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Synlett 2014; 25(3): 355-358
DOI: 10.1055/s-0033-1340322
letter
© Georg Thieme Verlag Stuttgart · New York

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

Andriy V. Tymtsunik
a   Taras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine   Fax: +380(44)5732643   Email: gregor@univ.kiev.ua
b   Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
,
Vitaliy A. Bilenko
b   Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
,
Oleksandr O. Grygorenko*
a   Taras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine   Fax: +380(44)5732643   Email: gregor@univ.kiev.ua
,
Igor V. Komarov
a   Taras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine   Fax: +380(44)5732643   Email: gregor@univ.kiev.ua
b   Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
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Publication History

Received: 21 September 2013

Accepted after revision: 06 November 2013

Publication Date:
06 December 2013 (online)

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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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    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
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  • References and footnotes

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  • 24 Diisopropyl 3-(2-Methoxy-2-oxoethylidene)cyclobutane-1,1-dicarboxylate (15) Colorless oil; Rf = 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; Rf = 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; Rf = 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. Rf = 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.