Saxitoxins Simplified

Welcome to this week’s Organic Synthesis Newsletter.

Monday 17^th February – Sunday 23^rd February 2025 | Volume 2, Issue 7

HIGHLIGHT OF THE WEEK
Scalable, Convergent Total Synthesis of (+)-Saxitoxin and Related Natural Products

Y. Guo,^† Y. Li,^† S. Chen, O. Poll, Y. Wu, C. K. Prier, K.-J. Xiao, P. S. Baran*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-qj8f5) 🔓

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 effects. Saxitoxin (STX), a potent neurotoxin from shellfish was first isolated in 1957 and offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels. However, its deadly nature, with just 1 mg potentially lethal and the complexity of its over 50 related toxins, challenge its clinical use. Hundreds of synthetic studies towards modifying STX to reduce its systemic toxicity have been disclosed thus far, yet a fully modular and scalable approach remains elusive. Here, the authors show how a 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), a hydroxylated naturally occurring STX analog previously under clinical investigation.

SCIENCE
Spiro-C(sp³)-Atom Transfer: Creating Rigid Three-Dimensional Structures with Ph₂SCN₂

Q. Sun, J.-N. Belting, J. Hauda, D. Tymann, P. W. Antoni, R. Goddard & M. M. Hansmann*

Science 2025, 387, 885–892 (DOI: 10.1126/science.ads5974)

The introduction of a single C(sp³)-atom surrounded by four C–C σ-bonds, which allows access to three-dimensional space, is an unresolved problem in synthetic chemistry. Here, the authors report the synthesis and application of the diazosulfur ylide, Ph₂S=C=N₂, which combines the reactivity of both sulfur ylides and diazo compounds to create carbon spiro-centers in a general fashion. New C–C and C–X (X = O or N) bonds can be created around the C(sp³)-atom that can be extended to four C–C σ-bonds in a single step without resorting to transition metal catalysis. Ph₂SCN₂ can also be used to access highly strained frameworks containing (oxa)spiro[2.2]pentanes as well as tricyclic spiro-compounds.

NATURE CHEMISTRY
Catalytic Difluorocarbene Insertion Enables Access to Fluorinated Oxetane Isosteres

T.-D. Tan,^† F. Zhou,^† K. P. Quirion, Y.-Q. Wang, D. Z. W. Ng, X. Luo, E. C. Y. Chan,* P. Liu* & M. J. Koh*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01730-7)

The authors describe a copper-catalysed approach for the skeletal expansion of oxygen heterocycles by reaction with a difluorocarbene species generated in situ to induce carbon atom insertion. The α,α-difluoro-oxetane products are potential surrogates of oxetane, β-lactone and carbonyl pharmacophores on the basis of their computed molecular properties and electrostatic potential maps. The utility of this approach is highlighted by synthesis of various drug-like molecules and fluorinated isosteres of biologically active compounds.

NATURE SYNTHESIS
Mechanochemical Activation of Metallic Lithium for the Generation and Application of Organolithium Compounds in Air

K. Kondo, K. Kubota & H. Ito*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00753-3) 🔓

The authors report a mechanochemical method for the direct generation of organolithium reagents from readily available organic halides and unactivated lithium metal (lithium wire) under bulk-solvent-free conditions. These reactions rapidly generate a diverse array of organolithium compounds at room temperature without special precautions against moisture and without temperature control. The addition of these compounds to various electrophiles proceeds smoothly in a one-pot fashion. This approach enables reactions with poorly soluble aryl halides and direct C–F bond lithiation that are inefficient under conventional solution-based conditions.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Enantioselective Total Synthesis of (−)-Rubriflordilactone B by a Bioinspired Skeletal Reorganization Approach

Y. Xie,^† J. Bao,^† Y. Wang,^† Y. Shen, Z. Liang, H. Tian & J. Gui*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18292)

Rubriflordilactone B is a Schisandra bisnortriterpenoid with a unique 5/5/7/6/5/5-hexacyclic framework that includes a characteristic tetrasubstituted aromatic ring. Here, the authors report a convergent, enantioselective total synthesis of this natural product by a bioinspired skeletal reorganization approach. Key transformations include a [2,3]-Wittig–Still rearrangement to assemble the western cyclohexenyl fragment, a Cu(II)-catalyzed tandem acyloin acylation–Wittig olefin to build the eastern butanolide fragment, a Friedel–Crafts cyclization to construct the seven-membered ring, and an E1cB reaction/transesterification/oxa-Michael addition cascade to forge the 5/5-fused bicyclic lactone.

