Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies

Accepted Manuscript Title: Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies Author: Lennart Brewitz Naoya Kumagai Masakatsu Shibasaki PII: DOI: Reference:

S0022-1139(16)30441-9 http://dx.doi.org/doi:10.1016/j.jfluchem.2016.12.008 FLUOR 8916

To appear in:

FLUOR

Received date: Revised date: Accepted date:

9-11-2016 9-12-2016 12-12-2016

Please cite this article as: Lennart Brewitz, Naoya Kumagai, Masakatsu Shibasaki, Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines as useful building blocks for SAR-studies, Journal of Fluorine Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.12.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan1-amines as useful building blocks for SAR-studies Lennart Brewitza, Naoya Kumagaia,*, and Masakatsu Shibasakia,* a

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan [email protected], [email protected]

Research highlights -

Chiral fluorinated α-isopropylbenzylamines were synthesized using a direct catalytic asymmetric Mannich-type reaction

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The novel fluorinated compounds were incorporated in known bioactive molecules to demonstrate their utility for SAR-studies

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Conformational analysis (NMR, X-ray) of the fluorinated bioactive molecules revealed a fluorine gauche effect

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Catalytic asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan1-amines as useful building blocks for SAR-studies Lennart Brewitza, Naoya Kumagaia,*, and Masakatsu Shibasakia,* a

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan [email protected], [email protected]

Abstract The first protocol for the asymmetric synthesis of 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines which function as fluorinated surrogates for α-isopropylbenzylamines in SAR-studies is presented herein. Crucial for the successful synthesis was the application of a recently developed direct catalytic asymmetric Mannich-type reaction of fluorinated amide for the key C−C bond-forming step. The utility of this versatile protocol was demonstrated by the synthesis of fluorinated analogues of a T-type selective Ca2+ channel blocker and a prolylcarboxypeptidase inhibitor. The predominant conformation of their fluorinated analogues was investigated by X-ray crystallography and NMR spectroscopy which revealed a strong influence of a fluorine caused gauche effect.

Keywords (max 6) Fluorinated α-isopropylbenzylamines Chiral 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines Trifluoromethyl Fluorine gauche effect Structure-activity relationship Cooperative catalysis

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1. Introduction

In recent years, chiral α-isopropylbenzylamines have been incorporated in a plethora of bioactive small molecules: for example, researchers in the pharmaceutical industry reported on selective T-type Ca2+ channel blocker 1 [1], selective Janus kinase 2 inhibitor 2 [2], and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitor 3 [3] that were all among the most effective compounds investigated in the respective studies (Figure 1a) [4]. (a) Potent bioactive molecules containing chiral a-isopropylbenzylamines N

O

OMe

O

N

N N

HN N

N

N

NH Ph

H2N F

Cl

F 1

NH

2

3

(b) Investigated fluorinated analogues (B-G) of chiral a-isopropylbenzylamines during SAR-studies NHR

reported in SAR-studies

NHR

Ar

Ar A

CF3 B

NHR Ar

CF2CF3

CF3

Ar

Ar

Ar

D

C

NHR

NHR

NHR

E

F

F

NHR Ar

F

F

G

F

(c) This work: asymmetric synthesis of K NHR Ar

recent synthesis

NHR Ar

H

CF3

A

unknown This work

NHR Ar F3 C

K

[Ox] F

NHR O Ar F3 C

F

NR NR2

Ar

O + F 3C

NR2 F

L M N direct catalytic asymmetric Mannich-type reaction

Figure 1. Fluorinated α-isopropylbenzylamines in context of bioactive molecules.

A valuable strategy to improve the pharmacological profile of potential small molecule drugs during SARstudies relies on the incorporation of fluorine atoms [5]. In this regard, fluorinated variants of the α-isopropylbenzylamine moiety are of great interest for pharmaceutical research and have already been examined to some extent (motifs B – G, Figure 1b) [3,6]. Strikingly, a simple replacement of one methyl group by a CF3-group (e.g. motif H, Figure 1c) has so far been neglected in these studies, which most likely associates to difficulties in installing this moiety by common trifluoromethylation methods [7]. This challenge has only been overcome recently; however, the newly developed reaction protocols are limited to the nonstereoselective introduction of a single CF3-group [8]. The additional replacement of the methine isopropyl hydrogen of amine H to afford 2,3,3,3-tetrafluoro-2methyl-1-arylpropan-1-amine (K, Figure 1c) might be very useful to fine-tune the molecular properties of the parent α-isopropylbenzylamine (A): It is anticipated that a fluorine gauche effect [9] determines the relative

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position of the methine fluorine and the amine nitrogen atoms, thereby allowing for a more rational inhibitor design. Unfortunately, amine K cannot be accessed currently by conventional fluorination or fluoroalkylation reactions. In contrast, we envisioned that our recently developed direct catalytic asymmetric Mannich-type reaction of fluorinated 7-azaindoline amide as a pronucleophile (N) might be suitable to furnish this particular class of compounds (Figure 1c). This C−C bond-forming reaction displays a broad substrate scope with metaand para-substituted aromatic as well as heteroaromatic N-Boc-aldimines being tolerated as electrophiles (M) [10]. High levels of asymmetric induction were achieved due to a judicious combination of a cooperative catalytic system [11] and the chelating 7-azaindoline amide moiety [12]. Following the synthetic plan outlined in Figure 1c, (1S,2R)-K and enantiomeric (1R,2S)-K should be accessible in a few additional synthetic operations from Mannich adduct L respectively its enantiomer. Herein, we demonstrate the versatility of the Mannich-type reaction of fluorinated α-F-α-CF3-7-azaindoline amide 8 to deliver various amines of type K in course of the asymmetric synthesis of fluorinated analogues of bioactive small molecules 1 and 3.

