•We report a novel click reaction for the synthesis of tetrahedral P-linked molecules•New P–F hubs enable sequential modifications through strategic catalyst selection•PFEx displays chemoselectivity, operating orthogonally to established click reactions Click chemistry has been a transformative force in molecular synthesis, streamlining the creation of functional molecules for applications in drug discovery and beyond. Advancing the frontiers of click chemistry demands the ongoing development of innovative transformations to further explore the vast chemical landscape. Phosphorus fluoride exchange (PFEx) mimics nature’s favored phosphate connectors, adding a biomimetic twist to the growing arsenal of click transformations. Demonstrating remarkable chemoselectivity, PFEx facilitates the execution of multiple click reactions in sequence, and its versatility has been showcased by the SuFEx-PFEx-CuAAC triad. A vital addition to the click-chemistry toolkit, PFEx enables the swift generation of intricate molecules and is well positioned to support drug discovery and other pivotal fields with its immense potential. Phosphorus fluoride exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from nature’s phosphate connectors, PFEx facilitates the reliable coupling of P(V)–F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)–O and P(V)–N linked products. The rate of P–F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P–F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research. Phosphorus fluoride exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from nature’s phosphate connectors, PFEx facilitates the reliable coupling of P(V)–F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)–O and P(V)–N linked products. The rate of P–F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P–F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research. Click chemistry is a versatile and powerful synthesis-based discovery method that relies on the formation of stable molecular connections. At its core, click chemistry encompasses a diverse and expanding set of robust and reliable reactions that enable the precise connection of discrete molecular modules. This approach mirrors the biogenesis of nature’s essential biopolymers, such as DNA, RNA, proteins, and carbohydrates.1Kolb H.C. Finn M.G. Sharpless K.B. Click chemistry: diverse chemical function from a few good reactions.Angew. Chem. Int. Ed. 2001; 40: 2004-2021https://doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5Crossref PubMed Scopus (11716) Google Scholar,2Moses J.E. Moorhouse A.D. The growing applications of click chemistry.Chem. Soc. Rev. 2007; 36: 1249-1262https://doi.org/10.1039/B613014NCrossref PubMed Scopus (2060) Google Scholar In fact, several of the processes scoring click status1Kolb H.C. Finn M.G. Sharpless K.B. Click chemistry: diverse chemical function from a few good reactions.Angew. Chem. Int. Ed. 2001; 40: 2004-2021https://doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5Crossref PubMed Scopus (11716) Google Scholar can be traced back to reversible chemistries commonly found in nature, such as Michael additions, Diels-Alder cycloadditions, and condensation reactions. However, it was the advent of the copper-catalyzed azide-alkyne cycloaddition (CuAAC)2Moses J.E. Moorhouse A.D. The growing applications of click chemistry.Chem. Soc. Rev. 2007; 36: 1249-1262https://doi.org/10.1039/B613014NCrossref PubMed Scopus (2060) Google Scholar,3Rostovtsev V.V. Green L.G. Fokin V.V. Sharpless K.B. