Cross-Coupling Approach to an Array of Macrocyclic Receptors

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A Cross-Coupling Approach to an Array of Macrocyclic Receptors Functioning as Chiral Solvating Agents Tadashi Ema, Takayuki Yamasaki, Sagiri Watanabe, Mahoko Hiyoshi, and Kazuto Takaishi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01327 • Publication Date (Web): 21 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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The Journal of Organic Chemistry

A Cross-Coupling Approach to an Array of Macrocyclic Receptors Functioning as Chiral Solvating Agents Tadashi Ema,* Takayuki Yamasaki, Sagiri Watanabe, Mahoko Hiyoshi, and Kazuto Takaishi Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Okayama 700-8530, Japan [email protected] Abstract: Chiral macrocyclic receptors 1 with multiple hydrogen-bonding sites in the cavity were synthesized and used as NMR chiral solvating agents (CSAs). The Suzuki–Miyaura cross-coupling reaction gave rapid access to a series of variants 1b–p of unsubstituted parent compound 1a. Among them, 1d with the 4-cyanophenyl group at the 3,3’-positions of the binaphthyl moiety was the most excellent CSA for a benchmark analyte compound, 2-chloropropionic acid (CPA); both of the quartet and doublet signals of CPA were split most completely in CDCl3. Binding constants (Ka) determined in CDCl3 by NMR titrations indicated that (R)-1d was the most enantioselective (Ka (S)/Ka (R) = 5.4). Interestingly, the Ka value of (R)-1d for (S)-CPA (5900) was greater than that of (R)-1a for (S)-CPA (3080), which strongly suggests an attractive interaction between the 4-cyanophenyl group of (R)-1d and (S)-CPA. The X-ray crystal structure of 1d indicates that one of the two H atoms meta to the cyano group is directed toward the cavity. DFT calculations suggested that this H atom of the 4-cyanophenyl group of (R)-1d forms a weak hydrogen bond with the Cl atom of (S)-CPA (C–H···Cl–C hydrogen bond).

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Introduction Chiral synthetic receptors find many applications such as chiral solvating agents (CSAs) for NMR analysis,1,2 chiral selectors for HPLC analysis,3,4 chiral hosts for mass spectroscopic analysis,5,6 chemical sensors for microarray analysis,7,8 chiroptical sensors,9 organocatalysts for asymmetric synthesis,10 and so on.11 Among various types of synthetic receptors, macrocycles have entropic advantages for the elaborate arrangement of functional groups, which is the key to specific functions.11a,11b,12 We have developed a series of chiral macrocyclic receptors with multiple hydrogen-bonding sites in the cavity.2,4,6,8 Macrocycle 1a (Figure 1), which is a CSA called Chirabite-AR, has a chiral discrimination ability for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, or epoxide functionality.2 Because CSAs can provide an easy, fast, and economical way of determining the enantiomeric purity just by mixing with a chiral compound in a small amount of deuterated solvent, the further development of CSAs is highly desirable.

Figure 1. Chemical structures of (R)-1 and (R)-2. The 3,3’-positions of the binaphthyl moiety of 1a are the “hot spots” for the fine tuning of the size and shape of the macrocyclic cavity.2c Scheme 1 shows two synthetic routes, where substituent R is introduced in either early or late stage. We previously employed route 1, which allows the introduction of only substituents that are inert under acidic or basic conditions, and which needs different BINOL derivatives with substituent R to synthesize a series of macrocycles 1.2c In contrast, route 2 can provide rapid access to a variety of macrocycles 1 from a single precursor 2 via cross-coupling reactions.8b,10 Although we were concerned about (i) steric hindrance around the I atoms in 2 and (ii) synthetic incompatibility with the four amide groups and the nitro group in 2, we decided to explore this fascinating synthetic strategy (route 2). Here we report the scope and limitation of the rapid synthesis of an array of 1 from 2 via the Suzuki–Miyaura cross-coupling 2 ACS Paragon Plus Environment

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reactions and the evaluation of 1 as a CSA. As a result of screening of 16 macrocycles 1a–p (Figure 1), 1d with the 4-cyanophenyl group was found to be the best CSA for a benchmark analyte compound, 2-chloropropionic acid (CPA). We propose that an important factor in the enantiomer discrimination of CPA is a hydrogen bond between one of the two H atoms meta to the cyano group of (R)-1d and the Cl atom of (S)-CPA. Scheme 1. Retrosynthetic analysis for macrocycle (R)-1.

