Practical Asymmetric Fluorination Approach to the Scalable Synthesis

Communication Cite This: Org. Process Res. Dev. 2018, 22, 650−654

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Practical Asymmetric Fluorination Approach to the Scalable Synthesis of New Fluoroaminothiazine BACE Inhibitors Pablo Garcia-Losada,*,† Mario Barberis,† Yuan Shi,‡ Erik Hembre,‡ Carolina Alhambra Jimenez,† Leonard L. Winneroski,‡ Brian M. Watson,‡ Chauncey Jones,‡ Amy C. DeBaillie,‡ Francisco Martínez-Olid,† and Dustin J. Mergott‡ †

Centro de Investigación Lilly S.A., Avda. de la Industria 30, Alcobendas, Madrid 28108, Spain Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States

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‡

S Supporting Information *

2. RESULTS AND DISCUSSION The use of fluorine in medicinal chemistry continues to provide a strong stimulus for the development of new synthetic methodologies that allow easier access to a wide range of fluorinated compounds.4 In particular, enantioselective fluorination of aldehydes in the presence of chiral amines has been evidenced as an efficient process for this transformation.5 However, at the outset of our effort there was minimal precedent for diastereoselective introduction of fluorine at the α-position of an aldehyde to obtain a quaternary center,6 and we were cognizant of the challenges associated with the formation of two adjacent quaternary carbon centers in such a congested steric environment. The synthetic route that initially demonstrated the feasibility of this carbon−fluorine bond-forming event is shown in Scheme 1. Starting from chiral amino alcohol 4, the key step to access the fluorinated target compound 3b was performed by achiral fluorination of the epimeric mixture of aldehydes 5a and 5b. In situ formation of the aldehyde pyrrolidine imine followed by treatment with Selectfluor® afforded a mixture of fluoroaldehydes, which were transformed into the desired amino alcohol diastereomers (3a and 3b) in a 7:1 ratio. NMR characterization of the two pure diastereomers 3a and 3b, which were isolated by chromatography,7 indicated that the minor diastereomer, obtained in only 5% yield, corresponded to the desired isomer 3b. This result indicated that the fluorination sequence would require significant improvement, especially if this process were to be used to prepare isomer 3b on a multigram scale. Alcohol Oxidation Step: Development, Optimization, and Scale-Up. The discovery route started from chiral amino alcohol 4, which after protection of the amino group was transformed into aldehyde mixture 5a/5b by TEMPO/bleach oxidation.8 Unfortunately, this reaction was challenging to scale-up because of the large amount of overoxidation byproduct together with the concurrent decomposition observed (Scheme 2). Different oxidation conditions were explored (Table 1), and the results confirmed that mild oxidants such as IBX and TEMPO (especially when Javel water9 was used as a stoichiometric co-oxidizing reagent) afforded the desired

ABSTRACT: Here we report an optimized protocol for the asymmetric introduction of a fluorine atom into a quaternary center facilitated by D-proline, Selectfluor®, and trifluoroethanol. The synthesis proceeds over four steps starting from a chiral amino alcohol precursor and provides the desired enantiomer with no erosion of chiral purity and good diastereoselectivity. The process optimization allowed diastereoselective preparation of the key intermediate on a multigram scale.

1. INTRODUCTION We previously reported the discovery of LY2886721 (1), a potent β-secretase (BACE) inhibitor that advanced to Phase II clinical trials.1 During the course of our research, we also sought to prepare (2), which contains a fluorine at the bridgehead position of the bicyclic aminothiazine (Figure 1).2

Figure 1. Retrosynthetic analysis of 2.

We hypothesized that the fluorinated amino alcohol tert-butyl N-[(3S,4S)-3-(5-acetamido-2-fluorophenyl)-4-fluoro-4(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (3b) could provide access to fluorinated bicyclic aminothiazine 2. Thus, we decided to develop a safe, enantioselective, and scalable route for the preparation of compound 3b with the required stereochemistry, taking advantage of the availability of the key chiral amino alcohol intermediate N-[3-[(3S,4R)-3amino-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4fluorophenyl]acetamide hydrochloride (4) previously reported in the literature.3 Herein we describe the development of an efficient four-step sequence to deliver 3b on a multigram scale. © 2018 American Chemical Society

