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Article

Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags

by
Kazuki Ishihara
,
Yamato Kato
,
Narisa Takeuchi
,
Yuka Hayashi
,
Yuna Hagiwara
,
Shyota Shibuya
,
Tohya Natsume
and
Masato Matsugi
*
Faculty of Agriculture, Meijo University, 1-501, Shiogamaguchi, Tempaku-ku, Nagoya 468-8502, Japan
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(22), 7632; https://doi.org/10.3390/molecules28227632
Submission received: 5 October 2023 / Revised: 26 October 2023 / Accepted: 10 November 2023 / Published: 16 November 2023
(This article belongs to the Special Issue Organic Ligands: Design, Synthesis and Application)
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Versions Notes

Abstract

:
The effect of the presence of fluorous tags in bisoxazoline ligands on the stereoselectivity of the cobalt-catalyzed asymmetric Henry reaction was investigated. In contrast to the stereoselectivity obtained with conventional nonfluorous ligands, using bisoxazoline bidentate ligands featuring two fluorous tags in adjacent positions on the aromatic ring yielded a reversed stereoselectivity. The stereoselectivity also reversed when the fluorous tags were replaced with alkyl chains of equivalent length, albeit to a considerably lesser degree, highlighting the effect of the fluorous tags.

Graphical Abstract

1. Introduction

Optically active C2-symmetrical bisoxazoline (BOX) ligands are among the most versatile ligands used in organic synthesis [1,2,3,4]. Since Evans et al. reported the asymmetric cyclopropanation reaction [5] using Cu/BOX complexes in 1991, various BOX ligands with structural tunability have been developed [6,7,8,9,10,11]. Using these ligands in reactions such as the Henry reaction [12,13,14], Mukaiyama aldol reaction [15], Michael additions [16,17], and Friedel–Crafts reactions [18] furnishes the target products in high asymmetric yields.
BOX ligands bearing fluorous tags are particularly interesting because they repel water and polar organic compounds while exhibiting a strong mutual affinity [19] among fluorous molecules. These ligands, which have been used in asymmetric reactions including allylic alkylation [20], cyclopropanation [21], and the Henry reaction [22], can be selectively isolated and recovered from reaction mixtures via solid-phase extraction using fluorous silica gel [23] or liquid-phase extraction using fluorous solvents [24]. By incorporating a fluorous tag into the BOX ligand for the first time in asymmetric Henry reactions, Cai et al. achieved high stereoselectivity and recovery [22]. Our study involves the use of BOX ligands incorporating two fluorous tags at different positions on the ligand in asymmetric Henry reactions.
Previously, we achieved the first asymmetric epoxidation of an isolated carbon–carbon double bond using an iron salen complex incorporating a fluorous tag at the 3,3′-position of the salen ligand [25]. Apart from its recycling ability, this complex exhibits a unique characteristic stemming from the two fluorous tags; namely, the conformational fixation via intramolecular stacking between neighboring fluorous tags forms a distorted asymmetric structure and creates a unique catalytic reaction field. We postulated that the introduction of two adjacent fluorous tags on freely rotatable substituents in BOX ligands could lock the coordination in place through a stacking between the tags, which would lead to different reactivity and stereoselectivity compared with conventional catalysts. Therefore, we synthesized a series of BOX ligands containing two fluorous tags and investigated their reactivity and stereoselectivity in the asymmetric Henry reaction [26], which is a useful carbon–carbon bond formation reaction. Here, we describe an asymmetric Henry reaction using BOX bidentate ligands 1a–1d with two fluorous tags introduced in spatially adjacent positions and pincer-type BOX tridentate ligand 1e (Figure 1). For bisoxazoline catalysts, fluorous tag catalysts via flexible benzyl spacers (1a and 1b) and more rigid aryl-type fluorous catalysts (1c and 1d) were investigated. Ligands with freely rotating methylene groups (1a and 1b) and ligands with rigid aromatic planar ring structures (1c and 1d) have different steric environments, potentially resulting in significant differences in stereoselectivity.

2. Results and Discussions

Scheme 1 outlines the synthetic pathway for bidentate ligands 1a and 1b. First, methylation of 4-iodo-L-phenylalanine 2 afforded 3, which was Boc-protected to yield compound 4. Subsequently, the introduction of C4F9 and C8F17 fluorous tags was achieved via Ullmann coupling, resulting in intermediates 5a and 5b, respectively. After ester reduction and removal of the Boc group, compounds 7a and 7b were obtained. The synthesis culminated with the condensation with dimethylmalonyl chloride and subsequent cyclization, furnishing oxazoline ligands 1a and 1b bearing the C4F9 and C8F17 tags, respectively.
Ligands 1c and 1d were synthesized following the reaction pathway outlined in Scheme 2. (S)-2-Phenylglycinol 9 was iodinated to obtain compound 10. After condensation with dimethylmalonyl chloride and subsequent deprotection of the TBS group, intermediate 11 was obtained. Then, a cyclization reaction using (diethylamino)sulfur trifluoride (DAST) afforded BOX intermediate 12. Finally, C4F9 and C8F17 fluorous tags were introduced via Ullmann coupling, affording BOX ligands 1c and 1d, respectively.
As a control ligand, unsubstituted ligand 14 [27] without fluorous tags was also synthesized from (S)-2-phenylglycinol 9 via a condensation reaction with dimethyl malonyl chloride followed by cyclization (Scheme 3).
First, the as-synthesized fluorous BOX ligands were investigated as chiral ligands in the Henry reaction. Using p-nitrobenzaldehyde and nitromethane as substrates, various metal sources were employed in the Henry reaction in the presence of ligand 1a in iPrOH. When Cu(OAc)2·H2O was utilized, the reaction proceeded with a 97% conversion and 69% enantiomeric excess (ee), predominantly yielding the S-aldol addition product (Table 1, entry 1). In contrast, no reaction occurred when using CuCl2, CuBr2, or Cu(OTf)2 (Table 1, entries 2–4). Meanwhile, Co(OAc)2 and Zn(OAc)2 gave high conversion rates but nearly racemic products (Table 1, entries 5 and 6). Therefore, Cu(OAc)2·H2O was selected as the metal source for subsequent reactions.
Next, fluorophobic (iPrOH and 50% iPrOH aqueous solution) and fluorophilic solvents (THF and FC-72) were employed as reaction media using ligands 1a–d to investigate the solvent effect in the reaction. Although differences in affinity between the fluorinated ligands and solvents were expected to affect the stereoselectivity, no remarkable impact on stereoselectivity was observed in reactions using 1a and 1b. When catalysts (1a and 1b) with fluorous tags via benzyl spacers were used, a moderate level of stereoselectivity was obtained in favor of the formation of S-aldol addition products in all cases. (Table 2, entries 1–7).
Interestingly, when fluorous ligands 1c and 1d were used as chiral sources, the reverse stereoselectivity was observed even though all ligands 1a–1d exhibited the same absolute stereochemistry (S,S), favoring the R-aldol addition product with moderate stereoselectivity (Table 2, entries 8–13 vs. entries 1–7, 14). This result suggests that the fluorinated aryl BOX ligands at the 2′ position (1c and 1d) create a distinct asymmetric environment compared with the other ligands used. Although there was no substantial difference in stereoselectivity based on differences in reaction solvent and tag length in either case, the combination of ligand 1c and iPrOH yielded the highest reverse stereoselectivity (53% ee) (Table 2, entry 8).
A control experiment was conducted using ligand 19, which is the nonfluorinated version of 1c, under the same conditions. Interestingly, as in the case of fluorinated ligand 1c, a preference for the aldol addition to the R-isomer was observed. However, the stereoselectivity drastically decreased to 14% ee (Table 2, entry 15). These results indicate that the steric bulkiness at the 2′-position on the aryl-type BOX ligand is a factor that reverses the stereoselectivity. Introducing a fluorous tag at the 2′-position does not substantially affect the reaction result, but it does affect the stereoselectivity more than the corresponding nonfluorous alkyl substituent. Note that ligand 19 was synthesized using the route depicted in Scheme 4.
Next, pincer-type fluorinated ligand 1e, which was synthesized using the route depicted in Scheme 5, was applied to the present reaction. Briefly, iodinated compound 15 was first protected with Boc and then the C4F9 tag was introduced via the Ullmann reaction, forming intermediate 20. Under acidic conditions, both the TBS and Boc groups were simultaneously removed, and the subsequent condensation reaction with 2,6-pyridinedicarbonyl dichloride yielded 22. Finally, ligand 1e was synthesized through a ring-closure reaction using DAST. Furthermore, unsubstituted ligand 24 [28] was synthesized as a control ligand via condensation and cyclization reactions with 2,6-pyridinedicarbonyl dichloride using (S)-2-phenylglycinol 9 as the substrate (Scheme 6).
Table 3 shows the results of asymmetric Henry reactions using pincer-type ligands 1e and 2. The combination of 1e and Co(OAc)2 afforded the R-addition product with slightly higher stereoselectivity than that obtained when using Cu(OAc)2·H2O or Zn(OAc)2 (Table 3, entries 1–3).
Solvent effects were investigated using a 50% iPrOH aqueous solution, THF, and FC-72 as reaction solvents (Table 3, entries 4–6). The reaction proceeded quantitatively in a 50% iPrOH aqueous solution but with little stereoselectivity. Using THF resulted in better stereoselectivity, and the target product was obtained with an optical purity of 42% ee. The reaction did not proceed when the fluorous solvent FC-72 was used.
The R-product was predominantly obtained in experiments conducted in THF with pincer-type ligand 24 lacking fluorous tags. However, the stereoselectivity was lower (8% ee) than when using fluorous 1e (Table 3, entry 5 vs. entry 7). This suggests that introducing the fluorous tags into the pincer-type ligand enhances the stereoselectivity of this reaction.

