Background
A recurring tension in medicinal design is this: you want stronger binding, better solubility/exposure, more controllable metabolism and selectivity—without tearing down and rebuilding the entire scaffold. Over the past decade-plus, “small, polar, sp³-rich” four-membered rings—oxetanes and azetidines—have steadily become popular molecular building blocks in medicinal chemistry.
A team led by James A. Bull (Imperial College London), in collaboration with Pfizer researchers, reported in Journal of the American Chemical Society the paper “Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery” (Symes et al., JACS 2024, 146(51), 35377–35389, DOI: 10.1021/jacs.4c14164), proposing an upgrade of oxetane/azetidine motifs into a condition-switchable, divergent small-ring sulfonyl fluoride platform:
1. Oxetane Sulfonyl Fluoride (OSF)
2. Azetidine Sulfonyl Fluoride (ASF)
These “small-ring sulfonyl fluoride platforms” can follow two distinct chemical pathways depending on conditions:
1. deFS (defluorosulfonylation pathway): under mild thermal activation (the paper’s representative examples are around 60 °C), OSF/ASF undergo defluorosulfonylation, behaving as if the carbon center is “ignited” to form a small-ring carbocation-like reactive intermediate, which is then trapped by a nucleophile. Overall, this manifests as an SN1-like carbon-centered coupling/functionalization.
Note: This can be understood as forming a carbocation-like ion pair / cationic precursor that is captured by a nucleophile. The exact nature of the intermediate may vary with aryl groups/substitution and stabilization modes, and it need not be equated with a fully free carbocation.
2. SuFEx (Sulfur(VI) Fluoride Exchange): under more anionic/basic conditions, the system follows the classic S(VI)–F exchange at sulfur, forming robust S(VI)–O / S(VI)–N linkages with O/N nucleophiles, enabling a “click-like” connection of the small ring to diverse fragments.
1 Why are oxetanes/azetidines worth attention?
1.1 What is the “design value” of four-membered rings?
Four-membered rings have two widely leveraged properties that make them behave like a small “design knob” in medicinal chemistry:
1. Small yet polar: they often do not increase molecular weight as dramatically as larger scaffolds, yet can significantly alter polarity, dipole moment, and the hydrogen-bonding environment, thereby affecting solubility, permeability, and exposure.
2. sp³-rich and more three-dimensional: compared with “flatter” fragments, introducing a small ring can change side-chain spatial orientation and overall 3D shape, influencing binding mode, selectivity, and metabolic site exposure.
1.2 The benefits are highly context-dependent
1. Studies and reviews repeatedly emphasize that replacing common motifs (e.g., gem-dimethyl or certain carbonyl-related fragments) with oxetanes (and some azetidine derivatives) can markedly shift solubility, lipophilicity, metabolic stability, and conformational preferences.
2. The effect of an oxetane/azetidine depends on where it sits in the molecule, the surrounding functional-group context, and the molecule’s overall electronics and conformation. The same swap may change properties by only a few-fold—or, if ionization state or conformation is rewritten, by orders of magnitude. This is not a universal “always better” upgrade, but a high-leverage modification that must be validated with data in the specific molecule.
3. Key takeaway: oxetane/azetidine is not “add it and it improves,” but rather a powerful structural option—ultimately requiring data to confirm the net gain.
2 Why has “sulfonyl fluoride (–SO₂F)” become a hot connection point in drug discovery?
You can view S(VI)–F motifs—such as sulfonyl fluorides (RSO₂F), fluorosulfates (ROSO₂F), and sulfamoyl fluorides (RSO₂NR′F)—as a class of latent electrophiles:
They are typically relatively stable under ambient/neutral conditions, yet under appropriate base, catalysis, or activation they can undergo selective SuFEx (S(VI)–F exchange) to efficiently form stable S(VI)–O / S(VI)–N linkages—combining operational stability with on-demand reactivity. (See the review by Dong/Krasnova/Finn/Sharpless, Angew. Chem. Int. Ed. 2014.)
Comparison: sulfonyl chloride vs sulfonyl fluoride — the trade-off between reactivity and controllability
1. Many sulfonyl chlorides are more reactive and more moisture-sensitive. They are indeed commonly used for rapid sulfonylation, but in complex, functional-group-dense settings they demand more cautious condition control.
