quinuclidine and ylide mediators. The results show the critical interplay of thermodynamic, steric, and electronic features of the substrate and mediator that govern the corresponding site-selectivity. Finally, we present unifying trends across multiple substrates and mediators to understand the site-selectivity for mediated electrocatalytic C(sp3)-H activations and push our efforts toward predicting regio-selectivity in the future.

C–C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial -bromoglutaramide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multistep sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Ni(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum–hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be easily transitioned to large scale through an electrochemical recirculating flow process. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.

Three critical advances in simplifying the adoption of P(V)-based stereopure, phosphorothioate-containing oligonu-cleotide synthesis are reported. A more inexpensive phosphorus-sulfur incorporation reagent (Ψ-Br) is introduced, a robust linker system was developed, and a systematic study of common nucleobase protecting groups performed to significantly reduce the barrier to adoption of this technology.

Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF2H radical has a nucleophilic character similar to alkyl radicals, but the CF3 radical is electrophilic. While the difference between •CH3 and •CF3 is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF3 becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl frag-ments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species are sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of relying exclusively on conventional polar-bond based retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. In fact, the presence of a quaternary center even in seemingly trivial structures can dominate the practitioner's entire retrosynthetic plan (referred to by Corey as a “keying element”). Here we report a simple catalyst and minimal reagents that convert two types of feedstock chemicals—carboxylic acids and olefins—into tetrasubstituted carbons via quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer then combines the fragments by an SH2 reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon-containing materials from simple chemical feedstocks.