Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters

Herein we describe the first construction of fluorinated tertiary stereocenters based on an alkene C(sp2)–C(sp2) bond cleavage. The new process, that takes advantage of a Rh-catalyzed carbyne transfer, relies on a branched-selective fluorination of tertiary allyl cations and is distinguished by a wide scope including natural products and drug molecule derivatives as well as adaptability to radiofluorination.


Introduction
The growing number of approved uorinated small-molecule pharmaceuticals is a testimony of the tremendous research efforts in synthetic organouorine chemistry 1 and their application in uorine-based drug design. 2 The most prevalent chemotypes found in uoro-pharmaceuticals feature monouorinated moieties (Ar-F, Het-F, and alkyl-CH 2 F) and triuoromethyl groups (Ar-CF 3 , Het-CF 3 , and alkyl-CF 3 ). 2d However, the appearance of uorinated tertiary stereocenters is very rare (Fig. 1A), despite this uorinated motif being an ideal bioisostere of tertiary stereocentersa prevalent motif in drug moleculesand being found in udrocortisonethe rst approved uorine-containing drug. The main reason for the lack of uorinated tertiary stereocenters in drug molecules can be attributed to a less developed area of research and difficulties of adopting the known synthetic methods for drug molecule design. 1d In this sense, it is of high contemporary interest to develop new synthetic concepts to such uorinated motifs based on unconventional disconnection approaches that can expand and complement known synthetic protocols.
Catalytic methodologies based on (i) uorination of alkenes, enol(ates), phenols and C-H bonds with electrophilic uorinating reagents 3 or in (ii) transformations of uorine-containing starting materials, 4 can be considered the most developed approaches for the regio-and enantioselective construction of uorinated tertiary stereocenters. However, they respectively employ electrophilic uorinating reagentswhich are derived from uorine gasand use pre-functionalized uorinated starting materials that could need multistep synthetic sequences. On the other hand, catalytic uorination of alkenes, allylic electrophiles, and C-H bonds with nucleophilic uoride sources represents in general an efficient option considering the availability of uoride sources. 5,6 Despite the variety of catalytic strategies developed, it is remarkable to observe that methodologies that employ C-C bonds as functional groups are scarce. 7 Such processes rely on the skeletal modication of an organic molecule, offering new disconnection approaches. 8 Examples of this class of uorinations that reach uorinated tertiary stereocenters are limited to the catalytic cleavage of C(sp 3 )-C(sp 2 ) bonds of redox-active esters, 9 carboxylic acids, 10 and C(sp 3 )-C(sp 3 ) bonds in cyclopropanes. 11 However, to the best of our knowledge, synthesis of tertiary uorinated stereocenters through catalytic alkene C(sp 2 )-C(sp 2 ) bond cleavage is previously unknown (Fig. 1A).
As part of a research programme focused on the development of a carbyne transfer platform in organic synthesis, we reported a catalytic strategy that generates Rh-carbynoids as I (III) -substituted Rh-carbenes by selective diazo activation of bespoke hypervalent iodine reagents with a rhodium paddlewheel catalyst (Fig. 1B). 12, 13 We found that Rh-carbynoids provoked the skeletal modication of alkenes by formally inserting a cationic monovalent carbon unit (: + C-R) between both sp 2 -hybridized carbons. This constructive C(sp 2 )-C(sp 2 ) bond cleavage process generated synthetically useful cation intermediates that converted to valuable chiral racemic allylic building blocks with a broad range of heteroatomic and carbon nucleophiles.
Recently, we wondered whether we could exploit our alkene skeletal modication platform for the catalytic conversion of 1,1-disubstituted alkenes into uorinated tertiary stereocenters (Fig. 1C). We hypothesized that the uoride nucleophilic attack would proceed with high branched selectivity considering that both the charge and the highest LUMO coefficient of the allyl cation may be centered at the a position, due to the double substitution with two stabilizing groups (alkyl and aromatic groups). 14,15 However, we recognized that constructing a sterically demanding tertiary allylic uoride could bring some problems associated with (i) parasitic proton eliminations promoted by uoride and (ii) generation of undesirable branched/linear mixtures due to lack of regiocontrol in the nucleophilic uoride attack. 16 The successful development of such nucleophilic branchedselective uorination of tertiary allyl cations would unlock a novel access to uorinated tertiary stereocenters using readily or commercially available 1,1-disubstituted alkenes and nucleophilic uoride sources. In addition, our strategy would represent also a novel approach to a class of allylic uorides difficult to obtain with traditional bimolecular nucleophilic substitutions or transition metal-catalyzed platforms. 1a, f,17 Herein, we would like to present the successful execution of this goal for a previously unknown disconnection approach to valuable uorinated tertiary stereocenters based on the skeletal modication of 1,1-disubstituted alkenes. The synthetic protocol is amenable to a broad range of 1,1-disubstituted alkenes and permits the installation of a uorinated tertiary stereocenter in natural products and drug molecule derivatives. Notably, the uorination of the allyl cation intermediates occurred with excellent branched selectivity. Follow-up alkene transformations of the products and adaptability to radio-uorination were demonstrated.
With these promising results, we were encouraged to optimize this novel uorination reaction by evaluating a diverse variety of commercially available uoride sources, hoping to improve the efficiency of the C-F bond-forming process while minimizing the parasitic proton elimination or water attack. We were pleased to nd that Et 3 N$3HF led to (AE)-3a in 71% isolated yield, and the formation of (AE)-4 and 5 was certainly suppressed (<5% yield). 21 However, while metallic uorides MF (M ¼ Na, K, Cs) and Olah's reagent [Py(HF) x ] promoted the conversion to diene 5, tetrabutylammonium diuorotriphenylsilicate (TBAT) or the tetrabutylammonium uoride bispinacol complex (TBAF(pin) 2 ) provided (AE)-3a in poor yields. 22,23 With the optimized reaction conditions in hand, we next investigated the scope of this uorination reaction by examining a broad range of a-substituted styrenes (Table 2). We were delighted to observe that substrates substituted in the para