2. Sulfonyl fluorides, because the S–F bond is stronger, are typically more stable and often display “react only upon suitable activation.” This combination of stability + activatability makes them better suited to selectivity and controllability in complex-molecule linkage chemistry and medicinal chemistry workflows.
3 What new tool does OSF/ASF create by combining “four-membered ring + sulfonyl fluoride”?
The key message of this JACS work can be compressed into one line:
OSFs/ASFs are a divergent four-membered small-ring platform—under mild thermal activation they follow deFS (defluorosulfonylation; carbon-center pathway) to generate reactive intermediates that can be trapped by nucleophiles; under anionic/strong-nucleophile conditions they switch to SuFEx (sulfur-center pathway) to access small-ring S(VI) derivatives.
1. deFS pathway (facilitating C–O / C–N cleavage to form an “ion-pair / cation-leaning” intermediate, then nucleophile capture): under mild heating (representative example 60 °C), OSFs/ASFs are activated and behave as precursors to carbocation-type reactivity, coupling with diverse nucleophiles to give a range of 3-substituted oxetane/azetidine fragments.
2. New chemical space unlocked: the authors prepared multiple new fragment classes, including:
(a) heterocycle derivatives (e.g., oxetane/azetidine-heterocycles formed via addition of various N-hetero nucleophiles),
(b) sulfoximine derivatives,
(c) phosphonate derivatives. They also point out that some of these structures lack straightforward “carbonyl analogues,” offering genuinely new design elements for drug discovery.
3. SuFEx pathway (sulfur-center “click-like” connection): under anionic conditions, OSF/ASF can enter SuFEx. The abstract explicitly highlights access to oxetane sulfur(VI) derivatives. The main text further notes that controlling solvent and nucleophile strength can “unlock/switch” SuFEx channels that were previously difficult to realize, yielding new strained-ring S(VI) linkage modules.
4. Drug-analogue demonstrations: the authors showcased synthesis of 11 oxetane analogues, spanning both marketed drugs and bioactive compounds, to demonstrate practicality in medicinal workflows and potential for downstream diversification.
5. Linker / PROTAC potential: the paper proposes using OSFs/ASFs as linker motifs, showing they can be equipped with pendant groups compatible with common couplings. They also report effective deFS coupling with an E3 ligase recruiter (e.g., pomalidomide), generating new degrader motifs and potential PROTAC linker designs.
4 deFS vs SuFEx: Route comparison and quick condition-window reference
Route comparison
Route | Condition “knobs” to turn | One-sentence mechanistic intuition | Typical nucleophiles / outcomes | Value for drug discovery |
A｜deFS (defluorosulfonylation coupling) | Polar solvent (MeCN) + mild heating (~60 °C) + mild base (K₂CO₃) | OSF/ASF takes an “unconventional channel,” effectively behaving as a carbocation-like cationic precursor trapped by a nucleophile, forming new C–N/C–X bonds | Amines (most common), also NH-azoles, sulfoximines, phosphorus nucleophiles, etc. → access to new fragments/new connection modes | Rapid parallel library build (especially amine libraries), good functional-group tolerance, suitable for late-stage diversification of complex molecules; can deliver new motifs lacking direct carbonyl analogues |
B｜SuFEx (S(VI)–F exchange) | Stronger anionic nucleophiles + less polar solvent (e.g., THF) + low temperature (to suppress deFS) | Treat –SO₂F as an S(VI) interface: F is replaced by an anionic nucleophile to enter oxetane/azetidine-S(VI) space | (1) Organolithium (RLi) → sulfones; (2) Lithium amides → sulfonamides; (3) Hard anions/phenolates (N₃⁻, ArO⁻) → sulfonyl azides / sulfonate esters | Provides entirely new linkage modules based on the “strained small ring + S(VI)” combination, as complementary linker/bioisostere options |
“Condition window” quick reference
Route | Representative window | Top 3 knobs to adjust first | Most common failure reasons | Fast troubleshooting tips |
deFS | MeCN (polar) / K₂CO₃ (mild base) / ~60 °C (mild heating) | Solvent polarity, temperature, base strength/equivalents | Slow/no conversion: substrate does not readily form a cation-leaning intermediate; or nucleophile is too weak/too hindered | Adjust temperature and concentration first; switch to a more suitable nucleophile / increase equivalents; if needed, compare alternative solvent systems |
SuFEx | THF (less polar) / strong anionic nucleophile (e.g., phenolate, alkoxide, organolithium) / start at low temperature | Nucleophile strength/hardness, solvent polarity, temperature (low temperature suppresses deFS) | deFS “wins the race”; or nucleophile is not sufficiently anionic/strong to drive S–F exchange | Switch to a less polar solvent and lower temperature first; increase nucleophile anionic strength; run control conditions to confirm the divergence has been shifted back |
Notes:
1. Some nucleophiles (e.g., TMSCF₃-based systems) can also proceed rapidly via SuFEx under MeCN/heating; “THF + low temperature” is a common strategy but not the only viable window.
