Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation

Fluoromethyl groups possess specific steric and electronic properties and serve as a bioisostere of alcohol, thiol, nitro, and other functional groups, which are important in an assortment of molecular recognition processes. Herein we report a catalytic method for the asymmetric synthesis of a variety of enantioenriched products bearing fluoromethylated stereocenters with excellent yields and enantioselectivities. Various N,P-ligands were designed and applied in the hydrogenation of fluoromethylated olefins and vinyl fluorides.


Introduction
Organouorine compounds, on the basis of their special chemical and biological properties, are widely used in pharmaceuticals, agrochemistry, and materials science. 1 In pharmaceuticals, the incorporation of a uorine atom or uorinated group into a biologically active compound usually modies the biological and physicochemical properties by improving potency, lipophilicity, metabolic stability, binding affinity, and bioavailability. 2 As a result, uoromethylated analogues have become a potential class of drug candidates in isostere-based drug design. 3 In terms of bioisosterism, monouoromethyl (CH 2 F) and diuoromethyl (CHF 2 ) groups are inert, isosteric and isopolar to an OH or SH group in biologically active compounds and pharmaceuticals. 4 The triuoromethyl (CF 3 ) group could be considered to be bioisosteric with an ethyl group or a potential nitro bioisostere based on its topological, steric, and electronic effect. 3c,5 In addition, mono/diuoromethylated analogues can also serve as a hydrogen donor in binding enzyme active sites. As a result, a variety of structurally diverse CH 2 F, CHF 2 , and CF 3 containing drugs have been developed (Fig. 1). 1f Hence, in modern organic chemistry and in drug discovery the development of versatile uoromethylated molecules in an efficient fashion (especially in enantioenriched version) are very active research areas. Although distinct approaches 6 are available for the asymmetric construction of the C(sp 3 )-CF 3 function, little attention has been devoted towards asymmetric construction of the C(sp 3 )-CH 2 F and C(sp 3 )-CHF 2 functions. The most common used strategies for the construction of the C(sp 3 )-CH 2 F stereogenic center are monouoromethylation using 1-uorobis (phenylsulfonyl)methane (FBSM), uoro-(phenylsulfonyl)methane (FSM), 2-uoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT), or a-uoro-a-nitro(phenylsulfonyl)methane as the uoromethide equivalent (Scheme 1A). 7 Other strategies consist of diasteroselective monouoromethylation of chiral N-(tert-butylsulnyl) aldimines/ketimines using uoromethyl phenyl sulfone. 8 Enantioenriched diuoromethylated compounds are synthesized by reacting nucleophiles or electrophiles with diuoromethylation reagents, for example, PhSO 2 CF 2 H, TMSCF 2 SPh, Me 3 SiCF 2 H, Me 3 SiCF 2 SO 2 Ph, HCF 2 -SO 2 Cl, etc., or asymmetric addition of CF 2 H containing prochiral compounds such as imines, olens, and carbonyl groups (Scheme 1B). 9 However, the existing methods oen require complex reaction conditions. Reduction of uoromethylalkenes, on the other hand, remains unexplored but could be a broadly effective strategy for the construction of enantioenriched stereogenic centers bearing either CH 2 F, CHF 2 or CF 3 group by using a single general strategy. 6r,9a,10 In asymmetric catalysis, enantioselective hydrogenation of alkenes using an appropriate transition metal catalyst and chiral ligand is one of the most fundamental and atomeconomical processes. Rh and Ru catalysts are widely used for asymmetric hydrogenation of olens having strong coordinating functional group such as amides or carboxylic acids in close proximity to the double bond. 11 For olens having weak coordinating groups or non-coordinating groups, Ir complexes are the most effective catalyst. 12 Several Ru II , 13 Rh I , 14 and Pd II (ref. 15) complexes were found effective for hydrogenation of some specic CF 3 substituted olens with a coordinating group near the substrate double bond (Scheme 1C, le). Fortunately, Ir complexes complement the substrate limitations of Rh/Ru catalyzed enantioselective hydrogenation and are efficient catalysts for enantioselective hydrogenation of CF 3 substituted unfunctionalized olens or CF 3 substituted olens with the weak chelating group. 16 Herein, we report a direct catalytic, and highly enantioselective hydrogenation of uoromethylated olens for the efficient synthesis of a wide array of chiral building blocks containing uoromethyl groups.

