
F luorine-containing compounds are of particular interest in the fields of material science, agrochemicals and pharmaceutical research 1, 2 . As fluorine has the highest electronegativity coupled to an enhanced bond strength of the C-F bond compared to a C-H bond, C-F bonds are often leveraged as replacements for C-H bonds when the latter presents a liability at a saturated (sp 3 ) carbon centre, especially for benzylic C-H bonds prone to metabolic oxidation 2, 3 . The catalytic, enantioselective formation of tertiary C-F bonds is synthetically challenging 4 and has traditionally been accomplished through bond formation adjacent (defined as α) to a pre-existing functional group (Fig. 1a ) [4] [5] [6] [7] . This is highlighted by (1) the functionalization of carbonyl derivatives via the reaction of an enolate or an enolate equivalent with either an electrophilic fluorinating reagent [8] [9] [10] [11] [12] [13] [14] [15] [16] or an arylating/alkylating reagent [17] [18] [19] [20] [21] , which leads to a plethora of α-functionalized carbonyl products, or (2) the reaction of mainly cyclic alkene substrates with an electrophilic fluorinating source followed by elimination to form an allylic fluoride product 22, 23 . Trapping of the reactive intermediate in this process with a nucleophile to yield the formal alkene difunctionalization product is also possible [24] [25] [26] [27] [28] . A recently reported strategy by Butcher and Hartwig provides an alternative approach to acyclic allylic fluorides that involves nucleophilic attack onto a π-allyl-iridium species derived from a styrenyl fluoride electrophile 29 . Although these methods constitute excellent entries to produce the desired tertiary C-F stereocentres, the specific synthetic positional limitation reflects the requirement of a functional group adjacent to the site at which the fluoride is placed. To access products that do not place the fluoride directly adjacent to either a carbonyl or an alkenyl group (Fig. 1b) , we envisioned a strategy by which an enantioselective Pd-catalysed Heck reaction of alkenyl fluoride substrates with arylboronic acids could be developed 30, 31 . By performing such a reaction, a tertiary C-F benzylic stereocentre could be constructed at modular locations from the carbonyl functional groups. A successful implementation of this strategy would enable direct synthetic access to previously unavailable building blocks as procedures to replace either the tertiary benzylic C-H or C-OH bonds with fluoride have yet to be reported at such sites.

Significant issues were anticipated in exploring this reaction sequence due to the general reactivity of alkenyl fluorides and accessibility of the substrate itself. Alkenyl fluorides are not traditional alkenes, as exemplified by their unique 13 C chemical shifts observed with a downfield shift of ~160 ppm, similar to that of an amide, for the C-F bond (Fig. 1b) . Comparatively, the other carbon has a chemical shift of ~105 ppm and the C-H bond attached has a rather upfield shift of 4.8 ppm, which suggests a highly electronically biased alkene. Thus, alkenyl fluorides have been reported as substrates for Heck-type reactions with insertions that occur at C B , but with various caveats [32] [33] [34] [35] [36] [37] [38] . The first is that trisubstituted alkenyl fluorides of type 1 have not been described as substrates in Heck reactions and, presumably, would be poorly reactive due to the high electronegativity of the F substituent and the congested nature of the alkene 35 . Consistent with this, our lab has reported that alkenes bearing only carbon substituents with smaller groups (for example, disubstituted versus trisubstituted alkenes) as well as substrates that are more electron rich (for example, alkyl versus aryl) react faster in Heck-type reactions 30, 31, 39 . The second issue is that if migratory insertion is effective, the resulting Pd-alkyl intermediate A (Fig. 1b) may have the propensity to undergo β-fluoride elimination according to reports that involve alkenyl fluorides as Heck coupling partners 32, 33, 37 . This would ultimately remove the F from the desired product and probably inhibit the necessary chain-walking process enabled by a cationic Pd catalyst as the fluoride would probably form neutral Pd intermediates 40 . Moreover, a significant obstruction to progress in this area has been access to the desired substrates (for example, 1a, Fig. 1d ), which traditionally requires a lengthy synthetic sequence to prepare 41, 42 . Recently, a simple method was reported by the Toste team, which overcomes previous limitations by enabling a modular preparation of geometrically pure allylic alkenyl fluoride derivatives in a two-step procedure (Fig. 1c) 
43
.
