A New Approach to Axially Chiral Biaryls via the Atrop-Diastereoselective Formation of Medium-Sized Lactone Bridge

Abstract

Biphenyl-2,6-diols, substituted at the C2′ position with alkanoic acid side chain containing a stereogenic center, underwent the highly atrop-stereoselective nine-membered lactone formation with differentiation of the diastereotopic hydroxy groups.

Key words

axial chirality - stereogenic center - biaryl - lactone - diastereoselective reaction

• References and Notes

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For the atrop-diastereoselective desymmetrization of a preformed biaryl precursor bearing rotationally restricted biaryl axis, see:
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The atrop-diastereoselective lactone-bridge formation of biaryl derivatives has been reported by Feldman et al., in which one of the diastereo-rotamers of di-ortho-substituted biaryl precursor rapidly cyclized to the lactone through a kinetic dynamic resolution. Note that such stereoselection is operative for the precursors, in which the biaryl linkages are freely rotating under the reaction conditions, and consequently not applicable to the synthesis of tri-ortho- and tetra-ortho-substituted biaryl lactones. See:
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Also see, for examples of the atrop-diastereoselective bridge formation of a preformed biaryl precursor bearing the rotationally unstable biaryl axis:
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• 8 Acid 1 was prepared as shown in Scheme 7.
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• 15 Stereochemistries of the products were unambiguously determined by X-ray crystal structure analyses. CCDC 1442185 (2a), 1442166 (2b), 1442179 (3a), 1442180 (3b), 1442154 (8a), 1442174 (8b), 1442167 (9a), 1442163 (9b), 1442151 (11a), 1442150 (11b), 1442183 (13a), 1442184 (13b), 1450682 (14a), 1442178 (14b), 1442168 [(±)-17a] contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• 17 The reactions were performed in the presence and in the absence of molecular sieves, which did not cause significant difference in the result.
• 18 Judging from silica-gel TLC analyses, the starting material 1 was gradually consumed at room temperature. During this period, the dim spots of lactones 2a and 2b were detected (R_f = 0.51 for 2a and 0.47 for 2b, CHCl₃–MeOH = 9:1) with the spot of 1 (R_f = 0.29) and a dark spot on the mark of the origin (R_f = ca. 0). The spots of 2a and 2b almost disappeared with a complete consumption of 1. Analyses of the reaction mixture by mass spectrometry and ¹H NMR — the reactions were separately performed in CD₂Cl₂ or CD₃CN — revealed the formation of the lactone–reagent adduct 5 [m/z = 436.1763 (ESI-TOF); 72% (5a/5b = 3.1:1) for the reaction in CD₃CN; 74% (5a/5b = 3.5:1) for the reaction in CD₂Cl₂]. On the other hand, the isolated lactone 2a was rapidly (<5 min) converted into 5a by the treatment with CMPI (C, 3.0 equiv) and Et₃N (3.0 equiv) in CD₂Cl₂ or CD₃CN at 25 °C. The isolated lactone 2b was similarly converted into 5b. These observations implied that lactones 2a and 2b, immediately after formation, underwent acylation of the remaining phenolic hydroxy group.
• 19 For the use of NaHCO₃ as the base in the Mukaiyama lactonization, see: Evans DA, Starr JT. J. Am. Chem. Soc. 2003; 125: 13531
• 20 The reactions were performed in the presence of molecular sieves, which led to a slight increase of the yield.
• 21 Analyses of the reaction mixture by ¹H NMR spectroscopy, which were separately performed by using CD₂Cl₂ as the solvent by keeping the other conditions unchanged, showed the formation of 5 in ca. 5–10%.
• 22 The NMR studies [lactone 2a, CMPI (C, 3.0 equiv), NaHCO₃ (20 equiv), CD₂Cl₂ or ClCD₂CD₂Cl, 35 °C] showed that the formation of adduct 5 in ClCD₂CD₂Cl was significantly slower than those in CD₂Cl₂. For 30 min: 6% in CD₂Cl₂, trace in ClCD₂CD₂Cl. For 120 min: 18% in CD₂Cl₂, 3% in ClCD₂CD₂Cl.
• 23 Typical Procedure of the Lactone Formation by CMPI (C) Carboxylic acid 1 (34.3 mg, 0.0948 mmol), CMPI (C, 98.7 mg, 0.386 mmol), NaHCO₃ (162 mg, 1.93 mmol), and 160 mg of powdered MS 4A were admixed in 1,2-dichloroethane (3 mL), and the mixture was stirred at 60 °C for 9 h. The mixture was cooled to 0 °C, and silica gel (63–200 μm, 2 g) was added. After evaporating the solvents, the resulting dry gel was loaded on the top of silica-gel column. Elution using hexane–EtOAc (3:7) gave a mixture of lactones 2a and 2b (27.8 mg, 85%, 2a/2b = 97:3). Separation by silica-gel chromatography, followed by recrystallization from hexane–acetone, gave each isomer as colorless prisms.
