Practical asymmetric fluorination approach to the scalable synthesis of

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Practical asymmetric fluorination approach to the scalable synthesis of new BACE fluoro-aminothiazine inhibitors Pablo Garcia-Losada, Mario Barberis, Yuan Shi, Erik Hembre, Carolina Alhambra Jimenez, Leonard L Winneroski, Brian M Watson, Chauncey Dale Jones, Amy C. DeBaillie, Francisco Jose Martínez-Olid, and Dustin James Mergott Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00069 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 24, 2018

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Organic Process Research & Development

Practical asymmetric fluorination approach to the scalable synthesis of new BACE fluoro-aminothiazine inhibitors

Authors: Pablo Garcia-Losada*1, Mario Barberis1, Yuan Shi2, Erik Hembre2, Carolina Alhambra Jimenez1, Leonard L Winneroski2, Brian M Watson2, Chauncey Jones2, Amy C DeBaillie2, Francisco Martínez-Olid1, and Dustin J Mergott2. 1

Centro de Investigación Lilly S.A., Avda. de la Industria, 30, Alcobendas-Madrid

28108, Spain 2

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center,

Indianapolis, Indiana 46285, United States

AUTHOR E MAIL ADDRESS: [email protected]

KEYWORDS: BACE inhibitor, asymmetric quaternary Carbon-Fluorine stereogenic center, D-Proline, Select-Fluor®.

ABSTRACT: Here, we report an optimized protocol for the asymmetric introduction of a fluorine atom into a quaternary center facilitated by D-proline, Select-Fluor® 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 at multi gram scale.

1.-Introduction We have previously reported the discovery of LY2886721 (1), a potent BACE inhibitor which advanced to Phase II clinical trials1. During the course of our research,

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Page 2 of 14

we also sought to prepare (2), which contains a fluorine at the bridgehead position of the

bicyclic aminothiazine (Figure 1).2

aminoalcohol

We hypothesized that fluorinated (N-[3-[(3S,4S)-3-amino-4-fluoro-4-

3b,

(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluoro-phenyl]acetamide)

could

provide

access to fluorinated bicyclic aminothiazine 2. Figure 1.

•HCl

3b

1 R=H 2 R=F

4

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)-3-amino4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluoro-phenyl]acetamide

4

previously

reported in the literature.3 Herein, we describe the development of an efficient 4-step sequence to deliver 3b on multi-gram scale. 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 an easier access to a wide range of fluorinated compounds.4 In particular, the 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


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associated with formation of the 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 below (Scheme 1). Scheme 1. Synthetic sequence validation

•HCl

4

iv); v); vi)

i); ii); iii)

5a/5b

vii); viii); ix)

6a/6b

+

3a 28% (96% e.e.)

3b 5% (96% e.e.)

i) TEA (2 eq.) BOC2O (1.2 eq.), 50 ºC / 2 h; ii) Citric acid; iii) TEMPO (0.2 eq.), NaOCl (2 eq.), THF, 5 ºC / 2h; iv) Pyrrolinidine (1.1 eq.), THF, 22 ºC/14 min.; v) Select-Fluor® (1.2 eq.), 22 ºC / 2,5 h; vi) NaHCO3 sat. aqueous solution; vii) NaBH4 (1.2 eq.) MeOH 22 ºC /1h ; viii) NaHCO3 sat. aqueous solution; ix) Chiral Chromatography

Starting from chiral amino alcohol 4, the key step to access fluorinated target compound 3b was performed by achiral fluorination of the epimeric mixture of aldehydes 5a/5b. In situ formation of aldehyde pyrrolidine imine, followed by treatment with Select─Fluor® afforded a mixture of fluoroaldehydes, which were transformed into the desired amino alcohol diastereomers (3a/3b) in a 7:1 ratio. NMR characterization of the two pure diastereomers 3a and 3b isolated by chromatography7, 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 was to be used to prepare isomer 3b on multi-gram scale. Alcohol oxidation step: development, optimization and scale-up The discovery route started from the chiral amino alcohol 4 which, after protection of the amino group, was transformed into an aldehyde mixture 5a/5b under TEMPO/bleach oxidation reaction8. Unfortunately, this reaction was challenging for