2. Results and discussion 2.1. Synthesis of amide 9 as a fluorinated analogue of T-type selective Ca2+ channel blocker 1 Since Roche withdrew FDA-approved antihypertensive and anti-anginal Posicor (Mibefradil) from the market due to adverse side effects when administered in combination with other drugs [13], the quest for T-type selective Ca2+ channel blockers has become eminent [14] with channel blocker 1 representing one class of promising candidates [1]. The synthesis of amide 9 as a fluorinated analogue of channel blocker 1 commenced with the direct catalytic asymmetric Mannich-type reaction of racemic α-F-α-CF3-7-azaindoline acetamide 5 and imine 4. As previously described, Mannich adduct 6 was obtained in excellent yield and with high antidiastereoselectivity as well as high enantioselectivity (Scheme 1) [10b]. The efficiency of the cooperative catalytic system comprised of Cu(I)/chiral bisphosphine ligand 10 as soft Lewis acid and Barton’s base as Brønsted base was improved by reducing the reported catalyst loading from 10 mol% to 6 mol%. To avoid detrimental effects on yield or selectivities, the concentration was increased from 0.5 M to 1.1 M. However, attempts to decrease the catalyst loadings any further resulted in incomplete conversions and reduced diastereoselectivities.

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Scheme 1. Synthesis of amide 9 as a fluorinated analogue of T-type selective Ca2+ channel blocker 1. Reagents and conditions: (a) [Cu(CH3CN)4]PF6 (6 mol%), 10 (7 mol%), Barton’s base (6 mol%), THF, rt, 93%, dr = 20:1 (anti:syn), 94% ee (anti); (b) LDA, H3N·BH3, THF, 0 °C; (c) TCDI, DMAP (30 mol%), CH2Cl2, rt, 63% (two steps); (d) HSi(TMS)3, AIBN, toluene, 85 °C; (e) TFA, CH2Cl2, rt; (f) 11, HATU, iPr2NEt, DMF, rt, 52% (three steps); (g) TFA, CH2Cl2, rt; (h) 12, K2CO3, CH3CN, 70 °C, 46% (two steps).

Reduction of Mannich adduct 6 to the corresponding primary alcohol proceeded smoothly following Myers’ protocol [15]. Efforts to deoxygenate derivatives of this alcohol by SN2-type reactions remained unfruitful, presumably due to the steric hindrance imposed by the neighboring CF3-group. Therefore, a radical BartonMcCombie deoxygenation reaction [16] involving the challenging formation of a non-stabilized primary alkyl radical was investigated: In order to avoid the formation of toxic byproducts, HSi(TMS)3 was selected as reducing agent rather than HSnBu3 even though its homolytic bond dissociation energy is roughly 5 kcal/mol higher [17]. Initial experiments revealed that the radical deoxygenation of the standard phenylthiocarbonate derivative of 7 suffered from low conversion [18]. Switching to more reactive pentafluorophenlythiocarbonate derivative of 7 resulted in complete conversion [19]; however, traces of byproducts formed during the reaction rendered product purification tedious. Gratifyingly, the use of an imidazolylthiocarbamate as radical precursor resulted in a much cleaner reaction while maintaining complete conversion [16,20]. Hence, the crude alcohol was directly converted into imidazolylthiocarbamate 7 in 63% yield over two steps without purification of the intermediate alcohol. After successful Barton-McCombie reaction, residual silyl species were easily removed after Boc-deprotection and amide bond-formation with N-Boc-isonipecotic acid 11 to afford amide 8 in 53% over three steps. Finally, the desired amide 9 was obtained as a fluorinated analogue of channel blocker 1 after Boc-removal, SN2-type reaction with tosylate 12 and HPLC purification in 46% yield over two steps. X-Ray analysis of a suitable single crystal of amide 9 confirmed the absolute configuration (Figure 2); thus, stereochemical integrity was maintained throughout the reaction sequence. Moreover, the crystal structure verified the predicted gauche-conformation of the vicinal methine C−F and C−Namide bonds; however, the experimental dihedral angle of 70.2° deviates slightly from the ideal angle of 60°. Intrinsically, the gauche effect is complemented by an antiperiplanar arrangement of the vicinal methine C−F and Cα-N−H bonds (dihedral

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angle: 173.8°). Also the vicinal methine C−F bond and a Cmethyl−H bond are arranged anti (dihedral angle: 180°). These data are in good agreement with an X-ray structure previously obtained from a Mannich adduct similar to 6, which shows a gauche arrangement of the vicinal methine C−F and C−Ncarbamate bonds with a dihedral angle of 68.7° [10b]. As the vicinal 3JHF-coupling constants depend on the dihedral angle in a Karplus-like correlation [21], the preferred conformation in solution can be determined by 1H NMR spectroscopy: The observed vicinal coupling constant of the Cα-N−H proton to the methine fluorine (3JHF = 28.2 Hz) in amide 9 indicated that the gauche-conformation is also predominantly populated in solution which is in agreement with literature-known compounds [22]. Hence, evidence is provided that the methine fluorine induces a conformational bias both in solid and solution state. Even though the conformational stabilization by the gauche effect is rather weak [9], it still might be a helpful tool to modulate the preferred conformation giving rise to acquire distinct pharmacodynamics properties.

Figure 2. Crystal structure of amide 9. Color code: white: hydrogen; gray: carbon; blue: nitrogen; red: oxygen; yellow: fluorine.

2.2. Synthesis of amide 20 as a fluorinated analogue prolylcarboxypeptidase inhibitor 3 During the development of prolylcarboxypeptidase inhibitor 3, it was determined that the αisopropylbenzylamine containing inhibitor 3 was more active compared to its α-methylbenzylamine analogue [3]. This activity difference was attributed to the increased steric shielding of the neighboring amide by the isopropyl group which reduces the propensity of the NH-functionality to engage in H-bonding. Thus, fluorinated analogues such as 20, which is not a bioisoster of 3, might improve the inhibitory properties simply by increased steric shielding of the N−H bond. Given the importance of chiral αisopropylbenzylamines in medicinal chemistry, the synthesis of a fluorinated analogue of inhibitor 3 seemed an ideal target to further validate the utility of the novel methodology established through the synthesis of fluorinated amide 9. Before performing the Mannich-type reaction to access the fluorinated α-isopropylbenzylamine part of amide 20, the required coupling partner 16, which is not commercially available, had to be synthesized: acid hydrochloride 16 was obtained in two steps from amine 13 and acrylate 14 via a DBU mediated aza-Michael

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reaction [23] followed by ester hydrolysis in acidic media (Scheme 2).