Received: March 10, 2018 Published: April 24, 2018 650

DOI: 10.1021/acs.oprd.8b00069 Org. Process Res. Dev. 2018, 22, 650−654

Organic Process Research & Development

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Scheme 1. Synthetic Sequence Validationa

a Reagents and conditions: (i) TEA (2 equiv), BOC2O (1.2 equiv), 50 °C, 2 h; (ii) citric acid; (iii) TEMPO (0.2 equiv), NaOCl (2 equiv), THF, 5 °C, 2 h; (iv) pyrrolinidine (1.1 equiv), THF, 22 °C, 14 min.; (v) Selectfluor® (1.2 equiv), 22 °C, 2.5 h; (vi) NaHCO3 sat. aqueous solution; (vii) NaBH4 (1.2 equiv), MeOH, 22 °C, 1 h ; (viii) NaHCO3 sat. aqueous solution; (ix) chiral chromatography

Scheme 2. Oxidation Stepa

a

(i) TEA (2 equiv), BOC2O (1.2 equiv), 50 °C, 2 h; (ii) citric acid; (iii) TEMPO (0.2 equiv), NaOCl (2 equiv), THF, 5 °C, 2 h.

Table 1. Optimization of the Oxidation Step entry

solvent

oxidant

equiv

catalyst

base

t (h)

4

5a/5bg

5c/5dg

yield (%)h

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

DMSO AcOEt AcOEt AcOEt CH2Cl2 AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt CH2Cl2 AcOEt

IBXa IBS/Oxoneb NaOCl NaOCl NCS SO3Pya SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO SO3Py/DMSO

1 0.1 1.7 3 1.3 6 3 3 3 3 1.8 2.3 2.3 2.3 2.3

none none TEMPO (0.1 equiv)/ KBr (0.1 equiv) TEMPO (0.2 equiv)/KBr (0.1 equiv)c TEMPO (0.1 equiv)/TBACl (0.1 equiv) none none none none none none none none none none

none none NaHCO3 NaHCO3 K2CO3 TEA TEA TEA TEA DIPEAd DIPEAe DIPEAf DBU TEA n-Pr3N

36 1 4 7 21 24 22 72 48 2 24 1.5 2 23 23

51 98 2 ≤1 19 20 3 3 1 1 4 ≤1 − 3 3

39 1 1 ≤1 66 65 80 78 81 81 95 99 − 86 97

10 1 87 99 15 8 − − − − − − − − −

22 − − − 31 52 77 69 63 76 72 83 − 70 71

Solid addition portionwise over the substrate. bPotassium 2-iodo-5-methylbenzenesulfonate. cTemperature = 0−5 °C. dTemperature = −10 °C, DIPEA (3 equiv). eTemperature = 0 °C, DIPEA (1.5 equiv). fTemperature = 0−5 °C, DIPEA(1.5 equiv). gConversions were calculated by HPLC. h Isolated yields after workup and purification. a

required for complete starting material consumption. In that regard, preactivated SO3Py complex in combination with Hünig’s base11 led to starting material consumption without overoxidation byproducts in less than 2 h (entry 12), while other bases such as triethylamine, pyridine, 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), and tri-N-propylamine resulted in prolonged reaction times (entries 10 and 13−15). The best reaction conditions (entry 12) were selected for scale-up. After confirmation that the addition order did not affect the outcome of the reaction, the scale-up was performed by adding a mixture of Hünig’s base and BOC-protected amino alcohol over a mixture of preactivated SO3Py complex in DMSO/ethyl acetate while the temperature was kept below 5 °C. Following this procedure, the 5a/5b mixture was isolated as an oil in 93% yield, but unfortunately, it was impossible to

compound with significant amounts of undesired byproducts 5c−f. Only Parikh−Doering oxidation conditions (SO3Py complex)10 circumvented the overoxidation problem, affording a mixture of two compounds (5a and 5b) in moderate yield and selectivity. Under the assumption that fluorination of the enamine intermediate was the stereodetermining step, the diastereomeric purity of the aldehyde was irrelevant for the final diastereoselectivity. Thus, we focused our efforts on maximizing the yield of the oxidation reaction by minimizing the overoxidation byproducts such as 5c−f. Optimization of the oxidation of alcohol 4 to aldehyde mixture 5a/5b showed that oxidant preactivation in dimethyl sulfoxide (DMSO) solution, combined with the addition of different organic amines, reduced the amount of oxidant 651