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes.Angew. Chem. Int. Ed. 2002; 41: 2596-2599https://doi.org/10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4Crossref PubMed Scopus (10085) Google Scholar,4Moorhouse A.D. Moses J.E. Click chemistry and medicinal chemistry: a case of “cyclo-addiction.”.ChemMedChem. 2008; 3: 715-723https://doi.org/10.1002/cmdc.200700334Crossref PubMed Scopus (197) Google Scholar,5Meng G. Guo T. Ma T. Zhang J. Shen Y. Sharpless K.B. Dong J. Modular click chemistry libraries for functional screens using a diazotizing reagent.Nature. 2019; 574: 86-89https://doi.org/10.1038/s41586-019-1589-1Crossref PubMed Scopus (145) Google Scholar reaction that solidified click chemistry as a leading paradigm for the rapid discovery of functional molecules. This unrivaled and irreversible process lacks a natural counterpart and has earned the reputation as the “cream of the crop” within the click-chemistry toolbox. The world of sulfur-based connective click chemistry was launched in 2014 with the development of sulfur-fluoride exchange (SuFEx) by Sharpless and co-workers.6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar SuFEx capitalizes on the latent reactivity of high oxidation state S–F bonds, which can be triggered by catalyst activation, to facilitate nearly perfect exchange6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar with diverse nucleophiles, including aryl and alkyl alcohols,7Smedley C.J. Homer J.A. Gialelis T.L. Barrow A.S. Koelln R.A. Moses J.E. Accelerated SuFEx click chemistry for modular synthesis.Angew. Chem. Int. Ed. 2022; 61e202112375https://doi.org/10.1002/anie.202112375Crossref PubMed Scopus (26) Google Scholar amines,8Wei M. Liang D. Cao X. Luo W. Ma G. Liu Z. Li L. A broad-spectrum catalytic amidation of sulfonyl fluorides and fluorosulfates.Angew. Chem. Int. Ed. 2021; 60: 7397-7404https://doi.org/10.1002/anie.202013976Crossref PubMed Scopus (30) Google Scholar,9Luy J.-N. Tonner R. Complementary base lowers the barrier in SuFEx click chemistry for primary amine nucleophiles.ACS Omega. 2020; 5: 31432-31439https://doi.org/10.1021/acsomega.0c05049Crossref PubMed Scopus (7) Google Scholar,10Mahapatra S. Woroch C.P. Butler T.W. Carneiro S.N. Kwan S.C. Khasnavis S.R. Gu J. Dutra J.K. Vetelino B.C. Bellenger J. et al.SuFEx activation with Ca(NTf2)2: a unified strategy to access Sulfamides, sulfamates, and sulfonamides from S(VI) fluorides.Org. Lett. 2020; 22: 4389-4394https://doi.org/10.1021/acs.orglett.0c01397Crossref PubMed Scopus (51) Google Scholar and carbanions.11Gao B. Li S. Wu P. Moses J.E. Sharpless K.B. SuFEx chemistry of thionyl tetrafluoride (SOF4) with organolithium nucleophiles: synthesis of sulfonimidoyl fluorides, sulfoximines, sulfonimidamides, and Sulfonimidates.Angew. Chem. Int. Ed. 2018; 57: 1957-1961https://doi.org/10.1002/ange.201712145Crossref Google Scholar,12Smedley C.J. Zheng Q. Gao B. Li S. Molino A. Duivenvoorden H.M. Parker B.S. Wilson D.J.D. Sharpless K.B. Moses J.E. Bifluoride ion mediated SuFEx trifluoromethylation of sulfonyl fluorides and iminosulfur oxydifluorides.Angew. Chem. Int. Ed. 2019; 58: 4552-4556https://doi.org/10.1002/anie.201813761Crossref PubMed Scopus (43) Google Scholar,13Zeng D. Ma Y. Deng W.