2. The tables reflect the paper’s representative divergence logic and example windows; real projects must re-map the condition space according to the specific substrate and nucleophile.
5 Why does the paper emphasize the PROTAC / molecular glue direction?
Targeted protein degradation (TPD) is often treated as the “application landing point” because it naturally splits drug design into two routes: PROTACs (bivalent, with a linker) and molecular glue degraders (monovalent, typically without a linker).
1. PROTAC: extremely sensitive to the linker
A PROTAC is typically composed of a target-protein ligand + an E3 ligase ligand + a linker. The linker’s length, flexibility/rigidity, polarity, and foldability can strongly affect solubility, cell permeability, and effective intracellular concentration, thereby influencing ternary complex formation and degradation efficiency.
2. Molecular glue degraders (MGDs): emphasize interface induction rather than linker optimization
Molecular glues are usually monovalent small molecules. They trigger ubiquitination and degradation by inducing or stabilizing protein–protein interactions (most commonly E3–target protein/new substrate interactions). Therefore, optimization tends to focus on interface remodeling/complex selectivity, rather than structural parameters of a linker.
3. Where OSFs/ASFs connect: attaching “new fragments/handles” to E3 recruiters, and proposed as potential PROTAC linkers
This work not only expands the chemical space of oxetane/azetidine, but also demonstrates productive deFS coupling with E3 recruiters such as pomalidomide, and proposes their use to form new degrader motifs and potential PROTAC linkers.
Terminology Box
(a) CRBN (cereblon): one of the substrate receptors of the CRL4^CRBN E3 ubiquitin ligase complex. Thalidomide/lenalidomide/pomalidomide (IMiDs) are classic representatives of CRBN molecular glue degraders, and are also commonly used as the E3-recruiting end of PROTACs.
6 Boundaries and practical notes
1. Four-membered rings are “high-leverage knobs,” but not universal upgrades: the effects of oxetane/azetidine on solubility, logD, conformation, and metabolic exposure depend strongly on the specific structural context and must be validated with data.
2. The “dual-channel” nature of OSFs/ASFs is both an advantage and a real-world complexity: the same platform can diverge into deFS and SuFEx, and both pathways are highly sensitive to “condition knobs” such as solvent, temperature, and anionic nucleophilicity, so the usable condition window must be mapped.
3. It is closer to “one more way to assemble molecules” than a replacement for classical couplings: the paper’s positioning is to expand chemical space and provide new design elements / linker motifs. In real projects, it should be used alongside established coupling reactions—leveraging each where it excels.
4. Do not conflate “molecular glues” with “PROTAC linkers”: one key challenge for PROTACs is the linker and overall physicochemical properties; molecular glues typically do not have linkers, and their core is induced interfaces and selectivity.