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Figure 2. Selected fluorination agents and chiral amines.

purify either by crystallization under all conditions tested or by alternative bisulfite aldehyde adduct formation. The mixture was used in the next step without additional purification. Fluorination Reaction: Reaction Optimization and Scale-Up. In the initial synthetic approach using the pyrrolidine imine, the results clearly indicated an intrinsic bias for the undesired diastereomer, and we sought to overcome this bias with a chiral reagent. We focused our initial effort on evaluating different chiral reagents in combination with different fluorinating agents (Figure 2). These studies showed that formation of diastereomer 6b was observed only with Selectfluor® (7a) as the fluorinating source. With all of the other fluorinating agents tested, only diastereomer 6a was observed along with decomposition products. Focusing on Selectfluor®, we investigated whether the chiral amine could be used as an organocatalyst to further improve the diastereoselectivity.6 Slow conversion and substantial formation of side products were observed, except with 0.3 equiv of amines 8a, 8c, 8d, and 8e. After further evaluation of the organocatalyst stoichiometry, conversion, and selectivity, we concluded that the best results were obtained when stoichiometric quantities were used. Chiral amine 8e appeared to be optimal, showing superior stereoselectivity and conversion relative to other amines. A deep process study was performed with Selectfluor® as the fluorinating agent and stoichiometric quantities of chiral reagent 8e, using different solvents and evaluating the imine formation and fluorination reaction under stepwise versus onepot conditions (Table 2). The imine and aldehyde signals were followed by 1H NMR spectroscopy as references to measure the conversion. The analysis showed that up to 90% conversion was observed when alcohols were used, particularly when the reaction was performed in methanol, ethanol, or trifluoroethanol, (entries 2, 8, and 12), which afforded an enriched mixture containing aldehyde 6b. Other solvents afforded only partial conversion or byproduct formation that did not allow the generation of a stable imine intermediate. These three conditions (entries 2, 8, and 12), were tested on a 5 g scale, and it was determined that trifluoroethanol was the optimal solvent, giving nearly complete conversion in 24 h. Conversely, reactions in methanol and

Table 2. Solvent Screening entry

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

dioxane EtOH ACN toluene NMP DMA MTBE MeOH IPA DCM MeTHF trifluoroethanol THF EtOH/Tol (1:5) MeOH/Tol (1:5) EtOH/DCM (1:5) MeOH/DCM (1:5) MeOH/MTBE (1:5) MeOH/MeTHF (1:5)

16 17 18 19 a

imine conversiond

6a 6b (area %)d (area %)d

6b/6a ratiod

65a 95a 75a 25b 64a 69a 40b 94c 73a 67a 57a 96c 75a 64a 94a

33 22 42 60 59 54 38 30 27 32 40 20 38 30 38

60 43 48 13 22 27 40 57 44 57 53 61 54 43 42

2 2 0.2 0.2 0.37 0.5 1 1.9 1.6 1.8 1.3 3 1.4 1.4 1.1

93c

23

51

2.1

94c

30

57

1.9

59a

38

53

1.2

a

38

52

1.2

81

Heterogenous suspension. bSticky, oily solid. solution. dDetermined by HPLC.

c

Homogeneous

ethanol afforded mixtures of the desired product together with a significant amount of byproduct formation. Finally, the impact of temperature and solvent quality on the conversion and selectivity were evaluated. No effect on either the diastereoselectivity or reaction rate was observed when the temperature was increased, but larger amounts of side products were obtained when the reaction was performed at above 35 °C. When freshly distilled trifluoroethanol or technical grade solvent was used, almost complete conversion was observed in 24 h, but the reaction time could be shortened to less than 4 h when dry solvent12 was used, showing that water removal improved the reaction time. 652



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On the basis of these results, Selectfluor® and amine 8e in dry trifluorethanol were selected as the optimal conditions for the fluorination of aldehyde epimeric mixture 5a/5b to generate the desired fluoroaldehyde derivative. The reaction was scaled up to a 1.6 mol scale, affording the desired product 6a/6b in a 1/7 ratio and 90% yield. Chiral amine and Selectfluor® byproducts were easily removed by extraction and simple salts by filtration. The material was isolated with sufficient purity to avoid chromatography, but all attempts to isolate the desired enantiomer from the reaction mixture by crystallization or bisulfite adduct formation were unsuccessful. Subsequently, the crude fluoroaldehyde mixture 6a/6b was transformed into the desired amino alcohol by treatment with sodium borohydride in ethanol. Starting material comsumption and conversion stalled at 98% after 2 h without isomerization under the reaction conditions, and it was shown that the addition of a reducing agent at 0 °C is beneficial for the outcome of the reaction compared with room temperature.