Scheme 2. Synthesis of amide 20 as a fluorinated analogue of prolylcarboxypeptidase inhibitor 3. Reagents and conditions: (a) [Cu(CH3CN)4]PF6 (6 mol%), ent-10 (7 mol%), Barton’s base (6 mol%), THF, rt, 96%, dr = 12:1 (anti:syn), 92% ee (anti); (b) LDA, H3N·BH3, THF, 0 °C; (c) TCDI, DMAP (30 mol%), CH2Cl2, rt, 50% (two steps); (d) HSi(TMS)3, AIBN, toluene, 85 °C; (e) TFA, CH2Cl2, rt; (f) 16, HATU, iPr2NEt, DMF, rt, 57% (three steps); (g) DBU (50 mol%), CH3CN, rt, 97%; (h) 4 M HCl, dioxane, rt, 82%.

Mannich-type reaction of amide 5 and imine 17 using ent-10 proceeded under identical reaction conditions to those described above affording enantiomerically antipodal Mannich adduct 18 in excellent yield and enantioselectivity albeit with a reduced diastereomeric ratio of 12:1 (anti:syn). Reduction of 18 followed by O-thioacylation and removal of the minor syn-diastereomer by HPLC furnished analytically pure imidazolylthiocarbamate 19 in 50% yield over two steps. Lastly, target amide 20 was obtained in 57% yield over three steps after Barton-McCombie deoxygenation, Boc-removal and amide bond-formation with acid hydrochloride 16. A similar vicinal coupling constant of (3JHF = 28.4 Hz) suggests that amide 20 also adopts a gauche-orientation of the vicinal methine C−F and C−Namide bonds.

3. Conclusions

An efficient asymmetric synthesis of previously inaccessible 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1amines (K, Figure 1c) which may function as fluorinated surrogates for α-isopropylbenzylamines in SARstudies has been disclosed. The utility of the novel protocol was highlighted by the incorporation of two specific 2,3,3,3-tetrafluoro-2-methyl-1-arylpropan-1-amines into literature-known bioactive molecules 1 and 3. A conformational analysis of these molecules revealed a preferred a gauche orientation of the methine C−F and C−Namide bonds both in solid and solution state. Arguably, these hitherto unknown fluorinated αisopropylbenzylamine analogues will attract attention in medicinal chemistry as their predictable conformation facilitates a rational design of fluorinated small bioactive molecules. Furthermore, this novel protocol demonstrates the particular utility of combining asymmetric catalysis with a

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fluorinated building block approach for the enantioselective synthesis of chiral fluorine containing molecules which are inaccessible by standard fluorination and fluoroalkylation reactions.

4. Experimental 4.1. General information All reactions were performed under Argon atmosphere unless noted otherwise. Air- and moisture-sensitive liquids were transferred via gas-tight syringes and stainless-steel needles. Work-up and purification procedures were carried out with reagent-grade solvents under ambient atmosphere. Flash column chromatography was performed on Merck 60 (230–400 mesh) silica gel. All materials were purchased from commercial suppliers (Sigma-Aldrich, TCI) and were used without further purification. [Cu(CH3CN)4]PF6 and chiral phosphine ligands were purchased from Sigma-Aldrich or Strem Chemicals, Inc. and were stored and handled in a glove box. Acetonitrile, dichloromethane, DMF, THF and toluene were passed through a solvent purification system (Glass Contour). Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 Fourier transform infrared spectrophotometer. NMR spectra were recorded on Bruker AVANCE III HD 400 or AVANCE III 500. Chemical shifts for protons are reported in parts per million (ppm) downfield from tetramethylsilane and referenced to residual protium in the NMR solvent (CDCl3: δ = 7.28 ppm; DMSO-d6: δ = 2.49 ppm; CD3CN: δ = 1.94 ppm). For

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C NMR,

chemical shifts are reported in the scale relative to the NMR solvents (CDCl 3: δ = 77.00 ppm; DMSO-d6: δ = 39.52 ppm; CD3CN: δ = 118.26, 1.32 ppm) as an internal reference and for

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F NMR, chemical shifts are

reported in the scale relative to trifluorotoluene as an external reference (δ = –62.8 ppm). NMR data are reported as follows: chemical shift, multiplicity (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q: quartet, m: multiplet, br: broad signal), coupling constant (Hz), and integration. High resolution mass spectra (ESI Orbitrap (+)) were measured on ThermoFisher Scientific LTQ Orbitrap XL. Single-crystal X-ray data were collected on a Rigaku R-AXIS RAPID II imaging plate area detector with graphite-monochromated CuKα radiation. Melting points were measured on a Yanagimoto Seisakusho Micro Melting Point apparatus. Optical rotations were measured using a 2 mL cell with a 1.0 dm path length on a JASCO polarimeter P-1030. HPLC analysis was conducted on a JASCO HPLC system equipped with Daicel chiral-stationary-phase columns (= 0.46 cm, length = 25 cm); Preparative HPLC purification was conducted using Daicel chiralstationary-phase columns with a larger diameter (= 2.0 cm, length = 25 cm). 4.2. Synthetic procedures 4.2.1. tert-Butyl ((1S,2S)-2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-2,3,3,3-tetrafluoro-1-(4fluorophenyl)propyl)carbamate (6)