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For an example of the use of PyBOP in macrolactonization, see:
• 28b Frank SA, Roush WR. J. Org. Chem. 2002; 67: 4316
• 29 Typical Procedure of the Lactone Formation by EDCI (D) To a solution of carboxylic acid 10 (50.0 mg, 0.138 mmol) in 1,2-dichloroethane (5 mL) were added EDCI (D, 30.5 mg, 0.158 mmol) and DMAP (92.5 mg, 0.720 mmol) at 0 °C. After stirring at 26 °C for 48 h, the reaction was quenched by adding 2 M HCl aq, and the products were extracted with EtOAc. The combined organic extracts were washed with sat. aq NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica-gel chromatography (CHCl₃–MeOH = 95:5) to give a mixture of lactones 11a and 11b (39.0 mg, 83%, 11a/11b = 94:6). Recrystallization from hexane–EtOAc gave 11a as colorless prisms. Concentration of the mother liquor followed by repeated recrystallization from hexane–EtOAc gave 11b as colorless prisms.
• 30 Upon treatment with EDCI (1.4 equiv) and DMAP (6.0 equiv) in 1,2-dichloroethane at 40 °C, the minor isomer 13b underwent no isomerization to 13a and was recovered quantitatively after 3 h.
• 31 ¹H NMR spectra of 8a and 9a exhibit the existence of hydrogen bonding between the hydroxy on the lactone and the carbonyl oxygen, which possibly offers additional stability. The signal of the hydrogen of the hydroxy group appears at δ = 3.33 ppm for 8a and 3.31 ppm for 9a (CDCl₃).
• 32 DFT calculations showed that the geometries of the biphenyl and the lactone frameworks in the preferred conformations of each isomer in solution are in good accordance with the corresponding structures obtained by X-ray single-crystal analysis, see Supporting Information.
• 33 Roush WR, Blizzard TA. J. Org. Chem. 1984; 49: 4332
• 34 Isolated ester 16, when subjected to the same conditions, gave lactones 14a and 14b (80% yield, dr = 10:90).
• 35 Typical Procedure of the Lactone Formation by Pivaloyl Chloride To a mixture of acid 1 (50.0 mg, 0.138 mmol) and 250 mg of MS 4A in 1,2-dimethoxyethane (5 mL) were added Et₃N (95.0 μL, 0.686 mmol) and pivaloyl chloride (35.0 μL, 0.284 mmol) at 0 °C. After stirring at 0 °C for 18 h, the solution was warmed to 24 °C, and stirring was continued for 24 h. The mixture was filtrated through a Celite pad with EtOAc and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl₃–MeOH = 95:5) to give a mixture of lactones 14a and lactone 14b (48.5 mg, 82%, 14a/14b = 6:94). After separation of the isomers by silica-gel chromatography, recrystallization of 14a from hexane–Et₂O gave colorless needles, and recrystallization of 14b from hexane–EtOAc gave colorless plates.
• 36 Upon treatment with pivaloyl chloride (0.4 equiv) and Et₃N (15 equiv) in DME at 26 °C, lactone 17b, the minor isomer, underwent no isomerization to 17a and was recovered in 96% after 3 h.
• 37 Acid (S)-12 was prepared from biphenyl aldehyde 18 ^4b via the Evans aldol reaction with oxazolidinone 22 ³⁹ (Scheme 8). For the determination of enantiomeric purity of (S)-12, see ref. 38. For the determination of the stereochemistry of 23, see Supporting Information.
• 38 Enantiomeric purity of acid (S)-12 was deduced from those of (S)-24 and (S,aR)-17a. Enantiomeric purity of (S)-24 was determined by chiral HPLC analysis of the corresponding methyl ester [CHIRALPAK^® IA (Daicel), 0.46 × 25 cm, hexane–2-PrOH (90:10), 1.0 mL/min, 20 °C, 274 nm]: t _R (S form) = 25.7 min, t _R (R form) = 22.8 min. Enantiomeric purity of (S,aR)-17a was determined by chiral HPLC analyses [CHIRALPAK^® IA (Daicel), 0.46 × 25 cm, hexane/2-PrOH (60:40), 0.50 mL/min, 20 °C, 274 nm]: t _R [(S,aR)-17a] = 15.4 min, t _R [(R,aS)-17a] = 9.3 min.