= 2.50 ppm, 13C = 39.52 ppm). Coupling constants are quoted to the nearest 0.1 Hz, and multiplicities are given by the following abbreviations and combinations thereof: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). The purities of all compounds tested were determined by LCMS and 1H NMR analyses to be >95%. Preparation of tert-Butyl N-[(3S)-3-(5-Acetamido-2fluorophenyl)-4-formyltetrahydrofuran-3-yl]carbamate (5a/5b). Amino Alcohol Protection Step. A solution of N-[3[(3S,4R)-3-amino-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4fluorophenyl]acetamide hydrochloride (4) (1 kg, 8.20 mol) and di-tert-butyl dicarbonate (2.15 kg, 9.84 mol) in tetrahydrofuran (11 L) was treated with triethylamine (2.28 L, 16.40 mol), and then the reaction mixture was heated at 50 °C for 2 h, cooled to 22 °C, and evaporated to dryness. The residue was partitioned between 10% aqueous citric acid solution (3 L) and methyl tertbutyl ether (5 L). The layers were separated, and the aqueous layer was washed three times with methyl tert-butyl ether (3 × 1 L). The organics were combined, washed with brine (2 L), and concentrated to dryness to afford tert-butyl N-[(3S,4R)-3(5-acetamido-2-fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (2.20 kg, 5.97 mol; 78% yield) as a yellow solid, consistent with previously reported data.2 The crude solid was put into the next step without purification. 1 H NMR (300.16 MHz, CDC13): δ 7.85−7.79 (m, 1H), 7.60−7.56 (m, 1H), 7.41−736 (m, 1H), 7.26 (d, J = 1.0 Hz, 7H), 7.04−6.95 (m, 2H), 4.26−4.11 (m, 2H), 3.80−3.72 (m, 3H), 2.15 (s, 5H), 2.05 (d, J = 0.8 Hz, 1H), 1.72−1.67 (m, 1H), 1.36 (s, 13H), 1.31−1.26 (m, 3H). Parikh−Doering Oxidation. Sulfur trioxide pyridine complex (1.46 kg, 9.16 mol) was dissolved in dimethyl sulfoxide (3.5 L). Next, in a separate flask, tert-butyl N-[(3S,4R)-3-(5acetamido-2-fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran3-yl]carbamate (1.5 kg, 4.05 mol) was dissolved in ethyl acetate (2 L), and the solution was cooled to 10 °C under a nitrogen atmosphere. To this solution was added Hünig’s base (670 mL, 4.05 mol), and the mixture was cooled to 0 °C, followed by the addition of the oxidant solution with the temperature kept below 5 °C. After 1 h of stirring at 5 °C, water (6 L) was added, and organic layer was separated. The aqueous layer was washed with ethyl acetate (10 L), and then the organics were combined, washed with 10% w/w citric acid solution (3 × 2L) and finally with brine (7 L). The solvent was evaporated, and the residue was dried under vacuum to yield tert-butyl N-[(3S)-3-(5-acetamido2-fluorophenyl)-4-formyltetrahydrofuran-3-yl]carbamate as a beige foam containing the isomer mixture 5a/5b in a 9:1 ratio (1.31 kg, 88%).2 The crude foamy solid was put into the next step without purification. 1 H NMR (300.16 MHz, CDC13): δ 9.87 (d, J = 2.8 Hz, 1H), 9.44 (t, J = 2.2 Hz, 1H), 7.63−7.55 (m, 3H), 7.43−7.31 (m, 2H), 7.26 (s, 3H), 7.04−6.98 (m, 2H), 5.30 (s, 1H), 4.49−4.28 (m, 5H), 4.12−4.06 (m, 2H), 3.75 (td, J = 7.6, 2.6 Hz, 1H), 3.21 (s, 4H), 2.62 (s, 1H), 2.15 (d, J = 4.4 Hz, 6H), 1.63 (s, 4H), 1.36−1.31 (m, 18H), 1.19 (s, 11H). Preparation of tert-Butyl N-[(3S,4S)-3-(5-Acetamido-2fluorophenyl)-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (3b). To a solution of 5a/ 5b (650 g, 1.77 mol) in dry trifluoroethanol12 (6.5 L) cooled at 0 °C under a nitrogen atmosphere was added D-proline (245 g, 2.13 mol) portionwise, with the internal temperature kept below 15 °C. The mixture was stirred at 10−15 °C for 2 h. Selectfluor® (823.9 g, 2.31 mol) was added portionwise during