3. Experimental Section

3.1. Materials and Reagents

All the laboratory chemicals were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), FUJIFILM Wako Pure Chemical Corporation (Richmond, VA, USA), Sigma-Aldrich Co. LLC (St. Louis, MO, USA), and Kanto Chemical Co., Inc. (Tokyo, Japan) and used without further purification unless otherwise stated. Solvents were removed using rotary evaporation under reduced pressure using a water bath at 40 °C–50 °C. Nonvolatile compounds were dried in vacuo at 0.01 mbar. All reactions were stirred magnetically and monitored using thin-layer chromatography using silica gel plates. Purification by chromatography was performed on silica gel 60 N (spherical, neutral, 63–210 µm, Kanto Chemical Co., Inc.).

3.2. Analytical Instruments

Melting points were determined in open-ended capillaries using a Bibby Scientific Ltd. (Stone, UK) Stuart® SMP-30 instrument or ATM-01 of AS ONE Corporation and are uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded using JNM-EX270 (1H: 270 MHz) and JNM-ECZ400S (1H: 400 MHz, 13C: 101 MHz, 19F: 376 MHz) spectrometers. Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in Hz. Abbreviations for multiplicity are as follows: s (singlet), d (doublet), t (triplet), m (multiplet), dd (double doublet), and br s (broad signal). High-performance liquid chromatography (HPLC) analyses were performed using Daicel Chiralpack IA-3 columns with UV Detector L2400 or SPD-20A. High-resolution mass spectra were obtained using ExactiveTM Plus Orbitrap (Thermo Fisher Scientific, Waltham, MA, USA). The spectra were calibrated with PierceTM LTQ Velos ESI Positive Ion Calibration Solution prior to data acquisition.

3.3. General Procedure for the Henry Reaction

A mixture of the ligand (0.012 mmol) and the metal salt (0.011 mmol) was stirred in a solvent (328 μL) at room temperature for 1 h. Aldehyde (0.22 mmol) and MeNO2 (2.19 mmol) were added to the reaction mixture, which was then stirred at room temperature for 22 h. The reaction mixture was concentrated. The conversion was determined by 1H NMR analysis of the crude product. The ee of the product was determined with HPLC of the crude product.