-P. Wang M. Jiang X. Divergent sulfur(VI) fluoride exchange linkage of sulfonimidoyl fluorides and alkynes.Nat. Synth. 2022; 1: 455-463https://doi.org/10.1038/s44160-022-00060-1Crossref Google Scholar This groundbreaking technique has opened new possibilities for chemical synthesis and holds tremendous potential for the development of novel functional materials and therapeutic agents. SuFEx reactions classically occur between sulfur-centered hubs14Barrow A.S. Smedley C.J. Zheng Q. Li S. Dong J. Moses J.E. The growing applications of SuFEx click chemistry.Chem. Soc. Rev. 2019; 48: 4731-4758https://doi.org/10.1039/C8CS00960KCrossref PubMed Google Scholar—sulfuryl fluoride (SO2F2),6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar thionyl tetrafluoride (SOF4),15Moissan H. Lebeau P. Invesigation of sulfur fluorides and sulfur oxyfluorides.Ann. Chim. Phys. 1902; 26: 145-178Google Scholar,16Li S. Wu P. Moses J.E. Sharpless K.B. Multidimensional SuFEx click chemistry: sequential sulfur(VI) fluoride exchange connections of diverse modules launched from an SOF4 hub.Angew. Chem. Int. Ed. 2017; 56: 2903-2908https://doi.org/10.1002/anie.201611048Crossref PubMed Scopus (95) Google Scholar ethenesulfonyl fluoride (ESF),6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar,17Krutak J.J. Burpitt R.D. Moore W.H. Hyatt J.A. Chemistry of ethenesulfonyl fluoride. Fluorosulfonylethylation of organic compounds.J. Org. Chem. 1979; 44: 3847-3858https://doi.org/10.1021/jo01336a022Crossref Scopus (89) Google Scholar,18Giel M.-C. Smedley C.J. Mackie E.R.R. Guo T. Dong J. Soares da Costa T.P.S. da Moses J.E. Metal-free synthesis of functional 1-substituted-1,2,3-triazoles from ethenesulfonyl fluoride and organic azides.Angew. Chem. Int. Ed. 2020; 59: 1181-1186https://doi.org/10.1002/anie.201912728Crossref PubMed Scopus (51) Google Scholar and 2-substituted-alkynyl-1-sulfonyl fluorides (SASFs)19Smedley C.J. Li G. Barrow A.S. Gialelis T.L. Giel M.-C. Ottonello A. Cheng Y. Kitamura S. Wolan D.W. Sharpless K.B. et al.Diversity oriented clicking (DOC): divergent synthesis of SuFExable pharmacophores from 2-substituted-alkynyl-1-sulfonyl fluoride (SASF) hubs.Angew. Chem. Int. Ed. 2020; 59: 12460-12469https://doi.org/10.1002/anie.202003219Crossref PubMed Scopus (55) Google Scholar—and aryl silyl ether nucleophiles. These reactions are typically activated by a suitable Lewis base amine (e.g., 1,8-di-aza-bicyclo-[5.4.0]undec-7-ene [DBU]),20Gembus V. Marsais F. Levacher V. An efficient organocatalyzed interconversion of silyl ethers to tosylates using DBU and p-toluenesulfonyl fluoride.Synlett. 2008; 2008: 1463-1466https://doi.org/10.1055/s-2008-1078407Crossref Scopus (66) Google Scholar,21Lee C. Cook A.J. Elisabeth J.E. Friede N.C. Sammis G.M. Ball N.D. The emerging applications of sulfur(VI) fluorides in catalysis.ACS Catal. 2021; 11: 6578-6589https://doi.org/10.1021/acscatal.1c01201Crossref PubMed Scopus (50) Google Scholar bifluoride ion,12Smedley C.J. Zheng Q. Gao B. Li S. Molino A. Duivenvoorden H.M. Parker B.S. Wilson D.J.D. Sharpless K.B. Moses J.E. Bifluoride ion mediated SuFEx trifluoromethylation of sulfonyl fluorides and iminosulfur oxydifluorides.Angew. Chem. Int. Ed. 2019; 58: 4552-4556https://doi.org/10.1002/anie.201813761Crossref PubMed Scopus (43) Google Scholar,22Gao B. Zhang L. Zheng Q. Zhou F. Klivansky L.M. Lu J. Liu Y. Dong J. Wu P. Sharpless