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scale-up due to the large amount of over oxidation by-product together with the concurrent decomposition observed (Scheme 2). Scheme 2. Oxidation step

•HCl

i); ii); iii)

+

4

5a/5b

+

5c/5d

+

5e

5f

i) TEA (2 eq.) BOC2O (1.2 eq.), 50 ºC / 2 h; ii) Citric acid; iii) TEMPO (0.2 eq.), NaOCl (2 eq.), THF, 5 ºC / 2h;

Different oxidation conditions were explored (Table 1), and the results confirmed that mild oxidants such as IBX or TEMPO (especially when Javel water9 was used as stoichiometric co-oxidizing reagent) afforded the desired compound with a significant amount of undesired by-products 5c-f. Only Parikh-Doering10 oxidation conditions (SO3Py complex) circumvented the over-oxidation problem, affording a mixture of two compounds (5a and 5b) in moderate yield and selectivity. Table 1. Oxidation step optimization t 5c/5d7 4 5a/5b7 (h) 36 1 DMSO IBX1 1 none none 51 39 10 1 2 ACOEt IBS/Oxone2 0.1 none none 98 1 1 4 3 AcOEt NaOCl 1.7 TEMPO(0.1 eq)/ KBr (0.1 eq) NaHCO3 2 1 87 7 4 AcOEt NaOCl 3 TEMPO(0.2 eq)/KBr (0.1 eq)3 NaHCO3 ≤1 ≤1 99 21 5 CH2Cl2 NCS 1.3 TEMPO(0.1 eq)/TBACl (0.1 eq) K2CO3 19 66 15 24 6 AcOEt SO3Py1 6 none TEA 20 65 8 22 7 AcOEt SO3Py/DMSO 3 none TEA 3 80 SO3Py/DMSO 72 8 AcOEt 3 none TEA 3 78 SO3Py/DMSO 48 9 AcOEt 3 none TEA 1 81 SO3Py/DMSO DIPEA 4 2 10 AcOEt 3 none 1 81 SO3Py/DMSO 1.8 DIPEA 5 24 11 AcOEt none 4 95 SO3Py/DMSO 2.3 1.5 12 AcOEt none DIPEA 6 ≤1 99 SO3Py/DMSO 2.3 2 13 AcOEt none DBU SO3Py/DMSO 2.3 23 14 CH2Cl2 none TEA 3 86 SO3Py/DMSO 2.3 23 15 AcOEt none n-Pr3N 3 97 1 Solid addition portionwise over the substrate; 2 Potassium 2-iodo-5-methylbenzenesulfonate; 3 Temperature: 0-5 ºC; 4 Temperature: -10 ºC / DIPEA (3 eq.); 5 Temperature: 0 ºC / 1.5 eq. DIPEA (1.5 eq.); 6 Temperature: 0-5 ºC / DIPEA(1.5 eq.). 7 Conversion calculated by HPLC; 8 Isolated yield after work-up and purification. Entry

Solvent

Oxidant

Eq

Catalyst

Base

Assuming that the fluorination of the enamine intermediate was the stereodetermining step, the diastereomeric purity of the aldehyde was irrelevant for the final


Yield8 22% 31% 52% 77% 69% 63% 76% 72% 83% 70% 71%

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diastereoselectivity. Thus, we focused our efforts on maximizing the yield of the oxidation reaction by minimizing the over oxidation by-products such as 5c-f. Optimization of the oxidation of alcohol 4 to aldehyde mixture 5a/b showed that oxidant preactivation in dimethylsulfoxide (DMSO) solution, combined with the addition of different organic amines, reduced the equivalents of oxidant required for complete starting material consumption. In that regard, preactivated SO3Py complex in combination with Hunig’s base,11 led to starting material consumption without over-oxidation by-products in less than 2 hours (entry 12), while other bases as triethylamine,

pyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), or tri-N-

propylamine resulted in a prolonged reaction time (entries 10, 13-15). The best reaction conditions (entry 12) were selected for scale up. After confirmation that addition order did not affect the outcome of the reaction, the scale-up was performed by adding a mixture of Hunig’s base and BOC-protected aminoalcohol over a mixture of preactivated SO3Py complex in DMSO/ethyl acetate keeping temperature below 5 ºC. Following this procedure, a mixture of aldehydes (5a/5b) was isolated as an oil in 93% yield, but unfortunately it was impossible to 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 it with a chiral reagent. We focused our initial effort on evaluating different chiral reagents, in combination with different fluorinating agents (Figure 2). Figure 2. Selected fluorination agents and chiral amines