3.4. Synthesis

  • Methyl (S)-2-amino-3-(4-iodophenyl)propanoate hydrochloride (3) [29]. Under N2 atmosphere, a solution of 4-iodo-L-phenylalanine 2 (5.02 g, 17.23 mmol) in dry-MeOH (80 mL) was stirred at 0 °C, then SOCl2 (1.5 mL, 20.55 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then stirred for 22 h. The reaction mixture was concentrated. After the addition of Et2O, the suspension was purified by filtration to give the desired product 3 (5.84 g, 17.10 mmol, 99%). White solid; mp 191–192 °C; 1H NMR (400 MHz, (CD3)2SO) δ 8.55 (br s, 3H), 7.70 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.30–4.26 (m, 1H), 3.69 (s, 3H), 3.14–3.04 (m, 2H).
  • Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoate (4) [30]. A solution of methyl (S)-2-amino-3-(4-iodophenyl)propanoate hydrochloride 3 (252.3 mg, 0.74 mmol) and Et3N (213 μL, 1.53 mmol) in dry-DCM (4 mL) was stirred at 0 °C. A solution of Boc2O (167.7 mg, 0.77 mmol) in dry-DCM (3 mL) was slowly added to the mixture. Then the reaction temperature rose to room temperature and the mixture was stirred for a further 20 h. The mixture was diluted with brine. The reaction mixture was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:1) to give the desired product 4 (250.2 mg, 0.62 mmol, 84%). White solid; mp 74–75 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.98–4.96 (m, 1H), 4.58–4.56 (m, 1H), 3.72 (s, 3H), 3.10–2.95 (m, 2H), 1.42 (s, 9H).
  • Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(perfluorobutyl)phenyl)propanoate (5a). To a mixture of 4 (1.03 g, 2.54 mmol), Cu powder (1.60 g, 25.12 mmol), 2,2′-bipyridyl (38.8 mg, 0.25 mmol), and DMF (5 mL) was added a 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (0.8 mL, 4.76 mmol). The mixture was stirred at 120 °C for 19 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. Then 1 M HCl aq. was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:3) to give the desired product 5a (1.08 g, 2.18 mmol, 86%). Yellow solid; mp 40–41 °C; 1H NMR (270 MHz, CDCl3) δ 7.52 (d, J = 8.1 Hz, 2H), 7.30–7.27 (m, 2H), 5.06–5.03 (m, 1H), 4.65–4.62 (m, 1H), 3.72 (s, 3H), 3.25–3.04 (m, 2H), 1.40 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −80.95 (3F), −110.79 (2F), −122.71 (2F), −125.51 (2F); 13C NMR (101 MHz, CDCl3) δ 172.03, 155.04, 140.77, 129.74, 127.64, 127.07,116.14–110.67, 80.26, 54.26, 52.44, 38.49, 28.31; HRMS-DART (m/z):[M + H]+ calcd for C19H21F9NO4: 498.1327, found: 498.1320.
  • tert-Butyl (S)-(1-hydroxy-3-(4-(perfluorobutyl)phenyl)propan-2-yl)carbamate (6a). Lithium chloride (348.0 mg, 8.21 mmol) and sodium borohydride (312.5 mg, 8.26 mmol) were added to a solution of 5a (2.03 g, 4.07 mmol) in dry-THF (15 mL) and dry-EtOH (30 mL) and the white suspension was stirred for 23 h. Then, 1 M HCl aq. was added to the reaction mixture until pH = 4. The solution was concentrated. The aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:1) to give the desired product 6a (1.82 g, 3.88 mmol, 95%). White solid; mp 89 °C; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.76 (d, J = 7.6 Hz, 1H), 3.90 (s, 1H), 3.71–3.54 (m, 2H), 2.93 (d, J = 6.8 Hz, 2H), 2.15 (s, 1H), 1.39 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −80.95 (3F), −110.68 (2F), −122.69 (2F), −125.54 (2F); 13C NMR (101 MHz, CDCl3) δ 155.94, 142.58, 129.67, 127.41, 127.07, 118.99–115.88, 79.96, 64.13, 53.43, 39.49, 37.40, 28.33; HRMS-DART (m/z):[M + H]+ calcd for C18H21F9NO3: 470.1378, found: 470.1373.
  • (S)-2-Amino-3-(4-(perfluorobutyl)phenyl)propan-1-ol hydrochloride (7a). To a solution of tert-butyl (S)-(1-hydroxy-3-(4-(perfluorobutyl)phenyl)propan-2-yl)carbamate 6a (0.85 g, 1.82 mmol) in ethyl acetate (6 mL) was added a conc. HCl (6 mL). The mixture was stirred at room temperature for 35 min. Excess water was separated as the toluene azeotrope. After the addition of Et2O, the suspension was purified by filtration to give the desired product 7a (0.71 g, 1.75 mmol, 95%). White solid; mp 166–167 °C; 1H NMR (400 MHz, (CD3)2SO) δ 8.06 (s, 3H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.28 (t, J = 4.4 Hz, 1H), 3.64–3.43 (m, 2H), 3.10–2.95 (m, 2H); 19F NMR (376 MHz, (CD3)2SO) δ −80.45 (3F), −109.43 (2F), −122.26 (2F), −125.11 (2F); 13C NMR (101 MHz, (CD3)2SO) δ 142.54, 130.75, 127.47, 126.10, 116.43–108.50, 60.17, 53.91, 35.02; HRMS-DART (m/z):[M − Cl]+ calcd for C13H13F9NO: 370.0853, found: 370.0844.
  • N1,N3-Bis((S)-1-hydroxy-3-(4-(perfluorobutyl)phenyl)propan-2-yl)-2,2-dimethylmalonamide (8a). Under N2 atmosphere, to a solution of 7a (1.39 g, 3.44 mmol) and Et3N (1 mL, 7.18 mmol) in dry-DCM (30 mL) was added solution of dimethylmalonyl dichloride (227 μL, 1.72 mmol) in dry-DCM (11 mL) at 0 °C. Then, the reaction temperature rose to room temperature and the mixture was stirred for 20 h. The mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:20) to give the desired product 8a (1.37 g, 1.64 mmol, 95%). White solid; mp 116–117 °C; 1H NMR (270 MHz, CDCl3) δ 7.49 (d, J = 8.1 Hz, 4H), 7.31 (d, J = 8.4 Hz, 4H), 6.49 (d, J = 8.4 Hz, 2H), 4.28 (br s, 2H), 3.74 (dd, J = 11.3, 3.2 Hz, 2H), 3.47 (dd, J = 11.3, 6.5 Hz, 2H), 2.95–2.73 (m, 4H), 1.16 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −81.02 (6F), −110.81 (4F), −122.77 (4F), −125.54 (4F); 13C NMR (101 MHz, CDCl3) δ 173.98, 141.95, 129.42, 127.35, 127.01, 121.74–111.20, 64.16, 52.50, 49.78, 36.71, 23.26; HRMS-DART (m/z):[M + H]+ calcd for C31H29F18N2O4: 835.1840, found: 835.1824.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(4-(perfluorobutyl)benzyl)-4,5-dihydrooxazole) (1a). Under N2 atmosphere, to a solution of 8a (444.2 mg, 0.53 mmol) in dry-DCM (30 mL) was added a solution of diethylaminosulfur trifluoride (155 μL, 1.17 mmol) in dry-DCM (15 mL) at −78 °C. After stirring at 0 °C for 11 h, the mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:20) to give the desired product 1a (337.3 mg, 0.42 mmol, 79%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 4H), 7.34 (d, J = 8.0 Hz, 4H), 4.45–4.39 (m, 2H), 4.22 (t, J = 8.8 Hz, 2H), 3.97–3.94 (m, 2H), 3.05–3.00 (m, 2H), 2.85–2.80 (m, 2H), 1.41 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −81.99 (6F), −110.76 (4F), −122.67 (4F), −125.54 (4F); 13C NMR (101 MHz, CDCl3) δ 169.70, 141.98, 129.96, 127.13, 126.88, 118.97–108.83, 71.79, 66.43, 41.06, 38.61, 24.08; HRMS-DART (m/z):[M + H]+ calcd for C31H25F18N2O: 799.1629, found: 799.1627.
  • Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(perfluorooctyll)phenyl)propanoate (5b). To a mixture of 4 (103.3 mg, 0.25 mmol), Cu powder (165.6 mg, 2.61 mmol), 2,2′-bipyridyl (4.0 mg, 0.03 mmol), and DMF (1 mL) was added a 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-8-iodooctane (130 μL, 0.49 mmol). The mixture was stirred at 120 °C for 21 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. Then, 1 M HCl aq. was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:3) to give the desired product 5b (0.17 g, 0.25 mmol, 97%). White solid; mp 70–71 °C; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.02 (d, J = 7.2 Hz, 1H), 4.66–4.61 (m, 1H), 3.72 (s, 3H), 3.24–3.05 (m, 2H), 1.40 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −80.83 (3F), −110.51 (2F), −121.17 (2F), −121.77 (6F), −122.63 (2F), −126.03 (2F); 13C NMR (101 MHz, CDCl3) δ 171.99, 154.99, 140.71, 129.68, 127.71, 127.04, 120.07–100.39, 80.21, 54.21,52.38, 38.46, 28.25; HRMS-DART (m/z):[M + H]+ calcd for C23H21F17NO4: 698.1199, found: 698.1188.
  • tert-Butyl (S)-(1-hydroxy-3-(4-(perfluorooctyl)phenyl)propan-2-yl)carbamate (6b). Lithium chloride (211.3 mg, 4.98 mmol) and sodium borohydride (188.8 mg, 4.99 mmol) were added to a solution of 5b (1.70 g, 2.43 mmol) in dry-THF (15 mL) and dry-EtOH (30 mL) and the white suspension was stirred for 13 h. Then, 1 M HCl aq. was added to the reaction mixture until pH = 4. The solution was concentrated. The aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:2) to give the desired product 6b (1.50 g, 2.24 mmol, 92%). White solid; mp 186–187 °C; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.74 (d, J = 7.2 Hz, 1H), 3.91 (s, 1H), 3.71–3.55 (m, 2H), 2.93 (d, J = 6.8 Hz, 2H), 2.10 (s, 1H), 1.39 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −80.62 (3F), −110.32 (2F), −121.14 (2F), −121.71 (6F), −122.58 (2F), −125.97 (2F); 13C NMR (101 MHz, CDCl3) δ 155.95, 142.83, 129.67, 127.27, 127.14, 118.64–108.61, 79.94, 64.04, 53.59, 37.52, 28.57; HRMS-DART (m/z):[M + H]+ calcd for C22H21F17NO3: 670.1250, found: 670.1227.
  • (S)-2-Amino-3-(4-(perfluorooctyl)phenyl)propan-1-ol hydrochloride (7b). To a solution of tert-butyl (S)-(1-hydroxy-3-(4-(perfluorooctyl)phenyl)propan-2-yl)carbamate 6b (1.44 g, 2.15 mmol) in ethyl acetate (8 mL) was added a conc. HCl (8 mL). The mixture was stirred at room temperature for 35 min. Excess water was separated as the toluene azeotrope. After the addition of Et2O, the suspension was purified by filtration to give the desired product 7b (1.28 g, 2.12 mmol, 98%). White solid; mp 98–99 °C; 1H NMR (400 MHz, (CD3)2SO) δ 8.10 (s, 3H), 7.65 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 5.41–5.40 (m, 1H), 3.54–3.37 (m, 2H), 3.05–2.92 (m, 2H); 19F NMR (376 MHz, (CD3)2SO) δ −80.13 (3F), −109.22 (2F), −120.95 (2F), −121.33 to −121.58 (m, 6F), −122.37 (2F), −125.63 (2F); 13C NMR (101 MHz, (CD3)2SO) δ 142.47, 130.74, 127.45, 126.47, 122.63–110.16, 60.22, 53.84, 35.08; HRMS-DART (m/z):[M − Cl]+ calcd for C17H13F17NO: 570.0726, found: 570.0722.
  • N1,N3-bis((S)-1-hydroxy-3-(4-(perfluorooctyl)phenyl)propan-2-yl)-2,2-dimethylmalonamide (8b). Under N2 atmosphere, to a solution of 7b (1.23 g, 2.04 mmol) and Et3N (595 μL, 4.27 mmol) in dry-DCM (12 mL) was added a solution of dimethylmalonyl dichloride (135 μL, 1.02 mmol) in dry-DCM (12 mL) at 0 °C. Then, the reaction temperature rose to room temperature and the mixture was stirred for 20 h. The mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:20) to give the desired product 8b (1.09 g, 0.88 mmol, 86%). White solid; mp 142 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 4H), 7.32 (d, J = 8.4 Hz, 4H), 6.44 (d, J = 8.4 Hz, 2H), 4.27–4.24 (m, 2H), 3.76–3.72 (m, 2H), 3.52–3.48 (m, 2H), 2.95–2.90 (m, 2H), 2.84–2.79 (m, 2H), 1.18 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −80.69 (6F), −110.57 (4F), −121.17 (4F), −121.80 (12F), −122.63 (4F), −126.02 (4F); 13C NMR (101 MHz, CD3OD) δ 174.38, 143.64, 129.69, 126.46, 126.40, 118.58, 115.99, 115.71, 113.51, 110.92, 110.62, 110.29, 108.27, 63.14, 52.59, 49.79, 36.28, 22.72; HRMS-DART (m/z):[M + H]+ calcd for C39H29F34N2O4: 1235.1584, found: 1235.1556.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(4-(perfluorohexyl)benzyl)-4,5-dihydrooxazole) (1b). The 8b (673.1 mg, 0.545 mmol) was dissolved in dry-1,2-DCE (110 mL) and heated to 80 °C. Thionyl chloride (4 mL, 5.48 mmol) was added and stirred at 80 °C for 5 h. The reaction mixture was concentrated and quenched with a saturated NaHCO3 solution. The mixture was extracted with DCM and the combined organic layers were dried over Na2SO4 filtered and the solvent was removed under reduced pressure. The residue was dissolved in a solution of NaOH (84.1 mg, 2.10 mmol) in MeOH (153 mL) and heated to 60 °C for 15 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between DCM and H2O. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:100) to give the desired product 1b (0.49 g, 0.41 mmol, 75%). White solid; mp 78–79 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 4H), 7.34 (d, J = 7.6 Hz, 4H), 4.46–4.39 (m, 2H), 4.24–4.19 (m, 2H), 3.97–3.93 (m, 2H), 3.02 (dd, J = 14.0, 5.2 Hz, 2H), 2.83 (dd, J = 13.6, 6.8 Hz, 2H), 1.41 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −80.65 (6F), −110.36 (4F), −121.19 (4F), −121.80 (12F), −122.63 (4F), −126.02 (4F); 13C NMR (101 MHz, CDCl3) δ 169.62, 141.93, 129.93, 127.18, 126.91, 126.85, 126.79, 121.86–110.25, 71.75, 66.40, 40.95, 38.57, 24.02; HRMS-DART (m/z):[M + H]+ calcd for C39H25F34N2O2: 1199.1373, found: 1199.1360.