7. OSF/ASF (Oxetane/Azetidine Sulfonyl Fluorides) “Dual-Channel Toolbox” Selection Navigation (corresponding to Product Tables A–C)
Your current goal / scenario | Which table to check first | Why start there |
You already have an OSF/ASF (or another S(VI)–F electrophilic end) and want to find an amine/heterocycle/four-membered ring “to attach” (to make sulfonamides, run SAR, build linkers) | Table A | Table A concentrates the nucleophilic/scaffold side to be attached: four-membered ring building blocks (oxetane/azetidine), common amines/heterocycles, and drug scaffolds suitable for late-stage derivatization—best when you want to start from “what am I attaching?” |
You want to compare/screen the reactivity of different S(VI)–F electrophilic sites, or you need a “benchmark sulfonyl fluoride/warhead” to get conditions working first | Table B | Table B is the warhead/electrophile and controls: benzenesulfonyl fluoride, p-toluenesulfonyl fluoride, 4-nitrobenzenesulfonyl fluoride, PMSF, multi-site S(VI)–F motifs, and —SO₂F installation tools—ideal for mapping reactivity windows, selectivity, and condition transfer |
You know you want sulfonamidation/SuFEx, but conversions are unstable: you need to choose bases, fluoride sources, solvents, activators to make the reaction “run smoothly” | Table C | Table C is the conditions & tools: solvents (anhydrous THF, LC–MS acetonitrile systems), base sets (TEA/DIPEA/DBU/TMG/BEMP, etc.), fluoride sources (KF/CsF/TBAF/KHF₂), strong bases/organometallics (NaH/n-BuLi), activators (Tf₂O), click coupling (CuAAC/azide)—best when starting from “how do I make the reaction clean and reproducible?” |
You want the “second channel”: attach a four-membered ring or an OSF/ASF derivative to probes/tags (visualization/enrichment/ligation) | Table C (click modules) + Table A (amine/alcohol building blocks) | Table C provides CuAAC/azide/copper sources/reductants as “ligation tools”; Table A provides functionalizable four-membered ring building blocks (amines/alcohols/salts). Together they function most like a chemical-biology interface |
Table A | The “attach-to-the-molecule” side: four-membered ring building blocks + nucleophilic substrates/drug scaffolds
(for forming sulfonamides/sulfonate esters/other SuFEx derivatives with OSF/ASF)
Category | CAS No. | Aladdin Cat. No. | Name | Spec/Purity | Product features / application (OSF/ASF-related) |
Four-membered ring building block (azetidine) | 45347-82-8 | Azetidin-3-ol | ≥98% | Key 4-membered N-containing 3-ol building block; used to build “3D fragments with an attachment point,” and further transformed into ASF / derivatives (e.g., sulfonamides/sulfonate esters). | |
Four-membered ring building block (oxetane) | 6246-05-5 | 3-(Aminomethyl)oxetane | ≥97% | Key oxetane linking building block (amine handle); introduces a 3D fragment into drug scaffolds and is convenient for derivatization with OSF/ASF (forming sulfonamides/linkers). | |
Four-membered ring building block (azetidine) | 102065-89-4 | 3-Aminoazetidine dihydrochloride | ≥97% | Key azetidine amine building block (HCl salt); used for introducing a four-membered ring fragment and subsequent sulfonamidation (typically requires basification/freebasing before OSF/ASF coupling). | |
Four-membered ring building block (oxetane) | 7748-36-9 | Oxetan-3-ol | ≥95% | Basic oxetane-3-ol building block; introduces a “3D + polarity” knob and can be further functionalized for connection to OSF/ASF or derivatives. | |
Four-membered ring building block (oxetane, amine salt) | 491588-41-1 | Oxetan-3-amine hydrochloride | ≥95% | Oxetane-3-amine salt; used to build oxetane-containing amine substrates and rapidly derivatize via sulfonamide formation with OSF/ASF (typically freebase first). | |
Amine substrate/fragment (for sulfonamidation) | 110-91-8 | M431466 | Morpholine | Synthetic grade | Common secondary amine fragment; reacts with the S(VI)–F end of OSF/ASF to form sulfonamides for rapid SAR building, linker construction, or increasing 3D/solubility features. |