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Cl Ph Ph O O S S O N O F

N+ N+ F 2BF4-

7a

7b

Cl N+ F TfO-

N+ F

7c

7d

Cl

N + Cl F BF -

Cl

TfO-

N

+

N

F F

2BF4-

4

7e

+

7f HO

OMe N H

N H

8a

8b

CO2Me

OH

N H

8c

N H

8d

8e

8g

Bn

t-Bu

8h

8f O

N

N N H

N H

CO2H

N H

O

O

N t-Bu

CO2 H

N H

O

Ph Ph N H

CO2tBu

Bn

8i

N Bn

N H

8j

N H

Bn

8k

These studies showed that formation of diastereomer 6b was observed only with Selectfluor® as fluorinating source (7a). With all 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 organocatalyst to further improve diastereoselectivity.6 Slow conversion and substantial formation of side products were observed, except with 0.3 equivalents of amines 8a, 8c, 8d and 8e. After further evaluation of organocatalyst stoichiometry, the 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 using Select-Fluor® as fluorinating agent using stoichiometric quantities of chiral reagent 8e with different solvents, evaluating the imine formation and fluorination reaction, stepwise versus one-pot conditions (Table 2), and following the imine and the aldehyde signals by 1H-NMR, as reference to measure the conversion.


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Table 2. Solvent selection screening Entry

Solvents

Imine 4 Conversion

6a (Area %)4

6b(Area %) 4

ratio (6b/6a) 4

1 Dioxane 651 33 60 2 EtOH 951 22 43 3 ACN 751 42 48 4 Toluene 252 60 13 1 5 NMP 64 59 22 6 DMA 691 54 27 7 MTBE 402 38 40 8 MeOH 943 30 57 1 9 IPA 73 27 44 10 DCM 671 32 57 11 MeTHF 571 40 53 3 12 Trifluoroethanol 96 20 61 13 THF 751 38 54 14 EtOH-Tol (1:5) 641 30 43 1 15 MeOH-Tol (1:5) 94 38 42 16 EtOH-DCM (1:5) 933 23 51 17 MeOH-DCM (1:5) 943 30 57 18 MeOH-MTBE (1:5) 591 38 53 1 19 MeOH-MeTHF (1:5) 81 38 52 1 Heterogenous suspension; 2 Sticky oily solid; 3 Homogeneous solution; 4 HPLC conversion

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 2.1 1.9 1.2 1.2

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 only afforded partial conversion or by-product formation that did not allow the generation of a stable imine intermediate. These three conditions (entries 2, 8, and 12), were tested at 5 g scale determining trifluoroethanol as optimal solvent with near complete conversion in 24 hours. Conversely, reactions in methanol and ethanol afforded mixtures of desired product together with a significant amount of by-product formation. Finally, temperature and solvent quality impact over conversion and selectivity were evaluated. No effect of either diastereoselectivity or reaction rate were observed increasing the temperature, but larger amounts of side products were obtained when reaction was performed above 35 ºC. When freshly distilled trifluoroethanol or technical grade solvent was used almost complete conversion was observed in 24 hours, but reaction time could be accelerated to less than 4 hours when dry solvent12 was used, showing that water removal enhanced reaction time.



Based on these results, Select-Fluor® 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 at 1.6 mol scale, affording the desired product 6a/6b in (1/7) ratio and 90% yield. Chiral amine and Select-Fluor® by-products were easily removed by extraction, and simple salts by filtration. 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 reaction conditions, and it was shown that the addition of reducing agent at 0 ºC is beneficial for the outcome of the reaction when compared to room temperature. 3.-Conclusions In summary, we have developed an efficient and practical fluorination reaction facilitated by D-proline in trifluoroethanol which generates a congested quaternary stereocenter in high yield and with good diastereoselectivity. Aldehyde mixture 5a/b was obtained via oxidation of alcohol 4. The α–fluorination of this aldehyde mixture followed by direct treatment of the crude alpha-fluoro aldehyde product with sodium borohydride, afforded the desired fluoro amino alcohol in 90% yield and with 7:1 diastereoselectivity of 3b over 3a, that was purified by silica gel pad filtration to give the desired diastereomer 3b in 70% overall yield and 98% e.e. 4.-Experimental Section - Materials and Methods All solvents were purchased from Sigma-Aldrich (Hy-Dry anhydrous solvents), and commercially available reagents were used as received. Technically pure trifluoro


