Catalytic Stereoconvergent Synthesis of Homochiral β-CF3, β-SCF3, and β-OCF3 Benzylic Alcohols

We describe an efficient catalytic strategy for enantio- and diastereoselective synthesis of homochiral β-CF3, β-SCF3, and β-OCF3 benzylic alcohols. The approach is based on dynamic kinetic resolution (DKR) with Noyori–Ikariya asymmetric transfer hydrogenation leading to simultaneous construction of two contiguous stereogenic centers with up to 99.9% ee, up to 99.9:0.1 dr, and up to 99% isolated yield. The origin of the stereoselectivity and racemization mechanism of DKR is rationalized by density functional theory calculations. Applicability of the previously inaccessible chiral fluorinated alcohols obtained by this method in two directions is further demonstrated: As building blocks for pharmaceuticals, illustrated by the synthesis of heat shock protein 90 inhibitor with in vitro anticancer activity, and in particular, needle-shaped crystals of representative stereopure products that exhibit either elastic or plastic flexibility, which opens the door to functional materials based on mechanically responsive chiral molecular crystals.


■ INTRODUCTION
Fluorine atoms profoundly influence the properties of bioactive molecules on multiple levels, which results in half of blockbuster drugs and one-third of newly approved drugs being fluoro-pharmaceuticals. 1−6 Other fast-growing market segments are those of fluorinated materials for use in the electronics industry and in energy storage 7,8 and of fluorinecontaining agrochemicals. 9 Organofluorine chemistry is essentially man-made, as only a dozen fluorinated natural products have been identified on Earth. 10 The consideration of new fluorinated chemotypes for advanced applications therefore inevitably follows the availability of the synthetic methods to access the relevant moieties. Outstanding progress was achieved in the preparation of a plethora of synthetic fluorine compounds. 11 A less developed area that is highly challenging but very rewarding is the asymmetric synthesis of stereogenic fluorinated molecules. 12−15 In this context, we embarked on the asymmetric construction of chiral carbon atoms featuring a fluorinated motif with emphasis on the trifluoromethyl group C*−CF 3 and its heteroatomic homologues C*−SCF 3 and C*−OCF 3 .
In particular, β-CF 3 -substituted alcohols and amines are emerging structural motifs in medicinal chemistry ( Figure 1A). For example, compound I, prepared as a mixture of stereoisomers, exhibits antibacterial activity, 16 and racemic compound II is an inhibitor of WD repeat-containing protein 5, which is overexpressed in some types of cancer. 17 Stereochemically defined trifluoromethylated omarigliptin exhibits better pharmacokinetic and pharmacodynamic profiles compared to the parent drug molecule and is clinically evaluated as a super-long-acting antidiabetic. 18 Surprisingly, however, there are no preceding literature reports on the asymmetric synthesis of the model 2-CF 3 -1indanol 2a, its amino analogue, or their higher homologues. Nonasymmetric approaches toward such cyclic benzo-fused βtrifluoromethyl alcohols or amines have received significant attention in the past decade and are based on photoredox, electrochemical, or transition-metal-catalyzed oxy-trifluoromethylation 19−26 or amino-trifluoromethylation 27−32 of the corresponding olefins. There are only a handful of literature reports on the synthesis of the homochiral β-trifluoromethyl secondary alcohol motif ( Figure 1B). The synthetic strategies are based on a two-step arrangement of the contiguous stereocenters employing diastereoselective addition of nucleophilic vinyllithium followed by substrate-controlled olefin hydrogenation, 33 or asymmetric cycloaddition followed by NaBH 4 reduction of the ketone intermediate. 34 A single-step approach via diastereoselective aldol or Reformatsky reactions using a chiral auxiliary has been described, 35,36 but to the best of our knowledge no single-step catalytic enantioselective access to this class of molecules has ever been reported.
Dynamic kinetic resolution based on Noyori−Ikariya transfer hydrogenation (DKR-ATH) seemed like a fitting synthetic strategy for addressing the challenging simultaneous control of both chiral centers of the target compound class. 37−41 DKR-ATH is a robust method for stereoconvergent access to enantiomerically pure secondary alcohols with multiple contiguous chiral centers starting from the readily available racemic α-substituted ketones, 42−50 including fluorinated examples. 51−58 This approach to β-CF 3 alcohols would involve in situ epimerization of α-CF 3 ketones via an enol or enolate-anion intermediate. Specifically, α-CF 3 enolates have been associated with decomposition due to fluoride elimination to furnish the corresponding unstable difluoroenone. 59−61 This was foreseen as the major obstacle toward an efficient DKR-ATH-based catalytic asymmetric synthesis of β-CF 3 alcohols.

