Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related S-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5'-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.

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Herein an efficient and direct copper-catalyzed coupling of oxazoline-containing aryl bromides with electron-deficient secondary phosphine oxides is reported. The resulting tertiary phosphine oxides can be reduced to prepare a range of PHOX ligands. The presented strategy is a useful alternative to known methods for constructing PHOX derivatives.Phosphinooxazoline (PHOX) ligands have found broad applications in transition metal catalysis. 1 Developed by Pfaltz,2 Helmchen,3 and Williams,4 PHOX ligands have become a preeminent class of P,N-ligands, 5 with t-BuPHOX (L1 , Scheme 1) representing a most prominent example. 6 We have recently demonstrated the utility of t-BuPHOX in palladiumcatalyzed enantioselective decarboxylative alkylation 7 and protonation 8 reactions. We, however, became aware of examples where t-BuPHOX provided only moderate results with respect to yields and enantioselectivities, and designed an electronically-modified version of this ligand, p-(CF 3 ) 3 -t-BuPHOX (L2). In some cases, the electron-withdrawing trifluoromethyl groups affected the reactivity of the corresponding transition metal complex, leading to significantly shorter reaction times and enhanced selectivities. For example, we were able to achieve 99% yield and 87% ee in our palladium-catalyzed, enantioselective allylic alkylation reaction of allyl enol carbonate 1 within only 10 min at 25 °C with the use of (S)-L2, while the use of (S)-L1 required 120 min reaction time to give 96% yield and 88% ee. 9 Further, this ligand was successfully applied in the catalytic asymmetric total synthesis of (+)-elatol where the key allylic alkylation of chloroallyl enol carbonate 2 was performed with (R)-L2, resulting in 82% yield of product in 87% ee, compared to only 81% ee and a poor 23% yield with the use of (S)-L1. 10 Moreover, we recently published a palladium-catalyzed, enantioselective enolate alkylation cascade, which provides products with up to 99% enantiomeric excess, 11 where (S)-p-(CF 3 ) 3 -t-BuPHOX was far superior to (S)-t-BuPHOX for the alkylation of β-keto ester 3.Previously, we published a convenient and scalable synthesis for t-BuPHOX,12 using an Ullmann-type coupling developed by Buchwald. 13 While this approach proved useful for the coupling aryl halides and secondary phosphines, most substituted secondary phosphines are not commercially available. Similarly, substituted secondary phosphines (e.g., bis(4-(trifluoromethyl)phenyl)phosphine) are difficult to prepare in the required purity due to their * Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 395 8436; stoltz@caltech.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, an...