  • (S)-2-((tert-Butyldimethylsilyl)oxy)-1-(2-iodophenyl)ethan-1-amine (10) [31]. To a suspension of (S)-2-amino-2-phenylethan-1-ol 9 (137.2 mg, 1.00 mmol) in THF (4 mL) at −78 °C was added n-BuLi (1.6 M solution in hexane, 1.25 mL) dropwise. The resulting purple solution was stirred at −78 °C for 30 min before a solution of TBSCl (tert-butyldimethylsilyl chloride) (317 mg, 2.10 mmol) in THF (2 mL) was added at the same temperature. The reaction mixture was allowed to warm to room temperature naturally and was stirred for 18 h. After removing the THF solvent under reduced pressure, the residue was redissolved in ether (5 mL). To this solution at −78 °C was added n-BuLi (1.6 M solution in hexane, 1.88 mL) dropwise. The reaction mixture was allowed to slowly warm to room temperature for 3 h and stirred at room temperature for 1 h. I2 (508 mg, 2.00 mmol) was added at −78 °C and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 h. Then, 10% Na2S2O3 solution (2 mL) was added and the resulting mixture was stirred vigorously for 10 min. To a suspension was added H2O (20 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 10 (212 mg, 0.56 mmol, 56%). Brown oil; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.6, 1.2 Hz, 1H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.33 (dt, J = 8.0, 1.6 Hz, 1H), 6.94 (dt, J = 7.2, 1.2 Hz, 1H), 4.32 (dd, J = 7.6, 3.6 Hz, 1H), 3.79 (dd, J = 9.6, 3.2 Hz, 1H), 3.41 (dd, J = 10.0, 7.6 Hz, 1H), 1.79 (br s, 2H), 0.90 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 144.40, 139.47, 129.11, 128.37, 128.30, 99.83, 67.53, 60.86, 26.04, 18.39, −5.14, −5.23; HRMS-DART (m/z):[M + H]+ calcd for C14H25INOSi: 378.0745, found: 378.0742.
  • N1,N3-Bis((S)-2-Hydroxy-1-(2-iodophenyl)ethyl)-2,2-dimethylmalonamide (11). Under N2 atmosphere, to a solution of 10 (201 mg, 0.533 mmol) and Et3N (77 μL, 0.558 mmol) in dry-THF (2 mL) was added dimethylmalonyl dichloride (34 μL, 0.254 mmol) at 0 °C. Then, the reaction temperature rose to room temperature and the mixture was stirred for 18 h. To the mixture was added TBAF (1 M solution in THF, 553 μL). The mixture was stirred at room temperature for 16 h. To a suspension was added saturated aqueous NH4Cl (10 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:20) to give the desired product 11 (125 mg, 0.201 mmol, 79%). White solid; mp 75–76 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 8.4, 1.2 Hz, 2H), 7.27–7.23 (m, 8H), 7.15 (dd, J = 7.6, 1.2 Hz, 2H), 6.97 (dt, J = 7.6, 1.6 Hz, 2H), 5.33–5.28 (m, 2H), 3.94 (dd, J = 12.0, 4.4 Hz, 2H), 3.79 (dd, J = 11.6, 6.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 173.79, 140.77, 140.21, 129.62, 128.69, 127.78, 99.20, 64.59, 59.70, 50.00, 23.86; HRMS-DART (m/z):[M + H]+ calcd for C21H25I2N2O4: 622.9904, found: 622.9904.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(2-iodophenyl)-4,5-dihydrooxazole) (12). Under N2 atmosphere, to a solution of 11 (1.92 g, 3.082 mmol) in dry-DCM (20 mL) was added a solution of diethylaminosulfur trifluoride (888 μL, 6.78 mmol) in dry-DCM (10 mL) at −78 °C. After stirring at 0 °C for 18 h, the mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 12 (1.25 g, 2.217 mmol, 69%). Yellow solid; mp 135–136 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 4.0 Hz, 4H), 7.00–6.96 (m, 2H), 5.49 (dd, J = 10.4, 7.6 Hz, 2H), 4.87 (dd, J = 10.0, 8.4 Hz, 2H), 3.98 (t, J = 8.0 Hz, 2H), 1.72 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 171.31, 145.54, 139.13, 129.28, 128.70, 127.68, 98.14, 74.95, 72.86, 39.41, 24.53; HRMS-DART (m/z):[M + H]+ calcd for C21H21I2N2O2: 586.9692, found: 586.9687.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(2-(perfluorobutyl)phenyl)-4,5-dihydrooxazole) (1c). To a mixture of 12 (50 mg, 0.0853 mmol), Cu powder (54.2 mg, 0.853 mmol), 2,2′-bipyridyl (1.3 mg, 0.00853 mmoml), and DMF (1 mL) was added a 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (29 μL, 0.171 mmol). The mixture was stirred at 120 °C for 12 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. Then, 1 M HCl aq. was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 1c (44.7 mg, 0.0580 mmol, 68%). White solid; mp 89–90 °C; 1H NMR (400 MHz, CDCl3) δ 7.58–7.50 (m, 6H), 7.43–7.39 (m, 2H), 5.64–5.58 (m, 2H), 4.70 (t, J = 8.8 Hz, 2H), 4.02 (t, J = 8.4 Hz, 2H), 1.74 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −80.81 (6F), −102.04 to −105.02 (m, 4F), −121.34 (4F), −125.54 (4F); 13C NMR (101 MHz, CDCl3) δ 171.45, 142.55, 132.86, 128.37, 128.28, 127.62, 125.49, 117.35, 116.00, 112.30, 111.79, 76.16, 66.09, 39.27, 24.47; HRMS-DART (m/z):[M + H]+ calcd for C29H21F18N2O2: 771.1316, found: 771.1308.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(2-(perfluorooctyl)phenyl)-4,5-dihydrooxazole) (1d). To a mixture of 12 (80 mg, 0.136 mmol), Cu powder (86.7 mg, 1.365 mmol), 2,2′-bipyridyl (2.1 mg, 0.0136 mmol), and DMF (1 mL) was added a 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-8-iodooctane (72 μL, 0.273 mmol). The mixture was stirred at 120 °C for 18 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. Then, 1 M HCl aq. was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 1d (62.9 mg, 0.0537 mmol, 39%). White solid; mp 108–109 °C; 1H NMR (400 MHz, CDCl3) δ 7.57–7.50 (m, 6H), 7.43–7.39 (m, 2H), 5.65–5.59 (m, 2H), 4.70 (t, J = 8.4 Hz, 2H), 4.02 (t, J = 8.4 Hz, 2H), 1.74 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −80.59 (6F), −101.81 to −104.80 (m, 4F), −120.35 (4F), −121.15 (4F), −121.61 to −121.76 (m, 8F), −122.58 (4F), −125.97 (4F); 13C NMR (101 MHz, CDCl3) δ 171.45, 142.53, 132.85, 128.39, 128.28, 127.61, 125.60, 121.25–107.94, 76.16, 66.08, 39.28, 24.46; HRMS-DART (m/z):[M + H]+ calcd for C37H21F34N2O2: 1171.1060, found: 1171.1079.
