An Efficient and Practical Method for the Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is the peer reviewed version of the following article: Borrego, L., Recio, R., Alcarranza, M., Khiar, N., & Fernández, I. (2018). An efficient and practical method for the enantioselective synthesis of tertiary trifluoromethyl carbinols. Advanced Synthesis & Catalysis, 360(6), 1273-1279., which has been published in final form at https://doi.org/10.1002/adsc.201701212 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited." 1 An efficient and practical method for the enantioselective synthesis of tertiary trifluoromethyl carbinols. Lorenzo G. Borrego,a, ∫ Rocío Recio,a, ∫ Manuel Alcarranza,a Noureddine Khiar,b* and Inmaculada Fernández.b* a Departamento de Química Orgánica y Farmacéutica, Universidad de Sevilla. C/ García González 12, 41012 Seville, Spain. Fax: +34954556737; Phone: +34954555993; e-mail: [email protected] b Departamento de Química Bioorgánica, Instituto de Investigaciones Químicas (IIQ), C.S.I.C-Universidad de Sevilla. C/ Américo Vespucio 49, 41092, Seville, Spain Fax: +34955600426; Phone: +34954489559; e-mail: [email protected] Abstract. An efficient sulfinamide/olefin based chiral ligand, MetSulfolefin, has been developed for the enantioselective rhodium-catalysed addition of aryl-boronic acids to trifluoromethyl ketones. This shelf-stable ligand is insensitive to air, oxygen and moisture, and it is obtained in only two high yielding steps from cheap commercially available (R)-tert-butanesulfinamide. The new ligand tolerates the use of hindered boronic acids and leads to the formation of a series of chiral trifluoromethyl-substituted tertiary carbinols in high yields and excellent enantioselectivities (up to >99% ee). Keywords: Tertiary trifluoromethylcarbinols; Chiral sulfinamide-olefin; Enantioselective rhodium-catalysed arylation; Shelf-stable ligand; Cost effective synthetic approximation The preparation of organofluorine compounds is an important goal in modern synthetic chemistry, consequence of their significance in important fields including pharmaceuticals, agrochemicals, material science and catalysis.1 Particularly enantiomerically enriched trifluoromethyl-substituted alcohols having a tetrasubstitued chiral center are important compounds with remarkable biological activities.2 Thus, the preparation of enantiomerically pure tertiary trifluoromethyl carbinols have been a standing area of interest in the last two decades. In this sense, numerous methods for the trifluoromethylation of carbonyl compounds have been attempted affording in general low enantioselectivities.3 A significant alternative that has been lately carried out is the asymmetric rhodiumcatalysed addition of arylboronic acids to trifluoromethyl ketones.4 Boronic acids are attractive nucleophiles because of their wide availability, good stability and non-toxic nature apart from being compatible with a large range of functional groups.5 In contrast to the Rh-catalysed addition of boronic acids to -unsaturated carbonyl compounds and aldehydes,6 the addition of carbon nucleophiles to trifluoromethyl ketones is still a challenging synthetic problem, as the methods developed so far, generally afford the fluorinated compounds with a tetrasubstitued chiral carbon with moderate yields and ee’s.7 In the few approaches developed for this transformation, the use of P-coordinating chiral ligands containing a phosphine,4b phosphite4f