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A flame-dried 20 mL glass test tube equipped with a magnetic stirring bar and a 3-way glass stopcock was charged with [Cu(CH3CN)4]PF6 (22.4 mg, 0.06 mmol, 6 mol%) and (S)-(–)-2,2′-bis[di(3,5-diisopropyl-4dimethylaminophenyl)phosphine]-6,6′-dimethoxy-1,1′-biphenyl (DIPA-MeO-BIPHEP, 10) (76.4 mg, 0.07 mmol, 7 mol%) in a glove box under Ar atmosphere. Afterwards, the glass test tube was removed from the glove box, evacuated for 30 min, and backfilled with argon. Anhydrous THF (0.30 mL, 1.1 M) was added at room temperature and the resulting clear colorless solution was stirred for 30 min before racemic 1-(2,3dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,3,3,3-tetrafluoropropan-1-one (5) [10b] (248.2 mg, 1.0 mmol, 1.0 equiv.), tert-butyl (E)-(4-fluorobenzylidene)carbamate (4) [24] (446.5 mg, 2.0 mmol, 2.0 equiv.) and Barton’s base (0.1 M in THF, 0.6 mL, 0.06 mmol, 6 mol%) were subsequently added. The reaction mixture was stirred at ambient temperature for 21 h. The dr and ee of the crude product were determined by HPLC analysis of an aliquot, which was taken from the reaction mixture and filtered through a short pad of silica: dr = 20:1 (anti:syn), 94% ee (anti). Then, the reaction mixture was loaded directly onto a silica gel column and eluted with n-hexane/ethyl acetate (3:1). Evaporation of solvent afforded 437 mg (93%) of the desired pure Mannich adduct 6 as a single diastereomer. White amorphous solid; 1H NMR (400 MHz, 343 K, DMSO-d6): δ = 8.17–8.15 (m, 1H), 7.96 (brs, 1H), 7.62 (dq, J = 7.5, 1.3 Hz, 1H), 7.53 (dd, J = 8.1, 5.7 Hz, 2H), 7.15–7.09 (m, 2H), 7.05 (dd, J = 7.4, 5.0 Hz, 1H), 6.06 (brdd, J = 25.1, 7.9 Hz, 1H), 3.88–3.81 (m, 1H), 3.61–3.53 (m, 1H), 2.88 (ddd, J = 16.1, 9.7, 6.3 Hz, 1H), 2.75 (ddd, J = 16.2, 8.8, 7.6 Hz, 1H), 1.37 ppm (s, 9H); 13C NMR (125 MHz, 343 K, DMSO-d6): δ = 161.7 (d, J = 245.2 Hz), 161.1 (d, J = 21.7 Hz), 155.1, 154.3 (br), 145.6, 133.3, 131.4, 130.5 (d, J = 8.0 Hz), 125.7, 121.5 (qd, J = 287.9, 30.6 Hz), 119.6, 114.7 (d, J = 21.4 Hz), 96.5 (dq, J = 218.5, 26.3 Hz), 78.7, 54.4 (brd, J = 11.7 Hz), 47.4 (d, J = 10.9 Hz), 27.8, 25.1 ppm; 19F NMR (376 MHz, 343 K, DMSO-d6): δ = –70.7 (s, 3F), –113.6 (s, 1F), –177.8 ppm (brs, 1F); IR (film): ~ = 3338 (br), 3061, 2979, 2934, 1710, 1681, 1598, 1510, 1420, 1392, 1368, 1344, 1308, 1255, 1228, 1208, 1164, 1008 cm–1; HRMS (ESI): m/z calculated for C22H23F5N3O3 [M+H]+: 472.1654, found: 472.1660;  24 = –62.6 (c = 0.55, CHCl3, 94% ee sample); HPLC D analysis (CHIRALPAK IE (0.46 cm  x 25 cm), 2-propanol/n-hexane = 1/6, flow rate = 1.0 mL/min, detection at 254 nm, tR = 37.2 min (minor), 65.7 min (major)). 4.2.2.

O-((S)-2-((S)-((tert-Butoxycarbonyl)amino)(4-fluorophenyl)methyl)-2,3,3,3-tetrafluoropropyl)-1H-

imidazole-1-carbothioate (7) To a suspension of borane-ammonia complex (123.5 mg, 4.0 mmol, 4.0 equiv.) in anhydrous THF (3.0 mL) was added lithium diisopropylamide (1.0 M in n-hexane/THF, 3.9 mL, 3.9 mmol, 3.9 equiv.) at 0 °C. The reaction mixture was stirred for 10 min at the same temperature and for additional 10 min at ambient temperature. Then, a solution of amide 6 (451 mg, 1.0 mmol, 1.0 equiv.) in anhydrous THF (3.0 mL) was subsequently added at 0 °C. After stirring for 75 min at 0 °C, the reaction mixture was quenched by the careful addition of saturated aqueous NH4Cl solution, diluted with water and extracted three times with

