Phil S. Baran’s research while affiliated with The Scripps Research Institute and other places

Free radicals were first discovered over 120 years ago by Gomberg and the first radical cross-couplings demonstrated by Kochi in the 1970's. Fueled by the need for general methods to couple C(sp3)-fragments, this area has seen an explosion of renewed interest. In contrast to widely employed polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (Suzuki, Negishi, Kumada, etc.), radical cross-coupling is advantageous when applied to the coupling of saturated systems due to the mild conditions employed and enhanced chemoselectivity associated with single electron chemistry. Indeed, the ability to employ ubiquitous carbon-based fragments (carboxylic acids, alcohols, amines, olefins, etc.) in cross-coupling has dramatically simplified access to a variety of complex molecules. Despite these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be impossible due to their near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of radical cross-coupling can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to solve this vexing challenge for the first time thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.

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.

The urgent demand for innovative pain therapies is underscored by pain affecting 20% of the global population, costing the U.S. $600 billion annually, more than cancer, heart disease, and diabetes combined, with current treatments lacking in efficacy or causing severe side effects1 . Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 19572, offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels, promising long-term anesthesia for conditions like anal fissures3 and chronic headaches4. However, its deadly nature, with just 1 mg potentially lethal, and the complexity of its over 50 related toxins5, challenge its clinical use. Efforts to modify STX aim to reduce its systemic toxicity while enhancing selectivity, potentially revolutionizing pain management and detoxification strategies, while also providing insights into cellular electrical transmission6. Hundreds of synthetic studies towards this end have been disclosed thus far, yet a fully modular and scalable approach to the family remains elusive. Here we show how a tactical combination of radical retrosynthesis, biocatalysis, and C–H functionalization logic can be combined to solve this problem resulting in a scalable approach to the STX family in less than 10 steps including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analog previously under clinical investigation7

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 characteri-zation 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 A-dependent lipid processing enzymes. This structural similarity included conservation of catalytic histidine residues, the muta-tion 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.

Electrochemical, fully stereoselective P(V)‐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. A comprehensive investigation into the mechanistic intricacies of the chemoselectivity was conducted, providing deeper insight into the underlying reaction pathways and selectivity factors. image

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-pNP, 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-pNP. A comparison of TMP-pNP 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.

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.

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.

Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp ³ character (Fsp ³ ) to enhance specificity as well as physiochemical properties. Although traditional flat, high-fraction sp ² molecules, such as pyridine, can be decorated through electrophilic aromatic substitution and palladium (Pd)–based cross-couplings, general strategies to derivatize three-dimensional (3D) saturated molecules are far less developed. In this work, we present an approach for the rapid, modular, enantiospecific, and diastereoselective functionalization of piperidine (saturated analog of pyridine), combining robust biocatalytic carbon-hydrogen oxidation with radical cross-coupling. This combination is directly analogous to electrophilic aromatic substitution followed by Pd-couplings for flat molecules, streamlining synthesis of 3D molecules. This study offers a generalizable strategy for accessing complex architectures, appealing to both medicinal and process chemists.