Results and Discussion We started our study with the Suzuki–Miyaura cross-coupling reaction of 2 with phenylboronic acid (Scheme 2). The results are shown in Table 1. Pd catalyst (5 mol%) was first screened in the presence of K3PO4 in aqueous THF. Interestingly, Pd(OAc)2 or Pd2(dba)3 gave no product, while PdCl2(PPh3)2 and Pd(PPh3)4 afforded 1b in 91% and 97%, respectively. Pd(P(t-Bu)3)2, Pd-PEPPSI-IPr,13 and PdCl2(dppf) gave less satisfactory results. Next, the base was optimized in the presence of Pd(PPh3)4. The use of K2CO3 gave 1b in a comparable yield (97%), whereas that of Cs2CO3 and Na2CO3 afforded 1b in 32% and 48%, respectively, and the use of NaOH resulted in a good yield (86%). Several organic solvents were then tested in the presence of Pd(PPh3)4 and K3PO4. Although the yield was less sensitive to the solvent, THF was the best solvent. The amount of Pd(PPh3)4 could be decreased to 1 mol% although a longer reaction time was needed. Scheme 2. Synthesis of (R)-1 via the Suzuki–Miyaura cross-coupling reactions.



Table 1. Optimization of the Suzuki–Miyaura Cross-Coupling Reaction of Macrocycle (R)-2 with Phenylboronic Acid to Give (R)-1b.a entry

Pd catalyst

base

solvent

yield (%)b

1 2 3 4

Pd(OAc)2 Pd2(dba)3 PdCl2(PPh3)2 Pd(PPh3)4

K3PO4 K3PO4 K3PO4 K3PO4

THF THF THF THF

0 0 91 97

5 6 7 8

Pd(P(t-Bu)3)2 Pd-PEPPSI-IPr PdCl2(dppf) Pd(PPh3)4

K3PO4 K3PO4 K3PO4 K2CO3

THF THF THF THF

53 82 90 97

9 10 11 12

Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4

Cs2CO3 Na2CO3 NaOH K3PO4

THF THF THF dioxane

32 48 86 86

13 14 15 16c

Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4

K3PO4 K3PO4 K3PO4 K3PO4

DME toluene CH3CN THF

77 79 80 86

17d

Pd(PPh3)4

K3PO4

THF

93

a

Conditions: macrocycle (R)-2 (0.1 mmol), PhB(OH)2 (0.3 mmol), Pd catalyst (5 mol%), base (0.3 mmol), solvent/H2O (3:1) (1.2 mL), 65 °C, 6 h. b Determined by 1H NMR using benzyl phenyl ether as an internal standard. c Pd(PPh3)4 (2 mol%). d Pd(PPh3)4 (1 mol%), 16 h.

We next examined various aryl boronic acids to investigate the reaction scope. The results are shown in Table 2. The benzene rings with the electron-withdrawing or electron-donating groups at the 4- or 3-positions were successfully introduced in the presence of Pd(PPh3)4 (5–10 mol%), with the exception of 1e with the 4-nitrophenyl group (Pd(PPh3)4 20 mol%). On the other hand, the 2-substituted benzene rings, the 2-naphthyl group, and the 9-anthryl group could be introduced in good yields by using 30 mol% Pd(PPh3)4. In sharp contrast, the pyridyl groups could not be incorporated at all under the same reaction conditions. After extensive screening of the reaction conditions, we found that the use of DMF instead of THF under harsh conditions produced 1o and 1p with the 4-pyridyl and 3-pyridyl groups, respectively, in modest yields (35–36%). This is probably due to the instability of pyridylboronic acids. Compound 1q with the 2-pyridyl group could not be obtained at all by this improved method. In further attempts to synthesize 1q, we employed lithium (or tetrabutylammonium) 2-pyridyltriolborate salt, developed by Yamamoto,14 and CuI (20 mol%) as an additive in dry DMF at 100 °C in the absence of base, but 1q could not be 4 ACS Paragon Plus Environment

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obtained at all. This is probably because the 3,3’-positions of the binaphthyl group in 2 are too crowded to allow the transmetalation. It should be noted that 1o and 1p with the pyridyl group cannot be synthesized via route 1 (Scheme 1). Table 2. Substrate Scope for the Suzuki–Miyaura Cross-Coupling Reaction of (R)-2 with Aryl Boronic Acid to Give (R)-1.a entry

1

yield (%)b

entry

1

yield (%)b

1c

1b

93

9

1j

97

2 3 4d 5

1c 1d 1e 1f

90 91 82 95

10 11e,f 12f 13f

1k 1l 1m 1n

90 78 98 63

6 7e 8e,f

1g 1h 1i

98 89 96

14d,g 15d,g 16d,h

1o 1p 1q

36 35 0

a

Conditions: macrocycle (R)-2 (0.1 mmol), RB(OH)2 (0.3 mmol), Pd(PPh3)4 (10 mol%), K3PO4 (0.3 mmol), THF/H2O (3:1) (1.2 mL), 65 °C, 6 h. b Isolated yield. c Pd(PPh3)4 (5 mol%). d