or phosphoradimite group4a prevails. Of these ligands, the best results have been obtained with the C2- symmetric P-chiral ligands BIPOPs,4b developed initially in the laboratories of Boeringer Ingelheim,8 whose synthesis require an arduous process of more than 10 steps of which one is a kinetic resolution.9 In the field of asymmetric catalysis, ligand design has played a central role for the development of efficient metal and organo-catalysed processes.10 However, modern asymmetric catalysis requires ligands that are not only highly enantioselective but also structurally simple, chemically stable, and that both enantiomers are easily accessible by practical, cost effective synthetic approximations. In this sense, sulfinylbased ligands present indubitable advantages for their application in asymmetric catalysis.11 They are air, oxygen, and moisture stable, and currently a number of highly efficient approaches allow the rapid synthesis of both enantiomers of sulfinyl-based ligands and to easily modulate their structure.12 Moreover, and much like the synthetically challenging P-chiral phosphines, they are ideally suited for the construction of diverse metal-ligand complexes with a well-defined chiral environment due to the close proximity of the chiral sulfur atom to the coordination sphere of the metal. Within the chiral sulfinyl ligands developed recently, mixed sulfur/olefin ligands have shown excellent behaviour in Rh-catalysed asymmetric catalysis.13 2 Scheme 1: Synthesis of Sulfinamide-olefin derivatives 1 - 5. In particular, simple tert-butylsulfinamide derivative 1 (Sulfolefin, figure 1), enclosing a chiral sulfur atom as the sole chiral center, proved to be efficient catalyst precursor for Rh-catalysed addition of arylboronic acids to activated ketones including trifluoromethyl ketones, albeit with moderate enantioselectivities.14 Taking into account these results, and in order to enhance the enantioselectivity, so that the process is synthetic interest, in the present work differently substituted tert-butylsulfinamide-olefin ligands (2 - 5) were synthesized. The ligands were designed in order to assess the importance of the substituents at both olefinic carbons (compounds 2 and 3, Figure 1), and at the allylic position (compounds 4 and 5, Figure 1). We have also evaluated the influence of the stereochemistry of the chiral allylic carbon of this type of ligands on the stereochemical outcome of the rhodium-catalysed reaction (Figure1). Figure 1.Sulfolefin type ligands used in this work Ligands 1-515 were obtained in excellent yields and in only 2 simple synthetic steps from commercially available (R)-tert-butanesulfinamide 6,16 Scheme 1, by condensation with the corresponding - insaturated carbonyl compound 7-11,17 followed by the reduction of the obtained tert-butylsulfinyl imines, 12-16.18 The chemoselective reduction of the C=N double bond with sodium borohydride yielded the desired sulfinamide-olefins in high chemical yields. The methyl and phenyl allylic substituted derivatives 415c and 515d were obtained as a pair of diastereomers, epimers at the allylic position, and were resolved by column chromatography (Scheme 1). The obtained sulfinamide/olefin derivatives were then assayed as chiral ligands in the enantioselective rhodiumcatalysed addition of p-tolylboronic acid 17 to trifluoromethyl p-chlorophenyl ketone 18, as model reaction. The reaction was carried out using 5 mol% of the chiral