position of the aromatic ring with halogens [(AE)-3b-e], tri-uoromethyl [(AE)-3f], ester [(AE)-3g], triuoromethoxy [(AE)-3h], acyloxy [(AE)-3i-j] and alkyne [(AE)-3k] were well tolerated.
However, methyl or methoxy substituents provided low levels of efficiency [(AE)-3l] or no product [(AE)-3m], as notable polymerizations were noticed with full starting material consumption. This observation might suggest that the corresponding allyl carbocation species are generated, before Et 3 N$3HF is added to the reaction, due to a signicant acceleration in the ringopening of cyclopropyl-I (III) intermediates (int-2) caused by the electron-rich aromatic rings. We later hypothesized that these electron-donating groups may not provoke such signicant acceleration in the ring-opening step when placed in a meta position. As predicted, the reactions carried out with meta-MeOand meta-Me-substituted a-methylstyrenes provided (AE)-3n-o with satisfactory yields and excellent branched/linear ratios. Moreover, para-and meta-disubstituted aromatic rings or naphthalene provided the desired products with high level of efficiencies [(AE)-3p,q].
In contrast to the exquisite branched selectivity obtained for para-and meta-substituted a-methylstyrenes, a different situation was observed for ortho-substituted derivatives. Equimolecular mixtures of branched/linear uorides were obtained (3r,s) when using substrates substituted with a methyl or a chlorine group. Although this is a clear limitation of our method, it underlines a potential subtle effect of the ortho substituent in preventing the aromatic ring from stabilizing the charge at the a position of the tertiary allyl cation.
Further demonstration of the potential of our methodology was validated in the uorination of a selection of natural products and drug molecule derivatives (3ah-an) ( Table 2). It is worth highlighting the excellent degree of chemoselectivity observed in substrates containing more than one alkene. The results indicate that highly substituted alkenes are less reactive; however, the excellent selectivity observed for b-elemene (3al) highlights that the initial alkene cyclopropanation to form a cyclopropyl-I (III) intermediate is sensitive to steric effects.
We next aimed to transform the alkenyl-carboxylate moiety of (AE)-3a into useful functionalities without compromising the integrity of the uorinated tertiary stereocenter (Table 3). Hydrogenation (6), dihydroxylation (7), epoxidation (8) 1,3-cycloaddition reactions (9) and oxidation (10) provided a series of uorinated derivatives that would be otherwise difficult to obtain by other means. To demonstrate the synthetic utility of our methodology in providing access to uorinated analogues of medically relevant agents containing a tertiary stereocenter, we sought to synthesize (AE)-F-urbiprofen 12. Although this uorinated analogue is known, it was synthesized using electrophilic reagents. 25 Initially, we performed our uorination reaction using a readily available styrene and obtained branched tertiary uoride (AE)-11 with high efficiency. Finally, oxidation with OsO 4 transformed (AE)-11 into the desired (AE)-F-urbiprofen 12 (Table 3). 18 Fluorine [

Conclusions
In summary, we have developed a new synthetic methodology for the construction of uorinated tertiary stereocenters from 1,1-disubstituted alkenes. The process relies on the generation of tertiary allyl cations, mediated by a catalytically-generated Rh-carbynoid, that undergoes nucleophilic uorination with an excellent branched/selectivity ratio. Notable features of this process are the broad scope of 1,1-disubstituted alkenes, including natural products and drug molecule derivatives, applications in the synthesis of a uorinated drug molecule -(AE)-F-urbiprofenand its translation to radiouorination with [ 18 F]TEAF. The generality of our methodology and synthetic applications, based on a Rh-catalyzed carbyne transfer with alkenes, stands as a testament of its potential utility to expand the chemical space in uorine-based drug design.

Data availability
The data for this work, including optimization tables, general experimental procedures, characterization data for all new compounds and X-ray data are provided in the ESI. †

Conflicts of interest
There are no conicts to declare.