Pd(PPh3)4 (20 mol%). e 0.3 mmol scale. f Pd(PPh3)4 (30 mol%). g DMF/H2O (3:1), 100 °C, 16 h. h DMF, 100 °C, 16 h. 2-Pyridyltriolborate lithium salt was used instead of boronic acid, and CuI (20 mol%) was added as an additive. Single crystals of 1d were obtained by recrystallization from EtOAc/hexane and were then subjected to X-ray analysis. The crystal structure of 1d is shown in Figure 2. The 4-cyanophenyl groups introduced by the cross-coupling reaction come into close contact with the upper amide groups. The distance between the centroid of the benzene ring and the amide N atom is 3.24–3.42 Å, which is much shorter than the sum of the van der Waals radii.15,16 This stacking interaction causes the out-of-plane distortion of the macrocyclic framework of 1d, in contrast to the almost flat macrocyclic framework of 1a.8 Although the rotational motion of the 4-cyanophenyl moieties in 1d were fixed at –163 °C in the crystalline state, 1H and 13C NMR spectra of 1d indicated that they rapidly rotated at room temperature in a CDCl3 solution on an NMR time scale. Among macrocycles 1 prepared in this study, only the 2,6-dimethoxyphenyl and 9-anthryl groups in 1l and 1n, respectively, were conformationally frozen at room temperature in a CDCl3 solution on an NMR time scale (Supporting Information).



(a)

(b)

Figure 2. The X-ray crystal structure of (R)-1d. The solvent molecules are omitted for clarity. (a) Front view and (b) side view.

Figure 3. Selected regions of 600 MHz 1H NMR spectra of racemic CPA (a) before and (b) after addition of (R)-1d (15 mM, 1 equiv) in CDCl3 at 22 °C. Filled and open circles represent (R)- and (S)-enantiomers, respectively. We investigated the capabilities of 16 chiral macrocycles (R)-1a–p as CSAs. 2-Chloropropionic acid (CPA) was selected as a benchmark analyte compound because of the challenging aspects as follows: (i) the small difference in size between the methyl group and the chlorine atom (effective van der Waals radii of 1.80 and 1.73 Å, respectively),17 (ii) the non-singlet NMR signals, and (iii) an aliphatic carboxylic acid that is difficult to analyze by means of other methods such as chiral HPLC. A series of 1 may enable us to find an excellent CSA for CPA. We evaluated the chiral discrimination abilities of 1a–p by measuring 1H NMR spectra for 1:1 mixtures of 1 and CPA in CDCl3. Selected regions of the NMR spectra are shown in Figure 3 and Table S1 (Supporting Information), and the chemical shift nonequivalences (∆∆δ) are summarized in Table 3. The enantiomeric signals of CPA were separated more or less by all the receptors 1, among which 1d showed the best performance. The non-singlet signals of the α and β protons of CPA were resolved 6 ACS Paragon Plus Environment

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completely upon addition of 1d (Figure 3), and the ∆∆δ values were large enough for practical use (Table 3). Table 3 and Table S1 indicate a clear tendency that the introduction of the electron-deficient benzene rings at the 3,3’-positions of the binaphthyl moiety has a beneficial effect on the signal separation ability of 1 for CPA. Unexpectedly, 1m and 1n bearing the 2-naphthyl and 9-anthryl groups, respectively, exhibited poor signal splitting abilities. Upon complexation with (R)-1, the 1H NMR signals for (R)-CPA appeared at the higher field in comparison with those for (S)-CPA with the exception of the doublet (β proton) signals for 1b, 1f, 1g, and 1j, where the para position of the benzene ring is unsubstituted or substituted with the electron-donating group. Table 3. Chemical Shift Differences (∆∆δ) of 2-Chloropropionic Acid (CPA) upon Addition of (R)-1 and Binding Constants of (R)-1 for CPA. 1

∆∆δ (ppm)a α β

Ka (M–1)b (R)

(S)

ratioc

1a 1b 1c

0.012 0.020 0.061

0.037 –0.012 0.045

3100 880 2170

3080 1880 5420

1.0 (–) 2.1 (S) 2.5 (S)

1d 1e 1f 1g

0.091 0.068 0.011 0.020

0.047 0.075 –0.014 –0.002

1090 1760 1630 2000

5900 4510 2660 2440

5.4 (S) 2.6 (S) 1.6 (S) 1.2 (S)

1h 1i 1j 1k

0.034 0.007 0.019 0.018

0.027 0.012 –0.002 0.007

1740 330 1630 690

2960 280 2990 1000

1.7 (S) 1.2 (R) 1.8 (S) 1.4 (S)

1l 1m 1n 1o

0.031 0.033 0.005 0.048

0.003 0.011 0.002 0.022

370 1630 160 310

410 3000 380 590

1.1 (S) 1.8 (S) 2.4 (S) 1.9 (S)

