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Synlett 2007(10): 1595-1599  
DOI: 10.1055/s-2007-982538
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Bicyclic Pyroglutamic Acid Featuring the Ugi Reaction and a Unique Stereoisomerization at the Angular Position by Grob Fragmentation Followed by a Transannular Ketene [2+2] Cycloaddition Reaction

Mitchell Vamos, Kerem Ozboya, Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343, La Jolla, CA 92093-0343, USA
e-Mail: ykoba@chem.ucsd.edu;
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Publication History

Received 24 January 2007
Publication Date:
06 June 2007 (online)

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Abstract

A stereoisomerization at the angular position of N-acylindoles during basic hydrolysis was discovered to give only the syn-bicyclic pyroglutamic acid, proceeding through a transannular [2+2] cycloaddition of a ketene-ketone intermediate generated by a Grob fragmentation.

Key words

isonitrile - Ugi reaction - pyroglutamic acid - diastereoselectivity - lactams

    References and Notes

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  • The application of indole-isonitrile 1 to natural product synthesis was demonstrated by our laboratory:
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  • 8 An Ugi 4C-3CR reaction with a chiral amine and a γ-ketoacid has been reported to give a 5:1 diastereomeric ratio: Marcaccini S. Pepino R. Torroba T. Miguel D. Garcia-Valverde M. Tetrahedron Lett.  2002,  43:  8591 
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  • 14 γ-Ketoacid 7 has been made from a different ketone starting material and is known to exist in the hemi-ketal form 7a (Figure 4): Mondon A. Menz H. Zander J. Chem. Ber.  1963,  96:  826 
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15

Although 7 is known to exist as the hemi-ketal 7a, presumably under equilibrium in the Ugi reaction conditions, that did not prevent it from reacting in the Ugi 4C-3CR.

17

8a: 1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.19, (d, J = 5.7 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.96 (d, J = 15.6 Hz, 1 H), 4.47 (t, J = 5.2 Hz, 1 H), 3.75 (s, 1 H), 3.63 (d, J = 16.0 Hz, 1 H), 3.42 (s, 3 H), 3.39 (s, 3 H), 2.92 (dd, J = 5.6, 14.0 Hz, 1 H), 2.83 (dd, J = 5.6, 14.0 Hz, 1 H), 2.32 (d, J = 16.0 Hz, 1 H), 2.19 (td, J = 4.0, 12.8 Hz, 1 H), 1.81 (m, 5 H), 1.58 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ = 175.7, 169.0, 158.7, 136.0, 131.1, 130.0, 128.6, 128.3, 127.5, 125.5, 124.7, 113.9, 107.1, 77.1, 73.7, 55.4, 54.6, 54.5, 45.5, 43.1, 37.2, 29.3, 25.6, 21.8, 19.9; HRMS: m/z calcd for C27H34N2O6: 482.2411; found: 482.2405.

18

Crystal data for 8a: C27H34N2O6, Mr = 482.56, triclinic, space group P1, a = 9.899 (3) Å, b = 12.169 (4) Å, c = 13.444 (4) Å, α = 79.540 (4)°, β = 80.366 (4)°, γ = 69.755 (4)°, V = 1484.6 (7) Å3, Z = 2, ρ calc = 1.080 Mg/m3, F(000) = 516, λ = 0.71073 Å, T = 200 (2) K, µ(MoKa) = 0.076 mm-1. Of the 16570 measured reflections, 11473 were independent [R(int) = 0.0283]. The final refinement converged at R1 = 0.0629 for I > 2σ(I), wR2 = 0.1654 for all data. The data for 8a, 9a and 10 were collected on a Bruker diffractometer with an APEX CCD detector, the structure was solved by direct methods (SHELXL-97) and refined with all data by full matrix least squares on F2. CCDC 634645 contains the supplementary crystallographic data of 8a. The data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:+44 (1223)336033 or deposit@ccdc.cam.ac.uk.

19

9a: 1H NMR (500 MHz, CDCl3): δ = 8.34 (d, J = 8.5 Hz, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.59 (d, J = 4.0 Hz, 1 H), 7.35 (t, 8.0 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 6.56 (d, J = 4.0 Hz, 1 H), 5.02 (d, J = 16.0 Hz, 1 H), 4.21 (d, J = 16.5 Hz, 1 H), 3.76 (s, 3 H), 3.62 (d, J = 16.0 Hz, 1 H), 2.59 (td, J = 5.5, 13.5 Hz, 1 H), 2.50 (br s, 1 H, OH), 2.40 (d, J = 16.0 Hz, 1 H), 2.31 (td, J = 3.5, 14.0 Hz, 1 H), 2.20 (m, 1 H), 1.82 (m, 3 H), 1.64 (m, 1 H), 1.54 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ = 176.8, 170.8, 159.1, 137.2, 129.6, 129.1, 128.8, 125.4, 124.7, 124.2, 121.0, 117.2, 114.2, 109.1, 79.0, 76.3, 55.4, 45.2, 44.6, 29.8, 26.4, 21.7, 19.8; HRMS: m/z calcd for C25H26N2O4: 418.1887; found: 418.1883.

