Gram-Scale Synthesis of 3,5-Methanonipecotic Acid, a Nonchiral Bicyclic β-Amino Acid

Abstract

A scalable synthesis was developed of 3,5-methanoni­pecotic acid (3-azabicyclo[3.1.1]heptane-1-carboxylic acid), a rare example of a conformationally constrained nonchiral β-amino acid, potentially useful in peptide engineering and peptidomimetic drug design. A retrosynthetic strategy based on disconnections exclusively within the symmetry planes of the target and the intermediate molecules was found to be useful and might deliver expedite syntheses in other similar cases.

Key words

amino acids - bicyclic compounds - heterocycles - conformation

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• 24 Diisopropyl 3-(2-Methoxy-2-oxoethylidene)cyclobutane-1,1-dicarboxylate (15) Colorless oil; R_f = 0.49 (hexanes–EtOAc, 5:1). IR (neat): 1718, 1626, 1625, 1101, 1082 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.69 (t, J = 2.0 Hz, 1 H), 5.05 (sept, J = 6.2 Hz, 2 H), 3.67 (s, 3 H), 3.58 (d, J = 2.0 Hz, 2 H), 3.30 (s, 2 H), 1.22 (d, J = 6.2 Hz, 12 H). ¹³C NMR (125 MHz, CDCl₃): δ = 170.3 (C), 166.3 (C), 157.7 (C), 114.7 (CH), 69.4 (CH), 51.2 (CH₃), 49.9 (C), 41.2 (CH₂), 39.1 (CH₂), 21.6 (CH₃). MS (CI): m/z = 299 [M + H]⁺. Anal. Calcd for C₁₅H₂₂O₆: C, 60.39; H, 7.43. Found: C, 60.18; H, 7.64.
• 25 Diisopropyl 3-(2-Methoxy-2-oxoethyl)cyclobutane-1,1-dicarboxylate (16) Colorless oil; R_f = 0.46 (hexanes–EtOAc, 5:1). IR (neat): 1720, 1265, 1164, 1097 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.03 (sept, J = 6.2 Hz, 1 H), 4.99 (sept, J = 6.2 Hz, 1 H), 3.61 (s, 3 H), 2.63–2.73 (m, 3 H), 2.42 (d, J = 6.7 Hz, 2 H), 2.18–2.24 (m, 2 H), 1.20 (d, J = 6.2 Hz, 6 H), 1.18 (d, J = 6.2 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 172.4 (C), 171.24 (C), 171.18 (C), 68.9 (CH), 68.8 (CH), 51.4 (CH₃), 49.8 (C), 40.4 (CH₂), 34.3 (CH₂), 25.9 (CH), 21.6 (CH₃). MS (CI): m/z = 301 [M + H]⁺. Anal. Calcd for C₁₅H₂₄O₆: C, 59.98; H, 8.05. Found: C, 59.67: H, 7.89.
• 26 [3,3-Bis(isopropoxycarbonyl)cyclobutyl]acetic Acid (20) Colorless solid; mp 80–82 °C; R_f = 0.65 (hexanes–EtOAc, 1:2). IR (KBr): 2987, 1724, 1705 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.38 (very br s, 1 H), 5.06 (sept, J = 6.1 Hz, 1 H), 5.02 (sept, J = 6.1 Hz, 1 H), 2.67–2.77 (m, 3 H), 2.48 (d, J = 6.5 Hz, 2 H), 2.22–2.27 (m, 2 H), 1.22 (d, J = 6.1 Hz, 6 H), 1.21 (d, J = 6.1 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 178.0, 171.28, 171.25, 69.00, 68.96, 49.9, 40.3, 34.3, 25.6, 21.6. MS (CI): m/z = 287 [M + H]⁺. Anal. Calcd for C₁₄H₂₂O₆: C, 58.73; H 7.74. Found: C, 58.95; H, 7.98.