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diethyl ether; the combined organic extracts were treated with aqueous NaOH (1 M) solution and stirred for 2 h at ambient temperature. Then, the layers were separated and the aqueous layer was extracted twice with diethyl ether; the combined organic extracts were dried over Na2SO4, filtered and evaporated. The target material is difficult to detect on TLC; therefore, the residue was filtered over a short silica plug (hexane/diethyl ether, 3:1) to give after solvent evaporation a white foam which was directly used in the next step without further purification. The white foam was dissolved in anhydrous dichloromethane (6.0 mL) and 1,1’-thiocarbonyldiimidazole (TCDI, 534.6 mg, 3.0 mmol, 3.0 equiv.) and DMAP (36.7 mg, 0.3 mmol, 0.3 equiv.) were subsequently added at ambient temperature. The clear yellow solution was stirred for 20 h before it was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate; the combined organic extracts were washed with 0.1 M aqueous HCl solution (three times), saturated aqueous NaHCO3 solution, brine, and finally dried over Na2SO4, filtered and evaporated to afford 295 mg (63 %, over two steps) of the pure desired imidazolylthiocarbamate 7 after careful purification by flash column chromatography (hexane/ethyl acetate, 5:1). White amorphous solid; 1H NMR (400 MHz, 300 K, CD3CN): δ = 8.29 (s, 1H), 7.65 (t, J = 1.4 Hz, 1H), 7.44– 7.41 (m, 2H), 7.16–7.10 (m, 2H), 7.05 (dd, J = 1.7, 0.8 Hz, 1H), 6.50 (brd, J = 7.3 Hz, 1H), 5.50 (brdd, J = 24.4, 9.9 Hz, 1H), 4.85 (t, J = 12.5 Hz, 1H), 4.68 (brt, J = 12.7 Hz, 1H), 1.36 ppm (s, 9H); 13C NMR (125 MHz, 300 K, CD3CN): δ = 184.0, 163.7 (d, J = 245.9 Hz), 155.8, 138.1, 132.7, 132.1, 131.3 (dd, J = 8.4, 1.4 Hz), 123.7 (qd, J = 286.8, 28.8 Hz), 119.3, 116.7 (d, J = 21.9 Hz), 95.1 (dq, J = 195.6, 29.3 Hz), 80.8, 69.1 (d, J = 29.3 Hz), 54.6 (brd, J = 20.6 Hz), 28.4 ppm; 19F NMR (376 MHz, 300 K, CD3CN): δ = –74.9 (s, 3F), – 114.6 (s, 1F), –184.7 ppm (s, 1F); IR (film): ~ = 3233 (br), 3135 (br), 3007, 2981, 2934, 1715, 1607, 1539, 1512, 1467, 1396, 1368, 1329, 1288, 1232, 1198, 1163, 1012 cm–1; HRMS (ESI): m/z calculated for C19H21F5N3O3S [M+H]+: 466.1218, found: 466.1220;  25 = –2.4 (c = 1.25, CHCl3, 94% ee sample). D 4.2.3. 1-Boc-N-((1S,2R)-2,3,3,3-tetrafluoro-1-(4-fluorophenyl)-2-methylpropyl)piperidine-4-carboxamide (8) To a solution of imidazolylthiocarbamate 7 (240 mg, 0.5 mmol, 1.0 equiv.) in anhydrous toluene (16.0 mL) were added tris(trimethylsilyl)silane (0.48 mL, 1.6 mmol, 3.0 equiv.) and AIBN (25.4 mg, 0.16 mmol, 0.3 equiv.). The reaction mixture was placed in a preheated oil bath and stirred at 85 °C for 150 min. Then, the reaction mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate; the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The target material is difficult to detect on TLC; therefore, the crude residue was simply filtered over a short silica plug (hexane/ethyl acetate, 1:1) and evaporated. The remaining clear slightly yellow oil was directly used in the next step without further purification. 1H NMR analysis of the crude material indicated complete deoxygenation. The crude N-Boc-amine was dissolved in anhydrous dichloromethane (8.0 mL) and trifluoroacetic acid (0.8

11

mL) was added. The resulting clear colorless solution was stirred at ambient temperature for 17 h, before it was quenched by the careful addition of saturated aqueous NaHCO3 solution and extracted three times with chloroform; the combined organic extracts were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and evaporated to give a clear yellow oil which was directly used in the next step. 1H NMR analysis of the crude material indicated complete Boc-removal. The crude primary amine was dissolved in anhydrous DMF (4.0 mL) and subsequently N-Boc-isonipecotic acid 11 (115 mg, 0.5 mmol, 1.0 equiv.), HATU (228.1 mg, 0.6 mmol, 1.2 equiv.) and Hünig’s base (0.35 mL, 2.0 mmol, 4.0 equiv.) were added at 0 °C. The resulting clear yellow solution was stirred at ambient temperature for 16 h, before it was diluted with ethyl acetate and washed subsequently with saturated aqueous NaHCO3 solution (twice) and brine, dried over Na2SO4, filtered and evaporated to afford 122 mg (52 %, over three steps) of the pure desired product 8 after careful purification by flash column chromatography (hexane/ethyl acetate, 4:1). White solid, m. p.: 71–72 °C; 1H NMR (400 MHz, 300 K, CDCl3): δ = 7.33–7.29 (m, 2H), 7.08–7.02 (m, 2H), 6.57 (brd, J = 9.0 Hz, 1H), 5.41 (dd, J = 28.3, 9.1 Hz, 1H), 4.10 (brs, 2H), 2.72 (brq, J = 11.6 Hz, 2H), 2.27 (tt, J = 11.5, 3.8 Hz, 1H), 1.80 (d, J = 12.0 Hz, 1H), 1.72–1.66 (m, 1H), 1.64–1.52 (m, 2H), 1.44 (s, 9H), 1.29 ppm (d, J = 22.7 Hz, 3H); 13C NMR (100 MHz, 300 K, CDCl3): δ = 172.9, 162.6 (d, J = 248.0 Hz), 154.6, 132.6 (d, J = 3.1 Hz), 130.0 (dd, J = 8.1, 1.3 Hz), 123.4 (qd, J = 285.2, 29.7 Hz), 115.8 (d, J = 21.5 Hz), 95.3 (dq, J = 190.9, 29.9 Hz), 79.6, 53.7 (d, J = 17.5 Hz), 43.1 (br, 2C), 42.9, 28.4, 28.3, 28.0, 18.5 ppm (d, J = 22.6 Hz); 19F NMR (376 MHz, 300 K, CDCl3): δ = –78.3 (s, 3F), –112.9 (s, 1F), –179.0 ppm (q, J = 24.0 Hz, 1F); IR (film): ~ = 3458 (br), 3313 (br), 3008, 2979, 2952, 1684, 1658, 1608, 1539, 1513, 1450, 1427, 1367, 1339, 1217, 1161, 1138, 1099, 946 cm–1; HRMS (ESI): m/z calculated for C21H28F5N2O3 [M+H]+: 451.2015, found: 451.2017;  27 = +42.7 (c = 1.08, CHCl3, 94% ee sample). D 4.2.4. 1-(3-Methoxyphenethyl)-N-((1S,2R)-2,3,3,3-tetrafluoro-1-(4-fluorophenyl)-2-methylpropyl)piperidine4-carboxamide (9) To a solution of N-Boc-amine 8 (122 mg, 0.27 mmol, 1.0 equiv.) in anhydrous dichloromethane (4.0 mL) was added trifluoroacetic acid (0.3 mL) at 0 °C. The clear solution was stirred at ambient temperature for 10 h, before it was carefully quenched by the addition of saturated aqueous NaHCO3 solution and three times extracted with chloroform; the combined organic extracts were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and evaporated to give a clear yellow oil which was directly used in the next step. 1H NMR analysis of the crude material indicated complete Boc-removal. To tosylate 12 (103 mg, 0.35 mmol, 1.3 equiv.) was added the crude secondary amine in anhydrous CH3CN (2.0 mL). K2CO3 (56 mg, 0.41 mmol, 1.5 equiv.) was added to the reaction mixture which was then stirred at 70 °C for 20 h. Afterwards, the brown suspension was cooled to ambient temperature, diluted with water and extracted three times with ethyl acetate; the combined organic extracts were washed with brine, dried over