■ RESULTS AND DISCUSSION
A model racemic ketone 2-CF 3 -1-indanone 1a was prepared in one step by triflic acid mediated annulation of benzene with 2-CF 3 -acrylic acid. 62 It was subjected to DKR-ATH using a commonly used formic acid/triethylamine 3:2 mixture as a source of hydrogen and chlorobenzene as a cosolvent, and five representative Noyori−Ikariya type Ru(II) catalysts were tested (Table 1, runs 1−5). C1 is the archetypical Noyori catalyst, 63,64 and the rest are the so-called tethered catalysts, which proved to be superior for the reduction of structurally complex ketones. 65 Chronologically, C2 was developed by Wills et al., 66 followed by oxy-tethered catalyst C3 by Ikariya et al., 67 sulfamoyl-DPEN-cored C4, 68 and benzosultam-cored C5 by Mohar and co-workers. 69 19 F NMR and chiral HPLC, respectively. The absolute configuration of 2a as (S,S) was determined by single-crystal X-ray diffraction (SCXRD) analysis of a product from the run with (S,S)-C2 (Table 1, entry 2).
Disappointedly, significant amounts of side products, indanone 3a and/or indanol 4a (up to 41% total), were also detected in the reaction mixtures, indicating that detrifluoromethylation indeed took place during DKR-ATH. The catalysts performed differently regarding side product for-  Table 1. Catalyst and Solvent Screening for Ru(II)-Catalyzed DKR-ATH of 1a a a DKR-ATH of 1a (50 mg, 0.25 mmol) was carried out using a Ru(II) catalyst (1 mol %), HCO 2 H/Et 3 N (F/A) (0.25 mL) and cosolvent (0.5 mL) at 40°C. The product ratio was determined by NMR analysis of reaction mixture aliquots, and the ratio of 2a stereoisomers (cis/trans > 99:1; > 99% ee in all cases) was determined after isolation by 19 F NMR and HPLC analysis using the chiral stationary phase. PhCl = chlorobenzene; DMF = N,N-dimethylformamide; dioxane = 1,4-dioxane; 1,2-DCE = 1,2-dichloroethane. mation, and C2 was chosen for further studies because of its wide availability and favorable reaction kinetics (Table S1). Control experiments indicated that the trifluoromethyl moiety is eliminated from the ketone 1a rather than the product cis-2a via a non-ruthenium-catalyzed process involving the formation of the Et 3 N/HF adduct (see the Supporting Information (SI)). To mitigate fluoride elimination, the use of HCO 2 H/Et 3 N in a 5:2 molar ratio with the most efficient (S,S)-C2 was attempted. Performing the DKR-ATH in neat HCO 2 H/Et 3 N 3:2 or 5:2 (Table 1, entries 6 and 7) revealed that, by increasing the relative amount of formic acid, the extent of detrifluoromethylation dramatically decreases while excellent stereoselectivities are still obtained. Further solvent screening revealed that the use of any cosolvent together with HCO 2 H/Et 3 N 5:2 was beneficial for the reaction yield as less than 3% of the side products were observed in chlorobenzene, DMF, 1,4-dioxane, or 1,2-dichloroethane (Table 1, entries 8−11). The first one was deemed optimal with only 1 mol % 1-indanol accompanying the target product 2a.
Computational modeling was further performed to corroborate the high level of stereoselectivities and realize the possible mechanism of 1a racemization being the core process of DKR. The reaction between 1a and the active form of precatalyst (S,S)-C2 was studied using the M06-2X-D3/ SMD(chlorobenzene)/def2-qzvp//def2-svp method. Four diastereomeric transition states are possible ( Figure 2).