Results and discussion
Diuoromethylated olens were rst chosen as the uoromethylated olen substrate for our study. We used (E)-ethyl 4,4-diuoro-3-phenylbut-2-enoate 1a as the model substrate and an iridium complex with a bicyclic backbone ligand as the catalyst for this asymmetric hydrogenation (Table 1). Hydrogenation of 1a using azabicyclo iridium oxazoline phosphine complex A (1 mol% catalyst, CH 2 Cl 2 , 10 bar H 2 ) gave excellent conversion in 4 h but poor enantioselectivity (95% conversion, 21% ee) of the desired product 2a (entry 1). However, the thiazole N,P-iridium complex B dramatically increased the enantioselectivity (91% ee) with very good conversion (91%, entry 2). Based on our previous knowledge of iridium-N,P catalyzed asymmetric hydrogenation, 16b we investigated the effect of varying the substituents on phosphine. Replacing the aliphatic i Pr group with aromatic group (Ph) resulted in a slight change of enantioselectivity to 92% ee with 72% conversion (entry 3). However, replacing the phenyl group with ortho-tolyl group on the bicyclic thiazole iridium-N,P catalyst (catalyst D) resulted in complete conversion (99%) to the desired product 2a with the same level of enantioselectivity (92% ee, entry 4).
to much lower conversion (17%) and slightly lower enantioselectivity of 90% ee (entry 11). Thus, among these effectively designed new catalyst, a phenyl ring with F atom at para position on thiazole moiety and ortho-tolyl group on phosphorus (catalyst G, 0.5 mol%) in PhCF 3 under 5 bar H 2 pressure for 4 h provided the superior result in enantioselectivity (96% ee) with excellent 99% conversion (entry 10).

The successful examples in
To further study the effectiveness of this developed method for the catalytic asymmetric synthesis of uoromethylated stereogenic centers, a different class of olens (vinyl uoride), which affords the chiral monouorinated molecule, was also evaluated. For these vinyl uorides, catalyst B (1 mol%) was the most suitable catalyst using 20 bar H 2 pressure for 24 h (see ESI † for optimization details). Employing the newly optimized reaction conditions, a variety of unfunctionalized naphthalene fused vinyl-uoride substrates were efficiently hydrogenated in excellent enantioselectivity (90-98% ee, Table 3, 4a-h) although in some cases the conversions are low (3c, 73%; 3d, 40%; 3e, 40%; 3h, 70%). Notably, substrates having the bulky secondary ( i Pr, Cy) substituent were hydrogenated in high levels of stereoselectivity (4d-e). Both substrates with electron-donating (Me, OMe) or electron-withdrawing (F) substituents were tolerated (3f-h), however; substrates bearing electron-donating substituents were slightly more favorable in terms of reactivity (3f-g). A small amount of de-F byproduct (3-11%) were detected in the hydrogenation, however considering the challenges generally associated with hydrogenation of vinyl-uoride, this efficient hydrogenation still highlights this catalytic protocol as general for uorine-containing olens to synthesize enantioenriched uoromethylated compounds.
Interestingly, in this work, an enantioconvergent outcome was observed, where the E and Z isomers of uoromethylated olens were successfully hydrogenated using catalyst ent-D. Both isomers produced the same enantiomer in favor. The three different types of uoromethylated olens, including CH 2 F, CHF 2 and CF 3 groups, underwent enantioconvergent hydrogenation (Table 4, entries 1-3). However, removal of uorine from the substrate (Table 4, entry 4) provided an enantiodivergent hydrogenation outcome (Table 4, entry 4), which suggested uorine played an important role in the enantio-discrimination step. Our recent work on an efficient convergent hydrogenation using Ir-N,P complexes with a weak chelating group on the double bond suggested that a-prochiral olens underwent an enantioconvergent hydrogenation while b-prochiral olens reacted in an enantiodivergent manner. 17 In this case, conversely, b-prochiral uoromethylated olen react in an enantioconvergent manner. We speculate that this could be due to the chelation effect or the electronic effect of the uorine atom. Further investigations are still in progress.
The efficacy of the asymmetric synthesis of uoromethylated compounds were investigated in gram-scale under standard reaction conditions. Product 2a was obtained in 97% yield with 96% ee (Scheme 2). This synthesized enantioenriched uromethylated compound was transformed into a variety of many useful chiral uorinated derivatives, such as alcohol, aldehyde, acid, Weinreb amide, ketone and nitrile (Scheme 2A) with almost perfect retention of enantiopurity. Interestingly, acid 11 provided (S)-3-(dichloromethyl)-2,3-dihydro-1H-inden-1-one 13 under Friedel-Cras reaction condition. In the presence of AlCl 3 , diuoromethyl group underwent halogen exchange while preserving enantiomeric purity. Based on these successful transformations, some diuoromethylated natural products were accessed (Scheme 2B). Weinreb amide 14 was further transformed into diuorinated analogue of natural products 15. Synthetically versatile intermediate alcohol was transferred into bromide 17 which could be further transformed into the diuorinated analogue of alpha-curcumene 18. 18

Conclusions
In summary, we have developed a catalytic, asymmetric methodology to synthesize various products bearing uoromethylated stereocenters, which are important bioisostere in drug discovery. Different types of uoromethylated olens and vinyl uorides were hydrogenated successfully by effective new catalyst design. In addition, an interesting enantioconvergency was observed, which indicated that uorine has the potential to control the enantioselectivity due to its special properties.

Data availability
All experimental data associated with this work are available in the ESI. †

Author contributions
P. G. Andersson and T. Zhou supervised the project and conceived experiments. J. Yang and S. Ponra designed the project, optimized the reaction, performed the major of experiments, and prepared the Supporting Information. X. Li, B. B. C. Peters, and L. Massaro prepared some of the starting materials and evaluated some hydrogenation reactions. P. G. Andersson, J. Yang, and S. Ponra wrote the paper. All authors discussed the results and commented on the manuscript.

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