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

doi:10.1055/s-2007-982538

LETTER

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;

Abstract

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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

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References

References and Notes

For reviews, see:

<A NAME="RS00407ST-1A">1a</A> Dömling A. Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168

<A NAME="RS00407ST-1B">1b</A> Ugi I. Angew. Chem., Int. Ed. Engl. 1962, 1: 8

<A NAME="RS00407ST-2">2</A> Feling RH. Buchanan GO. Mincer TJ. Kauffman CA. Jensen PR. Fenical W. Angew. Chem. Int. Ed. 2003, 42: 355

<A NAME="RS00407ST-3">3</A> Omura S. Fujimoto T. Otoguro K. Matsuzaki K. Moriguchi R. Tanaka H. Sasaki Y. J. Antibiot. 1991, 44: 113

<A NAME="RS00407ST-4">4</A> Mori T. Takahashi K. Kashiwabara M. Uemara D. Tetrahedron Lett. 1985, 26: 1073

For convertible isonitriles, see:

<A NAME="RS00407ST-5A">5a</A> Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168 ; and references therein

<A NAME="RS00407ST-5B">5b</A> Rikimaru K. Yanagisawa A. Kan T. Fukuyama T. Synlett 2004, 41

<A NAME="RS00407ST-5C">5c</A> Rikimaru K. Mori K. Kan T. Fukuyama T. Chem. Commun. 2005, 394

<A NAME="RS00407ST-5D">5d</A> Pirrung MC. Ghorai S. J. Am. Chem. Soc. 2006, 128: 11772

The application of indole-isonitrile 1 to natural product synthesis was demonstrated by our laboratory:

<A NAME="RS00407ST-6A">6a</A> Gilley CB. Buller MJ. Kobayashi Y. Angew. Chem. Int. Ed. 2007, in revision

<A NAME="RS00407ST-6B">6b</A> Isaacson J. Gilley CB. Kobayashi Y. J. Org. Chem. 2007, 72: 3913

<A NAME="RS00407ST-7A">7a</A> Short KM. Ching BW. Mjalli AMM. Tetrahedron 1997, 53: 6653

<A NAME="RS00407ST-7B">7b</A> Short KM. Mjalli AMM. Tetrahedron Lett. 1997, 38: 359

<A NAME="RS00407ST-7C">7c</A> Hanusch-Kompa C. Ugi I. Tetrahedron Lett. 1998, 39: 2725

<A NAME="RS00407ST-8">8</A> 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

<A NAME="RS00407ST-9">9</A> Fürstner A. In Organozinc Reagents: A Practical Approach Knochel P. Jones P. Oxford University Press; New York: 1999. p.287

<A NAME="RS00407ST-10">10</A> For a discussion of ring size and endo/exo selectivity, see: Screttas CG. Smonou IC. J. Org. Chem. 1998, 53: 893

<A NAME="RS00407ST-11A">11a</A> Carey FA. Sundberg RJ. In Advanced Organic Chemistry 4th ed.: Plenum; New York: 2000. p.172

<A NAME="RS00407ST-11B">11b</A> Johnson F. Chem. Rev. 1968, 68: 375

<A NAME="RS00407ST-12">12</A> More JD. Finney NS. Org. Lett. 2002, 4: 3001

<A NAME="RS00407ST-13">13</A> The synthesis of the γ-ketoester as the ethyl ester in high enantiopurity has been reported: García Ruano JL. Barros D. Maestro MC. Alcudia A. Fernández I. Tetrahedron: Asymmetry 1998, 9: 3445

<A NAME="RS00407ST-14">14</A> 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

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.

<A NAME="RS00407ST-16">16</A> The solvent alcohol is purported to open the imidate intermediate in the Ugi 4C-3CR with γ-ketoacids: Harriman GCB. Tetrahedron Lett. 1997, 38: 5591

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.

Crystal data for 8a: C₂₇H₃₄N₂O₆, M_r = 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.

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.

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.

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.

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.

<A NAME="RS00407ST-23">23</A> Grob CA. Angew. Chem., Int. Ed. Engl. 1969, 8: 535

<A NAME="RS00407ST-24">24</A> Corey EJ. Reddy LR. Org. Lett. 2006, 8: 1717

Crystal data for 9a: C₂₅H₂₆N₂O₄, M_r = 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.

Crystal data for 10: C₁₇H₂₁NO₅, M_r = 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.

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