Synthesis and Structural Characteristics of Geminally Disubstituted β-Amino Acids

Abstract

The syntheses of seven new β-amino acids containing aryl, alkyl, and heteroaryl substituents are outlined. The synthetic strategy employs densely functionalized chiral isoxazolines as key intermediates, enabling the preparation of single stereoisomers of these challenging targets. Solid-state characterization of two of the sterically encumbered targets is also reported.

cycloadditions - β-amino acid - diastereoselectivity - isoxazolidine - amino alcohol

References

Recent reviews on applications of β-amino acids:

1a Steer DL. Lew RA. Perlmutter P. Smith AI. Aguilar MI. Curr. Med. Chem.  2002,  9:  811 

1b Hill DJ. Mio MJ. Prince RB. Hughes TS. Moore JS. Chem. Rev.  2001,  101:  3893 

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1e Gademann K. Hintermann T. Schreiber JV. Curr. Med. Chem.  1999,  6:  905 

1f Enantioselective Synthesis of β-Amino Acids   Juaristi E. Wiley-VCH; New York: 1997. 

1g Seebach D. Matthews JL. Chem. Commun.  1997,  2015 

See:

2a Juaristi E. López-Ruiz H. Curr. Med. Chem.  1999,  6:  983 

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3 Griffith OW. Annu. Rev. Biochem.  1986,  55:  855 

4 Preparation of racemic C3-substituted b-amino acids, see: Dobrev A. Ivanov C. Monatsh. Chem.  1968,  99:  1050 

Approaches to C3-substituted β-amino acids:

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5b Kobayashi K. Matoba T. Irisawa S. Takanohashi A. Tanmatsu M. Morikawa O. Konishi H. Bull. Chem. Soc. Jpn.  2000,  73:  2805 

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9 Conditions were similar to those used for ketoxime ethers: Moody CJ. Gallagher PT. Lightfoot AP. Slawin AMZ. J. Org. Chem.  1999,  64:  4419 

Examples of carbon nucleophiles added to isoxazolines:

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14

General Procedure for Preparation of 10a-e, 11a-b:
To a solution of 8 or 9 (0.8 mmol, 1 equiv) in toluene (5 mL) cooled in a dry ice-acetone bath, BF₃·OEt₂ (O.31 mL, 2.5 mmol, 3.1 equiv) was added dropwise, and the resulting solution was stirred for 0.5 h with continued cooling. A solution of the organolithium reagent (5.8 mmol, 7.2 equiv) was then added over 15 min. After TLC analysis indicated complete consumption of starting material (typically 3-5 h), the reaction was quenched with 15 mL sat. NaHCO₃. The mixture was extracted with Et₂O (3 × 20 mL), and the combined extracts were washed with H₂O (3 × 15 mL), brine (1 × 15 mL), dried over Na₂SO₄, and concentrated. The crude mixture was passed through a short plug of silica (9:1 hexanes-EtOAc) and after concentration, the residue was dissolved in 4 mL THF, cooled in an ice-H₂O bath, and TBAF (4 equiv) was added dropwise. The reaction was allowed to warm to ambient temperature while monitoring by TLC. Following the consumption of starting material, the reaction mixture was diluted with H₂O (10 mL) and extracted with Et₂O or EtOAc. Combined extracts were washed with brine (1 × 10 mL), dried over Na₂SO₄, concentrated, and purified by flash chromatography. Only the major diastereomer was carried on in subsequent steps.