ligand, in diethyl ether, under reflux during 3 hours, using KF or K2CO3 as the base, and the results are collected in table 1. As can be seen from Table 1, the assayed ligands 1- 4 were active catalyst precursors for the addition reaction, as the final trifluoromethylcarbinol19 was obtained in good chemical yield (entries 1-10, table 1). A significant decrease in the chemical yields of the additions was observed in the case of both diastereomers of the phenyl derivatives 5S and 5R (entries 11 and 12, table 1), indicating the lower catalytic activity of these ligands. Neither potassium fluoride nor potassium carbonate, used as bases significantly influences the chemical yield nor the stereoselectivity of the process (entries 1-10, table 1). Comparison of the results obtained with the different ligands clearly illustrates the lack of influence of the nature of the substituent at the allylic position or its stereochemistry, R or S, on the enantioselectivity of the process. In the case of both diastereomeric methyl derivatives, 4R and 4S, the ee’s were similar to that previously obtained with the non-substituted sulfolefin 1 (compare entries 7 and 9 vs 1, Table 1), but a small decrease in the enantioselectivity was observed in the case of the phenyl substituted ligands 5S and 5R (entries 11 3 and 12, table 1), indicating the lower inductive capacity of both of them. Table 1.Enantioselective Rh-catalysed addition of ptolylboronic acid to the trifluoromethyl p-cholorophenyl ketone using sulfinamide/olefins 1 - 5 as chiral ligands.a Entry Ligand L* Base Yield (%) ee (%) 1 1 KF 90 74 2 K2CO3 81 76 3 2 KF 86 78 4 K2CO3 74 78 5 3 KF 99 94 6 K2CO3 77 96 7 4R KF 93 74 8 K2CO3 84 72 9 4S KF 81 72 10 K2CO3 80 70 11 5S KF 51d 60 12 5R KF 33d 68 aAll reaction were conducted using 0.67 mmol of ketone 18, 1.34 mmol of boronic acid 17, 2.01 mmol of base (KF or K2CO3), 5 mol % of ligand 1-5, and 2.5 mol % of [Rh(C2H4)2Cl]2 under reflux in diethyl ether for 3 hours.bIsolated product. cDetermined by chiral stationary phase HPLC using Chiralcel OJ-H® column dThe starting ketone 18 was not consumed despite prolonging the reaction time overnight. Fortunately, the modification of the nature of the substituents at the vinylic position gave better results. Thus, a slight but not very significant increase in the enantiomeric excess was obtained when the phenyl group in ligand 1 was substituted by the napthyl group in 2 (entry 3 vs 1, table 1). However, the excellent result obtained with the ligand 3, with a methyl substituent at the double bond, highlights the importance of the substituent at the non-terminal position of the olefin in this type of ligands. Thus, we were pleased to find that with this ligand the reaction affords the desired carbinol 19 with an interesting 90-96% ee (entries 5 and 6, table 1). This represents a significant improvement of the result obtained with the Sulfolefin ligand 1, in terms of enantioselectivity of the rhodium catalysed arylboronic addition of 17 to the trifluoromethyl ketone 18 (compare entries 5 and 6 vs 1 and 2, table 1). Encouraged by the good result obtained with this sulfinamide-olefin 3, which we have denominated MetSulfolefin, we decided to determine the scope of the reaction with this ligand using boronic acids with varied steric and electronic nature and different trifluoromethyl ketones. Taking into account that, as previously indicated in table 1, similar enantioselectivities were obtained