For the R Ru ,λ-catalyst structural arrangement, 73,74 observed in the solid-state of (S,S)-C2, 66 computations predict the ratio of the reaction rates leading to each stereoisomer as ∼10 9 (S,S):1800 (R,R):400 (S,R):1 (R,S). 75 This transforms into a cis/trans ratio of 2.5 × 10 6 and enantioselectivity of 99.9996% for the cis product. 76 The discrepancy between experimentally and theoretically predicted % ee is likely due to the additional mechanisms of the generation of chirality. 77 However, the calculation reproduces and points to a high level of stereodiscrimination. Two spatial regions of the catalyst simultaneously control the final stereoselectivity: the region of the tethered η 6 -arene ligand and the region of the SO 2 moiety. 71,77 Dynamic equilibrium and interplay of attraction and repulsion in each region through various noncovalent interactions lead to stabilization/destabilization of the corresponding stereoselectivity-determining transition states. The presence of the α-CF 3 functionality is crucial for exceptionally high stereoselectivity. As a comparison, DKR-ATH of 2-methyl-1-indanone using C3 yielded the corresponding alcohol with a lower cis-selectivity (cis/trans = 98:2, 98% ee), 45 whereas DKR-ATH of 2-acetamido-1-indanone (hydrogen bond donor α-substituent) using C5 was transselective (cis/trans = 9:91). 71 A 3:2 mixture of HCO 2 H/Et 3 N is a typical choice for DKR with Noyori−Ikariya catalysts, 78 whereas a 5:2 mixture is usually used for ATH of simple ketones and imines. 79−82 Although generally not explained, an Et 3 N or Et 3 N/HCO 2 H mixture might serve as a catalyst for the DKR-enabling rapid in situ racemization of the α-substituted ketones, consistent with the 3:2 choice. 83 Indeed, computations point that direct noncatalyzed epimerization of 1a is energetically prohibitive ( Figure S1, top). On the contrary, 1a racemization catalyzed by Et 3 N ("enolate-anion" pathway) and the concerted Et 3 N/ HCO 2 H process ("enol" pathway) are energetically plausible with the preference to the former by 4.3 kcal·mol −1 ( Figure S1, middle and bottom). Increasing the relative concentration of formic acid, associated with decreased fluoride elimination, pushes the major racemization pathway toward the concerted Et 3 N/HCO 2 H process.
With optimal conditions in hand, we turned our attention to DKR-ATH of various α-trifluoromethyl substituted benzofused cyclic ketones 1b−1m (Table 2). These were prepared as described for 1a, 62 via radical desulfur-fragmentation followed by reconstruction of enol triflates 84 and radical trifluoromethylation of the corresponding olefins 85 and enol acetates, 86 respectively (see the SI). The ketones 1a−1m were all converted to the corresponding stereopure alcohols 2a−2m using the optimized reaction conditions (1 mol % of C2 in HCO 2 H/Et 3 N 5:2 and chlorobenzene at 40°C) with reaction times to reach full conversion being between 1 and 6 h. Their (S,S)-absolute configuration was assigned based on SCXRD analysis of indan-cored 2a, 2d, and 2f and tetralin-cored 2k. The values of cis/trans ratio and ee in Table 2 are given as ">99", but the other three possible stereoisomers were in fact present below the limit of detection for most cases, 87 and the ee of the benzosuberol 2m was determined to be 99.2%. The tetramethyl substituted indanone 1c required a higher catalyst loading (5 mol %) to reach full conversion. The reaction yield was affected by competing detrifluoromethylaton which was generally more expressed during DKR-ATH of indan-cored ketones compared to their six-membered analogs. Nevertheless, the decomposition products 3a−3h and 4a−4h were readily removable by flash chromatography. 7-Acetamido analog 2h was formed in only 37% NMR yield with fast decomposition coupled to fast reduction in HCO 2 H/Et 3 N 3:2, which still outperformed the 5:2 ratio with 25% NMR yield and full conversion achieved only after 18 h. The tetralin derivatives 1i−1k were devoid of detrifluoromethylation, and the corresponding stereopure products 2i−2k were isolated directly after the extraction.
The method was then extended to the synthesis of stereopure 2-SCF 3 and 2-OCF 3 carbinols 2n−2p, where no side reactions were observed in either HCO 2 H/Et 3 N ratio tested. Stereoselectivities for both trifluoromethylthioethers 2n and 2o were determined to be cis/trans = 99.9:0.1 and 99.8% ee by 19 F NMR and chiral GC, respectively, which gives an estimate of the detection limit. The starting 2-SCF 3 ketones 1n and 1o were prepared by means of Billard's reagent under acidic conditions from the corresponding bare ketones. 88 2-Trifluoromethoxy-1-indanol 2p was obtained with somewhat lower stereopurity (cis/trans = 99:1, 96% ee) with the same sense of enantioselectivity (SCXRD analysis); its ketone precursor 1p was accessed via silver mediated oxidative trifluoromethylation of 2-hydroxy-1-indanone. 89 Pushing it further, the linear analogue 1q was successfully reduced within 7 h using the same standard conditions, delivering the product 2q as a 3:1 mixture of anti and syn diastereomers with 97.4% and 90.4% ee, respectively. The reduction of 1-SCF 3 -2indanone 1r to the corresponding alcohol 2r was unfortunately not highly enantioselective (45% ee), although a 95:5 cis/trans ratio was achieved.