  • N1,N3-Bis((S)-2-Hydroxy-1-phenylethyl)-2,2-dimethylmalonamide (13) [27]. Under N2 atmosphere, to a solution of 9 (600 mg, 4.374 mmol) and Et3N (635 μL, 4.582 mmol) in dry-DCM (6 mL) was added dimethylmalonyl dichloride (275 μL, 2.083 mmol) at 0 °C. Then, the reaction temperature rose to room temperature and the mixture was stirred for 18 h. The reaction mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:5) to give the desired product 13 (765 mg, 2.064 mmol, 99%). Yellow solid; mp 128–130 °C; 1H NMR (400 MHz, CDCl3) δ 7.35–7.22 (m, 10H), 7.10 (d, J = 7.6 Hz, 2H), 5.14–5.10 (m, 2H), 3.96–3.90 (m, 2H), 3.83–3.77 (m, 2H), 2.79–2.76 (m, 2H), 1.61 (s, 6H).
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (14) [32]. To a solution of 13 (765 mg, 2.065 mmol), DMAP (25.2 mg, 0.207 mmol) and Et3N (1.46 mL, 10.532 mmol) in DCM (8 mL) was added tosyl chloride (826.7 mg, 4.337 mmol). After stirring at room temperature for 36 h, the mixture was washed with saturated aqueous NH4Cl and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3; the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:1) to give the desired product 14 (424.3 mg, 1.269 mmol, 61%). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.34–7.26 (m, 10H), 5.26–5.21 (m, 2H), 4.70–4.65 (m, 2H), 4.19–4.15 (m, 2H), 1.68 (s, 6H).
  • tert-Butyl (S)-(2-((tert-butyldimethylsilyl)oxy)-1-(2-iodophenyl)ethyl)carbamate (15). A solution of 10 (639.7 mg, 1.695 mmol) and Et3N (285 μL, 2.048 mmol) in dry-DCM (8 mL) was stirred at 0 °C. A solution of Boc2O (449.2 mg, 2.058 mmol) in dry-DCM (4 mL) was slowly added to the mixture. Then the reaction temperature rose to room temperature and the mixture was stirred for a further 20 h. The mixture was diluted with brine. The reaction mixture was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 15 (637 mg, 1.424 mmol, 84%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 1H), 7.32–7.29 (m, 2H), 6.96–6.92 (m, 1H), 5.51 (br s, 1H), 4.94 (br s, 1H), 3.88–3.71 (m, 2H), 1.43 (br s, 9H), 0.83 (s, 9H), −0.08 (s, 3H), −0.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.32, 142.31, 139.61, 129.02, 128.12, 127.97, 98.49, 79.73, 64.68, 59.64, 28.42, 25.90, 18.33, −5.55; HRMS-DART (m/z):[M + H]+ calcd for C19H33INO3Si: 478.1274, found: 478.1271.
  • tert-Butyl (S)-(2-((tert-butyldimethylsilyl)oxy)-1-(2-butylphenyl)ethyl)carbamate (16). To a mixture of K3PO4 (216.4 mg, 1.019 mmol), toluene (15 mL), 15 (60.8 mg, 0.127 mmol), and butylboronic acid (68.2 mg, 0.669 mmol) was added Pd(OAc)2 (9.2 mg, 0.0410 mmol) and SPhos (19.7 mg, 0.0480 mmol). The mixture was stirred at 100 °C for 22 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. The saturated aqueous NH4Cl was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:10) to give the desired product 16 (26.8 mg, 0.0657 mmol, 52%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31–7.27 (m, 1H), 7.18–7.13 (m, 3H), 5.14–4.99 (m, 2H), 3.85–3.81 (m, 1H), 3.69–3.67 (m, 1H), 2.70–2.66 (m, 2H), 1.68–1.37 (m, 13H), 0.95 (t, J = 7.6 Hz, 3H), 0.85 (s, 9H), −0.055 to −0.058 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 155.39, 140.31, 138.28, 129.43, 127.14, 126.41, 125.84, 79.23, 66.15, 60.40, 33.69, 32.35, 28.46, 25.77, 22.94, 18.26, 13.92, −5.45, −5.56; HRMS-DART (m/z):[M + H]+ calcd for C23H42NO3Si: 408.2934, found: 408.2933.
  • (S)-2-Amino-2-(2-butylphenyl)ethan-1-ol (17). To 16 (59.3 mg, 0.145 mmol) was added 4 M HCl in AcOEt (2 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. Then, 4 M NaOH aq. was added to the residue. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:5) to give the desired product 17 (14.6 mg, 0.0755 mmol, 52%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.38–7.36 (m, 1H), 7.24–7.16 (m, 3H), 4.34–4.30 (m, 1H), 3.69 (dd, J = 10.8, 4.4 Hz, 1H), 3.56 (dd, J = 10.8, 8.8 Hz, 1H), 2.74–2.59 (m, 2H), 1.60–1.53 (m, 2H), 1.45–1.36 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 140.30, 140.07, 129.82, 127.37, 126.47, 125.59, 67.52, 52.43, 34.16, 32.54, 22.85, 14.07; HRMS-DART (m/z):[M + H]+ calcd for C12H20NO: 194.1545, found: 194.1540.
  • N1,N3-Bis((S)-1-(2-butylphenyl)-2-hydroxyethyl)-2,2-dimethylmalonamide (18). Under N2 atmosphere, to a solution of 17 (17 mg, 0.088 mmol) and Et3N (13 μL, 0.097 mmol) in dry-DCM (2 mL) was added dimethylmalonyl dichloride (5.8 μL, 0.044 mmol) at 0 °C. Then, the reaction temperature rose to room temperature and the mixture was stirred for 3 h. The reaction mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:20) to give the desired product 18 (19.4 mg, 0.040 mmol, 91%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.22–7.17 (m, 10H), 6.96 (d, J = 7.6 Hz, 2H), 5.41–5.36 (m, 2H), 3.89–3.76 (m, 4H), 2.70–2.66 (m, 4H), 1.66–1.37 (m, 14H), 0.94 (t, J = 7.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 174.08, 140.75, 136.18, 130.11, 127.96, 126.53, 125.66, 66.54, 52.01, 49.89, 33.59, 32.50, 23.67, 22.79, 14.06; HRMS-DART (m/z):[M + H]+ calcd for C29H43N2O4: 483.3223, found: 483.3221.
  • (4S,4′S)-2,2′-(Propane-2,2-diyl)bis(4-(2-butylphenyl)-4,5-dihydrooxazole) (19). To a solution of 18 (18.8 mg, 0.039 mmol), DMAP (1.4 mg, 0.0117 mmol) and Et3N (27 μL, 0.195 mmol) in DCM (0.5 mL) was added tosyl chloride (22.3 mg, 0.117 mmol). After stirring at room temperature for 24 h, the mixture was diluted with DCM. The mixture was washed with saturated aqueous NH4Cl and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:5) to give the desired product 19 (6.2 mg, 0.0139 mmol, 36%). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.29–7.13 (m, 8H), 6.96 (d, J = 7.6 Hz, 2H), 5.53–5.48 (m, 2H), 4.75–4.70 (m, 2H), 4.04–4.00 (m, 2H), 2.66–2.53 (m, 4H), 1.72 (s, 6H), 1.59–1.34 (m, 8H), 0.94 (t, J = 7.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.47, 140.39, 139.41, 129.24, 127.30, 126.66, 126.32, 75.55, 65.65, 39.14, 33.68, 32.78, 24.64, 22.83, 14.05; HRMS-DART (m/z):[M + H]+ calcd for C29H39N2O2: 447.3012, found: 447.3008.