using potassium carbonate or potassium fluoride as base, all the new additions were conducted with KF, and the results are collected in table 2. The reaction is not dependent on the electronic factors of both boronic acids and ketones. In this sense, boronic acids with electron donor (17, 20, 25 and 26) or acceptor substituents (24) on the aryl group gave the products of addition with very high yields (compare entries 1-12, table 2). One of the first conclusions to be drawn from the data collected in the table is the superiority of the methyl-substituted ligand 3 compared to Sulfolefin 1 in terms of stereoselectivity (entries 1-4, table 1). The enantioselectivities obtained in the additions of aryl boronic acids 17 and 20 to the ketone 18 are significantly higher in the case of Metsulfolefin 3 as ligand, with 96% and 94% ee respectively (entries 1 and 3, table 2), compared to the ee's obtained with the Sulfolefin 1 that are under 65% (entries 2 and 4, table 2). It should be noted that with ligand 3 not only the para-substituted aryls could be introduced with very high enantioselectivities and good yields (entries 1, 3 and 8, table 2), but also the meta- and orthosubstituted aryls (entries 6, 7, 9 and 10, table 2). Thus, the addition of 3-methylboronic acid 25 to the trifluoromethyl ketone 19 gives the corresponding trifluoromethylcarbinol34, as a single enantiomer (entries 9 table 2) in very high chemical yields (91%). Interestingly the addition of the more challenging hindered boronic acids, which are less reactive and less enantioselective with the catalysts developed to date, affords the desired products with good yields and practically perfect enantioselectivities. In this sense, addition of 1- naphtylboronic acid 22 and 2-methylboronic acid 26 to the trifluoromethyl ketone 18 gives the corresponding trifluoromethyl carbinols 32 and 35 in high chemical yields and in 96 and >99% ee respectively (entries 6 and 10). Table 2: Reaction scope of the enantioselective rhodium catalysed addition of arylboronic acids to trifluoromethyl ketones with MetSulfolefin 3 as chiral ligand.a 4 Entr y. Boronic acid (Ar) Ketone (R) Product L* yield (%)b ee (%)c 1 17 (4-Me-C6H4) 18 (4-Cl) 3 99 96 2 1 99 64 3 20 (4-MeO-C6H4) 18 (4-Cl) 3 81 94 4 1 90 62 5 21 (C6H4) 18 (4-Cl) 3 94 90 6 22 (1-Napht) 18 (4-Cl) 3 71 96 7 23 (2-Napht) 18 (4-Cl) 3 86 90 8 24 (4-F-C6H4) 18 (4-Cl) 3 83 94 9 25 (3-Me-C6H4) 18 (4-Cl) 3 91 >99 10 26 (2-Me-C6H4) 18 (4-Cl) 3 83 >99 11a 26 (2-Me-C6H4) 27 (H) 3 94 94 12a 26 (2-Me-C6H4) 28 (3-F) 3 92 >99 aAll reactions were conducted using 0.67 mmol of the ketone, 1.34 mmol of the arylboronic acid, 2.01 mmol of KF, 5 mol % of ligand 1 or 3, and 2.5 mol % of [Rh(C2H4)2Cl]2 under reflux in diethyl ether for 3 h.bIsolated product. cDetermined by chiral stationary phase HPLC using Chiralcel OJ-H® column As far as we know these are the best enantioselectivities obtained in these types of transformations to date. In the case of the nonsubstituted ketophenone 27 the corresponding adduct 36 was obtained with a high 94% ee and 94% chemical yields (entry 11, table 2). The enantioselectivity was higher in the case of the meta-fluoro substituted ketone 28 allowing the formation of the corresponding carbinol 37 in >99% ee and 92% chemical yield (entry 12, table 2). Clearly, the presence of the "flag methyl" group19 in the olefinic position of ligand 3 has improved significantly the enantioselectivity in the rhodium-catalysed additions of arylboronic acids to trifluoromethyl ketones, highlighting subtle effects in the steric and electronic reorganizations of the coordinated transition states, figure 2. In this sense, although the sulfolefin-type ligands can coordinate the rhodium in different ways, NMR and RX studies have shown that they generally act as bidentate ligands capable of coordinating the metal through the sulfur and the double bond.13d, 14 (a) (b) Figure 2.