12

Na2SO4, filtered through a short silica plug and evaporated to afford 60 mg (46 %, over two steps) of the pure desired product 9 after purification by preparative HPLC (CHIRALPAK IB, 2-propanol/n-hexane, 1:13, flow rate = 20.0 mL/min, detection at 254 nm). White solid, m. p.: 138–140 °C; 1H NMR (400 MHz, 300 K, CDCl3): δ = 7.33–7.30 (m, 2H), 7.23–7.19 (m, 1H), 7.11–7.05 (m, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.77–6.74 (m, 2H), 6.39 (brd, J = 8.9 Hz, 1H), 5.41 (dd, J = 28.2, 9.0 Hz, 1H), 3.81 (s, 3H), 3.05–3.02 (m, 2H), 2.80–2.76 (m, 2H), 2.61–2.57 (m, 2H), 2.15 (tt, J = 11.5, 4.1 Hz, 1H), 2.04 (tdd, J = 11.4, 7.3, 2.6 Hz, 2H), 1.91–1.69 (m, 4H, contains H2O peak and therefore appears as 5H), 1.29 ppm (d, J = 22.7 Hz, 3H); 13C NMR (125 MHz, 300 K, CDCl3): δ = 173.3, 162.6 (d, J = 247.9 Hz), 159.6, 141.9, 132.7 (d, J = 3.2 Hz), 130.0 (dd, J = 8.2, 1.7 Hz), 129.3, 123.4 (qd, J = 285.7, 29.7 Hz), 121.0, 115.9 (d, J = 21.6 Hz), 114.5, 111.3, 95.3 (dq, J = 190.7, 29.9 Hz), 60.5, 55.1, 53.7 (d, J = 17.5 Hz), 53.0(5), 53.0, 43.2, 33.7, 28.8, 28.4, 18.6 ppm (brd, J = 22.2 Hz); 19F NMR (376 MHz, 300 K, CDCl3): δ = – 78.3 (s, 3F), –113.0 (s, 1F), –179.0 ppm (q, J = 29.6 Hz, 1F); IR (film):~ = 3309 (br), 3051, 3004, 2946, 2804, 2763, 1651, 1605, 1539, 1512, 1490, 1454, 1382, 1318, 1298, 1261, 1220, 1187, 1160, 1139, 1096 cm– 1

; HRMS (ESI): m/z calculated for C25H30F5N2O2 [M+H]+: 485.2222, found: 485.2226;  25 = +27.8 (c = D

0.60, CHCl3, 94% ee sample). 4.2.5. tert-Butyl 3-(4-phenylpiperidin-1-yl)propanoate (15) To a solution of 4-phenylpiperidine 13 (645 mg, 4.0 mmol, 1.0 equiv.) in anhydrous acetonitrile (2.0 mL) was added subsequently tert-butyl acrylate 14 (0.88 mL, 6.0 mmol, 1.5 equiv.) and DBU (0.30 mL, 2.0 mmol, 0.5 equiv.) at ambient temperature. The reaction mixture was stirred for 7 h before it was directly purified by flash column chromatography (hexane/ethyl acetate, 10:1 to 2:1) to afford 1.12 g (97 %) of pure ester 15. Clear colorless oil; 1H NMR (400 MHz, 300 K, CDCl3): δ = 7.33–7.30 (m, 2H), 7.25–7.19 (m, 3H), 3.06–3.01 (m, 2H), 2.74–2.70 (m, 2H), 2.55–2.45 (m, 3H), 2.13 (td, J = 11.5, 2.9 Hz, 2H), 1.88–1.74 (m, 4H), 1.48 ppm (s, 9H); 13C NMR (100 MHz, 300 K, CDCl3): δ = 172.0, 146.3, 128.4, 126.8, 126.1, 80.3, 54.1, 54.0, 42.6, 33.7, 33.5, 28.1 ppm; IR (film):~ = 3029, 2977, 2933, 2804, 2771, 1730, 1604, 1495, 1454, 1391, 1367, 1349, 1250, 1156, 1126 cm–1; HRMS (ESI): m/z calculated for C18H28NO2 [M+H]+: 290.2115, found: 290.2121. 4.2.6. 3-(4-Phenylpiperidin-1-yl)propanoic acid hydrochloride (16) Ester 15 (1.12 g, 3.9 mmol, 1.0 equiv.) was dissolved in HCl solution (15 mL, 4 M in dioxane) at 0 °C and stirred at room temperature for 14 h. The white precipitate was collected via suction filtration, rinsed with diethyl ether and dried under high vacuum to afford 0.86 g (82%) of acid 16 as HCl adduct. The white solid was directly used in the next step without further purification. HRMS (ESI): m/z calculated for C14H20NO2 [M–Cl–]+: 234.1489, found: 234.1488. 4.2.7. tert-Butyl ((1R,2R)-2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-2,3,3,3-tetrafluoro-1-(4-