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ethanol was purchased via Sigma-Aldrich from Solvay Fluor GMBH manufacturer. Chiral alcohol 4 was synthesized and characterized following standard procedures described in literature.3 All reactions were followed by TLC analysis (TLC plates GF254, Merck) or liquid chromatography mass spectrometry (LCMS) using Agilent 1100 equipped with a solvent degasser, binary pump, auto sampler, thermostated column compartment with 2-position/10-port valve, and a diode array detector (Agilent Technologies, Waldbronn, Germany). The UV wavelength was set at 214 nm. Electrospray mass spectrometry measurements were performed on a 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, 13C =75 MHz), Bruker Avance III HD 500 MHz (1H = 500 MHz, 13C = 125 MHz, 19F = 470 MHz). Chemical shifts are reported in ppm 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 = 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 purity of all compounds tested was determined by LCMS and 1H NMR to be >95%. Preparation of tert-butyl N-[(3S)-3-(5-acetamido-2-fluoro-phenyl)-4-formyltetrahydrofuran-3-yl]carbamate (5a/5b).



Aminoalcohol

protection

step:

A

solution

of

N-[3-[(3S,4R)-3-amino-4-

(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluoro-phenyl]acetamide hydrochloride (4) (1Kg, 8.20 mol) and Di-tert-butyl dicarbonate (2.15 Kg, 9.84 mol) in tetrahydrofurane (11 L) was treated with triethylamine (2.28 L, 16.40 mol), and then the reaction was heated at 50 ºC for 2h. Then the reaction mixture was cooled to 22 ºC and evaporated to dryness. The residue was partitioned between 10% aqueous citric acid solution (3 L) and methyl tert-butyl ether (5 L). The layers were separated and aqueous washed three times with methyl tert-butyl ether (3 x 1 L). The organics were combined and were washed with brine (2 L) and concentrated to dryness to afford tert-butyl N[(3S,4R)-3-(5-acetamido-2-fluoro-phenyl)-4-(hydroxymethyl)tetrahydrofuran-3yl]carbamate (2.20 Kg, 5.97 mol; 78% yield) as a yellow solid, consistent with previously reported data2. 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). Then in a separate flask tert-butyl N[(3S,4R)-3-(5-acetamido-2-fluoro-phenyl)-4-(hydroxymethyl)tetrahydrofuran-3yl]carbamate (1.5 Kg, 4.05 mol) was dissolved in ethyl acetate (2 L) and cooled to 10 ºC under nitrogen atmosphere. To this solution Hünig's base (670 ml, 4.05 mol) was added and the mixture was cooled to 0 ºC followed by the addition of the oxidant solution keeping temperature below 5 ºC. After 1h stirring at 5 ºC, water (6 L) was added and organic layer was


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separated. The aqueous layer was washed with ethyl acetate (10 L), and then the organics were combined, washed with citric acid solution (10% w/w) three times (3 x 2L) and finally with brine (7 L). The solvent was evaporated and the residue dried under vacuum to yield of tert-butyl N-[(3S)-3-(5-acetamido-2-fluoro-phenyl)-4formyl-tetrahydrofuran-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, 1 H), 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-2-fluoro-phenyl)-4-fluoro4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (3b). To a solution of compound tert-butyl N-[(3S)-3-(5-acetamido-2-fluoro-phenyl)-4formyl-tetrahydrofuran-3-yl]carbamate

(6a/6b)

(650

g,

1.77

mol)

in

dry

trifluoroethanol12 (6.5 L) cooled at 0 ºC under nitrogen atmosphere, D-Proline (245 g, 2.13 mol) was added portionwise, keeping internal temperature below 15 ºC. The mixture was stirred at 10 -15 °C for 2 hours. Select-Fluor® (823.9 g, 2.31 mol) was added portion wise during 30 min, and then was stirred at 10-15 ºC for 4 hours. Then, the solvent was evaporated and the crude partitioned between saturated sodium bicarbonate (3 L) and ethyl acetate (5 L). The layers were separated, aqueous was extracted with ethyl acetate (2 x 2 L) and then phase was discarded. Organics were combined, washed with brine (1 L), and solvent was evaporated to yield a mixture of isomers 6a/6b (650 g, 1.69 mmol) used without purification in next step.