(a) Conformations, A(minor) and B(major), proposed for the square planar complex intermediate [3- RhL2]. (b) Structure of the transition states, B1 and B2, proposed for the attack of the aryl group to the si and re face of the trifluoromethyl ketone. In the square planar complex intermediate, figure 2, and due to an unfavourable steric interaction with the cis vinylic methyl group of ligand 3, the phenyl group cannot be coplanar with the double bond, figure 2(a), and rotates slightly out of this plane to give a new conformation, figure 2(b), in order 5 minimize this interaction. In the new conformation, the phenyl ring points to the same side than the tert-butyl group, key element in the observed enantioselectivity, thus enhancing the whole stereochemical outcome of the process. In this sense, of the two possible intermediates B1 and B2, formed through substrate coordination to the aryl rhodium intermediate in the proposed catalytic cycle of the Rh-catalysed addition of boronic acid to activated ketone, intermediate B1 is much more favorable than intermediate B2 with ligand 3. Thus, insertion of the aromatic ring to the carbonyl group in intermediate B1 (siface attack), followed by transmetallation explains the formation of the observed major isomer, figure 2. In conclusion, we have developed an efficient sulfinamide/olefin based chiral ligand, MetSulfolefin, for the enantioselective rhodiumcatalysed addition of aryl-boronic acids to trifluoromethyl ketones. This shelf stable ligand is insensitive to air, oxygen and moisture, and it is obtained in only two high yielding steps from cheap commercially available (R)-tert- butanesulfinamide. The new ligand leads to the formation of a series of chiral trifluoromethylsubstituted tertiary carbinols in high yields and excellent enantioselectivities (up to 100% ee). To the best of our knowledge "MetSulfolefin" can be considered as one of the best chiral ligands developed for this rhodium-catalysed process, up to now. The presence of a methyl group at the nonterminal vinylic position of this new chiral ligand seems to be the key to its success. Applications of this ligand in other rhodium-catalysed processes are currently under investigation and the results will be reported in due course Experimental Section (R,E)-N-2-Methyl-3-phenylprop-2-en-2-yl tertbutylsulfinamide, Metsulfolefin 3. To a solution of -methylcinnamaldehyde (1.05 mL, 7.50 mmol, 100 mol%) and (R)-tert-butanesulfinamide 6 (1.0 g, 8.25 mmol, 110 mol%) in dry THF (25 mL), at room temperature under argon atmosphere, Ti(OEt)4 (1.73 mL, 8.25 mmol, 110 mol%) was added. Once the starting material was consumed (24 h), the reaction mixture was hydrolysed with a saturated NaCl aqueous solution (25 mL). The resulting suspension was filtered through a pad of Celite. The aqueous phase was extracted with CH2Cl2 (3 x 40 mL) and the combined organic phases were dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (EtOAc:hexane, 1:10) to give 1.53 g of (R,E,E)-N-2- Methyl-3-phenyl-prop-2-en-1-ylidene tertbutylsulfinamide, 14. 