13

chlorophenyl)propyl)carbamate (18) A flame-dried 20 mL glass test tube equipped with a magnetic stirring bar and a 3-way glass stopcock was charged with [Cu(CH3CN)4]PF6 (11.2 mg, 0.03 mmol, 6 mol%) and (R)-(–)-2,2′-bis[di(3,5-diisopropyl-4dimethylaminophenyl)phosphine]-6,6′-dimethoxy-1,1′-biphenyl (DIPA-MeO-BIPHEP, ent-10) (38.2 mg, 0.04 mmol, 7 mol%) in a glove box under Ar atmosphere. Afterwards, the glass test tube was removed from the glove box, evacuated for 30 min, and backfilled with argon. Anhydrous THF (0.15 mL, 1.1 M) was added at room temperature and the resulting clear colorless solution was stirred for 30 min before racemic 1-(2,3dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,3,3,3-tetrafluoropropan-1-one (5) [10b] (124.1 mg, 0.5 mmol, 1.0 equiv.), tert-butyl (E)-(4-chlorobenzylidene)carbamate (17) [25] (239.7 mg, 1.0 mmol, 2.0 equiv.) and Barton’s base (0.1 M in THF, 0.3 mL, 0.03 mmol, 6 mol%) were subsequently added. The reaction mixture was stirred at ambient temperature for 20 h. The dr and the ee of the crude reaction product were determined by HPLC analysis of an aliquot, which was taken from the reaction mixture and filtered through a short pad of silica: dr = 12:1 (anti:syn), 92% ee (anti). Then, the reaction mixture was loaded directly onto a silica gel column and eluted with n-hexane/ethyl acetate (3:1). Evaporation of solvent afforded 235 mg (96%) of the desired pure amide 18 as a 12:1 diastereomeric mixture. Analytical data of the major diastereomer are given below: White amorphous solid; 1H NMR (400 MHz, 343 K, DMSO-d6): δ = 8.17–8.15 (m, 1H), 7.97 (brs, 1H), 7.64– 7.62 (m, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.38–7.35 (m, 2H), 7.06 (dd, J = 7.4, 5.0 Hz, 1H), 6.09 (brd, J = 16.5 Hz, 1H), 3.89–3.82 (m, 1H), 3.65–3.58 (m, 1H), 2.90 (ddd, J = 16.3, 9.5, 6.1 Hz, 1H), 2.77 (ddd, J = 16.6, 8.7, 7.3 Hz, 1H), 1.37 ppm (s, 9H); 13C NMR (125 MHz, 343 K, DMSO-d6): δ = 161.0 (d, J = 22.0 Hz), 155.0, 154.3 (br), 145.6, 134.2, 133.4, 132.9, 130.2, 127.9, 125.7, 121.5 (qd, J = 287.9, 30.4 Hz), 119.7, 96.3 (dq, J = 218.4, 26.6 Hz), 78.8, 54.4 (brd, J = 15.1 Hz), 47.5 (d, J = 10.6 Hz), 27.7, 25.1 ppm; 19F NMR (376 MHz, 343 K, DMSO-d6): δ = –70.6 (s, 3F), –177.5 ppm (brs, 1F); IR (film):~ = 3342 (br), 3061, 2979, 2934, 1709, 1681, 1596, 1493, 1420, 1392, 1368, 1343, 1306, 1277, 1253, 1209, 1165, 1091, 1015 cm–1; HRMS (ESI): m/z calculated for C22H23ClF4N3O3 [M+H]+: 488.1359, found: 488.1360;  24 = +38.6 (c = 0.65, D CHCl3, 92% ee sample); HPLC analysis (CHIRALPAK IE (0.46 cm  x 25 cm), 2-propanol/n-hexane = 1/4, flow rate = 1.0 mL/min, detection at 254 nm, tR = 25.1 min (major), 50.4 min (minor)). 4.2.8.

O-((R)-2-((R)-((tert-Butoxycarbonyl)amino)(4-chlorophenyl)methyl)-2,3,3,3-tetrafluoropropyl)-1H-

imidazole-1-carbothioate (19) To a suspension of borane-ammonia complex (61.7 mg, 2.0 mmol, 4.0 equiv.) in anhydrous THF (1.5 mL) was added lithium diisopropylamide (1.0 M in n-hexane/THF, 1.95 mL, 2.0 mmol, 3.9 equiv.) at 0 °C. The reaction mixture was stirred for 10 min at the same temperature and for additional 10 min at ambient temperature. Then, a solution of amide 18 (235 mg, 0.5 mmol, 1.0 equiv.) in anhydrous THF (1.5 mL) was subsequently added at 0 °C. After stirring for 75 min at 0 °C, the reaction mixture was quenched by the

14

careful addition of saturated aqueous NH4Cl solution, diluted with water and extracted three times with diethyl ether; the combined organic extracts were treated with aqueous NaOH (1 M) solution and stirred for 2 h at ambient temperature. Then, the layers were separated and the aqueous layer was extracted twice with diethyl ether; the combined organic extracts were dried over Na2SO4, filtered and evaporated. The target material is difficult to detect on TLC; therefore, the residue was filtered over a short silica plug (hexane/diethyl ether, 3:1) to give after solvent evaporation a white foam which was directly used in the next step without further purification. The white foam was dissolved in anhydrous dichloromethane (3.0 mL) and 1,1’-thiocarbonyldiimidazole (TCDI, 262.3 mg, 1.5 mmol, 3.0 equiv.) and DMAP (18.4 mg, 0.15 mmol, 0.3 equiv.) were subsequently added at ambient temperature. The clear yellow solution was stirred for 20 h before it was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate; the combined organic extracts were washed with 0.1 M aqueous HCl solution (three times), saturated aqueous NaHCO3 solution, brine, and finally dried over Na2SO4, filtered over a short silica plug, and evaporated. At this stage the minor syn-diastereomer of the Mannich-type reaction was removed by preparative HPLC (CHIRALPAK IB, 2-propanol/n-hexane = 1/40, flow rate = 20.0 mL/min, detection at 254 nm) to afford 121 mg (50 %, over two steps) of the pure desired imidazolylthiocarbamate 19. White amorphous solid; 1H NMR (400 MHz, 300 K, CD3CN): δ = 8.28 (s, 1H), 7.64 (t, J = 1.4 Hz, 1H), 7.42– 7.37 (m, 4H), 7.04 (dd, J = 1.8, 0.8 Hz, 1H), 6.50 (brd, J = 7.8 Hz, 1H), 5.49 (brdd, J = 24.5, 9.9 Hz, 1H), 4.87 (t, J = 12.8 Hz, 1H), 4.70 (brt, J = 12.5 Hz, 1H), 1.36 ppm (s, 9H); 13C NMR (125 MHz, 300 K, CD3CN): δ = 184.0, 155.7, 138.1, 135.4, 135.2, 132.0, 130.9 (d, J = 1.3 Hz), 129.9, 123.6 (qd, J = 286.7, 28.7 Hz), 119.3, 95.0 (dq, J = 194.4, 29.4 Hz), 80.8, 69.1 (d, J = 29.2 Hz), 54.7 (brd, J = 20.2 Hz), 28.3 ppm; 19F NMR (376 MHz, 300 K, CD3CN): δ = –74.9 (s, 3F), –184.4 ppm (s, 1F); IR (film):~ = 3229 (br), 2979, 2931, 1715, 1540, 1495, 1466, 1396, 1328, 1288, 1232, 1199, 1163, 1093, 1013, 915 cm–1; HRMS (ESI): m/z calculated for C19H21ClF4N3O3S [M+H]+: 482.0923, found: 482.0925;  27 = +3.8 (c = 0.20, CHCl3, 92% ee sample). D 4.2.9.