3. CONCLUSIONS We have developed an efficient and practical fluorination reaction facilitated by D-proline in trifluoroethanol that generates a congested quaternary stereocenter in high yield with good diastereoselectivity. Aldehyde mixture 5a/5b was obtained via oxidation of alcohol 4. The α-fluorination of this aldehyde mixture followed by direct treatment of the crude αfluoro aldehyde product with sodium borohydride afforded the desired fluoro amino alcohol in 90% yield with 7:1 diastereoselectivity for 3b over 3a, which was purified by silica gel pad filtration to give the desired diastereomer 3b in 70% overall yield with 98% ee. 4. EXPERIMENTAL SECTION All of the solvents were purchased from Sigma-Aldrich (Hy-Dry anhydrous solvents), and commercially available reagents were used as received. Technically pure trifluoroethanol was purchased via Sigma-Aldrich from the manufacturer, Solvay Fluor GMBH. Chiral alcohol 4 was synthesized and characterized following standard procedures as described in the literature.3 All of the reactions were followed by thin-layer chromatography (TLC) analysis (GF254TLC plates , Merck) or liquid chromatography−mass spectrometry (LCMS) using an Agilent 1100 instrument equipped with a solvent degasser, binary pump, autosampler, thermostated column compartment with a two-position/10-port valve, and a diode array detector (Agilent Technologies, Waldbronn, Germany). The UV wavelength was set at 214 nm. Electrospray ionization mass spectrometry (ESI-MS) measurements were performed on an MSD quadrupole mass spectrometer (Agilent Technologies, Palo Alto, CA, USA) interfaced to the above HPLC system. MS measurements were acquired in positive ionization mode over the mass range of 100−700. Data acquisition and integration for LC/UV and MS detection was performed using Chemstation software (Agilent Technologies). NMR spectra were recorded at ambient temperature using standard pulse methods on any of the following spectrometers and signal frequencies: Bruker Avance DPX 300 MHz (1H = 300 MHz, 13 C = 75 MHz), Bruker Avance III HD 500 MHz (1H = 500 MHz, 13C = 125 MHz, 19F = 470 MHz). Chemical shifts are reported in parts per million and are referenced to the following solvent peaks: chloroform (1H = 7.26 ppm, 13C = 77.16 ppm), methanol (1H = 3.31 ppm, 13C = 49.00 ppm), and DMSO (1H 653



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30 min, and then the mixture was stirred at 10−15 °C for 4 h. Next, the solvent was evaporated, and the crude material was partitioned between saturated sodium bicarbonate (3 L) and ethyl acetate (5 L). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 2 L) and then discarded. The organic layers were combined and washed with brine (1 L), and the solvent was evaporated to yield a mixture of isomers 6a and 6b (650 g, 1.69 mmol), which was used without purification in the next step. The 6a/6b mixture (650 g, 1.69 mol) was dissolved in ethanol (6.5 L), and the solution was cooled to 0 °C under a nitrogen atmosphere. Sodium borohydride (89.5 g, 2.37 mol) was added, and the mixture was stirred and warmed to 22 °C during 2 h. The solvent was evaporated, and the crude material was partitioned between methylene chloride (3 L) and water (5 L). The aqueous layers were washed twice with methylene chloride (2 × 1 L), and then the organics were combined and washed with brine. The solvent was evaporated, and the residue was filtered over a silica gel pad (heptane/ethyl acetate) to afford tert-butyl N-[(3S,4S)-3-(5-acetamido-2-fluorophenyl)-4fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (3b) (476 g, 70% overall yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6): δ 10.03 (s, 1H), 7.67 (m, 1H), 7.63 (m, 1H), 7.43 (bs, 1H), 7.08 (m, 1H), 5.07 (m, 1H), 4.74 (m, 1H), 4.13 (m, 1H), 4.03 (m, 1H), 3.94 (m, 1H), 3.88 (m, 1H), 3.21 (m, 1H), 2.02 (s, 3H), 1.31 (s, 9H). 13C NMR (125 MHz, DMSO-d6): δ 168.7, 156.4, 155.2, 136.2, 127.2, 120.8, 119.7, 116.4, 105.8, 78.9, 78.1, 72.6, 65.1, 60.8, 28.5, 24.3. 19F NMR (470.6 MHz, DMSO-d6): δ −164.7, −117.2.