14 (6.13 mmol, 82% yield) as yellow liquid. [α]D20: - 401.4 (c1, CHCl3). 1H-NMR (500 MHz, CDCl3): δ 8.30 (s, 1H), 7.46-7.45 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.10 (bs, 1H), 2.20 (d, J = 1.2 Hz, 3H), 1.24 (s, 9H) ppm. 13C-NMR (125 MHz, CDCl3): δ 167.2, 144.2, 136.0, 135.3, 128.8, 128.6, 57.5, 27.6, 13.2 ppm. HRMS: Calc. for C14H19NOS [M+H]+: 250.1260; found 250.1255 (-2.2111 ppm). To a solution of the N-tert-butylsulfinylimine 14 (750 mg, 3 mmol, 100 mol%) in dry MeOH (20 mL), under argon atmosphere, at 0°C, NaBH4 (113.8 mg, 6 mmol, 200 mol%) was added. Once the starting material was consumed, a saturated NH4Cl aqueous solution was added. The aqueous phase was extracted with EtOAc (3 x 40 mL) and the combined organic phases were dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (EtOAc/hexane 1:3) to give 651.5 mg of 3 (2.59 mmol, 86% yield) as a white solid. M.p.: 72-73°. [α]D20: -47.9 (c 1, CHCl3). 1H-NMR (500 MHz, CDCl3): δ 7.35-7.32 (m, 2H), 7.27-7.26 (m, 2H), 7.24-7.21 (m, 1H), 6.50 (bs, 1H), 3.82 (AB fragment of an ABX system, Δν = 58.7 ppm, J = 7.5, 5.1 and 14.0 Hz, 2H), 3.32 (t, J = 6.0 Hz, 1H), 1.91 (d, J = 0.8 Hz, 3H), 1.26 (s, 9H) ppm.13C-NMR (125 MHz, CDCl3): δ 137.5, 135.5, 129.0, 128.3, 127.7, 126.8, 56.0, 54.2, 22.8, 16.4 ppm. HRMS: Calc. for C14H21NOS [M+H]+: 274.1236; found 274.1231 (-1.9480 ppm). Rhodium-catalysed 1,2-addition of boronic acids to trifluoromethyl ketones. Typical Procedure. To a mixture of the arylboronic acid (1.34 mmol), KF (2.01 mmol), the chiral ligand 3 (8.42 mg, 0.03 mmol, 5 mol %) and [Rh(C2H4)2Cl]2 (0.015 mmol, 2.5 mol %) was added the trifluoromethyl ketone (0.67 mmol) and Et2O (10 mL). After stirring the mixture at reflux for 3 hours, the reaction mixture was directly purified by flash chromatography on silica gel (Hexane/CH2Cl24:1) to afford the desired trifluoromethyl carbinol. The enantioselectivity was determined by chiral HPLC. Acknowledgements This work was supported by the "Ministerio de Economía y Competitividad" CTQ2016-78580-C2-2-R), and the Junta de Andalucía (P11-FQM-08046). We gratefully thank CITIUS for NMR facilities References [1] (a) J. Wang, M. Sánchez Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432- 2506; (b) I. Ojima, J. R. McCarthy, J. T. Welch, In Biomedical Frontiers of Fluorine Chemistry; ACS Editions: Washington DC, 1996; (c) T. Hiyama, In Organofluorine compounds. Chemistry and Applications; Yamamoto, H., Eds.; Springer: New York, 2000. 6 [2] (a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763-2793; (b) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5, 873-888; (c) P. Tian, H.-Q. Dong, G.-Q. Lin, ACS Catal. 2012, 2, 95-119; (d) B. Jiang, Y.-G. Si, Angew. Chem, Int. Ed. 2004, 43, 216-218; (e) M. L. P. Price, W. J. Jorgensen, J. Am. Chem. Soc. 2000, 122, 9455-9466; (f) L. Tan, C.-Y. Chen. R. D. Tillyer, E. J. J. Grabowski, P. J. Reider, Angew. Chem. Int. Ed. 1999, 38, 711-713; (g) F. Xu, R. A. Reamer, R. Tyllier, J. M. Cummins, E. J. J. Grabowski, P. J. Reider, D. B. Collum, J. C. Huffman, J. Am. Chem. Soc. 2000, 122, 11212- 11218. [3] (a) Chang, Y.; Cai, C. Tetrahedron Lett. 2005, 46, 3161-3164; (b) S. Roussel, T. Billard, B. R. Langlois, Chem. Eur. J. 2005, 11, 939-944; (c) G. K. S. Prakash, J. Hu, J. A. Olah, J. Org. Chem. 2003, 68, 4457-4463; (d) B. R. Langlois, T. Billard, Synthesis 2003, 2, 185-194 (e) J. Joubert, S. Roussel, C. Christophe, T. Billard, B. T. Langlois, T. Vidal, Angew. Chem. Int. Ed. 2003, 42, 3133-3136; (f) G. K. S. Prakash, J. Hu, G. A. Olah, Org. Lett. 2003, 5, 3253-3256; (g) S. Roussel, T. Billard, B. R. Langlois, Synlett, 2004, 2119-2122; (h) S. Mizuta, N. Shibata, S. Akiti, H. Fujimoto, S. Nakamura, T. Toru, Org. Lett. 2007, 9, 3707-3710; (i) H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Org. Lett. 2010, 12, 5104-5107; (j) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1-PR43. [4] (a) S. L. X. Martina, B. C. J. Richard, J. G. de Vries, F. L. Feringa, A. J. Minnard, Chem. Commun. 2006, 4093-4095; (b) R. Luo, K. Li, Y. Hu, W. Tang, Adv. Synth. Catal. 2013, 355, 1297-1302; (c) L. S. Dobson, G. Pattison, Chem. Commun. 2016, 52, 11116- 11119; (d) V. Valdivia, I. Fernández, N. Khiar, Org. Biomol. Chem. 2014, 12, 1211-1214; (e) J. R. White, G. J. Price, P. K. Plucinsky, C. G. Frost, Tetrahedron Lett. 2009, 50, 7365-7368; (f) V. R. Jumde, S. Faccheti, A. Iuliano, Tetrahedron: Asymmetry 2010, 21, 2775-2781. [5] (a) D. G. Hall, In Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine. Wiley-VCH: Weinheim, 2005; (b) R. Shintai, M. Inoue, T. Hayashi, Angew. Chem. Int. Ed. 2006, 45, 3353-3356; (c) H. F. Duan, J.-H. Xie, X.-C. Qiao, L. X. Wang, Q.-L. Zhou, Angew. Chem., Int. Ed. 2008, 47, 4351-4353. [6] (a) G. Berthon, T. Hayashi, In Catalytic Asymmetric Conjugate Reactions. Córdova, A., Eds.; Wiley- VCH: Weinheim, 2010, chap. 1; (b) K. Yoshida, T. Hayashi, In Modern Rhodium-Catalysed Organic Reactions. P. A. Evans, Eds,; Wiley-VCH: Weinheim, 2005, chap. 3; (c) H. J. Edwards, J. D. Hargrave, S. D. Penrose, C. G. Frost, Chem. Soc. Rev. 2010, 39, 2093-2105; (d) C. Defieber, H. Grútzmacher, E. M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4482-4502; (e) J. B. Johnson, T. Rovis, Angew. Chem. Int. Ed. 2008, 47, 840-871. [7] (a) V. L. Steven, In Quaternary Stereocenters. Challenges and Solutions for Organic Synthesis. J. Christoffers, A. Baro, Eds.; Wiley-VCH: Weinheim, 2005; (b) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 389-401; (c) J. Christoffers, A. Baro, Adv. Synth.Catal. 2005, 247, 1473-1482; d) B. M. Trost, C. Jiang, Synthesis 2006, 3, 369-396. [8] W. Tang, B. Qu, A. G. Capacci, S. Rodriguez, X. Wei, N. Haddad, B. Narayanan, S. Ma, N. Grinberg, N. K. Yee, D. Krishnamurthy, C. Senanayake, Org. Lett. 2010, 12, 176-179. [9] G. Li, X.-J. Wang, Y. Zhang, Z. Tan, P. DeCroos, J. C. Lorenz, X. Wei, N. Grinberg, N. K. Yee, C. H. Senanayake, J. Org. Chem. 2017, 82, 5456-5460. [10] (a) Nelson, J. H. In Chiral Auxiliaries and Ligands in Asymmetric Synthesis; J. Seyden-Penne, Ed.; Wiley-Interscience: New York, 1995; (b) D. A. Evans, J. S. Johnson, In Comprehensive Asymmetric Catalysis, Vol. I-III,; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer: Berlin, 1999; (c) C. S. Kramer, S. Bräse, In Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. P. Dalko, Ed. Wiley- VCH: Weinheim, 2013; (d) W. Zhang, Y. Shi, X. Zhang, Acc. Chem. Res. 2007, 40, 1278-1290; (e) A. Pfaltz, W.J. Drury, PNAS 2004, 101, 5723-5726. [11] I. Fernández, N. Khiar, In Organosulfur Chemistry in Asymmetric Synthesis; T. Toru, C. Bolm, Eds.; Wiley-VCH-Verlag:Weinheim, 2008, pp. 265; (b) B. M. Trost, M. Rao, Angew. Chem. Int. Ed. 2015, 54, 5026-5043;(c) G. Sipos, E. M. Drinkel, R. Dorta, Chem. Soc. Rev. 2015, 44, 3834-3860. [12] (a) E. Wojaczynska, J. Wojaczynkski, Chem. Rev. 2010, 110, 4303-4356; (b) M. C. Carreño, G. Hernández-Torres, M. Ribagorda, A. Urbano, Chem. Commun. 