1p

0.012

0.009

110

80

1.4 (R)

a

Signal separation calculated from ∆∆δ = ∆δ(S) – ∆δ(R). b In CDCl3 at 22 °C. The Ka values were calculated by the nonlinear least-squares method. Binding isotherms and calculated values with

standard deviations are given in the Supporting Information. The Ka values for 1a were taken from ref. 2c. c Ratio of the Ka values. We determined the binding constants (Ka) of all the receptors 1 for CPA by NMR titrations (Table 3).2,18 The signal for the lower amide NH group of 1 was downfield shifted upon addition of CPA in all cases, which suggests the hydrogen bond formation. Although unsubstituted macrocycle 7 ACS Paragon Plus Environment


1a showed no enantioselectivity,2c 1b with the phenyl group was found to show modest enantioselectivity (2.1). To our delight, derivatives 1c–e with the electron-withdrawing group at the para position of the phenyl group exhibited higher enantioselectivity (2.5–5.4). It is interesting to note that the functional group at the para position, which points away from the binding cavity (Figure 2), can affect the enantioselectivity. Compound 1d with the 4-cyanophenyl group was the most enantioselective (5.4). It should be noted that the Ka value of (R)-1d for (S)-CPA (5900) is greater than the corresponding value of (R)-1a (3080), which strongly suggests an attractive interaction between the 4-cyanophenyl group of (R)-1d and (S)-CPA. The same trend can be seen in the Ka values for 1c and 1e with the electron-withdrawing groups in the aromatic substituents. On the other hand, among all the receptors 1, the unsubstituted receptor (R)-1a showed the largest Ka value for (R)-CPA (3100), which indicates that any aromatic substituent at the 3,3’-positions of the binaphthyl moiety in (R)-1b–p causes steric repulsion with respect to (R)-CPA. In contrast, 1f–l with the electron-donating group and 1m with the naphthyl group gave poor results (ratio of the Ka values 300 °C; [α]25D +67.6 (c 1.01, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.75 (d, J = 15.4 Hz, 2H), 3.81 (d, J = 15.4 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.43 (dt, J = 0.9, 7.7 Hz, 2H), 7.57 (dt, J = 0.6, 7.6 Hz, 2H), 7.62 (d, J = 8.2 Hz, 4H), 7.68 (d, J = 8.1 Hz, 2H), 7.79–7.80 (m, 6H), 7.99 (d, J = 8.2 Hz, 2H), 8.04 (s, 2H), 8.14 (d, J = 7.8 Hz, 2H), 8.25 (s, 2H), 9.02 (s, 1H), 9.16 (d, J = 0.9 Hz, 2H), 9.23 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 72.1, 110.0, 110.2, 122.3, 125.0, 125.3, 125.6 (q, JCF = 3.7 Hz), 125.7, 126.7, 127.2, 128.0, 128.5, 128.7, 129.8, 130.1 (q, JCF = 32.5 Hz), 131.2, 131.7, 133.3, 135.9, 141.2, 141.7, 148.1, 149.0, 150.0, 151.4, 161.1, 165.7; IR (KBr) 3381, 3061, 1701, 1585, 1541, 1456, 1323, 1246, 1126, 1067, 851 cm–1; HRMS (FAB) calcd for C56H36F6N7O8 1048.2530, found 1048.2521 ([M + H]+). 11 ACS Paragon Plus Environment


Chiral Macrocycle (R)-1d. Following general procedure A (10 mol% cat.), (R)-1d was obtained in 91% yield (88 mg) as a white solid: mp 267–269 °C; [α]24D –28.5 (c 0.99, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.77 (s, 4H), 7.20 (d, J = 8.5 Hz, 2H), 7.43 (dt, J = 1.2, 7.8 Hz, 2H), 7.57 (dt, J = 1.0, 7.6 Hz, 2H), 7.65 (d, J = 8.2 Hz, 4H), 7.73 (d, J = 8.0 Hz, 2H), 7.79–7.83 (m, 6H), 8.00 (d, J = 8.2 Hz, 2H), 8.04 (s, 2H), 8.14 (d, J = 7.7 Hz, 2H), 8.32 (s, 2H), 8.91 (s, 1H), 9.13 (s, 2H), 9.16 (s, 2H); 13