Results and discussion
Using this route, substrate 1a was prepared and submitted to various conditions for Heck-type reactions of alkenyl alcohols previously reported by our lab (Fig. 1d ) 30, 31 . The use of an allylic alcohol as the starting point for reaction optimization was anticipated to The carbon-fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity. The development of catalytic, enantioselective methods to set stereocentres that contain a benzylic C-F bond is a rapidly evolving goal in synthetic chemistry. Although there have been notable advances that enable the construction of secondary stereocentres that contain both a C-F and a C-H bond on the same carbon, significantly fewer strategies are defined to access stereocentres that incorporate a tertiary C-F bond, especially those remote from pre-existing activating groups. Here we report a general method that establishes C-F tertiary benzylic stereocentres by forging a C-C bond via a Pd-catalysed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners, as well as the ability to install the stereocentres remotely from pre-existing functional groups.
Results and discussion
slow the β-fluoride elimination by accelerating β-hydride elimination towards the alcohol and terminating the chain-walking process through an irreversible formation of the aldehyde 30, 31 . Unfortunately, poor reactivity was observed under these conditions, with the best preliminary result of 24% yield using dimethylformamide as the solvent, a Cu salt and a PyrOx ligand (Fig. 1d, entry 1 ). An extensive evaluation of the reaction conditions revealed three significant changes that were required to obtain a robust reaction: (1) methanol (MeOH) was identified as a uniquely effective solvent that nearly doubled the yield compared to the use of any other common solvent (Fig. 1d , entry 2 ( Supplementary Fig. 1 gives the complete screening details)), (2) the addition of dibenzylideneacetone (dba), which may rescue any long-lived Pd(0) intermediates that undergo slow oxidation, was essential (entry 3) and (3) in contrast to related oxidative Heck reactions, Cu salts are detrimental to the reaction outcome (entry 5) 30, 31 . The inspiration for the use of dba was found through the observation that Pd(dba) 2 gave modestly improved yields when used instead of a Pd(ii) complex as the precatalyst (Supplementary Fig. 1 gives details). In all, the reaction yield was improved to 90% for the model substrate. Of particular note, by exploiting the simple chiral PyrOx ligand, which is readily prepared in two steps and commercially available, an exceptionally high enantiomeric ratio (e.r.) of 99:1 was observed. Using the other alkene stereoisomer (Fig. 1d , entry 4) leads to the conservation of a high enantioselectivity (98:2 e.r.) with the other enantiomer of the product formed in a reduced yield. Owing to the ease of access to the Z-alkene isomer and the better performance in terms of yield, this alkene isomer was utilized throughout the remainder of the study.
Results and discussion
Applying the optimized conditions, the scope of the reaction was first evaluated by exploring the nature of the arylboronic acid coupling partner (Table 1) . In general, the use of aryl rings that are more electron rich gave enhanced yields compared to those of the more electron poor examples (for example, 2a-2d versus 2e and 2f). This is presumably due to a faster relative rate of migratory insertion with more nucleophilic arenes 30 . In all cases, though, the enantioselectivity remained high in an e.r. range of 95:5 to 99:1. Both m-methoxy (2g) and m-acetamide (2h) groups were tolerated well under the reaction conditions. Multisubstituted arenes, which include halogen-substituted arylboronic acids, were also effective coupling partners (2i-2n), highlighted by 2l and 2m. Finally, ortho substitution on the arene was allowed, as demonstrated by the success of 2n, which was produced in a reduced yield but high enantioselectivity. Unfortunately, a number of heteroaromatic boronic acids were tested for this reaction with no product detected in most cases ( Supplementary Fig. 2 gives a complete list).