2009, 6129-6144; (c) C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Han, I. Gallou, Aldrich. Chim. Acta 2005, 38, 93-104; (d) I. Fernández, N. Khiar, Chem. Rev. 2003, 103, 3651-3705. [13] (a) R. Mariz, X. J. Luan, M. Gatti, A. Linden, R. Dorta, J. Am. Chem. Soc. 2008, 130, 2172-2173; (b) J. J. Burgi, R. Mariz, M. Gati, E. Drinkel, X. J. Luan, S. Blummenrit, A. Linden, R. Dorta, Angew. Chem. Int. Ed. 2009, 48, 2768-2771; (c) T. Thaler, L.-N. Guo, A. K. Steib, M. Raducan, K. Karaghiosoff, P. Maer, P. Knochel, Org. Lett. 2011, 13, 3182-3185; (d) X. Feng, Y. Wang, B. Wei, J. Yang, H. Du, Org. Lett. 2011, 13, 3300-3303; (e) G. Chen, J. Gui, L. Li, J. Liao, Angew. Chem. 2011, 123, 7823-7827; Angew. Chem. Int. Ed. 2011, 50, 7681-7685; (f) X. Feng, B. Wei, J. Yang, H. Du, Org. Biomol. Chem. 2011, 9, 5927-5929; (g) F. Xue, X.-C. Li, B.-S. Wan, J. Org. Chem. 2011, 76, 7256-7262; (h) Y. Wang, X. Feng, H. Du, Org. Lett. 2011, 13, 4954-4957. [14] (a) V. Valdivia, N. Bilbao, J. F. Moya, C. Rosales- Barrios, A. Salvador, R. Recio, I. Fernández, N. Khiar, RSC Adv. 2016, 6, 3041-3047; (b) N. Khiar, A. Salvador, V. Valdivia, A. Chelouan, A. Alcudia, E. Álvarez, I. Fernández, J. Org. Chem. 2013, 78, 6510-6521; (c) N. Khiar, V. Valdivia, A. Salvador, A. Chelouan, A. Alcudia, I. Fernández, 7 Adv. Synth. Catal. 2013, 355, 1303-1307; (d) N. Khiar, A. Salvador, A. Chelouan, A. Alcudia, I. Fernández, Org. Biomol. Chem. 2012, 10, 2366-2368. [15] (a) T.-S. Zhu, S.-S. Jin, M.-H. Xu, Angew. Chem. Int. Ed. 2012, 51, 780 –783; (b) S.-S. Jin, H. Wang, T.-S. Zhu, M.-H. Xu, Org. Biomol. Chem. 2012, 10, 1764-1768; (c) A. Adamkiewicz, J. Mlynarski, Eur. J. Org. Chem. 2016, 5, 1060-1065; (d) Z.-J. Liu, J.-T. Liu, Chem. Comm. 2008, 41, 5233-5235. [16] M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010, 110, 3600–3740. [17] (a) A. Nordqvist, C. Björkelid, M. Andaloussi, A.M. Jansson, S. L. Mowbray, A. Karlén, M. Larhed, J. Org. Chem. 2011, 76, 8986–8998. (b) N. Solin, L. Han, S. Che, O. Terasaki, Catal. Commun. 2009, 10, 1386–1389. [18] (a) J.L. García-Ruano, I. Fernández, M. del Prado, A. Alcudia, Tetrahedron: Asymmetry 1996, 7, 3407- 3414. (b) G. K. Surya-Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001, 3, 2847-2850. (c) J. P. McMahon, J. A. Ellman, Org. Lett. 2005, 7, 5393- 5396. [19] The term "flag methyl" was introduced by the Ciba Geygi group in the development of Imatinib [R. Capdeville, E. Buchdunger, J. Zimmermann, A. Matter, Nat. Rev. Drug Discov. 2002, 1, 493-502]. Thus, the improved activity and selectivity of the rhodium catalysed addition of arylboronic acids to trifluoromethyl ketones with ligand 3, the methylated analogue of sulfolefin 1, could be considered similar to the well known effect of methylation of substrates in medicinal chemistry, favouring a conformation suitable for the ligand-enzyme interaction. 8 COMMUNICATION An efficient and practical method for the enantioselective synthesis of tertiary trifluoromethyl carbinols Adv. Synth. Catal. Year, Volume, Page – Page Lorenzo G. Borrego,a, ∫ Rocío Recio,a, ∫ Manuel Alcarranza,aNoureddine Khiar,b* and Inmaculada Fernández.b* tBu S O N H MetSulfolefin CH3 F3C O MetSulfolefin (5 mol%) [Rh(C2H4)2Cl2]2 (2.5 mol %) Et2O, reflux KF HO CF3 R R B(OH)2 XX up to 99% up to > 99% ee - Shelf stable - Obtained in 2 high yielding steps - Both enantiomers are easily accesible. - Cheap commercially available starting materials