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Compound mixture of isomers 6a/6b (650 g, 1.69 mol) was dissolved in ethanol (6.5 L) and cooled to 0 ºC under nitrogen atmosphere. Sodium borohydride (89.5 g, 2.37 mol) was added and the mixture stirred and warmed to 22 ºC during 2 hours. The solvent was evaporated, and the crude was partitioned in methylene chloride (3 L) and water (5 L). The aqueous layers was washed twice with methylene chloride (2 x 1 L), and then organics were combined, washed with brine and the solvent was evaporated. The residue was filtered over a silica gel pad (heptane/ethyl acetate) to afford tertbutyl

N-[(3S,4S)-3-(5-acetamido-2-fluoro-phenyl)-4-fluoro-4-

(hydroxymethyl)tetrahydrofuran-3-yl]carbamate 3b (476 g, overall yield: 70%) as a white solid. 1

H-NMR (500 MHz, DMSO-d6): 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) ;

13

C-NMR (125 MHz,

DMSO-d6): 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): -164.7, -117.2. Supporting Information Available Detailed Analytical data characterization and NMR spectra for compounds 3a and 3b was provided. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding author E-Mail: [email protected] ORCID Pablo Garcia-Losada 0000-0002-8307-0033 Notes. The authors declare no competing financial interest. Acknowledgements ACS Paragon Plus Environment

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The authors want to thank Paul Tan, and Patric 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. US patent 20140371212, 2014. 3 Kolis, S. P.; Hansen, M. M.; Arslantas, E.; Brändi, L.; Buser, J.; DeBailie, A. C.; Frederick, A. L.; Hoard, D.W.; Hollister, A.; Huber, D.; Kulll, T.; Linder, R. J.; Martin, T. J.; Richery, R.N.; Stutz, A.; Waibel, M. Ward, J.A.; Znfir, A. Org. Process Res. Dev. 2015, 19, 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; Toste Chem. Rev. 2015, 115, 826-870; Jorgensen K. A.; Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J. Chem. Eur. J. 2006, 12, 6039; Barbas, C. F., Nobuyuki, M.; Steiner D. Angew. Chem. Int. Ed. 2005, 44, 3706. 5 JØrgensen K. A., Marigo, M.; Fielenbach, D.; Braunton, A.; Kiaersgaard, A. Angew. Chem. Int. Ed. 2005, 44, 3703 –3706 6 MacMillan, D.; Beeson, T. D 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 supporting information for NMR characterization. 8 R. Ciriminna, R,; Pagliaro, M. Org. Process Res. Dev. 2010, 14 , 245. 9 Javel water definition: an aqueous solution containing hypochlorite and some sodium chloride; Heiman, D. F.; Stephen, G.; Senderoff, J.; 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. Proc. Res. & Dev. 2006, 10, 163; Swern, D.;Omura K. Tetrahedron 1978, 34, 1651; John, S. Ng; Liu, C.; Behling, J. R.; Yen, C. H.; Campbell, A.L.; Fuzail, K. S.; Yonan, E.; Mehotra, D.V. Org. Proc. Res. & Dev. 1997, 1, 45; Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J.A., Brown Ripin, D. H. Chem. Rev. 2006, 106, 2943. 11 Urban, F. J.; Breitenbach, R.; Murtiashaw, C. W.; Vanderplas, B. C. Tetrahedron Asymm. 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 III, A. B.; 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 purchased from Solvay Fluor GMBH, or purified following the procedure reported EP patent EP1427524 B1, by Böse, O.; Peterkord, K.



Table of contents graphic 254x190mm (96 x 96 DPI)


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Practical asymmetric fluorination approach to the scalable synthesis of

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