Can acyclic conformational control be achieved via a sulfur–fluorine gauche effect?

Abstract

Herein detailed conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed, thus extending the scope of the fluorine gauche effect to the 3rd Period (X = SR, SOR, SO2R; φFCCS ≈ 60°).

The influence of electronic perturbations on the Sulfur–Fluorine Gauche Effect

“…To provide a fully experimental validation of this working hypothesis, and complement the existing theoretical treatment, [3,4] three sets of electronically modulated compound classes were prepared and subjected to a solution phase conformer population analysis (Figure 2A). Specifically, the electronics of the parent sulfide, sulfoxide and sulfone scaffolds (1e, 2e, 3e) were perturbed through the introduction of electron-donating and electron-withdrawing substituents [R = NH 2 (a), OH (b), OMe (c), Me (d), H (e), F (f), Cl (g), CO 2 H (h), CO 2 Et (i) and NO 2 (j)].…”

“…Whilst this notion is well studied and has found widespread application with second period elements (N, O, F), [2] it was only recently extended to a third period element by this laboratory; a phenomenon termed the Sulfur-Fluorine Gauche Effect. [3] This extension to sulfur-based systems seemed highly prudent on account of the multiple oxidations states associated with sulfur (II, IV, VI). It was envisaged that sequential oxidation could be exploited as a mechanism by which the conformational equilibrium of the F-C1-C2-S(O) n fragment could be regulated.…”

“…Conformational equilibria in F-C1-C2-S(O) n R systems: the Sulfur-Fluorine Gauche Effect. [3] Recently, a computational study by Baranac-Stojanovid and co-workers delineated the origins of this unprecedented conformational preference and concluded that primarily electrostatic interactions are responsible for this phenomenon. [4] Whilst in sulfur analogues of cyclic proline-derived systems the population of the gauche conformer increases noticeably following the trend sulfide < sulfone < sulfoxide, the effect of more subtle, remote electronic modulation has yet to be established and was the motivation for this investigation.…”

Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

“…1D). We focused on b-bromosulfides as model substrates because (i) they form highly electrophilic episulfonium ions that readily undergo diastereospecific bond-forming reactions with nucleophiles (21); (ii) the positively charged sulfur of the episulfonium ion can interact with the in situ-formed urea-fluoride complex in a manner reminiscent of the HB-fluoride-sulfonium prereaction complex characteristic of the enzyme (26)(27)(28)(29); (iii) meso-episulfonium ions are suitable for enantioselective desymmetrization with a chiral urea catalyst; and (iv) the fluorination products contain both fluorine and sulfur, which are important elements in drug design, thus underlining the value of the products for medicinal chemistry (4)(5)(6)30).…”

“…after one recrystallization. Despite recent interest in the preparation and properties of molecules containing the F-C-C-S(O) n (n = 0, 1 and 2) motif (30,33), no alternative method to access these scaffolds in enantiopure form has been developed to date.…”