We were pleased to find out that some of the novel enantiopure compounds prepared by our method crystallize as needle-shaped crystals which are elastically (2a, 2d, 2p, and 4d) or plastically (2o) flexible (Figure 3 and SI). Mechanically responsive molecular crystals are being recognized as an unexplored platform for applications ranging from adaptive systems and actuators to biocompatible devices and all-organic soft robots. 90−94 The crystal structures of 2a, 2d, 2o, 2p, and 4d exhibit some of the same features that were identified in other crystals with elastic 95−98 or plastic deformation behavior: 99−101 in particular, a short crystal axis (∼5 Å), anisotropic packing, corrugated crystal packing, and a prominent intermolecular interaction that is highly directional (i.e., hydrogen-bonded chains parallel to the short a-crystallographic axis in structures with P2 1 2 1 2 1 symmetry and parallel to the short b-crystallographic axis in compounds crystallizing in P2 1 space group) with much weaker interactions in the perpendicular directions. The slippage of molecular layers lined with trifluoromethyl groups has previously been established to be the mechanism of the observed plastic deformation. 101 In our case, chiral OH and the semisaturated benzo-fused scaffold clearly also contribute to mechanic responsiveness as detrifluoromethylated bromoindanol 4d was also to some degree elastically flexible. 102 Moreover, for plastically flexible 2o, two polymorphs (RT P2 1 , and 100 K P2 1 2 1 2 1 ) were identified. On the other hand, the single crystals of 2f (P2 1 2 1 2 1 ), 2k (P1), and 2n (P2 1 2 1 2 1 ) exhibit a typical brittle behavior, suggesting that subtle differences in molecular structure and crystal packing determine the sweet spot of homochiral single-component flexible crystals.
From the medicinal chemistry point of view, the stereopure products 2 represent hitherto synthetically inaccessible building blocks featuring intrinsic nonplanarity, potential for specific interactions with the protein binding sites, and several growth vectors. 103−105 Selected stereopure products 2 were thus prepared on the 1 mmol scale, and relevant further synthetic transformations were demonstrated (Scheme 1). 2g was transformed to trans-configured 5 via iron-catalyzed diastereoselective Friedel−Crafts benzylation of 2-chloroanisole. 106,107 This hydroxy-substituted 1-arylindan motif is characteristic of resveratrol dimer natural products. 108,109 2o was converted to azide 6 (trans/cis = 92:8) via nucleophilic substitution (S N 2) of the corresponding mesylate ester. It was further reduced to the corresponding amine 7 which was Table 2. Scope of the DKR-ATH a a Unless otherwise specified, the reactions were carried out using (S,S)-C2 (1 mol %) in HCO 2 H/Et 3 N 5:2 and chlorobenzene at 40°C . b NMR yield based on integration of 2 relative to 1,3 and 4. Isolated yields after extraction and optional column chromatography were 1−15% lower. c 5 mol % of (S,S)-C2 used. d HCO 2 H/Et 3 N 3:2 used. isolated as a single stereomer after chromatography. 2i was Oalkylated to obtain stereopure clickable building block 8. 2d was converted to biaryl 9 via Suzuki coupling reaction, illustrating that unprotected 2-CF 3 -carbinols are compatible with palladium catalysis. And finally, stereopure 2a and 2c were reoxidized using pyridinium chlorochromate to obtain enantioenriched 1a and 1c with 57% and 92% ee, respectively. To showcase the direct applicability of the developed synthetic methods in a medicinal chemistry setting, alkyne 8 was incorporated into 10 which represents a novel structural class of heat shock protein 90 (Hsp90) inhibitors. Compound 10 was designed using a molecular-dynamics-derived pharmacophore model ( Figure S2). 110,111 It was shown to inhibit Hsp90 in the luciferase refolding assay and display antiproliferative activity in the SkBr3 breast cancer cell line (IC 50 = 51 ± 2 μM).

■ CONCLUSION
In conclusion, we have successfully developed a highly efficient dynamic kinetic resolution strategy for the Noyori−Ikariya asymmetric transfer hydrogenation of racemic α-CF 3 , α-SCF 3, and α-OCF 3 aryl ketones with excellent stereoselectivities (up to 99.9% ee, up to 99.9:0.1 dr) and suppressed detrifluoromethylation. The origin of DKR (in situ epimerization of the ketone substrate and stereoselectivity) were investigated by DFT calculations. Applicability in the field of medicinal chemistry was demonstrated by several further transformations of the stereopure products including incorporation into a promising in vitro anticancer compound. Moreover, an unprecedented class of homochiral small organic molecules, which crystallize as mechanically responsive single-component crystals, was identified. Overall, the presented synthetic methodology opens the door to new chiral fluorinated bioactive lead compounds and to materials science applications based on adaptive chiral molecular crystals.