Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules

Abstract

The pentafluorosulfanyl group (SF5) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF5-compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into organic molecules. However, recent synthetic progress, the availability of some SF5-building blocks from commercial suppliers and the discovery of interesting properties of SF5-substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF5-substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000. Object *Cover Letter or Page containing Author DetailsAll of the referees' suggestions have been accepted, with the only exception of Referee's 2 point 5 "Reactions of ArylSF5 systems should be divided into sections …electrophilc substitutions, nucleophilic substitutions, reactions of diazo systems,…" because in that section the chemistry is inherently heterogeneous and we feel that such a subclassification would be very challenging to achieve and would make less homogeneous the discussion of the topic. Molecolare, via Mancinelli 7, 20131 Milano, Italy Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are reviewed in this article, with an emphasis on the work published in the last decade. *Graphical Abstract -Synopsis Highlights We review the synthesis of SF 5 -compounds, with an emphasis on work published after year 2000.  We review the reactivity of SF 5 -substituted organic molecules.  We review the biological properties of SF 5 -substituted drug candidates. Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; e-mail: m.zanda@abdn.ac.uk b C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, via Mancinelli 7, 20131 Milano, Italy AbstractThe pentafluorosulfanyl group (SF 5 ) is a highly stable chemical function which has been attracting a great deal of interest owing to its peculiar chemical, structural, physicochemical and biological properties. Progress in the area of SF 5 -compounds has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF 5 -group into organic molecules. However, recent synthetic progress, the availability of some SF 5 -building blocks from commercial suppliers and the discovery of interesting properties of SF 5 -substituted molecules in materials science, biology and drug discovery are giving new momentum to research in this fascinating area of fluorine chemistry. Synthesis, reactivity and biological properties of SF 5 -substituted organic molecules are herein reviewed with an emphasis on the work published after year 2000.

Polyfluorinated Groups in Medicinal Chemistry

“…In the last decade the organic chemistry of the SF 5 group has been extensively investigated, leading to a large and ready availability of building blocks and reagents bearing this substituent [46,47]. Several studies on SF 5 properties have already been published reporting its chemical and hydrolytically stability [47,48], the steric demand and symmetry (volume of SF 5 is slightly less than t-butyl and greater than CF 3 ) [49], the electron-withdrawing effect [21,50], the electronegativity (SF 5 = 3.65, CF 3 = 3.36), and the nontoxicity of its degradation products [51]. These unique properties make the pentafluorosulfanyl group an attractive substituent in medicinal chemistry applications and confirm that the SF 5 is not only a simple CF 3 analogue.…”

Preparation and Evaluation of Potent Pentafluorosulfanyl‐Substituted Anti‐Tuberculosis Compounds

“…[12] The SF 5 group is large, very electronegative, lipophilic, and more resistant to acid hydrolysis than either CF 3 or OCF 3 . [12] While, SF 5 -bearing building blocks are typically >5x more expensive than the analogous CF 3 compounds, they are particularly attractive to medicinal chemists due to their reported effects on slowing rates of metabolism.…”

“…[12] The SF 5 group is large, very electronegative, lipophilic, and more resistant to acid hydrolysis than either CF 3 or OCF 3 . [12] While, SF 5 -bearing building blocks are typically >5x more expensive than the analogous CF 3 compounds, they are particularly attractive to medicinal chemists due to their reported effects on slowing rates of metabolism. [13] To the best of our knowledge, there are no reported TB inhibitors bearing the pentafluorosulfanyl moiety and certainly none within the IAP or ITA chemical classes reported to date.…”

Untitled

“…Professor Haufe commented: "A couple of years ago we used intermediately formed ester enolates in Ireland-Claisen-type rearrangements to prepare α-fluoro-and α-trifluoromethyl carboxylic acid derivatives. 2 Now, in a fruitful cooperation with the group of Professor Joseph S. Thrasher, Clemson University in South Carolina (USA), not only fluorinated carbon centers but also sulfur-containing groups [SF 5 (CF 2 ) n (n = 0-2)] are being investigated 3 in order to achieve a better understanding of the intrinsic physicochemical properties of those groups." Among them, the fairly uncommon pentafluorosulfanyl (SF 5 ) group has gained much attention recently.…”