K.B. Bifluoride-catalysed sulfur(VI) fluoride exchange reaction for the synthesis of polysulfates and polysulfonates.Nat. Chem. 2017; 9: 1083-1088https://doi.org/10.1038/nchem.2796Crossref PubMed Google Scholar or other catalysts.10Mahapatra S. Woroch C.P. Butler T.W. Carneiro S.N. Kwan S.C. Khasnavis S.R. Gu J. Dutra J.K. Vetelino B.C. Bellenger J. et al.SuFEx activation with Ca(NTf2)2: a unified strategy to access Sulfamides, sulfamates, and sulfonamides from S(VI) fluorides.Org. Lett. 2020; 22: 4389-4394https://doi.org/10.1021/acs.orglett.0c01397Crossref PubMed Scopus (51) Google Scholar,21Lee C. Cook A.J. Elisabeth J.E. Friede N.C. Sammis G.M. Ball N.D. The emerging applications of sulfur(VI) fluorides in catalysis.ACS Catal. 2021; 11: 6578-6589https://doi.org/10.1021/acscatal.1c01201Crossref PubMed Scopus (50) Google Scholar,23Revathi L. Ravindar L. Leng J. Rakesh K.P. Qin H.-L. Synthesis and chemical transformations of fluorosulfates.Asian J. Org. Chem. 2018; 7: 662-682https://doi.org/10.1002/ajoc.201700591Crossref Scopus (60) Google Scholar Although the direct S–F exchange between sulfur-containing hubs and aryl and alkyl alcohols is more challenging, modified SuFEx conditions reported by Moses and co-workers have made it possible by employing a BTMG (2-tert-butyl-1,1,3,3-tetramethylguanidine, Barton’s base) catalyst with a hexamethyldisilazane (HMDS) additive, termed “accelerated SuFEx click chemistry” (ASCC).7Smedley C.J. Homer J.A. Gialelis T.L. Barrow A.S. Koelln R.A. Moses J.E. Accelerated SuFEx click chemistry for modular synthesis.Angew. Chem. Int. Ed. 2022; 61e202112375https://doi.org/10.1002/anie.202112375Crossref PubMed Scopus (26) Google Scholar,24Liu C. Yang C. Hwang S. Ferraro S.L. Flynn J.P. Niu J. A general approach to O-Sulfation by a sulfur(VI) fluoride exchange reaction.Angew. Chem. Int. Ed. 2020; 59: 18435-18441https://doi.org/10.1002/anie.202007211Crossref PubMed Scopus (13) Google Scholar,25Liang D.-D. Streefkerk D.E. Jordaan D. Wagemakers J. Baggerman J. Zuilhof H. Silicon-free SuFEx reactions of sulfonimidoyl fluorides: scope, enantioselectivity, and mechanism.Angew. Chem. Int. Ed. 2020; 59: 7494-7500https://doi.org/10.1002/anie.201915519Crossref PubMed Scopus (39) Google Scholar Among nature’s most essential connectors are phosphate esters and anhydrides. These unions are important in the makeup of nucleic acids, nucleotide coenzymes, nucleoside triphosphates (e.g., ATP), metabolic intermediates, and intermediates in many biochemical processes.26Westheimer F.H. Why nature chose phosphates.Science. 1987; 235: 1173-1178https://doi.org/10.1126/science.2434996Crossref PubMed Scopus (1256) Google Scholar Although phosphorus reagents are ubiquitous in synthetic organic chemistry, carbon5Meng G. Guo T. Ma T. Zhang J. Shen Y. Sharpless K.B. Dong J. Modular click chemistry libraries for functional screens using a diazotizing reagent.Nature. 