Amine substrate/bifunctional fragment | 110-85-0 | Piperazine | UltraBio™, anhydrous, ≥99%(T) | Diamine scaffold; can form mono-/bis-sulfonamides with OSF/ASF for bifunctional linkers, bivalent fragments, or probe design (stoichiometry control needed to avoid over-bis-substitution). | |
N-heterocycle base / nucleophilic catalyst | 288-32-4 | Imidazole | Anhydrous, ACS, ≥99% | Both a base and an N-nucleophile; can serve as a model heterocycle/amine substrate to form sulfonamides with sulfonyl fluorides (including OSF/ASF) during condition scouting. | |
Heterocycle substrate / nucleophile control | 288-13-1 | Pyrazole | ≥98%(GC) | Common N-heterocycle pharmacophore; forms pyrazole sulfonamides with sulfonyl fluorides—useful for probing OSF/ASF compatibility with heterocycle nucleophiles. | |
Heterocycle substrate / nucleophile control | 288-88-0 | 1,2,4-Triazole | ≥99% | Common N-heterocycle; forms heterocycle sulfonamides for mapping OSF/ASF nucleophile scope and selectivity. | |
Drug case/control (CRBN ligand) | 50-35-1 | (±)-Thalidomide | Moligand™, ≥98% | Prototypical IMiD CRBN ligand; used with lenalidomide/pomalidomide as “ligand-end” controls to assess how OSF/ASF linkage strategies affect overall properties. | |
Drug case/control (CRBN ligand) | 191732-72-6 | Lenalidomide | Moligand™, ≥99% | Representative IMiD/CRBN ligand; illustrates a “fragment/linker combination” concept—OSF/ASF can serve as a derivatizable or click-capable connecting end in bifunctional designs. | |
Drug case/control (CRBN ligand) | 19171-19-8 | Pomalidomide | Moligand™, ≥99% | IMiD/CRBN ligand; a control for evaluating linker/warhead combination strategies aligned with the “derivatizable end” concept of OSF/ASF. | |
Drug case/control (amine substrate) | 54910-89-3 | Fluoxetine | Moligand™, ≥99% | Marketed drug example containing an amine; can serve as a “real scaffold” substrate to demonstrate rapid derivatization/structure–property comparison via OSF/ASF sulfonamidation (primarily a methodological example). | |
Drug salt / control | 56296-78-7 | Fluoxetine hydrochloride | ≥98%(HPLC) | Amine salt substrate; typically requires basification/freebasing before late-stage derivatization—useful for assessing OSF/ASF coupling sensitivity to salt vs free-base form. | |
Drug case/control (amine substrate) | 88150-42-9 | Amlodipine | Moligand™, ≥98% | Marketed amine-containing drug; can demonstrate late-stage derivatization via OSF/ASF sulfonamidation for structure comparison and property scanning. | |
Drug salt / control | 111470-99-6 | Amlodipine besylate | ≥98% | Sulfonate salt example; useful for discussing the role of sulfonate/sulfonyl-related functions in salt forms (but not an S(VI)–F), more for control/context understanding. |
Table B | The “warhead/control” side: S(VI)–F electrophiles (sulfonyl fluorides/fluorosulf(on)yl) and —SO₂F installation tools
Category | CAS No. | Aladdin Cat. No. | Name | Spec/Purity | Product features / application (OSF/ASF-related) |
S(VI)–F control electrophile / protease inhibitor | 329-98-6 | Phenylmethanesulfonyl fluoride (PMSF) | Moligand™, ≥98%(GC) | Classic covalent sulfonyl fluoride inhibitor (Ser proteases); a baseline control for S(VI)–F reactivity and covalent protein labeling—useful for comparing OSF/ASF selectivity and stability. | |
S(VI)–F electrophile (control / condition scouting) | 368-43-4 | Benzenesulfonyl fluoride | ≥99% | One of the most commonly used sulfonyl fluoride controls; ideal for quickly developing SuFEx/sulfonamidation conditions before transferring to target OSF/ASF. | |
S(VI)–F electrophile (control / sulfonylation) | 455-16-3 | p-Toluenesulfonyl fluoride | ≥98% | Classic aryl sulfonyl fluoride control; often used to establish baseline sulfonamidation/SuFEx conditions, then transferred to more 3D-rich OSF/ASF. | |