15

10a: Mp 73-75 °C; [α]_D = -85.0 (c 0.44, CHCl₃).
10b: [α]_D = -85.0 (c 0.44, CHCl₃).
10c: [α]_D = -97.3 (c 0.70, CHCl₃). IR (thin film): 3392, 2956, 2930, 2871, 1469, 1368 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.78 (d, 3 H, J = 6.6 Hz), 0.82 (d, 3 H, J = 7.0 Hz), 1.21 (d, 3 H, J = 6.6 Hz), 1.43-1.49 (m, 1 H), 1.79-1.81 (m, 2 H), 1.91 (dd, 1 H, J = 12.5, 8.1 Hz), 2.84 (dd, 1 H, J = 12.8, 7.7 Hz), 3.70-3.77 (m, 1 H), 3.89-3.94 (m, 1 H), 6.32-6.34 (m, 2 H), 7.36-7.37 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.53, 23.66, 23.88, 25.57, 43.59, 46.31, 68.53, 69.73, 85.40, 106.72, 110.52, 141.77, 155.97. HRMS (ESI): m/z calcd for [C₁₃H₂₁NO₃ + Na]⁺: 262.1419; found: 262.1420.
10d: [α]_D = -86.8 (c 0.59, CHCl₃). IR (thin film): 3392, 2955, 2926, 2871, 1565, 1453, 1368 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.80 (d, 3 H, J = 6.8 Hz), 0.85 (d, 3 H, J = 6.6 Hz), 1.21 (d, 3 H, J = 6.3 Hz), 1.49-1.52 (m, 1 H), 1.72-1.87 (m, 3 H), 2.19-2.26 (br s, 1 H), 2.29 (s, 3 H), 2.62-2.92 (m, 1 H), 3.64-3.82 (m, 1 H), 3.91-3.95 (m, 1 H), 5.45 (br s, 1 H), 5.91 (s, 1 H), 6.17 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.80, 19.44, 23.70, 23.98, 25.57, 43.36, 46.31, 68.41, 69.85, 85.72, 106.34, 107.49, 151.54, 153.79. HRMS (ESI): m/z calcd for [C₁₄H₂₃NO₃ + Na]⁺: 276.1576; found: 276.1575.
10e: [α]_D = -52.6 (c 1.26, CHCl₃). IR (thin film): 3402, 2955, 2929, 2870, 1446, 1368 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.82-0.85 (m, 6 H), 1.20 (d, 3 H, J = 6.3 Hz), 1.46-1.54 (m, 1 H), 1.73 (m, 1 H), 1.85 (dd, 1 H, J = 13.9, 5.6 Hz), 2.04-2.06 (m, 1 H), 2.11-2.17 (m, 1 H), 2.80-2.88 (m, 1 H), 3.74 (m, 1 H), 3.89-3.94 (m, 1 H), 5.54 (br s, 1 H), 6.96-6.99 (m, 2 H), 7.23 (dd, 1 H, J = 4.6, 1.8 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 19.68, 23.93, 24.03, 25.27, 46.88, 49.25, 69.71, 70.43, 85.22, 124.10, 124.54, 126.87, 148.85. HRMS (ESI): m/z calcd for [C₁₃H₂₁NO₂S + Na]⁺: 278.1191; found: 278.1182.
11a: Mp 72-74 °C. IR (thin film): 3343, 3217, 2969, 1455 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.73 (t, 3 H, J = 7.4 Hz), 0.86 (d, 3 H, J = 6.2 Hz), 0.88-0.99 (m, 1 H), 1.09-1.22 (m, 1 H), 1.41 (s, 3 H), 2.00-2.50 (br s, 1 H), 3.16 (d, 1 H, J = 5.5 Hz), 3.71-3.74 (m, 1 H), 4.24-4.27 (m, 1 H), 5.54-6.02 (br s, 1 H), 7.12-7.18 (m, 2 H), 7.24-7.35 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.70, 18.19, 24.91, 27.74, 59.28, 67.96, 68.53, 89.18, 127.10, 128.34, 129.80, 136.16. HRMS (ESI): m/z calcd for [C₁₄H₂₁NO₂ + Na]⁺: 258.1470; found: 258.1469.
11b: IR (thin film): 3441, 2969, 1494 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.44 (t, 3 H, J = 7.6 Hz), 0.76 (d, 3 H, J = 6.1 Hz), 0.84-0.93 (m, 1 H), 1.49-1.57 (m, 1 H), 1.96 (s, 1 H), 3.57 (d, 1 H, J = 4.9 Hz), 3.85-3.91 (m, 1 H), 3.73 (dd, 1 H, J = 4.9, 9.0 Hz), 6.14 (br s, 1 H), 7.24-7.35 (m, 4 H), 7.39-7.42 (m, 4 H), 7.66 (d, 2 H, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 9.35, 18.91, 29.53, 61.01, 68.25, 74.98, 87.95, 126.59, 127.11, 127.62, 128.54, 129.05, 129.73, 136.22, 143.41. HRMS (ESI): m/z calcd for [C₁₉H₂₃NO₂ + H]⁺: 298.1807; found: 298.1797.