2019; 574: 86-89https://doi.org/10.1038/s41586-019-1589-1Crossref PubMed Scopus (145) Google Scholar and sulfur1Kolb H.C. Finn M.G. Sharpless K.B. Click chemistry: diverse chemical function from a few good reactions.Angew. Chem. Int. Ed. 2001; 40: 2004-2021https://doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5Crossref PubMed Scopus (11716) Google Scholar,6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar,27Knouse K.W. Flood D.T. Vantourout J.C. Schmidt M.A. Mcdonald I.M. Eastgate M.D. Baran P.S. Nature chose phosphates and chemists should too: how emerging P(V) methods can augment existing strategies.ACS Cent. Sci. 2021; 7: 1473-1485https://doi.org/10.1021/acscentsci.1c00487Crossref PubMed Scopus (20) Google Scholar are more prevalent as synthetic connectors, a sentiment expressed in Westheimer’s thesis “Why nature chose phosphates”: “We can understand the choices made both by chemists and by the process of natural selection. They are both correct.”26Westheimer F.H. Why nature chose phosphates.Science. 1987; 235: 1173-1178https://doi.org/10.1126/science.2434996Crossref PubMed Scopus (1256) Google Scholar,28Kamerlin S.C.L. Sharma P.K. Prasad R.B. Warshel A. Why nature really chose phosphate.Q. Rev. Biophys. 2013; 46: 1-132https://doi.org/10.1017/S0033583512000157Crossref PubMed Scopus (236) Google Scholar The first synthetic phosphate esters were prepared in France over 200 years ago,29Franz Anton Voegeli accessed triethyl phosphate (ca. 1848), and Clermont and Moschnin synthesized tetraethyl pyrophosphate in 1854.Google Scholar,30Organophosphorus compounds appeared in the literature more frequently after the Second World War, when the element’s importance was recognized.Google Scholar,31Petroianu G.A. History of methyl phosphoric esters: Hall, Weger, and Lossen.Pharmazie. 2009; 64: 840-845PubMed Google Scholar,32Petroianu G.A. The synthesis of phosphor ethers: who was Franz Anton Voegeli?.Pharmazie. 2009; : 269-275https://doi.org/10.1691/ph.2009.8244Crossref PubMed Scopus (16) Google Scholar laying the foundation for the rich body of chemistry that followed.33Cadogan J.I.G. Organophosphorus Reagents in Organic Synthesis. Academic Press, 1979Google Scholar,34Timperley C. Best Synthetic Methods: Organophosphorus (V) Chemistry. Newnes, 2014Google Scholar,35Murphy P.J. Organophosphorus Reagents: A Practical Approach in Chemistry. Oxford University Press, 2004Google Scholar,36Corbridge D.E.C. Phosphorus: Chemistry, Biochemistry and Technology.Sixth Edition. CRC Press, 2013Crossref Google Scholar,37Kurti L. Czako B. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier, 2005Google Scholar,38Kolodiazhnyi O.I. Phosphorus Ylides: Chemistry and Applications in Organic Synthesis. John Wiley & Sons, 2008Google Scholar,39Juge S. Genet J.P. Asymmetric synthesis of phosphinates, phosphine oxides and phosphines by Michaelis Arbuzov rearrangement of chiral oxazaphospholidine.Tetrahedron Lett. 1989; 30: 2783-2786https://doi.org/10.1016/S0040-4039(00)99124-XCrossref Scopus (98) Google Scholar,40Juge S. Stephan M. Laffitte J.A. Genet J.P. Efficient asymmetric synthesis of optically pure tertiary mono and diphosphine ligands.Tetrahedron Lett. 1990; 31: 6357-6360https://doi.org/10.1016/S0040-4039(00)97063-1Crossref Scopus (277) Google Scholar,41Han Z.S. Goyal N. Herbage M.A. Sieber J.D. Qu B. Xu Y. Li Z. Reeves J.T. Desrosiers J.-N. Ma S. et al.Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents.J. Am. Chem. Soc. 2013; 135: 2474-2477https://doi.org/10.1021/ja312352pCrossref PubMed Scopus (119) Google Scholar,42Corey E.J. Chen Z. Tanoury G.J. A new and highly enantioselective synthetic route to P-chiral phosphines and diphosphines.J. Am. Chem. Soc. 1993; 115: 11000-11001https://doi.org/10.1021/ja00076a072Crossref Scopus (101) Google Scholar,43Knouse K.W. deGruyter J.N. Schmidt M.A. Zheng B. Vantourout J.C. Kingston C. Mercer S.E. Mcdonald I.M. Olson R.E. Zhu Y. et al.Unlocking P(V): reagents for chiral phosphorothioate synthesis.Science. 