C NMR (d6-acetone, 100 MHz) δ 73.1, 109.8, 110.1, 112.4, 118.9, 126.4, 126.7, 127.1, 127.3, 128.6, 129.7, 131.3, 132.2, 132.6, 132.7, 133.2, 134.46, 134.52, 136.8, 142.1, 143.5, 149.8, 150.4, 151.1, 152.4, 163.2, 166.2; IR (KBr) 3389, 3057, 2230, 1697, 1585, 1539, 1452, 1312, 1244, 1152 cm–1; HRMS (FAB) calcd for C56H36N9O8 962.2687, found 962.2695 ([M + H]+). Chiral Macrocycle (R)-1e. Following general procedure A (20 mol% cat.), (R)-1e was obtained in 82% yield (82 mg) as a white solid: mp >300 °C; [α]23D –31.7 (c 1.02, THF); 1H NMR (d6-acetone, 400 MHz) δ 3.78 (d, J = 15.3 Hz, 2H), 4.07 (d, J = 15.3 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.50– 7.54 (m, 4H), 7.63 (dt, J = 0.8, 7.6 Hz, 2H), 7.80 (t, J = 8.1 Hz, 2H), 8.01 (d, J = 8.8 Hz, 4H), 8.05 (d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.2 Hz, 2H), 8.24–8.29 (m, 8H), 8.97 (d, J = 1.4 Hz, 2H), 9.43 (s, 1H), 10.16 (s, 2H); 13C NMR (d6-acetone, 100 MHz) δ 73.2, 109.7, 110.0, 124.5, 126.5, 126.7, 127.2, 127.4, 128.8, 129.7, 131.5, 132.2, 132.6, 132.9, 134.2, 134.5, 136.9, 142.1, 145.7, 148.1, 149.7, 150.5, 151.1, 152.5, 163.3, 166.1; IR (KBr) 3379, 3082, 1697, 1585, 1454, 1346, 1244, 1190, 1152, 1049 cm–1; HRMS (FAB) calcd for C54H36N9O12 1002.2483, found 1002.2470 ([M + H]+). Chiral Macrocycle (R)-1f.8b Following general procedure A (10 mol% cat.), (R)-1f was obtained in 95% yield (96 mg) as a red solid: mp >300 °C; [α]23D –81.6 (c 1.01, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.72 (s, 12H), 3.72 (d, J = 15.4 Hz, 2H), 3.86 (d, J = 15.4 Hz, 2H), 6.69 (s, 4H), 7.21 (d, J = 8.5 Hz, 2H), 7.33 (dt, J = 1.1, 7.7 Hz, 2H), 7.46–7.52 (m, 6H), 7.74 (d, J = 4.2 Hz, 4H), 7.92 (d, J = 8.2 Hz, 2H), 7.95 (s, 2H), 8.06 (t, J = 4.4 Hz, 2H), 8.49 (s, 2H), 8.90 (s, 1H), 9.17 (d, J = 1.1 Hz, 2H), 9.26 (s, 2H). Chiral Macrocycle (R)-1g. Following general procedure A (10 mol% cat.), (R)-1g was obtained in 98% yield (92 mg) as a yellow solid: mp >300 °C; [α]25D +38.9 (c 1.01, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.14 (s, 6H), 3.76 (d, J = 15.3 Hz, 2H), 3.85 (d, J = 15.4 Hz, 2H), 7.12 (d, J = 7.8 Hz, 4H), 7.21 (d, J = 8.6 Hz, 2H), 7.36 (dt, J = 1.3, 7.7 Hz, 2H), 7.50 (dt, J = 1.2, 7.6 Hz, 2H), 7.53– 7.55 (m, 4H), 7.72 (d, J = 7.8 Hz, 2H), 7.78 (t, J = 8.0 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.99 (s, 2H), 8.11 (d, J = 7.8 Hz, 2H), 8.39 (s, 2H), 8.91 (s, 1H), 9.09 (s, 2H), 9.19 (d, J = 1.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.0, 71.9, 109.6, 110.2, 125.4, 125.7, 126.2, 127.1, 127.2, 128.4, 128.8, 129.1, 129.3, 131.2, 131.3, 133.0, 134.5, 134.6, 135.9, 137.8, 141.4, 148.5, 149.1, 150.0, 151.8, 161.2, 166.4; IR (KBr) 3387, 3055, 2916, 1697, 1585, 1522, 1452, 1312, 1244, 1150 cm–1; HRMS (FAB) calcd for C56H42N7O8 940.3095, found 940.3104 ([M + H]+). Chiral Macrocycle (R)-1h. Following general procedure A (10 mol% cat., 0.3 mmol scale), (R)-1h was obtained in 89% yield (252 mg) as a yellow solid: mp >300 °C; [α]24D +56.8 (c 1.01, CHCl3); 1

H NMR (CDCl3, 400 MHz) δ 2.22 (s, 6H), 3.78 (d, J = 15.3 Hz, 2H), 3.86 (d, J = 15.4 Hz, 2H), 7.01 (d, J = 7.7 Hz, 2H), 7.20–7.25 (m, 4H), 7.36 (dt, J = 1.3, 7.7 Hz, 2H), 7.44–7.52 (m, 6H), 12 ACS Paragon Plus Environment

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7.73–7.78 (m, 4H), 7.94 (d, J = 8.1 Hz, 2H), 8.00 (s, 2H), 8.08 (d, J = 6.4 Hz, 2H), 8.46 (s, 2H), 8.91 (s, 1H), 9.11 (s, 2H), 9.17 (d, J = 1.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.4, 71.9, 109.7, 110.3, 125.4, 125.7, 126.3, 126.4, 127.1, 127.3, 128.5, 128.6, 128.7, 129.8, 131.3, 131.4, 133.0, 134.7, 135.9, 137.4, 138.4, 141.6, 148.4, 149.1, 150.0, 151.5, 161.3, 166.3; IR (KBr) 3385, 3055, 2916, 1697, 1585, 1522, 1452, 1312, 1246, 1150, 1053 cm–1; HRMS (FAB) calcd for C56H42N7O8 940.3095, found 940.3110 ([M + H]+). Chiral Macrocycle (R)-1i. Following general procedure A (30 mol% cat., 0.3 mmol scale), (R)-1i was obtained in 96% yield (270 mg) as a yellow solid: mp >300 °C; [α]21D +117 (c 1.00, CHCl3); 1