Enantioselective Ring Opening of Azetidines via Charge Recognition in Hydrogen-Bond-Donor Catalysis

J. J. Gair,^† M. Isomura,^† C. C. Wagen, D. A. Strassfeld & E. N. Jacobsen*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00165)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-3cvgr) 🔓

The authors report the highly enantioselective ring-opening of 3-substituted azetidines by alkyl and acyl halides promoted by a chiral squaramide hydrogen-bond donor catalyst, which had been identified previously to promote enantioselective opening of oxetanes. This remarkable generality is interpreted to arise from catalyst recognition of the conserved electrostatic features of the dipolar enantioselectivity-determining transition states in the ring-opening S_N2 mechanisms with simultaneous tolerance of variation of the specific functional group and steric features of the reactions.

Facile Synthesis of Housanes by an Unexpected Strategy

Y. Liu, S. Tranin, Y.-C. Chang, E. B. Piper, T. Fessard, R. Van Hoveln,* C. Salome* & M. K. Brown*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c13298)

Rigid bicyclic hydrocarbons have emerged as important building blocks in drug discovery; however, despite progress in this area, bicyclo[2.1.0]pentanes (housanes) remain understudied. Here, the authors report an unconventional synthesis of borylated housanes, which involves a strain-release diboration of bicyclo[1.1.0]butane and intramolecular deborylative alkylation. The versatility of the bridgehead boronic ester was demonstrated in several functionalizations.

Copper-Catalyzed Selective Amino-alkoxycarbonylation of Unactivated Alkenes with CO

S.-S. Yan, R. Jackstell & M. Beller*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c13723) 🔓

The authors report a copper-catalyzed 1,2-amino-alkoxycarbonylation of unactivated alkenes with CO and alkylamine precursors in the presence of a Lewis acid additive. The protocol allows direct access to valuable β-amino acid derivatives from easily available starting materials, features high chemo- and regioselectivities, good functional group tolerance, and substrate scope including diverse bioactive compounds and drug-like molecules.

Enantioselective Alkyl–Acyl Radical Cross-Coupling Enabled by Metallaphotoredox Catalysis

T. Li, Z. Xu, Y. Huang, W. Zu & H. Huo*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15275)

The authors report a novel metallaphotoredox platform that enables highly enantioselective decarboxylative coupling of carboxylic acid derivatives with aldehydes. The strategy leverages independent control over radical generation and subsequent enantioselective bond formation through fine-tuning of a common photocatalyst and a simple chiral bis(oxazoline) nickel catalyst. This redox-neutral protocol requires no exogenous oxidants or reductants and demonstrates broad substrate scope and functional group compatibility in the synthesis of enantioenriched α-aryl and α-amino ketones, the latter of which can be readily transformed into valuable β-amino alcohols.

Brønsted Acid-Catalyzed Reduction of Furans

N. Frank, M. Leutzsch & B. List*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18485) 🔓

Bioderived furans play a pivotal role in advancing defossilized chemical pathways. The complete reduction of furans currently relies on impractical metal-catalyzed hydrogenations at high pressures and temperatures. In addition, the Birch reduction of unbiased furans to 2,5-dihydrofurans remains an unsolved synthetic challenge. Here, the authors report a mild Brønsted acid-catalyzed reduction of furans to 2,5-dihydro- and/or tetrahydrofuran derivatives using silanes as reducing agents. In particular, the first formal Birch reduction of furan itself is achieved.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
“Naked Nickel”-Catalyzed Heteroaryl-Heteroaryl Suzuki–Miyaura Coupling

R. Saeb, B. Roh & J. Cornella*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202424051)

The authors report that the air-stable “naked nickel” [Ni(^4-CF₃stb)₃] is a competent catalyst in the Suzuki-Miyaura cross-coupling reaction between heteroaryl bromides and heteroaromatic boron-based nucleophiles. The catalytic system is characterized by its ability to avoid decomposition or deactivation in the presence of multiple Lewis-basic sites. The protocol permits the formation of C‒C bonds between two heteroaryl moieties in the absence of complex exogenous ligands, thus minimizing screening procedures and simplifying reaction setups.