• 27 Diisopropyl 3-{[(tert-Butoxycarbonyl)amino]methyl}-cyclobutane-1,1-dicarboxylate (19) Colorless oil. R_f = 0.26 (hexanes–EtOAc, 5:1). IR (neat): 3365, 1712, 1525 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.04 (sept, J = 6.1 Hz, 1 H), 5.01 (sept, J = 6.1 Hz, 1 H), 4.61 (br s, 1 H), 3.18 (d, J = 5.9 Hz, 0.5 H), 3.12 (br s, 1.5 H), 2.45–2.58 (m, 3 H), 2.18–2.23 (m, 2 H), 1.41 (s, 9 H), 1.21 (d, J = 6.1 Hz, 6 H), 1.20 (d, J = 6.1 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 171.4, 171.1, 156.1, 79.3, 68.93, 68.86, 49.5, 45.2, 32.0, 29.4, 28.5, 21.6. MS (ESI): m/z = 358 [M + H]⁺. Anal. Calcd for C₁₈H₃₁NO₆: C, 60.48; H, 8.74; N, 3.92. Found: C, 60.70; H, 8.46; N, 4.12.
• 28 Methyl 2-Oxo-3-azabicyclo[3.1.1]heptane-1-carboxylate (21) White crystals; mp 115–116 °C. IR (KBr): 3220 [ν(N–H)], 1741 [ν(C=O)], 1676 cm^–1 [ν(C=O)]. ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.61 (br s, 1 H), 3.60 (s, 3 H), 3.29 (s, 2 H), 2.53–2.57 (m, 1 H), 2.35–2.42 (m, 2 H), 1.79–1.85 (m, 2 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 172.6 (C), 170.9 (C), 51.5 (C), 51.4 (CH₃), 44.8 (CH₂), 32.7 (CH₂), 27.6 (CH). MS (CI): m/z = 170 [M + H]⁺. Anal. Calcd for C₈H₁₁NO₃: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.53; H, 6.58; N, 8.52.
• 29 tert-Butyl 1-(Hydroxymethyl)-3-azabicyclo[3.1.1]-heptane-3-carboxylate (22) White crystals; mp 97–98 °C. IR (KBr): 3449, 3448, 1666, 1408, 1176 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.50 (br s, 2 H), 3.47 (s, 2 H), 3.42 (s, 2 H), 2.45 (br s, 0.5 H), 2.38 (br s, 0.5 H), 1.90 (br s, 2 H), 1.80 (br s, 1 H), 1.47 (s, 9 H), 1.34 (br s, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 156.5 (C), 79.4 (C), 67.8 and 67.4 (CH₂), 52.2 and 51.8 (CH₂), 50.2 and 49.8 (CH₂), 42.7 (C), 32.6 and 32.4 (CH₂), 28.71 (CH₃), 28.67 (CH). MS (CI): m/z = 228 [M + H]⁺. Anal. Calcd for C₁₂H₂₁NO₃: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.08; H, 9.14; N, 6.48.
• 30 3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-1-carboxylic Acid (24) White crystals; mp 172–174 °C. ¹H NMR (500 MHz, CDCl₃): δ = 9.38 (br s, 1 H), 3.65 (s, 0.8 H), 3.62 (s, 1.2 H), 3.47 (s, 1.2 H), 3.44 (s, 0.8 H), 2.32–2.41 (m, 3 H), 1.53–1.55 (m, 2 H), 1.42 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 178.5 and 178.1 (C), 156.32 and 156.30 (C), 80.1 and 80.0 (C), 49.9 and 49.6 (CH₂), 49.3 and 48.8 (CH₂), 44.1 (C), 34.33 and 34.28 (CH₂), 28.7 (CH₃), 28.6 (CH). MS (ESI): m/z = 242 [M + H]⁺. Anal. Calcd for C₁₂H₁₉NO₄: C, 59.73; H, 7.94; N, 5.80. Found: C, 59.48; H, 8.27; N, 5.53.
• 31 3-Azabicyclo[3.1.1]heptane-1-carboxylic Acid Hydrochloride (9·HCl) White crystals; mp >250 °C (dec.). IR (KBr): 3423, 2987 (br), 1724, 1592, 1398 cm^–1. ¹H NMR (500 MHz, D₂O): δ = 3.69 (s, 2 H), 3.53 (s, 2 H), 2.60–2.68 (m, 2 H), 2.57–2.61 (m, 1 H), 1.82–1.87 (m, 2 H). ¹³C NMR (125 MHz, D₂O): δ = 175.7 (C), 47.2 (CH₂), 46.7 (CH₂), 43.9 (C), 33.3 (CH₂), 28.1 (CH). Anal. Calcd for C₈H₁₂ClNO₄: C, 43.35; H, 5.46; Cl, 16.00; N, 6.32. Found: C, 43.62; H, 5.09; Cl, 16.25; N, 6.39.