Results and discussion
The substrate scope of the alkenyl fluoride reaction partner was explored broadly, enabled by the simple synthetic procedure to access them (Table 1) 43 . Different hydrocarbon substituents generally performed well (2o-2t) . Surprisingly, a large cyclohexyl group (2t) attached to the alkene was allowed, which led to a modest product yield in high enantioselectivity (98:2 e.r.). The incorporation of an array of functional groups on the alkene was also tolerated well. This includes various halides on the alkyl chain (F, Cl and Br (2u-2w)) and a tosylate group (2x), which are substrates that can be reactive under Pd catalysis 44 . These illustrative examples suggest that the current catalyst system is precisely tuned to engage with the alkenyl fluoride in the presence of reactive functionality. Additionally, an alcohol (2y), an ether (2z), a sulfone (2aa) and an aniline (2ab) were all competent substrates in this reaction. Simple basic amines were not compatible with the reaction, probably due to displacement of the chiral ligand, and styrenylfluorides did not undergo the reaction, presumably as a consequence of their mitigated nucleophilicity (vide infra ( Supplementary Fig. 3 gives  details) ). Of particular note, the enantioselectivity remained consistently high in all cases. Further evaluation of the substrate scope was aimed at highlighting the unique strategic advantage of using a Heck-type reaction of alkenyl fluorides to set stereocentres remote from a pre-existing functional group. Specifically, the scope evaluation in Table 1 focuses on alkenyl fluorides that contain an allylic alcohol, which, by virtue of the reaction, forms an aldehyde product (the aldehyde was reduced in situ with NaBH 4 to avoid decomposition issues associated with the isolation of the β-fluoro-aldehyde). By adding methylene units between the alcohol and the alkenyl fluoride, a successful reaction would offer a direct route to a remotely located fluorinated benzylic stereocentre (Fig. 2a) . In the event, a homoallylic alcohol underwent the desired reaction in reasonable chemical yields and consistently high enantioselectivity (3a-3d Yields are of isolated 3. Enantioselectivity determined by SFC equipped with a chiral stationary phase. a 30 mol% Pd(CH 3 CN) 2 (OTs) 2, 36 mol% PyrOx (shown on the right) and 60 mol% dba were used. R = (CH 2 ) 4 CH 3 for all the substrates. b, Equimolar amounts of alkenyl fluoride 4a and disubstituted alkenol 4b reacted smoothly with excess boronic acid under the optimal conditions identified for alkenyl fluorides. c, The reaction progress showcases that disubstituted alkenol 4b reacts significantly faster than alkenyl fluoride 4a. Reactions were performed in triplicate (the s.d. is displayed). d, No Heck products were detected when equimolar amounts of 4c and 4d were reacted with excess boronic acid; substrates that contain competitive binding groups, such as a trisubstituted alkene (4e) and a nitrile (4f), do not react under our current conditions. e, The results detailed in b-d combined with the previous mechanistic studies shows that the alkenyl fluoride is less efficient at binding the catalyst than either simple di-or trisubstituted alkenes, and for the migratory insertion step the alkenyl fluoride has a higher reactivity than the trisubstituted alkenes, but a lower reactivity than the disubstituted alkenes.
Results and discussion
from the resulting alcohol functional group. Additional methylene units were incorporated from the pre-existing functional group as highlighted by 3e and 3f, which have four and six carbons between the installed stereocentre and the oxygen-containing functional group. Although poorer yields were observed for these cases, the enantioselectivity remained excellent.
Results and discussion
As described above, a key mechanistic question is: how does the reactivity of alkenyl fluorides compare to that of their nonfluorinated derivatives in terms of catalyst binding and migratory insertion aptitude? To probe this question, several relative rate experiments were performed (Fig. 2b-d) . Experiments with equimolar amounts of alkenyl fluoride 4a and disubstituted alkenol 4b and excess boronic acid were conducted under the optimal conditions identified for alkenyl fluorides (Fig. 2b) . The reaction progress showcases that the disubstituted alkenol 4b reacted significantly faster than alkenyl fluoride 4a (Fig. 2c) . Of particular interest, 4b was nearly consumed prior to the reaction of the alkenyl fluoride, which suggests that migratory insertion is faster for the more electron rich alkene. Perhaps of greater interest is the experiment of equimolar amounts of 4c and 4d with excess boronic acid to evaluate the relative rates of a simple alkenyl fluoride (4c) versus those of the trisubstituted alkene (4d) in which, surprisingly, no Heck products were detected (Fig. 2d) . Note that trisubstituted alkene 4d, a competent substrate under previously reported reaction conditions (88% yield) 30 , does not react under the current conditions even in the absence of the alkenyl fluoride (Supplementary Mechanistic Experiments gives details). Taken together, these results suggest that 4d, the trisubstituted alkene, is a considerably better ligand for the Pd catalyst, which thus inhibits the reaction of the alkenyl fluoride. Consistent with this hypothesis, substrates that contain competitive binding groups, such as a trisubstituted alkene (4e) and a nitrile (4f), do not react under our current conditions, although other factors may contribute to their poor reactivity (Fig. 2d) .