  • tert-Butyl (S)-(2-((tert-butyldimethylsilyl)oxy)-1-(2-(perfluorobutyl)phenyl)ethyl)carbamate (20). To a mixture of 15 (3.5 g, 7.33 mmol), Cu powder (4.66 g, 73.31 mmol), 2,2′-bipyridyl (144.5 mg, 0.733 mmol), and DMF (10 mL) was added a 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (2.46 mL, 14.661 mmol). The mixture was stirred at 120 °C for 16 h. The mixture was filtered through Celite, and the solids were washed with MeOH. The filtrate was concentrated. Then, 1 M HCl aq. was added to the suspension. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:10) to give the desired product 20 (2.0 g, 3.51 mmol, 48%). Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.62–7.51 (m, 3H), 7.39 (t, J = 7.6 Hz,1H), 5.34 (br s, 1H), 5.06 (br s, 1H), 3.94–3.90 (m, 1H), 3.64–3.62 (m, 1H), 1.37 (br s, 9H), 0.83 (s, 9H), −0.09 (s, 3H), −0.12 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −80.75 (3F), −101.78 to −104.10 (m, 2F), −120.90 (2F), −125.42 (2F); 13C NMR (101 MHz, CDCl3) δ 159.41, 141.39, 136.25, 131.69, 131.69, 128.86, 128.72, 127.32, 119.91, 119.06, 117.73, 116.18, 77.29, 76.34, 66.67, 28.32, 25.85, 18.31, −5.65, −5.76; HRMS-DART (m/z):[M + H]+ calcd for C23H33F9NO3Si: 570.2086, found: 570.2088.
  • (S)-2-Amino-2-(2-(perfluorobutyl)phenyl)ethan-1-ol (21). To 20 (2 g, 3.51 mmol) was added 4 M HCl in AcOEt (17.5 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated. Then, 4 M NaOH aq. was added to the residue. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:10) to give the desired product 21 (760.7 mg, 2.14 mmol, 61%). Yellow solid; mp 70–72 °C; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.61–7.56 (m, 2H), 7.42 (t, J = 7.4 Hz, 1H), 4.42–4.38 (m, 1H), 3.75–3.71 (m, 1H), 36.0–3.55 (m, 1H), 1.78 (br s, 3H); 19F NMR (376 MHz, CDCl3) δ −80.88 (3F), −102.09 to −104.25 (m, 2F), −120.61 to −122.47 (m, 2F), −125.54 (2F); 13C NMR (101 MHz, CDCl3) δ 143.70, 132.47, 128.54, 128.15, 127.57, 126.01, 119.97, 118.97, 117.39, 116.11, 67.66, 52.80; HRMS-DART (m/z):[M + H]+ calcd for C12H11F9NO: 356.0697, found: 356.0695.
  • N2,N6-Bis((S)-2-hydroxy-1-(2-(perfluorobutyl)phenyl)ethyl)pyridine-2,6-dicarboxamide (22). Under N2 atmosphere, to a solution of 21 (400 mg, 1.126 mmol) and Et3N (157 μL, 1.126 mmol) in dry-DCM (5mL) was added pyridine-2,6-dicarbonyl dichloride (114.9 mg, 0.563 mmol) at 0 °C. Then, the reaction temperature rose to room temperature, stirring the mixture for 3 h. The reaction mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:10) to give the desired product 22 (445.3 mg, 0.529 mmol, 94%). White solid; mp 95–96 °C; 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 6.4 Hz, 2H), 8.33–8.29 (m, 2H), 8.04–8.00 (m, 1H), 7.69–7.44 (m, 8H), 5.54 (br s, 2H), 4.10–4.06 (m, 2H), 3.98–3.94 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −80.67 (6F), −101.70 to −104.28 (m, 4F), −121.01 (4F), −125.34 (4F); 13C NMR (101 MHz, CDCl3) δ 163.13, 148.50, 139.60, 139.54, 132.50, 129.46, 128.13, 128.06, 126.26, 125.21, 119.78, 118.98, 117.90, 116.40, 66.75, 52.48; HRMS-DART (m/z):[M + H]+ calcd for C31H22F18N3O4: 842.1323, found: 842.1326.
  • 2,6-Bis((S)-4-(2-(perfluorobutyl)phenyl)-4,5-dihydrooxazol-2-yl)pyridine (1e). Under N2 atmosphere, to a solution of 22 (416.7 mg, 0.495 mmol) in dry-DCM (5 mL) was added a solution of diethylaminosulfur trifluoride (195 μL, 1.486 mmol) in dry-DCM (2 mL) at −78 °C. After stirring at 0 °C for 16 h, the mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted with DCM. The combined organic layers were Na2SO4 and concentrate. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:3) to give the desired product 1e (350.9 mg, 0.436 mmol, 88%). Yellow solid; mp 63–64 °C; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 7.6 Hz, 2H), 7.99 (t, J = 8.0 Hz, 1H), 7.61–743 (m, 8H), 5.85–5.79 (m, 2H), 4.94–4.88 (m, 2H), 4.29–4.25 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −80.80 (6F), −102.22 to −104.85 (m, 4F), −121.34 (4F), −125.54 (4F); 13C NMR (101 MHz, CDCl3) δ 164.60, 146.72, 141.96, 141.92, 137.75, 132.90, 128.52, 127.90, 126.66, 125.65, 119.88–116.11, 76.44, 66.88; HRMS-DART (m/z):[M + H]+ calcd for C31H18F18N3O2: 806.1112, found: 806.1113.
  • N2,N6-Bis((S)-2-hydroxy-1-phenylethyl)pyridine-2,6-dicarboxamide (23) [33]. Under N2 atmosphere, to a solution of 9 (823 mg, 6.0 mmol) and Et3N (836 μL, 6.0 mmol) in dry-DCM (5 mL) was added pyridine-2,6-dicarbonyl dichloride (612 mg, 3.0 mmol) at 0 °C. Then, the reaction temperature rose to room temperature, stirring the mixture for 6 h. The reaction mixture was concentrated. The crude was purified by silica gel chromatography (MeOH:CHCl3 = 1:5) to give the desired product 23 (1.13 g, 2.79 mmol, 93%). White solid; mp 79–80 °C; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 7.2 Hz, 2H), 8.16 (d, J = 8.0 Hz, 2H), 7.83 (t, J = 7.6 Hz, 1H), 7.35–7.24 (m, 10H), 5.21–5.17 (m, 2H), 3.92–3.91 (m, 2H), 3.52 (br s, 2H).
  • 2,6-Bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine (24) [33]. To a solution of 23 (1 g, 2.466 mmol), DMAP (60 mg, 0.493 mmol) and Et3N (1.37 mL, 9.866 mmol) in DCM (0.5 mL) was added tosyl chloride (1.18 g, 6.166 mmol). After stirring at room temperature for 18 h, water was added to the mixture. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography (ethyl acetate:n-hexane = 1:1) to give the desired product 24 (801.8 mg, 2.170 mmol, 88%). White solid; mp 169 °C; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 2H), 7.92 (t, J = 7.6 Hz, 1H), 7.39–7.29 (m, 10H), 5.49–5.44 (m, 2H), 4.96–4.91 (m, 2H), 4.45–4.41 (m, 2H).