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14a: IR (thin film): 3316, 2956, 1712, 1166 cm^-1. ¹H NMR (500 MHz, CD₃OD): δ = 0.93 (d, 6 H, J = 6.6 Hz), 1.32 (s, 3 H), 1.42 (s, 9 H), 1.52 (dd, 1 H, J = 13.9, 5.1 Hz), 1.69-1.78 (m, 1 H), 1.86 (dd, 1 H, J = 13.5, 6.3 Hz), 2.48 (d, 1 H, J = 13.9 Hz), 2.80 (d, 1 H, J = 14.2 Hz). ¹³C NMR (125 MHz, CD₃OD): δ = 24.67, 25.14, 25.28, 28.85, 31.12, 44.68, 47.42, 54.80, 79.55, 156.57, 174.88. HRMS (ESI): m/z calcd for [C₁₃H₂₅NO₄ + Na]⁺: 282.1681; found: 282.1684.
14b: mp 136-138 °C. IR (thin film): 3305, 2926, 1712, 1651, 1165 cm^-1. ¹H NMR (500 MHz, CD₃OD): δ = 0.65 (s, 3 H), 0.78 (s, 3 H), 1.37 (s, 9 H), 1.51-1.60 (m, 1 H), 1.83-1.92 (m, 1 H), 2.13 (dd, 1 H, J = 13.8, 5.0 Hz), 3.03 (d, 1 H, J = 14.2 Hz), 3.21 (d, 1 H, J = 14.2 Hz), 7.19 (t, 1 H, J = 7.2 Hz), 7.27-7.31 (m, 2 H), 7.32-7.36 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.67, 24.43, 27.76, 29.69, 41.58, 49.32, 59.67, 81.46, 125.37, 126.32, 127.77, 144.83, 157.74, 175.28. HRMS (ESI): m/z calcd for [C₁₈H₂₇NO₄ + Na]⁺: 344.1838; found: 344.1848.
14c: mp 108-110 °C. IR (thin film): 3361, 29.18, 1714, 1490, 1043 cm^-1. ¹H NMR (500 MHz, CD₃OD): δ = 0.72 (d, 3 H, J = 6.6 Hz), 0.76 (d, 3 H, J = 6.6 Hz), 1.40 (s, 9 H), 1.57-1.66 (m, 1 H), 1.95-2.03 (m, 2 H), 3.02 (d, 1 H, J = 14.4 Hz), 3.16 (d, 1 H, J = 14.4 Hz), 6.22 (dd, 1 H, J = 3.2, 0.7 Hz), 6.35 (dd, 1 H, J = 3.2, 1.7 Hz), 7.40 (dd, 1 H, J = 1.7, 0.7 Hz). ¹³C NMR (125 MHz, CD₃OD): δ = 24.40, 25.05, 28.68, 31.12, 41.16, 46.84, 57.60, 80.15, 106.77, 111.35, 142.02, 156.37, 157.42, 173.88. HRMS (ESI): m/z calcd for [C₁₆H₂₅NO₅ + Na]⁺: 334.1630; found: 334.1629.
14d: mp 95-97 °C. IR (thin film): 3313, 2956, 1714, 1165 cm^-1. ¹H NMR (500 MHz, CD₃OD): δ = 0.74 (d, 3 H, J = 6.6 Hz), 0.77 (d, 3 H, J = 6.6 Hz), 1.40 (s, 9 H), 1.58-1.64 (m, 1 H), 1.90-1.99 (m, 2 H), 2.23 (s, 3 H), 2.99 (d, 1 H, J = 15.0 Hz), 3.09 (d, 1 H, J = 14.6 Hz), 5.90 (dd, 1 H, J = 2.9, 1.1 Hz), 6.04 (d, 1 H, J = 3.3 Hz). ¹³C NMR (125 MHz, CD₃OD): δ = 13.40, 24.31, 24.45, 25.08, 28.71, 41.63, 46.82, 57.57, 80.23, 107.17, 107.38, 151.57, 155.45, 156.37, 174.53. HRMS (ESI): m/z calcd for [C₁₇H₂₇NO₅ + Na]⁺: 348.1787; found: 348.1784.
14e: mp 127-129 °C. IR (thin film): 3024, 2924, 1712, 1649, 1394, 1170 cm^-1. ¹H NMR (400 MHz, CD₃OD): δ = 0.71 (d, 3 H, J = 6.6 Hz), 0.85 (d, 3 H, J = 6.6 Hz), 1.37 (s, 9 H), 1.61-1.70 (m, 1 H), 1.87 (dd, 1 H, J = 14.0, 5.5 Hz), 2.20 (dd, 1 H, J = 13.9, 5.5 Hz), 3.00 (d, 1 H, J = 1.4 Hz), 3.24 (d, 1 H, J = 14.4 Hz), 6.88-6.91 (m, 2 H), 7.23 (dd, 1 H, J = 4.6, 1.5 Hz). ¹³C NMR (125 MHz, C₆D₆): δ = 23.99, 24.35, 24.69, 27.90, 30.17, 50.33, 58.83, 81.56, 123.13, 123.55, 126.15, 151.49, 158.20, 174.61. HRMS (ESI): m/z calcd for [C₁₃H₂₅NO₄ + Na]⁺: 350.1402; found: 350.1401.
15a: mp 100-102 °C. IR (thin film): 3304, 2974, 1706, 1164 cm^-1. ¹H NMR (500 MHz, CD₃OD): δ = 0.84 (t, 3 H, J = 7.5 Hz), 1.18 (s, 3 H), 1.44 (s, 9 H), 1.52-1.61 (m, 1 H), 2.37-2.46 (m, 1 H), 4.49 (s, 1 H), 7.23-7.29 (m, 3 H), 7.36-7.39 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 7.84, 20.29, 28.38, 28.77, 56.47, 57.62, 79.11, 127.52, 128.00, 130.06, 134.84, 154.24, 177.18. HRMS (ESI): m/z calcd for [C₁₇H₂₅NO₄ + Na]⁺: 330.1681; found: 330.1672.
15b: mp 204-206 °C. IR (thin film): 3440, 2973, 1703, 1498, 1166 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 0.53-0.56 (m, 3 H), 1.93-2.02 (m, 1 H), 2.62-2.64 (m, 1 H), 4.59 (s, 1 H), 4.97-5.04 (m, 2 H), 7.26-7.51 (m, 15 H). ¹³C (for methyl ester derived from 15b, 125 MHz, CDCl₃): δ = 8.77, 29.48, 29.70, 51.83, 59.33, 64.84, 66.03, 125.99, 127.06, 127.97, 128.08, 128.17, 128.23, 128.46, 129.97, 133.81, 136.93, 142.95, 154.78, 172.81. HRMS (ESI): m/z calcd for [C₂₅H₂₅NO₄ + Na]⁺: 426.1681; found: 426.1691.