Photoredox Autocatalysis: Towards a Library of Generally Applicable Reductive Photocatalysts

J. Kaur, M. J. P. Mandigma, N. A. Bapat & J. P. Barham*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202423190) 🔓

The authors report the identification of a photoredox autocatalytic pathway to access cyclic biaryl sulfonamides (BASNs). The reaction does not require exogenous catalyst as the visible light absorbing deprotonated product itself, with potent excited state reductive power, acts as the photocatalyst for its own synthesis. This finding implicated BASN as a novel organophotocatalyst architecture and allowed a rapid, modular, and low-cost combinatorial synthesis of a BASN library that expedited optimal photocatalyst screening. Furthermore, BASN was revealed as a widely applicable organophotocatalyst for diverse transition metal-free transformations such as: intramolecular (spiro)-cyclizations, defunctionalizations, and C–C/C–heteroatom couplings.

Water-Stable 2-Pyridylboron Reagents: Pd-Catalyzed 2-Pyridylation Reaction of Aryl Halides

W. Li,^† Y. Chen,^† R. Yuan, X. Jia, Y. Yao & L. Zhang*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202500315)

A general strategy to prepare water-stable 2-pyridylboron reagents (zwitterionic 2-pyridinium trifluoroborates) has been developed. The application of which in a neutral Suzuki-Miyaura coupling with a halide scavenger enables the efficient 2-pyridylation reaction of aryl halides.

CHEMRXIV
Total Synthesis of Dactyloquinone A and Spiroetherone A

G. Schoenn, C. Kouklovsky, R. Guillot, T. Magauer & G. Vincent*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-91q45) 🔓

The authors report the total synthesis of dactyloquinone A and spiroetherone A from a meroterpenoid scaffold. For dactyloquinone A, an intramolecular hydrofunctionalisation via a metal-hydride hydrogen atom transfer (MHAT) process was utilised to form the key C–O bond, and for spiroetherone A, a stereospecific quinol-enedione rearrangement was employed. The initially postulated structure of spiroetherone A was first synthesized but was found to be epimeric at the spirocyclic carbon, which was confirmed by total synthesis involving epimerization of the spirocycle via a late-stage singlet oxygen [4+2] cycloaddition to a cyclohexadiene derived from the initial enedione.

ORGANIC LETTERS
Merging Photoexcited Nitroarenes with Lewis Acid Catalysis for the Anti-Markovnikov Oxidation of Alkenes

J. M. Paolillo, M. R. Saleh, E. W. Junk & M. Parasram*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c00389) 🔓

The authors describe the oxidation of alkenes to carbonyls and acetonides via the interplay of photoexcited nitroarenes and Lewis acid catalysis. A wide range of alkenes were oxidized to aldehyde and ketone products with anti-Markovnikov selectivity and to acetonides when acetone was employed as a co-solvent.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
(un)Intellectual Property

📰 (un)intellectual property. What do a “Smart Shoe for Visually Impaired” and an “Artificial Intelligence Powered Skin Cancer Inspection Device” have in common? They’re both design registrations filed with the U.K.’s Intellectual Property Office (IPO) and represent 2 of 3000 designs submitted in the past two years by suspected “patent mills” that sell researchers inventorship of unusual medical devices. That’s a staggering 3.3% of all designs registered in the U.K. in that period. The former of which, a shoe with a camera and USB ports, is already fairly troubling but the latter, a pistol with a screen attached, raises several questions (does it shoot the skin cancer off?).

These patent mills target researchers in countries such as India and Pakistan, where scientists are under pressure to publish and/or patent inventions to advance their career, and for a fee ($23 to $398) these companies make that happen. While the U.K. IPO has said it would not comment on arrangements in other jurisdictions relating to academic recognition, perhaps it’s time—and I’m sure we’d all agree—to focus on quality of research and not quantity.