2018; 361: 1234-1238https://doi.org/10.1126/science.aau3369Crossref PubMed Scopus (127) Google Scholar,44Xu D. Rivas-Bascón N. Padial N.M. Knouse K.W. Zheng B. Vantourout J.C. Schmidt M.A. Eastgate M.D. Baran P.S. Enantiodivergent formation of C–P bonds: synthesis of P-chiral phosphines and methylphosphonate oligonucleotides.J. Am. Chem. Soc. 2020; 142: 5785-5792https://doi.org/10.1021/jacs.9b13898Crossref PubMed Scopus (47) Google Scholar,45Kuwabara K. Maekawa Y. Minoura M. Maruyama T. Murai T. Chemoselective and stereoselective alcoholysis of binaphthyl phosphonothioates: straightforward access to both stereoisomers of biologically relevant P-stereogenic phosphonothioates.J. Org. Chem. 2020; 85: 14446-14455https://doi.org/10.1021/acs.joc.0c00687Crossref PubMed Scopus (8) Google Scholar,46Koizumi T. Yanada(nee Ishizaka) R. Takagi H. Hirai H. Yoshii E. Grignard reaction of 2-phenyl-tetrahydropyrrolo-1,5,2-oxazaphospholes, observation of the stereospecific inversion of configuration.Tetrahedron Lett. 1981; 22: 571-572https://doi.org/10.1016/S0040-4039(01)90157-1Crossref Scopus (26) Google Scholar,47Mondal A. Thiel N.O. Dorel R. Feringa B.L. P-chirogenic phosphorus compounds by stereoselective Pd-catalysed arylation of phosphoramidites.Nat. Catal. 2022; 5: 10-19https://doi.org/10.1038/s41929-021-00697-9Crossref Scopus (12) Google Scholar,48DiRocco D.A. Ji Y. Sherer E.C. Klapars A. Reibarkh M. Dropinski J. Mathew R. Maligres P. Hyde A.M. Limanto J. et al.A multifunctional catalyst that stereoselectively assembles prodrugs.Science. 2017; 356: 426-430https://doi.org/10.1126/science.aam7936Crossref PubMed Scopus (98) Google Scholar,49Featherston A.L. Kwon Y. Pompeo M.M. Engl O.D. Leahy D.K. Miller S.J. Catalytic asymmetric and stereodivergent oligonucleotide synthesis.Science. 2021; 371: 702-707https://doi.org/10.1126/science.abf4359Crossref PubMed Scopus (33) Google Scholar,50Forbes K.C. Jacobsen E.N. Enantioselective hydrogen-bond-donor catalysis to access diverse stereogenic-at-P(V) compounds.Science. 2022; 376: 1230-1236https://doi.org/10.1126/science.abp8488Crossref PubMed Scopus (16) Google Scholar Today, organophosphates are indispensable molecules; several notable examples include lifesaving antiviral drugs (e.g., (−)-remdesivir [1]), anticancer chemotherapy agents (e.g., (±)-cyclophosphamide [2]), and pesticides (e.g., terbufos [3]). The chemical, physical, and biological properties are modulated by the three other substituents projecting out along tetrahedral exit vectors from the phosphorus core. The laboratory synthesis of phosphorus linkages typically hinges on the nucleophilic exchange of P(V) electrophiles—for example, the reaction between phosphoryl chloride (POCl3) and both primary and secondary amines to afford the P(V)–N linked products. However, this halide substitution event is not always optimal; preventing unwanted degradation or over-substitution can be difficult. At this point, one can take direction from the genesis of SuFEx chemistry. In their seminal work, Sharpless and co-workers revisited early reports on the exceptional stability of sulfonyl fluorides to aqueous conditions by Steinkopf,51Steinkopf W. Über aromatische Sulfofluoride.J. Prakt. Chem. 1927; 117: 