20

9c: 1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.5 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.08 (d, J = 7.0 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.57 (d, J = 9.0 Hz, 2 H), 5.60 (t, J = 7.0 Hz, 1 H), 4.59 (d, J = 14.5 Hz, 1 H), 4.17 (d, J = 14.5 Hz, 1 H), 3.53 (s, 3 H), 3.15 (dd, J = 8.0, 16.5 Hz, 1 H), 2.95 (dd, J = 5.5, 16.0 Hz, 1 H), 2.82 (d, J = 17.5 Hz, 1 H), 2.65 (d, J = 17.5 Hz, 1 H), 2.00 (dd, J = 4.0, 14.0 Hz, 1 H), 1.65 (m, 1 H), 1.58 (m, 2 H), 1.29 (m, 2 H), 1.11 (m, 1 H); HRMS: m/z calcd for C25H26N2O4: 418.1887; found: 418.1893.

21

9d: 1H NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.12 (behind peak), 7.03 (t, J = 7.5 Hz, 1 H), 6.44 (d, J = 9.0 Hz, 2 H), 5.85 (t, J = 7.5 Hz, 1 H), 4.70 (d, J = 15.5 Hz, 1 H), 4.30 (d, J = 15.0 Hz, 1 H), 3.54 (s, 3 H), 3.10 (dd, J = 7.0, 15.0 Hz, 1 H), 2.93 (dd, J = 9.0, 15.0 Hz, 1 H), 2.93 (behind peak), 2.79 (d, J = 16.5 Hz, 1 H), 2.47 (d, J = 16.5 Hz, 1 H), 2.04 (td, J = 4.5, 14.0 Hz, 1 H), 1.84 (m, 2 H), 1.47 (m, 2 H), 1.29 (td, J = 3.0, 12.5 Hz, 1 H), 1.10 (m, 1 H); HRMS: m/z calcd for C25H26N2O4: 418.1887; found: 418.1889.

22

10: 1H NMR (500 MHz, CDCl3): δ = 7.23 (d, J = 8.5 Hz, 2 H), 6.80 (d, J = 8.0 Hz, 2 H), 4.66 (d, J = 15.5 Hz, 1 H), 4.24 (d, J = 15.5 Hz, 1 H), 3.78 (s, 3 H), 3.20 (br s, 1 H, OH), 2.77 (d, J = 16.0 Hz, 1 H), 2.46 (d, J = 16.5 Hz, 1 H), 2.14 (m, 2 H), 1.81 (tt, J = 4.5, 19.0 Hz, 2 H), 1.67 (td, J = 4.0, 14.5 Hz, 1 H), 1.53 (m, 1 H), 1.41 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ = 175.9, 175.6, 159.0, 130.2, 129.4, 114.0, 74.3, 72.3, 55.4, 44.5, 44.4, 36.0, 27.9, 20.5, 20.3; HRMS: m/z calcd for C17H21NO5: 319.1414; found: 319.1417.

25

Crystal data for 9a: C25H26N2O4, Mr = 418.48, monoclinic, space group P2(1)/c, a = 17.172 (6) Å, b = 27.378 (11) Å, c = 13.501 (5) Å, α = 90°, β = 100.125 (5)°, γ = 90°, V = 6248 (4) Å3, Z = 12, ρ calc = 1.335 Mg/m3, F(000) = 2664, λ = 0.71073 Å, T = 100 (2) K, µ(MoKa) = 0.091 mm-1. Of the 50332 measured reflections, 13977 were independent [R(int) = 0.0772]. The final refinement converged at R1 = 0.2393 for I > 2σ(I), wR2 = 0.5894 for all data. CCDC 634643 contains the supplementary crystallographic data of 9a.

26

Crystal data for 10: C17H21NO5, Mr = 319.35, orthorhombic, space group Pccn, a = 31.323 (2) Å, b = 9.3197 (6) Å, c = 10.4743 (6) Å, α = 90°, β = 90°, γ = 90°, V = 3057.6 (3) Å3, Z = 8, ρ calc = 1.387 Mg/m3, F(000) = 1360, λ = 1.54178 Å, T = 100 (2) K, µ(MoKa) = 0.846 mm-1. Of the 12336 measured reflections, 2763 were independent [R(int) = 0.0266]. The final refinement converged at R1 = 0.0472 for I > 2σ(I), wR2 = 0.1227 for all data. CCDC 634647 contains the supplementary crystallographic data of 10.

27

A single diastereomer of the N,O-acetal 12a (Figure [5] ), the relative stereochemistry of which was not determined, was formed.