H NMR (CDCl3, 400 MHz) δ 2.35 (s, 6H), 3.61 (d, J = 15.4 Hz, 2H), 3.79 (d, J = 15.4 Hz, 2H), 7.02 (t, J = 7.5 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.38–7.45 (m, 6H), 7.52–

7.57 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 8.1 Hz, 2H), 7.93 (s, 2H), 7.97 (d, J = 8.2 Hz, 2H), 8.15 (d, J = 7.9 Hz, 2H), 9.18 (d, J = 0.9 Hz, 2H), 9.21 (s, 1H), 9.29 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.9, 72.0, 109.5, 110.4, 125.2, 125.4, 126.2, 126.4, 127.1, 127.4, 128.1, 128.5, 129.3, 129.8, 130.7, 131.4, 133.0, 134.8, 135.9, 136.1, 137.4, 141.4, 148.4, 148.9, 150.0, 152.0, 161.0, 166.1; IR (KBr) 3395, 3057, 2916, 1699, 1585, 1518, 1456, 1312, 1246, 1150 cm–1; HRMS (FAB) calcd for C56H42N7O8 940.3095, found 940.3101 ([M + H]+). Chiral Macrocycle (R)-1j. Following general procedure A (10 mol% cat.), (R)-1j was obtained in 97% yield (94 mg) as a yellow solid: mp >300 °C; [α]25D –23.9 (c 0.99, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.61 (s, 6H), 3.69 (d, J = 15.4 Hz, 2H), 3.86 (d, J = 15.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 4H), 7.26 (d, J = 7.6 Hz, 2H), 7.37 (dt, J = 1.3, 7.7 Hz, 2H), 7.51 (dt, J = 1.2, 7.5 Hz, 2H), 7.57 (d, J = 8.8 Hz, 4H), 7.74–7.81 (m, 4H), 7.94 (d, J = 8.2 Hz, 2H), 7.97 (s, 2H), 8.12 (dd, J = 1.6, 7.1 Hz, 2H), 8.37 (s, 2H), 8.98 (s, 1H), 9.18 (d, J = 1.4 Hz, 2H), 9.24 (s, 2H); 13C NMR (CDCl3, 100 MHz)

δ 55.1, 71.8, 109.7, 110.3, 114.1, 125.3, 125.6, 126.2, 126.9, 127.3, 128.4, 129.2, 129.6, 130.4, 131.3, 132.9, 134.3, 135.8, 141.5, 148.5, 149.2, 149.8, 151.6, 159.3, 161.4, 166.3; IR (KBr) 3381, 3055, 2913, 2835, 1697, 1585, 1516, 1452, 1314, 1246, 1152, 1051, 1032 cm–1; HRMS (FAB) calcd for C56H42N7O10 972.2993, found 972.2982 ([M + H]+). Chiral Macrocycle (R)-1k. Following general procedure A (10 mol% cat.), (R)-1k was obtained in 90% yield (93 mg) as a white solid: mp >300 °C; [α]23D +97.5 (c 1.00, THF); 1H NMR (d8-THF, 400 MHz) δ 3.60 (s, 12H), 3.74 (d, J = 15.4 Hz, 2H), 4.05 (d, J = 15.4 Hz, 2H), 6.25 (t, J = 2.2 Hz, 2H), 6.76 (d, J = 2.3 Hz, 4H), 7.28 (d, J = 8.4 Hz, 2H), 7.38 (dt, J = 1.2, 7.7 Hz, 2H), 7.51 (dt, J = 1.1, 7.5 Hz, 2H), 7.65 (dd, J = 0.6, 7.8 Hz, 2H), 7.75 (t, J = 8.0 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 8.07 (s, 2H), 8.13 (d, J = 8.0 Hz, 2H), 8.31 (s, 2H), 9.00 (d, J = 1.4 Hz, 2H), 9.09 (s, 1H), 10.17 (s, 2H); 13C NMR (d8-THF, 100 MHz) δ 55.4, 73.5, 99.6, 108.7, 109.6, 109.7, 126.3, 126.7, 127.1, 127.7, 129.2, 131.0, 131.9, 132.2, 134.1, 136.1, 137.0, 140.5, 141.4, 150.1, 150.6, 150.8, 153.1, 162.1, 162.9, 166.0; IR (KBr) 3375, 2936, 2837, 1697, 1589, 1541, 1456, 1315, 1153, 1072 cm–1; Anal. Calcd for C58H45N7O12: C, 67.50; H, 4.40; N, 9.50. Found: C, 67.22; H, 4.64; N, 9.86; HRMS (FAB) calcd for C58H46N7O12 1032.3204, found 1032.3204 ([M + H]+).