1-82https://doi.org/10.1002/prac.19271170101Crossref Google Scholar,52Steinkopf W. Jaeger P. Über aromatische sulfofluoride. II. Mitteilung.J. Prakt. Chem. 1930; 128: 63-88https://doi.org/10.1002/prac.19301280104Crossref Google Scholar Davies and Dick,53Davies W. Dick J.H. Benzenesulphonyl fluoride derivatives.J. Chem. Soc. 1932; : 2042-2046https://doi.org/10.1039/JR9320002042Crossref Scopus (10) Google Scholar,54Davies W. Dick J.H. Aliphatic sulphonyl fluorides.J. Chem. Soc. 1932; 1932: 483-486https://doi.org/10.1039/JR9320000483Crossref Scopus (21) Google Scholar and others. Analogous to the P–Cl substitution chemistry, S–Cl exchange often leads to poor outcomes. However, the staggering reactivity gap offered by switching from S–Cl bonds to S–F bonds opened the door to SuFEx: a second near-perfect click reaction alongside CuAAC. This disparity in reactivity of S–halide-bond-containing species can be accounted for through consideration of the unique properties of the S(VI)–F bond. The shorter S–F bond (1.54 Å vs. S–Cl = 1.99 Å55Fernández L.E. Varetti E.L. A scaled quantum mechanical force field for the sulfuryl halides: II.Spectrochim. Acta A Mol. Biomol. Spectrosc. 2005; 62: 221-225https://doi.org/10.1016/j.saa.2004.12.030Crossref PubMed Scopus (5) Google Scholar,56Müller H.S.P. Gerry M.C.L. Microwave spectroscopic investigation of thionyl chloride, SOCl2: hyperfine constants and harmonic force field.J. Chem. Soc. Faraday Trans. 1994; 90: 3473-3481https://doi.org/10.1039/FT9949003473Crossref Scopus (12) Google Scholar) has a predicted bond dissociation energy (BDE) almost double that of chloride57Takacs G.A. Heats of formation and bond dissociation energies of some simple sulfur- and halogen-containing molecules.J. Chem. Eng. Data. 1978; 23: 174-175https://doi.org/10.1021/je60077a020Crossref Scopus (20) Google Scholar (Figure 1A) and exclusively cleaves heterolytically because of the strongly electronegative fluorine.6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar This makes S(VI)–F groups stable toward nucleophilic addition (e.g., hydrolysis),58Ciuffarin E. Senatore L. Isola M. Nucleophilic substitution at four-co-ordinate sulphur. Mobility of the leaving group.J. Chem. Soc. Perkin Trans. 1972; 2: 468-471https://doi.org/10.1039/P29720000468Crossref Google Scholar thermolysis, oxidation,53Davies W. Dick J.H. Benzenesulphonyl fluoride derivatives.J. Chem. Soc. 1932; : 2042-2046https://doi.org/10.1039/JR9320002042Crossref Scopus (10) Google Scholar and reduction.51Steinkopf W. Über aromatische Sulfofluoride.J. Prakt. Chem. 1927; 117: 1-82https://doi.org/10.1002/prac.19271170101Crossref Google Scholar Crucially, however, S(VI)–F bonds can be reliably activated for nucleophilic exchange when the correct catalyst-reagent combination is employed.6Dong J. Krasnova L. Finn M.G. Sharpless K.B. Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry.Angew. Chem. Int. Ed. 2014; 53: 9430-9448https://doi.org/10.1002/anie.201309399Crossref PubMed Scopus (617) Google Scholar A similar predisposition exists when phosphorus is considered instead of sulfur. The shorter P–F bond (1.52 Å vs. P–Cl = 2.01 Å in CH3POFCl60Durig J.R. Casper J.M. Vibrational spectra and structure of organophosphorus compounds. X. Methyl torsional frequencies and barriers to internal rotation of some CH3PXY2 compounds.J. Phys. Chem. 1971; 75: 1956-1963https://doi.org/10.1021/j100682a009Crossref