Results and discussion
This information suggests that alkene binding to form intermediate C is reversible after forming B via boronic acid transmetallation (Fig. 2e) . This hypothesis was developed on the basis of previous mechanistic studies 45 and the observation of poorer yields with less nucleophilic boronic acids. Thus, the faster-reacting alkene undergoes a turnover-limiting migratory insertion in C, which is probably under Curtin-Hammett control. Enantioselectivity is determined in this step, wherein the stereochemical model depicted in D showcases that the recognition element of carbon versus hydrogen on the proximal alkene carbon, relative to the alcohol, defines the stereochemical outcome. In terms of the general reactivity of alkenyl fluorides, the results detailed above are consistent with the alkenyl fluoride being significantly less efficient at binding the catalyst than either simple di-or trisubstituted alkenes, with the latter acting as an inhibitor, probably as a result of the enhanced electron density of these alkenes. In contrast, the migratory insertion step is less sensitive to alkene electronics; in fact, the alkenyl fluoride reacts significantly faster than the trisubstituted alkene under the reaction conditions. This observation suggests that the steric component of the alkene has the greatest impact on the consequential migratory insertion step.
Results and discussion
In this work, we describe a synthetic strategy to access enantiomerically enriched tertiary fluorides, which would be difficult to form using conventional approaches. The scope of the reaction is broad with uniformly high enantioselectivity. Remote tertiary fluoride stereocentres can be readily prepared with our strategy, which provides chemists with a new platform to explore fluorine-containing molecular scaffolds. Although halogens have often been leveraged as reactive functional groups in transition-metal-catalysed reactions that form C-C bonds, this report demonstrates that catalytic systems can be developed that retain the C-F bond. More broadly, we envision that this work will inspire further investigation of the transitionmetal-catalysed C-C bond-forming reaction previously developed for non-fluorinated alkenes with their fluorinated analogues as a means to forge stereocentres that contain C-F bonds.
Methods
In the general procedure for the enantioselective construction of remote tertiary C-F bonds, to a dry 5 ml Schlenk flask equipped with a stir bar was added Pd(CH 3 CN) 2 (OTs) 2 (10.6 mg, 0.020 mmol, 10.0 mol%), ligand (6.5 mg, 0.024 mmol, 12.0 mol%), dba (9.4 mg, 0.04 mmol, 20 mol%), 3 Å molecular sieves (MS) (50.0 mg, 250 mg mmol -1 ) and MeOH (1.2 ml). To this flask, a three-way adaptor fitted with a balloon of O 2 was added, and the flask was evacuated via house vacuum and refilled with O 2 three times while stirring. The resulting mixture was stirred for 20 min. To this, a MeOH solution (0.8 ml) of the fluorinated alkenyl alcohol (0.2 mmol) and corresponding boronic acid (0.6 mmol, 3 equiv.) was added by syringe. The resulting mixture was stirred for 72 h at room temperature (r.t., 25 °C). The mixture was transferred to a 10 ml scintillation vial equipped with a stir bar and a 5 ml Schlenk flask was washed by 2 ml MeOH added to the vial. Sodium borohydride (8.0 equiv.) was added and the resulting mixture was stirred for 1 h. The solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (1:20 acetone:hexane to 1:10 acetone:hexane) to give the corresponding alcohol. Isolated yields were calculated based on the isolated mass. Full experimental details and characterization of the compounds are given in the Supplementary Information.
Data availability
All the characterization data and experimental protocols are provided in this article and its Supplementary Information. Data are also available from the corresponding author upon request.

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