• 39 Liang Q, Zhang J, Quan W, Sun Y, She X, Pan X. J. Org. Chem. 2007; 72: 2694
• 40 Characterization Data for Selected Compounds Compound 2a: mp 249.7–250.5 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (s, 3 H), 2.16 (d, 1 H, J = 14.0 Hz), 2.41 (d, 1 H, J = 12.9 Hz), 2.45 (dd, 1 H, J ₁ = 12.9 Hz, J ₂ = 1.1 Hz), 3.24 (dd, 1 H, J ₁ = 14.0 Hz, J ₂ = 1.1 Hz), 3.48 (br s, 1 H), 3.67 (s, 3 H), 3.68 (s, 3 H), 5.45 (br s, 1 H), 6.80 (dd, 1 H, J ₁ = 7.9 Hz, J ₂ = 0.9 Hz), 6.90 (d, 1 H, J = 9.0 Hz), 6.93 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 0.9 Hz), 6.97 (d, 1 H, J = 9.0 Hz), 7.35 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 7.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 33.2, 39.9, 43.0, 56.1, 56.4, 72.8, 111.2, 112.6, 113.2 (2 C), 117.8, 120.9, 127.4, 130.3, 151.7, 151.8, 152.4, 154.1, 169.0. IR (ATR): 3405, 3250, 3110, 2966, 2932, 2834, 1753, 1712, 1616, 1590, 1477, 1455, 1439, 1103, 1083, 871, 822, 808, 784, 765 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₉H₂₀O₆Na [M + Na]⁺; 367.1158; found: 367.1163. Compound 2b: mp 250.4–251.3 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.26 (br s, 1 H), 1.42 (s, 3 H), 2.27 (d, 1 H, J = 12.8 Hz), 2.34 (dd, 1 H, J ₁ = 12.2 Hz, J ₂ = 1.7 Hz), 2.61 (d, 1 H, J = 12.2 Hz), 3.22 (dd, 1 H, J ₁ = 12.8 Hz, J ₂ = 1.7 Hz), 3.65 (s, 3 H), 3.81 (s, 3 H), 4.60 (br s, 1 H), 6.81 (dd, 1 H, J ₁ = 8.3 Hz, J ₂ = 0.9 Hz), 6.87 (d, 1 H, J = 9.0 Hz), 6.92 (dd, 1 H, J ₁ = 8.3 Hz, J ₂ = 0.9 Hz), 6.93 (d, 1 H, J = 9.0 Hz), 7.35 (dd, 1 H, J ₁ = J ₂ = 8.3 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 26.3, 40.6, 45.0, 55.4, 56.3, 74.4, 111.1, 112.3, 113.12, 113.15, 117.9, 120.4, 127.4, 130.4, 151.5, 151.6, 152.5, 154.1, 168.4. IR (ATR): 3360, 3152, 3002, 2980, 2926, 2840, 1730, 1612, 1586, 1507, 1478, 1455, 1108, 1065, 898, 885, 868, 833, 812, 798, 757, 742 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₉H₂₀O₆Na [M + Na]⁺: 367.1158; found: 367.1153. Anal. Calcd for C₁₉H₂₀O₆: C, 66.27; H, 5.85. Found: C, 66.28; H, 5.67. Compound 11a: mp 201.0–202.5 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (d, 3 H, J = 6.8 Hz), 1.69 (dd, 1 H, J ₁ = 13.0 Hz, J ₂ = 11.2 Hz), 2.04 (dd, 1 H, J ₁ = 12.6 Hz, J ₂ = 12.4 Hz), 2.19–2.35 (m, 1 H), 2.22 (ddd, 1 H, J ₁ = 12.6 Hz, J ₂ = 2.4 Hz, J ₃ = 1.2 Hz), 2.91 (ddd, 1 H, J ₁ = 13.0 Hz, J ₂ = 1.4 Hz, J ₃ = 1.2 Hz), 3.65 (s, 3 H), 3.81 (s, 3 H), 4.80 (br s, 1 H), 6.79 (dd, 1 H, J ₁ = 8.0 Hz, J ₂ = 1.2 Hz), 6.82 (d, 1 H, J = 8.8 Hz), 6.89 (d, 1 H, J = 8.8 Hz), 6.93 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz), 7.34 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 22.7, 32.7, 35.0, 38.9, 54.7, 55.2, 109.2, 110.9, 111.9, 112.1, 117.1, 118.3, 129.0, 130.0, 150.1, 150.2, 151.0, 153.2, 170.9. IR (ATR): 3492, 2970, 2934, 2921, 2836, 1762, 1616, 1593, 1575, 1486, 1464, 1439, 1102, 1080, 1069, 889, 871, 857, 805, 780, 769, 742 