S(VI)–F electrophile (more activated, control) | 349-96-2 | 4-Nitrobenzenesulfonyl fluoride | ≥95% | Typically more reactive due to the strong electron-withdrawing para-NO₂ group; useful as a high-reactivity control to bracket the OSF/ASF window between stability and reactivity. | |
Multi-site S(VI)–F electrophilic scaffold | 2172794-56-6 | (4-Acetamidophenyl)(fluorosulfonyl) sulfamoyl fluoride | ≥98% | Contains two S(VI)–F reactive sites (fluorosulfonyl and sulfamoyl fluoride); suitable for concept tests of multi-site SuFEx/dual-warhead/dual-link designs. Stoichiometry and selectivity require special attention. | |
Fluorosulfonylation / —SO₂F installation reagent | 2179072-33-2 | 1-(Fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate | ≥95% | An electrophilic reagent type for installing fluorosulfonyl/—SO₂F-related fragments; can serve as an upstream “transfer/activation” tool for building OSF/ASF or other S(VI)–F warheads. |
Table C | General SuFEx / S(VI)–F reaction toolbox: solvents/bases/strong bases/fluoride sources/activation/click coupling
(for condition screening and process troubleshooting)
Category | CAS No. | Aladdin Cat. No. | Name | Spec/Purity | Product features / application (OSF/ASF-related) |
Analytical / LC–MS solvent system | 75-05-8 | A433526 | Acetonitrile solution | MS grade (MS), UltraPureChrom™, UHPLC grade, contains 0.1% (v/v) formic acid | Suitable for LC–MS/UPLC characterization of OSF/ASF and SuFEx derivatives (note: acidic systems are for analysis, not for storing/scale-up of most S(VI)–F reaction mixtures). |
Reaction solvent (anhydrous) | 109-99-9 | T431417 | Tetrahydrofuran (THF) | For DNA/peptide synthesis (max 0.005% H₂O) | Typical anhydrous solvent; compatible with NaH/organolithium systems, used for building four-membered ring derivatives or running SuFEx/sulfonylation precursor steps (helps control hydrolysis). |
Mild organic base / acid scavenger | 121-44-8 | Triethylamine | For protein sequencing, ≥99.5%(GC), ampoule | Common base for acid scavenging; used to neutralize acid and improve conversion in sulfonyl fluoride coupling with amines/alcohols (also used to freebase hydrochloride salts). | |
Mild organic base / acid scavenger | 7087-68-5 | N-Ethyldiisopropylamine solution | For peptide synthesis, ~2 M in 1-methyl-2-pyrrolidinone | Typical “Hünig’s base” (DIPEA); used to scavenge acid/accelerate S(VI)–F coupling with amines under milder conditions and during screening. | |
Inorganic base / basification | 584-08-7 | P485463 | Potassium carbonate | Anhydrous, high purity, reagent grade, ≥99% | Mild inorganic base; commonly used for SN2 introduction of four-membered ring fragments and for deprotonating alcohols/amines; also used as a base in some SuFEx couplings. |
Strong organic base (common in SuFEx) | 80-70-6 | 1,1,3,3-Tetramethylguanidine (TMG) | ≥99% | Strong base/acid scavenger; often used to promote sulfonyl fluoride–amine/phenol coupling and SuFEx screening by trapping HF generated during reaction. | |
Strong non-nucleophilic base (SuFEx catalysis) | 6674-22-2 | DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) | ≥99% | Common base/catalyst for SuFEx and sulfonamidation; useful for establishing “fast conditions” for OSF/ASF (manage hydrolysis risk; control temperature and stoichiometry). | |
Strong non-nucleophilic base (SuFEx catalysis) | 5807-14-7 | TBD (also known as Hhpp) (1,5,7-Triazabicyclo[4.4.0]dec-5-ene) | ≥98% | Strong base system (often used to promote S(VI)–F couplings/acid scavenging); used to push SuFEx into a “faster/cleaner” window (control water and temperature). | |
Superb ase, non-nucleophilic (common in SuFEx) | 98015-45-3 | BEMP (2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine) | ≥98% | Typical superbase; used for difficult substrates, weak nucleophiles, or when stronger acid scavenging is needed in SuFEx/sulfonamidation. | |
