Enantioselective organocatalytic fluorination-induced Wagner-Meerwein rearrangement.

Despite the fact that only 21 fluorinated molecules are known to be biosynthesized, it is notable that about 20–25% of all modern pharmaceuticals and agrochemicals incorporate at least one fluorine atom. Nevertheless, the practice of introducing fluorine atoms into bioactive compounds is rather recent, as the first synthetic fluorinated drug, namely 5-fluorouracil, was synthesized as late as in 1957. Ever since, the research aimed at incorporating fluorine atoms into small organic molecules has attracted and intrigued synthetic organic chemists. Yet, despite the importance of fluorine, carbon–fluorine bond formation remains a challenge. Performing this task in concert with bringing chirality into the target molecule, and doing so with only a catalytic quantity of the enantioinducing reagent is of even greater practical importance. Halocyclization of olefins is an important class of organic transformations. Among these reactions, halolactonizations have been studied extensively and applied in the synthesis of many bioactive molecules. Very recently, catalytic enantioselective versions of the aforementioned transformation were also reported. Far less studied is the related halogenation/ semipinacol rearrangement cascade. In this last reaction, an allylic alcohol (1) undergoes a Wagner–Meerwein alkyl migration, which is initiated by the formation of the halonium ion intermediate 2 (Scheme 1). Whereas the chlorinationand bromination-induced Wagner–Meerwein rearrangements of electron-rich cyclic enol ethers were recently shown to be amenable to asymmetric catalysis, the development of a truly enantioselective catalytic fluorination-induced variant remains underexplored. This is partly related to the inherently high reactivity of most electrophilic fluorinating reagents, and leaves little room for the introduction of a chiral catalyst. In the course of the last ten years, it has been extensively demonstrated that ionic catalysts incorporating at least one chiral ion are able to render enantioselective those transformations which proceed through reaction intermediates bearing an opposite electrostatic charge. Specifically in the field of asymmetric-counteranion-directed catalysis, binol-derived phosphoric acids have been disclosed as privileged precursors of chiral anions. Reasoning that our postulated halonium ion intermediate 2 bears a net positive charge, we were interested to see if a chiral anion could induce asymmetry into the Wagner–Meerwein rearrangement. Among the four possible halogen atoms, we were particularly attracted by fluorine as initiator for the Wagner– Meerwein transposition. Furthermore, to the best of our knowledge, chiral-binol-derived phosphoric acids have only been used to promote semipinacol rearrangements of electron-rich cyclic enol ethers. The transposition of simple allylic alcohols remains a great challenge because it cannot be initiated by a proton alone. Nevertheless, such a reaction could be of great synthetic interest, as it would lead to the formation of valuable all-carbon quaternary stereogenic centres. Herein, we report some of our recent results on this subject. Our catalytic system was inspired from the one recently reported for related fluorocyclization reactions. Optimization studies were carried out with the strained allylic alcoholA1, Selectfluor as the fluorinating reagent, and a set of synthetic axially chiral phosphoric acids (L), derived from (Ra)-binol (Table 1). In the course of the preliminary catalyst screening, the employment of highly sterically congested phosphoric acids (L4–L8), which are related to the known (Ra)-TRIP scaffold, turned out to be crucial for accessing practical enantioselectivities of the product b-fluoro spiroketone B1 (Table 1, entries 4–6). Interestingly, acids bearing isopropyl (L4) and cyclopentyl (L6) substituents at positions X and Y outperformed the acid L5 which bears cyclohexyl groups at these same positions. Among the numerous solvents tested, highly hydrophobic, yet strongly solubilizing solvents (toluene, fluorobenzene, and diisopropylether) were better than hydrophobic solvents of lower solubilizing ability (cyclohexane). Since nonpolar solvents favor ion pairing, the present reaction is an example of anionic phase-transfer catalysis (PTC), where a lipophilic chiral anion extracts the insoluble Scheme 1. The concept of halonium-ion-promoted Wagner–Meerwein transposition of allylic alcohols, and the idea of inducing chirality by means of a chiral counterion. Hal=F, Cl, Br, or I.