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1203. Zaborenko, N.; Linder, R. J.; Braden, T. M.; Campbell, B. M.; Hansen, M. M.; Johnson, M. D. Org. Process Res. Dev. 2015, 19, 1231. (4) Preshlock, S.; Tredwell, M.; Gouverneur, V. Chem. Rev. 2016, 116, 719. Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826−870. Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jørgensen, K. A. Chem. - Eur. J. 2006, 12, 6039. Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706. (5) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703−3706. (6) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544. Fjelbye, K.; Marigo, M.; Clausen, R. P.; Juhl, K. Org. Lett. 2016, 18, 1170. (7) See the Supporting Information for NMR characterization. (8) Ciriminna, R.; Pagliaro, M. Org. Process Res. Dev. 2010, 14, 245. (9) Javel water definition: an aqueous solution containing hypochlorite and some sodium chloride. See: Heiman, D. F.; Senderoff, S. G.; Katzenellenbogen, J. A.; Neeley, R. J. J. Med. Chem. 1980, 23, 994. (10) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505. Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. Org. Process Res. Dev. 2006, 10, 163. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. Liu, C.; Ng, J. S.; Behling, J. R.; Yen, C. H.; Campbell, A. L.; Fuzail, K. S.; Yonan, E.; Mehrotra, D. V. Org. Process Res. Dev. 1997, 1, 45. Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943. (11) Urban, F. J.; Breitenbach, R.; Murtiashaw, C. W.; Vanderplas, B. C. Tetrahedron: Asymmetry 1995, 6, 321. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825. Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc. 2000, 122, 9036. Smith, A. B., III; Lee, D.; Adams, C. M.; Kozlowski, M. C. Org. Lett. 2002, 4, 4539. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693. (12) Technically pure trifluoroethanol was purchased from Solvay Fluor GMBH or purified following the procedure reported by Böse and Peterkord (Bö s e, O.; Peterkord, K. European Patent EP1427524B1, 2007).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00069. Detailed analytical data and NMR spectra for compounds 3a and 3b (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pablo Garcia-Losada: 0000-0002-8307-0033 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Paul Tan and Patrick C. May for their assessment and helpful discussion. REFERENCES

(1) May, P. C.; Willis, B. A.; Lowe, S. L.; Dean, R. A.; Monk, S. A.; Cocke, P. J.; Audia, J. E.; Boggs, L. N.; Borders, A. R.; Brier, R. A.; Calligaro, D. O.; Day, T. A.; Ereshefsky, L.; Erickson, J. A.; Gevorkyan, H.; Gonzales, C. R.; James, D. E.; Jhee, S.; Komjathy, S. F.; Li, L.; Lindstrom, T. D.; Mathes, B. M.; Martényi, F.; Sheehan, S. M.; Stout, S. L.; Timm, D. E.; Vaught, G. M.; Watson, B. M.; Winneroski, L. L.; Yang, Z.; Mergott, D. J. J. Neurosci. 2015, 35, 1199−1210. (2) Mergott, D. J.; Green, S. J.; Shi, Y.; Watson, B. M.; Leonard, L. L.; Hembre, E. J. U.S. Patent 20140371212, 2014. (3) Kolis, S. P.; Hansen, M. M.; Arslantas, E.; Brändli, L.; Buser, J.; DeBaillie, A. C.; Frederick, A. L.; Hoard, D. W.; Hollister, A.; Huber, D.; Kull, T.; Linder, R. J.; Martin, T. J.; Richey, R. N.; Stutz, A.; Waibel, M.; Ward, J. A.; Zamfir, A. Org. Process Res. Dev. 2015, 19, 654


Practical Asymmetric Fluorination Approach to the Scalable Synthesis

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