PubMed Scopus (21) Google Scholar; Figure 1A) has a higher predicted BDE of 602 kJ/mol.59Grant D.J. Matus M.H. Switzer J.R. Dixon D.A. Francisco J.S. Christe K.O. Bond dissociation energies in second-row compounds.J. Phys. Chem. A. 2008; 112: 3145-3156https://doi.org/10.1021/jp710373eCrossref PubMed Scopus (52) Google Scholar Consequently, in compounds bearing both P–Cl and P–F bonds, it is the P–Cl bond (BDE = 331 kJ/mol61Huang X. Zhao X. Zhang M. Xu Y. Zhi H. Yang J. Green synthesis of triaryl phosphates with POCl3 in water.ChemistrySelect. 2017; 2: 11007-11011https://doi.org/10.1002/slct.201702215Crossref Scopus (4) Google Scholar) that preferentially reacts with incoming nucleophiles (e.g., amines and alkoxides) and hydrolyzes with KOH at 0°C,62Stölzer C. Simon A. Über Fluorphosphorverbindungen, I.Chem. Ber. 1960; 93: 1323-1331https://doi.org/10.1002/cber.19600930613Crossref Scopus (8) Google Scholar leaving the P–F bond untouched. Furthermore, P–F bonds are found to be more thermally stable than P–Cl bonds,63Dehnicke K. Shihada A.-F. Structural and bonding aspects in phosphorus chemistry-inorganic derivatives of oxohaloqeno phosphoric acids.in: Electrons in Oxygen and Sulphur-Containing Ligands Structure and Bonding. Springer, 1976: 51-82https://doi.org/10.1007/3-540-07753-7_2Crossref Google Scholar survive refluxing in aniline,64Refer to Table S8 for more details.Google Scholar and remain intact under reductive conditions64Refer to Table S8 for more details.Google Scholar (see Scheme 1C). However, the activation of P–F bonds toward exchange with nucleophiles can be facilitated similarly to that of S–F compounds (i.e., trifluoromethylation with TMSCF3 mediated by KF).12Smedley C.J. Zheng Q. Gao B. Li S. Molino A. Duivenvoorden H.M. Parker B.S. Wilson D.J.D. Sharpless K.B. Moses J.E. Bifluoride ion mediated SuFEx trifluoromethylation of sulfonyl fluorides and iminosulfur oxydifluorides.Angew. Chem. Int. Ed. 2019; 58: 4552-4556https://doi.org/10.1002/anie.201813761Crossref PubMed Scopus (43) Google Scholar,65Worowska I. Dąbkowski W. Michalski J. Synthesis of tri- and tetracoordinate phosphorus compounds containing a PCF3 group by nucleophilic trifluoromethylation of the corresponding PF compounds.Angew. Chem. Int. Ed. 2001; 40: 2982-2984https://doi.org/10.1002/1521-3757(20010803)113:15<2982::AID-ANGE2982>3.0.CO;2-ICrossref Google Scholar,66Abbott A. Sierakowski T. Kiddle J.J. Clark K.K. Mezyk S.P. Detailed investigation of the radical-induced destruction of chemical warfare agent simulants in aqueous solution.J. Phys. Chem. B. 2010; 114: 7681-7685https://doi.org/10.1021/jp101720jCrossref PubMed Scopus (9) Google Scholar This pattern of reactivity is then, of course, sufficient to entice curiosity for the amenability of the P–F bond for the development of click-chemistry reactions. Organo(fluoro)phosphates are highly versatile molecules, but their historic association as toxic nerve agents67Delfino R.T. Ribeiro T.S. Figueroa-Villar J.D. Organophosphorus compounds as chemical warfare agents: a review.J. Braz. Chem. Soc. 2009; 20: 407-428https://doi.org/10.1590/S0103-50532009000300003Crossref Scopus (205) Google Scholar,68Franca T.C.C. Kitagawa D.A.S. Cavalcante S.F.de A. da Silva J.A.V. Nepovimova E. Kuca K. Novichoks: the dangerous fourth generation of chemical weapons.Int. J. Mol. Sci. 2019; 201222https://doi.org/10.3390/ijms200