1-Boc-N-((1R,2S)-2,3,3,3-tetrafluoro-1-(4-chlorophenyl)-2-methylpropyl)piperidine-4-carboxamide

(20) To a solution of imidazolylthiocarbamate 19 (121 mg, 0.25 mmol, 1.0 equiv.) in anhydrous toluene (8.0 mL) were added tris(trimethylsilyl)silane (0.23 mL, 0.75 mmol, 3.0 equiv.) and AIBN (12.4 mg, 0.08 mmol, 0.3 equiv.). The reaction mixture was placed in a preheated oil bath and stirred at 85 °C for 150 min. Then, the reaction mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate; the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The target material is difficult to detect on TLC; therefore, the crude residue was simply filtered over a short silica plug (hexane/ethyl acetate, 1:1) and evaporated. The remaining clear colorless oil was directly used in the next step without further purification. 1H NMR analysis of the crude reaction mixture indicated complete

15

conversion to the target material. The crude N-Boc-amine was dissolved in anhydrous dichloromethane (4.0 mL) and trifluoroacetic acid (0.4 mL) was subsequently added. The resulting clear colorless solution was stirred at ambient temperature for 17 h, before it was quenched by the careful addition of saturated aqueous NaHCO 3 solution and three times extracted with chloroform; the combined organic extracts were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and evaporated to give a clear orange oil which was directly used in the next step. 1H NMR analysis of the crude material indicated complete Boc-removal. The crude primary amine was dissolved in anhydrous DMF (2.0 mL) and subsequently acid hydrochloride 16 (67.4 mg, 0.25 mmol, 1.0 equiv.), HATU (114.1 mg, 0.3 mmol, 1.2 equiv.) and Hünig’s base (0.22 mL, 1.25 mmol, 5.0 equiv.) were added at 0 °C. The resulting clear yellow solution was stirred at 0 °C for 30 min and at ambient temperature for 16 h before it was diluted with ethyl acetate and washed subsequently with saturated aqueous NaHCO3 solution (twice) and brine, dried over Na2SO4, filtered over a short silica plug and evaporated to afford 67 mg (57 %, over three steps) of the pure desired product 20 after purification by preparative HPLC (CHIRALPAK IC, 2-propanol/n-hexane = 1/9, flow rate = 20.0 mL/min, detection at 254 nm). White solid; 1H NMR (400 MHz, 300 K, CDCl3): δ = 10.47 (brd, J = 9.0 Hz, 1H), 7.39–7.35 (m, 4H), 7.33– 7.28 (m, 3H), 7.27–7.24 (m, 2H), 5.42 (dd, J = 28.4, 9.1 Hz, 1H), 3.22–3.09 (m, 2H), 2.69 (ddd, J = 12.8, 8.2, 3.9 Hz, 1H), 2.63–2.56 (m, 2H), 2.45 (ddd, J = 17.2, 7.5, 3.8 Hz, 1H), 2.37 (ddd, J = 17.2, 8.2, 3.8 Hz, 1H), 2.21–2.14 (m, 2H), 2.02–1.91 (m, 3H), 1.88–1.78 (m, 1H), 1.34 ppm (dq, J = 22.6, 1.0 Hz, 3H); 13C NMR (125 MHz, 300 K, CDCl3): δ = 171.4, 145.8, 136.1, 134.3, 129.8 (d, J = 1.7 Hz), 129.0, 128.6, 126.7, 126.4, 123.6 (qd, J = 285.8, 29.7 Hz), 95.4 (dq, J = 191.4, 29.8 Hz), 53.8, 53.7 (d, J = 17.8 Hz), 53.5, 53.4, 42.4, 33.7, 32.9, 31.5, 18.6 ppm (brd, J = 22.3 Hz); 19F NMR (376 MHz, 300 K, CDCl3): δ = –78.2 (s, 3F), –177.4 ppm (m, 1F); IR (film):~ = 3156 (br), 3028, 2941, 2812, 1672, 1541, 1494, 1455, 1320, 1217, 1190, 1160, 1090, 1014 cm–1; HRMS (ESI): m/z calculated for C24H28ClF4N2O [M+H]+: 471.1821, found: 471.1809;  27 D = +32.1 (c = 0.40, CHCl3, 92% ee sample).

Acknowledgements This work was financially supported by JST ACT–C, JSPS KAKENHI Grant Number 25713002, and The Naito Foundation. Dr. Ryuichi Sawa, Dr. Kiyoko Iijima, and Ms. Yumiko Kubota are gratefully acknowledged for assistance in obtaining NMR and HRMS spectra. Dr. Tomoyuki Kimura is acknowledged for assistance in X-ray crystallography.

References

16

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