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₉H₂₀O₅Na [M + Na]⁺: 351.1208; found: 351.1219. Compound 11b: mp 190.5–192.5 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.08 (d, 3 H, J = 7.2 Hz), 2.11 (dd, 1 H, J ₁ = 13.4 Hz, J ₂ = 3.0 Hz), 2.19 (dd, 1 H, J ₁ = 12.5 Hz, J ₂ = 5.4 Hz), 2.24–2.40 (m, 1 H), 2.46 (dd, 1 H, J ₁ = 12.5 Hz, J ₂ = 3.2 Hz), 3.16 (dd, 1 H, J ₁ = 13.4 Hz, J ₂ = 5.0 Hz), 3.65 (s, 3 H), 3.79 (s, 3 H), 4.62 (br s, 1 H), 6.78 (dd, 1 H, J ₁ = 8.1 Hz, J ₂ = 1.2 Hz), 6.85 (d, 1 H, J = 9.2 Hz), 6.91 (d, 1 H, J = 9.2 Hz), 6.92 (dd, 1 H, J ₁ = 8.4 Hz, J ₂ = 1.2 Hz), 7.32 (dd, 1 H, J ₁ = 8.4 Hz, J ₂ = 8.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 16.9, 31.90, 31.94, 37.5, 55.4, 56.4, 110.6, 111.9, 112.8, 113.1, 118.0, 120.4, 128.4, 130.0, 151.5, 151.8, 152.9, 154.1, 170.3; IR (ATR) 3400, 2975, 2927, 2835, 1731, 1619, 1573, 1465, 1439, 1095, 1086, 895, 866, 825, 808, 776, 736 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₉H₂₁O₅ [M + H]⁺: 329.1389; found: 329.1389. Compound 14a: mp 221.5–225.5 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.10 (s, 9 H), 1.56 (s, 3 H), 2.01 (d, 1 H, J = 13.7 Hz), 2.28 (d, 1 H, J = 13.5 Hz), 3.51 (dd, 1 H, J ₁ = 13.7 Hz, J ₂ = 1.2 Hz), 3.57 (dd, 1 H, J ₁ = 13.5 Hz, J ₂ = 1.2 Hz), 3.64 (s, 3 H), 3.82 (s, 3 H), 4.56 (br s, 1 H), 6.86 (dd, 1 H, J ₁ = 7.8 Hz, J ₂ = 1.0 Hz), 6.87 (d, 1 H, J = 9.0 Hz), 6.90 (d, 1 H, J = 9.0 Hz), 6.92 (dd, 1 H, J ₁ = 8.5 Hz, J ₂ = 1.0 Hz), 7.35 (dd, 1 H, J ₁ = 8.5 Hz, J ₂ = 7.8 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 26.7, 31.0, 37.4, 39.29, 39.35, 55.5, 56.3, 79.7, 111.2, 111.5, 112.9, 113.1, 117.9, 120.4, 126.9, 130.4, 151.1, 151.8, 153.0, 153.9, 167.2, 207.0. IR (ATR): 3396, 2960, 2927, 2853, 1736, 1724, 1615, 1588, 1477, 1457, 1436, 1080, 1070, 863, 795, 779, 767, 756, 738 cm^–1. HRMS (ESI-TOF): m/z calcd for C₂₄H₂₈O₇Na [M + Na]⁺: 451.1733; found: 451.1718. Compound 14b: mp 204.0–205.0 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 1.10 (s, 9 H), 1.56 (s, 3 H), 2.71 (d, 1 H, J = 12.8 Hz), 2.72 (dd, 1 H, J ₁ = 12.1 Hz, J ₂ = 1.6 Hz), 3.11 (d, 1 H, J = 12.1 Hz), 3.46 (dd, 1 H, J ₁ = 12.8 Hz, J ₂ = 1.6 Hz), 3.65 (s, 3 H), 3.83 (s, 3 H), 4.58 (br s, 1 H), 6.81 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 1.0 Hz), 6.88 (d, 1 H, J = 9.2 Hz), 6.94 (d, 1 H, J = 9.2 Hz), 6.95 (dd, 1 H, J ₁ = 8.2 Hz, J ₂ = 1.0 Hz), 7.38 (dd, 1 H, J ₁ = J ₂ = 8.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 22.7, 27.1, 36.2, 39.4, 41.0, 55.4, 56.4, 83.5, 111.4, 112.2, 113.0, 113.3, 117.8, 121.0, 126.7, 130.5, 151.5 (2C), 152.7, 154.1, 168.0, 177.5. IR (ATR): 3336, 2978, 2960, 2941, 2835, 1748, 1690, 1614, 1587, 1478, 1457, 1437, 1104, 1074, 889, 866, 845, 834, 817, 804, 776, 739 cm^–1. HRMS (ESI-TOF): m/z calcd for C₂₄H₂₈O₇Na [M + Na]⁺: 451.1733; found: 451.1729. Anal. Calcd for C₂₄H₂₈O₇: C, 67.28; H, 6.59. Found: C, 67.03; H, 6.59.