4. Conclusions

In asymmetric Henry reactions, using a ligand featuring dual fluorous tags strategically positioned adjacent to the chiral ligand effectively reverses the stereoselectivity of the resulting product. While the degree of stereoselectivity in the aldol product does not surpass that of other catalytic systems reported in the literature [34,35], the introduction of fluorous tags at the 2′-aryl position of the BOX ligand can dynamically modify the asymmetric environment in the transition state of this reaction. Future work will involve the application of this approach to asymmetric synthesis reactions using other asymmetric transition metal complexes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28227632/s1, Copies of 1H NMR spectra and HPLC chromatograms of asymmetric Henry reaction; Copies of 1H NMR, 19F NMR, 13C NMR spectra of compounds (1, 3–8, 10–24) can be found in Supplementary Materials.

Author Contributions

Conceptualization, K.I. and M.M.; investigation, K.I., N.T., Y.H. (Yuka Hayashi), Y.H. (Yuna Hagiwara), S.S., T.N. and Y.K.; project administration, K.I.; supervision, M.M.; validation, K.I.; visualization, K.I.; writing—original draft, K.I. and M.M.; writing—review and editing, Y.K. and M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by JSPS KAKENHI 22K05469.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data from this study are reported in the text or in Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Molecules 28 07632 g001
Figure 1. Fluorous bisoxazoline ligands containing two fluorous tags (1a–e).
Figure 1. Fluorous bisoxazoline ligands containing two fluorous tags (1a–e).
Molecules 28 07632 g001
Molecules 28 07632 sch001
Scheme 1. Synthetic route to fluorous bisoxazoline ligands 1a and 1b.
Scheme 1. Synthetic route to fluorous bisoxazoline ligands 1a and 1b.
Molecules 28 07632 sch001
Molecules 28 07632 sch002
Scheme 2. Synthetic route to fluorous bisoxazoline ligands 1c and 1d.
Scheme 2. Synthetic route to fluorous bisoxazoline ligands 1c and 1d.
Molecules 28 07632 sch002
Molecules 28 07632 sch003
Scheme 3. Synthesis of nonfluorous bisoxazoline ligand 14.
Scheme 3. Synthesis of nonfluorous bisoxazoline ligand 14.
Molecules 28 07632 sch003
Molecules 28 07632 sch004
Scheme 4. Synthesis of nonfluorous butylated bisoxazoline ligand 19.
Scheme 4. Synthesis of nonfluorous butylated bisoxazoline ligand 19.
Molecules 28 07632 sch004
Molecules 28 07632 sch005
Scheme 5. Synthesis of pincer-type fluorous bisoxazoline ligand 1e.
Scheme 5. Synthesis of pincer-type fluorous bisoxazoline ligand 1e.
Molecules 28 07632 sch005
Molecules 28 07632 sch006
Scheme 6. Synthesis of pincer-type nonfluorous bisoxazoline ligand 24.
Scheme 6. Synthesis of pincer-type nonfluorous bisoxazoline ligand 24.
Molecules 28 07632 sch006
Table 1. Asymmetric Henry reaction using fluorous bisoxazoline 1a.
Table 1. Asymmetric Henry reaction using fluorous bisoxazoline 1a.
Molecules 28 07632 i001
EntryMetal SourceConv. (%) 1ee (%) 2,3
1Cu(OAc)2·H2O9769
2CuCl2no reaction-
3CuBr2no reaction-
4Cu(OTf)2no reaction-
5Co(OAc)2959
6Zn(OAc)2963
1 Determined by 1H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral high-performance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex:iPrOH = 80:20, 1.0 mL/min). 3 The absolute configuration of the aldol adduct was determined by comparison with previously published data [13].
Table 2. Asymmetric Henry reaction using fluorous ligands 1a–d and control ligand 14.
Table 2. Asymmetric Henry reaction using fluorous ligands 1a–d and control ligand 14.
Molecules 28 07632 i002
EntryLigandSolventConv. (%) 1ee (%) 2Config. 3
11aiPrOH9769S
21aiPrOH/H2O (1/1)9441S
31aTHF7941S
41aFC-729345S
51biPrOH9158S
61biPrOH/H2O (1/1)8744S
71bFC-721433S
81ciPrOH9453R
91ciPrOH/H2O (1/1)9536R
101cTHF4542R
111cFC-729532R
121diPrOH9847R
131dTHF3735R
1414iPrOH9827S
1519iPrOH9814R
1 Determined by 1H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral high-performance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex:iPrOH = 80:20, 1.0 mL/min). 3 The absolute configuration of the aldol adduct was determined through comparison with previously published data [13]. * Represents the asymmetric carbon.
Table 3. Asymmetric Henry reaction using pincer-type fluorous ligand 1e and control ligand 24.
Table 3. Asymmetric Henry reaction using pincer-type fluorous ligand 1e and control ligand 24.
Molecules 28 07632 i003
EntryLigandMetal SourceSolventConv. (%) 1ee (%) 2Config. 3
11eCo(OAc)2iPrOH9725R
21eCu(OAc)2·H2OiPrOH9810R
31eZn(OAc)2iPrOH9413R
41eCo(OAc)2iPrOH/H2O (1/1)962R
51eCo(OAc)2THF7242R
61eCo(OAc)2FC-72no reaction--
724Co(OAc)2THF998R
1 Determined by 1H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral high-performance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex:iPrOH = 80:20, 1.0 mL/min). 3 The absolute configuration of the aldol adduct was determined through comparison with previously published data [13]. * Represents the asymmetric carbon.
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Ishihara, K.; Kato, Y.; Takeuchi, N.; Hayashi, Y.; Hagiwara, Y.; Shibuya, S.; Natsume, T.; Matsugi, M. Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags. Molecules 2023, 28, 7632. https://doi.org/10.3390/molecules28227632

AMA Style

Ishihara K, Kato Y, Takeuchi N, Hayashi Y, Hagiwara Y, Shibuya S, Natsume T, Matsugi M. Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags. Molecules. 2023; 28(22):7632. https://doi.org/10.3390/molecules28227632

Chicago/Turabian Style

Ishihara, Kazuki, Yamato Kato, Narisa Takeuchi, Yuka Hayashi, Yuna Hagiwara, Shyota Shibuya, Tohya Natsume, and Masato Matsugi. 2023. "Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags" Molecules 28, no. 22: 7632. https://doi.org/10.3390/molecules28227632

APA Style

Ishihara, K., Kato, Y., Takeuchi, N., Hayashi, Y., Hagiwara, Y., Shibuya, S., Natsume, T., & Matsugi, M. (2023). Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags. Molecules, 28(22), 7632. https://doi.org/10.3390/molecules28227632

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