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Crystallographic data for 14b: C₁₈H₂₇NO₄, colorless square rods crystallized from EtOH at 22 °C, orthorhombic, space group P2 (1)2 (1)2 (1), a = 7.9578 (15) Å, α = 90°, b = 11.135 (2) Å, β = 90°, c = 20.543 (4) Å, γ = 90°, U = 1820.3 (6) ų, Z = 4, D _c = 1.173 mg/m³, µ = 0.082 mm^-1, R = 0.0300, wR2 = 0.0737, GOF = 1.034, T = 113 (2) K, F(000) = 696, 2590 independent reflections were collected on a Bruker SMART CCD-based X-ray diffractometer with an LT-2 low temperature device and a MoKα source (wavelength = 0.71073 Å).
Crystallographic data for 15a: C₁₇H₂₅NO₄·(C₂H₅OH), colorless needles crystallized from EtOH at 4 °C, monoclinic, space group P2 (1)/c, a = 9.7981 (9) Å, α = 90°, b = 22.641 (2) Å, β = 112.690 (2)°, c = 9.7517 Å, γ = 90°, U = 1995.8 (3) ų, Z = 4, D _c = 1.176 mg/m³, µ = 0.084 mm^-1, R = 0.0397, wR2 = 0.0867, GOF = 1.011, T = 113 (2) K, F(000) = 768, 4948 independent reflections were collected on a Bruker SMART CCD-based X-ray diffractometer with an LT-2 low temperature device and a MoKα source (wavelength = 0.71073 Å).