Chiral Macrocycle (R)-1l. Following general procedure A (30 mol% cat., 0.3 mmol scale), (R)-1l was obtained in 78% yield (241 mg) as a white solid: mp 268–269 °C; [α]25D +259 (c 1.02, CHCl3); 1

H NMR (CDCl3, 400 MHz) δ 3.66 (s, 6H), 3.76 (d, J = 15.8 Hz, 2H), 3.81 (s, 6H), 4.00 (d, J = 15.8 Hz, 2H), 6.40 (d, J = 7.8 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 8.4 Hz, 2H), 7.37–7.44 (m, 4H), 7.48 (dt, J = 1.9, 7.2 Hz, 2H), 7.71–7.78 (m, 4H), 7.89 (s, 2H), 7.93 (d, J = 8.2 Hz, 2H), 8.14 (dd, J = 1.3, 7.5 Hz, 2H), 8.58 (s, 2H), 9.14 (d, J = 1.3 Hz, 2H), 9.22 (s, 1H), 9.87 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 55.9, 57.0, 72.2, 104.7, 105.0, 109.4, 110.1, 115.1, 125.1, 125.5, 125.7, 126.7, 127.0, 127.4, 128.4, 129.4, 130.0, 131.4, 132.7, 133.2, 135.8, 141.0, 149.0, 149.4, 149.6, 152.7, 157.7, 157.8, 161.8, 167.2; IR (KBr) 3368, 2938, 2837, 1697, 1585, 1522, 1456, 1314, 1250, 1107 cm–1; HRMS (FAB) calcd for C58H46N7O12 1032.3204, found 1032.3196 ([M + H]+). Chiral Macrocycle (R)-1m. Following general procedure A (30 mol% cat.), (R)-1m was obtained in 98% yield (99 mg) as a white solid: mp >300 °C; [α]24D –39.7 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.73 (d, J = 15.3 Hz, 2H), 3.93 (d, J = 15.3 Hz, 2H), 7.21–7.25 (m, 2H), 7.31 (dt, J = 1.2, 7.5 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.44 (dt, J = 1.3, 7.6 Hz, 2H), 7.53–7.58 (m, 4H), 7.64– 7.70 (m, 4H), 7.72–7.80 (m, 6H), 8.00 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H), 8.08 (s, 2H), 8.11 (s, 2H), 8.29 (s, 2H), 8.78 (s, 1H), 8.89 (s, 2H), 9.20 (d, J = 1.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 72.0, 109.7, 110.2, 125.4, 125.5, 126.35, 126.37, 126.4, 127.0, 127.1, 127.60, 127.64, 127.8, 128.3, 128.6, 129.1, 131.3, 131.7, 132.6, 133.1, 133.3, 134.7, 135.0, 135.9, 141.5, 148.2, 148.9, 150.0, 151.9, 161.3, 166.1; IR (KBr) 3389, 3055, 1697, 1585, 1539, 1456, 1314, 1246, 1152 cm–1; HRMS (FAB) calcd for C62H42N7O8 1012.3095, found 1012.3086 ([M + H]+). Chiral Macrocycle (R)-1n. Following general procedure A (30 mol% cat.), (R)-1n was obtained in 63% yield (69 mg) as a yellow solid: mp >300 °C; [α]25D +492 (c 1.02, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.60 (d, J = 15.4 Hz, 2H), 3.69 (d, J = 15.4 Hz, 2H), 7.08 (s, 2H), 7.10–7.14 (m, 2H), 7.20 (t, J = 7.4 Hz, 2H), 7.24 (dd, J = 0.4, 8.1 Hz, 2H), 7.49–7.75 (m, 16H), 7.94 (dd, J = 2.1, 7.4 Hz, 2H), 8.03 (dt, J = 1.5, 8.2 Hz, 4H), 8.08 (d, J = 8.0 Hz, 2H), 8.15 (s, 2H), 8.17 (s, 2H), 8.89 (s, 3H), 9.27 (d, J = 1.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 72.4, 109.4, 110.1, 124.3, 125.3, 125.5, 126.0, 126.5, 126.7, 127.0, 127.3, 127.6, 127.77, 127.84, 128.7, 128.8, 129.0, 130.4, 130.5, 131.10, 131.12, 131.2, 131.3, 131.5, 133.3, 133.5, 135.9, 141.0, 147.6, 148.4, 150.2, 153.6, 161.0, 165.4; IR (KBr) 3379, 3051, 1697, 1584, 1516, 1456, 1312, 1244, 1150 cm–1; Anal. Calcd for C70H45N7O8: C, 75.60; H, 4.08; N, 8.82. Found: C, 75.62; H, 4.26; N, 8.67; HRMS (FAB) calcd for C70H46N7O8 1112.3408, found 1112.3422 ([M + H]+). Chiral Macrocycle (R)-1o. Following general procedure B (20 mol% cat.), (R)-1o was obtained in 36% yield (33 mg) as a yellow solid: mp 285 °C (dec); [α]23D +39.3 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.78 (d, J = 15.2 Hz, 2H), 3.85 (d, J = 15.3 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.45 (dt, J = 1.1, 7.7 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.65 (m, 8H), 7.86 (d, J = 8.1 Hz, 2H), 7.89 (s, 2H), 7.97 (d, J = 6.1 Hz, 2H), 8.44 (s, 2H), 8.63 (d, J = 4.8 Hz, 4H), 8.91 (s, 1H), 8.99 (s, 2H), 9.54 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 72.2, 109.86, 109.91, 124.3, 125.2, 125.7, 127.0, 127.1, 128.6, 128.9, 131.1, 131.7, 131.9, 133.7, 135.6, 141.3, 147.9, 149.2, 149.6, 149.8, 150.7, 161.4, 14 ACS Paragon Plus Environment