Strong organic base (common in SuFEx) | 29166-72-1 | 2-tert-Butyl-1,1,3,3-tetramethylguanidine | ≥95% | Strong base (often used in fast SuFEx/sulfonamidation conditions); an upgrade option for weak nucleophiles or when stronger acid scavenging is required. | |
Fluoride source (SuFEx activation / desilylation) | 7789-23-3 | Potassium fluoride | For analysis, ACS, premium grade | Basic F⁻ source; used for desilylation/activation in SuFEx and related fluorine chemistry; water control is important. | |
Fluoride source (higher solubility, promotes SuFEx) | 13400-13-0 | Cesium fluoride | UltraBio™, ≥99%(F) | One relatively more soluble F⁻ source; often improves efficiency and reproducibility in some SuFEx/desilylation systems. | |
Fluorinating reagent (SO₂Cl → SO₂F, etc.) | 7789-29-9 | Potassium bifluoride (KHF₂) | Chemical pure (CP), ≥98% | Common fluorinating reagent / bifluoride source; can convert certain sulfonyl/sulfuryl precursors into sulfonyl fluorides (SO₂F), a frequent upstream tool for building OSF/ASF warheads. | |
Strong base / generation of nucleophiles | 7646-69-7 | S110860 | Sodium hydride | 60% dispersion in mineral oil | Generates alkoxides/amidate-type anions; used for derivatizing four-membered ring alcohols/amines, introducing linkers, or coupling with S(VI)–F (strictly anhydrous; safety attention required). |
Organometallic strong base / lithiation | 109-72-8 | n-Butyllithium solution | 2.0 M in cyclohexane | Strong base/lithiation reagent; used to construct or functionalize four-membered ring fragments (as precursors for later —SO₂F installation or other attachment points). Requires strictly anhydrous, inert handling. | |
Activator (leaving-group installation) | 358-23-6 | Trifluoromethanesulfonic anhydride (Tf₂O) | ≥99% | Strong activator; converts alcohols into excellent leaving groups (e.g., triflates) for SN2 introduction of four-membered rings or to create reaction handles for subsequent OSF/ASF attachment. | |
P-nucleophile / control substrate | 762-04-9 | Diethyl phosphite | ≥99% | P(III) nucleophile; used to build phosphorus-containing fragments and as a “nucleophile control” to evaluate possible side reactions/capture behavior of S(VI)–F (including OSF/ASF) for troubleshooting. | |
P-nucleophile / control substrate | 868-85-9 | Dimethyl phosphite | ≥98% | Similar to diethyl phosphite: used for phosphorus fragment synthesis or as a nucleophile/side-reaction control to assess OSF/ASF condition impacts on P-containing functionality. | |
Click chemistry (CuAAC) system | 7758-99-8 | Copper(II) sulfate pentahydrate | For plant cell culture, ≥98% | Cu(II) precursor for CuAAC; reduced in situ (with sodium ascorbate) to Cu(I) to “click” azide/alkyne-bearing four-membered ring or OSF/ASF derivatives onto probes/tags. | |
Click chemistry (CuAAC) system | 134-03-2 | Sodium ascorbate | For cell culture, ≥99% | Common reductant (Cu(II) → Cu(I)) for CuAAC; enables mild click labeling of azide/alkyne-bearing four-membered ring derivatives. | |
Click chemistry (CuAAC) catalyst | 7681-65-4 | Copper(I) iodide | Anhydrous, ≥99.995% metals basis | Direct Cu(I) source for CuAAC click coupling (useful when avoiding sodium ascorbate systems or when aiming for “drier” conditions). | |
Azidation / bioorthogonal interface | 4648-54-8 | Trimethylsilyl azide | ≥93% | Azide source; introduces an azide handle onto four-membered rings/linkers for the “second channel” (labeling/enrichment/probe ligation) compatible with CuAAC. |
Note: Table C is compiled as a general SuFEx / sulfonyl fluoride condition-screening toolbox, covering common solvents/bases/strong bases/fluoride sources and click-coupling systems; it is not identical to the paper’s exact step-by-step conditions for OSF/ASF.
Note: The above are representative Aladdin products. For more specifications, please refer to the product list at the end of the article or search by product name/CAS on the Aladdin website.
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