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165.2; IR (KBr) 3389, 3057, 1695, 1585, 1533, 1452, 1315, 1244, 1152 cm–1; HRMS (FAB) calcd for C52H36N9O8 914.2687, found 914.2690 ([M + H]+). Chiral Macrocycle (R)-1p. Following general procedure B (20 mol% cat.), (R)-1p was obtained in 35% yield (32 mg) as a yellow solid: mp 269–273 °C; [α]23D –92.1 (c 1.02, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.58 (d, J = 15.1 Hz, 2H), 3.81 (d, J = 15.2 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.41–7.43 (m, 2H), 7.46 (dt, J = 0.9, 7.6 Hz, 2H), 7.58 (dt, J = 0.7, 7.5 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.71 (t, J = 8.0 Hz, 2H), 7.98–8.02 (m, 6H), 8.17 (d, J = 7.2 Hz, 2H), 8.43 (dd, J = 1.4, 5.0 Hz, 2H), 8.54 (s, 2H), 9.17 (d, J = 1.0 Hz, 2H), 9.33 (s, 1H), 9.44 (s, 2H), 10.18 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 72.2, 109.9, 110.0, 124.1, 124.8, 125.3, 126.7, 127.1, 128.3, 128.8, 129.8, 130.9, 131.1, 132.5, 133.2, 134.1, 136.2, 136.7, 141.2, 148.2, 148.5, 149.1, 149.9, 150.7, 151.7, 161.8, 165.6; IR (KBr) 3381, 3057, 1697, 1585, 1537, 1452, 1315, 1244, 1152 cm–1; HRMS (FAB) calcd for C52H36N9O8 914.2687, found 914.2689 ([M + H]+). X-ray Crystallographic Analysis. Single crystals of (R)-1d were obtained by recrystallization from EtOAc/hexane, and the crystals were mounted on a micro mesh. The X-ray experiments were carried out on a Rigaku VariMax with Saturn. To determine the cell constant and orientation matrix, 12 oscillation photographs were taken with an oscillation angle of 0.5° and exposure time of 2 s per degree for each frame. Intensity data were collected by taking 1440 oscillation photographs with an oscillation angle of 0.5° and exposure time of 20 s per degree for each frame at –163 °C. Refraction data were corrected for both Lorentz and polarization effects. Crystal data for (R)-1d: C64H51N9O12, colorless crystal, crystal dimensions 0.25 × 0.21 × 0.11 mm3, orthorhombic, space group P212121, a = 14.274(4), b = 14.345(4), c = 27.420(8) Å, V = 5614 (3) Å3, Z = 4, ρcalcd = 1.346 g cm–3, 2θ ≤ 55.4°, 77411 total reflections, 13050 unique reflections, 930 parameters, R1 = 0.0407 (I > 2.0σ(I)), Rw = 0.1070 (all data). The final structure was validated by the PLATON CIF check. Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR spectra of 1 and CPA complexed with 1, NOESY spectra, binding isotherms, thermal ellipsoid model of crystal structure of (R)-1d, and computational details (PDF) X-ray crystallographic data for (R)-1d (CIF) Acknowledgments. We thank Dr. Hiromi Ota (Okayama University) for X-ray analysis. We also thank Prof. Yasunori Yamamoto (Hokkaido University) for his kind advice on the Suzuki–Miyaura reaction. We are also grateful to the SC-NMR Laboratory of Okayama University for the measurement of NMR spectra. References (1) Book: (a) Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy; Wiley: Hoboken, New Jersey, 2007. For recent examples, see: (b) Wolf, C.; Cook, A. M.; 15 ACS Paragon Plus Environment


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Cross-Coupling Approach to an Array of Macrocyclic Receptors

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