Download PDF
Synlett 2008(15): 2244-2248  
DOI: 10.1055/s-2008-1078173
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Functionalized Pyroglutamic Acids, Part 1: The Synthetic Utility of N-Acylindole and the Ugi Reaction with a Chiral Levulinic Acid

Matthew J. Buller, Cynthia B. Gilley, Brian Nguyen, Lisa Olshansky, Breena Fraga, 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;
Further Information

Publication History

Received 2 May 2008
Publication Date:
28 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A variety of pyroglutamic acid derivatives are readily synthesized via N-acylindole intermediates obtained by the Ugi reaction. For the preparation of functionalized pyroglutamic acid derivatives, the diastereoselectivity of the Ugi 4-center 3-component condensation reaction with a chiral γ-keto acid and convertible isocyanide is described.

Key words

pyroglutamic acid - Ugi reaction - convertible isocyanide - diastereoselectivity - β-lactone

    References and Notes

  • 1a Short KM. Mjalli AMM. Tetrahedron Lett.  1997,  38:  359 
    Google Scholar
  • 1b Harriman GCB. Tetrahedron Lett.  1997,  38:  5591 
    Google Scholar
  • 1c Hanusch-Kompa C. Ugi I. Tetrahedron Lett.  1998,  39:  2725 
    Google Scholar
  • 1d Tye H. Whittaker M. Org. Biomol. Chem.  2004,  2:  813 
    Google Scholar
  • For recent reviews on multicomponent condensation reactions, see:
  • 1e Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
    Google Scholar
  • 1f Dömling A. Chem. Rev.  2006,  106:  17 
    Google Scholar
  • 2a Passerini M. Simone L. Gazz. Chim. Ital.  1921,  51:  126 
    Google Scholar
  • 2b Passerini M. Gazz. Chim. Ital.  1923,  53:  331 
    Google Scholar
  • For convertible isocyanides, see:
  • 3a Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 ; see page numbers 3183 and 3184 and references therein
    Google Scholar
  • 3b Keating TA. Armstrong RW. J. Am. Chem. Soc.  1996,  118:  2574 
    Google Scholar
  • 3c Rikimaru K. Yanagisawa A. Kan T. Fukuyama T. Synlett  2004,  41 
    Google Scholar
  • 3d Rikimaru K. Mori K. Kan T. Fukuyama T. Chem. Commun.  2005,  394 
    Google Scholar
  • 3e Pirrung MC. Ghorai S. J. Am. Chem. Soc.  2006,  128:  11772 
    Google Scholar
  • 4a Gilley CB. Buller MJ. Kobayashi Y. Org. Lett.  2007,  9:  3631 
    Google Scholar
  • 4b Vamos M. Ozboya K. Kobayashi Y. Synlett  2007,  1595 
    Google Scholar
  • 4c Kreye O. Westermann B. Wessjohann LA. Synlett  2007,  3188 
    Google Scholar
  • Ammonium acetate or HMDS could be used to prepare unprotected γ-lactams:
  • 5a Isaacson J. Loo M. Kobayashi Y. Org. Lett.  2008,  10:  1461 
    Google Scholar
  • 5b Isaacson J. Gilley CB. Kobayshi Y. J. Org. Chem.  2007,  72:  3913 
    Google Scholar
  • 6 Arai E. Tokuyama H. Linsell MS. Fukuyama T. Tetrahedron Lett.  1998,  39:  71 
    CrossrefGoogle Scholar
  • 7 Faggi C. Marcaccini S. Pepino R. Pozo MC. Synthesis  2002,  2756 
    Article in Thieme ConnectGoogle Scholar
  • 8 Lueoend RM. Walker J. Neier RW. J. Org. Chem.  1992,  57:  5005 
    CrossrefGoogle Scholar
  • 9 For a recent application of the Amadori rearrangement in natural product synthesis, see: Guzi TJ. Macdonald TL. Tetrahedron Lett.  1996,  37:  2939 
    CrossrefGoogle Scholar
  • 14 See the following paper: Gilley CB. Buller MJ. Kobayashi Y. Synlett  2008,  2249 
    Article in Thieme ConnectGoogle Scholar
10

Solvent effects in the stereoselective Ugi 4C-3C reaction of 4-oxopentanoic acid(10), PMBNH2, and isocyanide 1 was examined in H2O, MeOH, i-PrOH, CH2Cl2, MeCN, THF, EtOAc and dioxane. No Ugi product 11 was observed by the reaction in those solvents; instead, N-(4-methoxybenzyl)-acetamide was isolated as a product (28-52%). The reaction in hexafluoroisopropanol, (CF3)2CHOH, furnished the desired Ugi products 11a and 11b in 70% yield as 1.2:1 diastereomixture.

11

The formation of the N,O-acetal 13 was enhanced and the stability was increased by the γ-lactam. For example, the linear anilide was converted into N-acylindole without formation of N,O-acetal as shown in Scheme  [7] .

Scheme 7

12

The formation of 3-mer, 4-mer and 5-mer of the anti isomer shown in Figure  [¹] were detected by mass spectrometry.

Figure 1

13

¹H NMR data of the selected compounds are shown below. Compound 5b: ¹H NMR (300 MHz, CDCl3): δ = 7.21-7.38 (m, 5 H), 7.17 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 2 H), 4.97 (d, J = 12.3 Hz, 1 H), 4.73 (d, J = 12.3 Hz, 1 H), 4.46 (d, J = 15.3 Hz, 1 H), 4.31 (d, J = 15.6 Hz, 1 H), 3.75 (s, 3 H), 2.36-2.61 (m, 2 H), 2.23-2.31 (m, 1 H), 1.80-1.91 (m, 1 H), 1.43 (s, 3 H). Compound 5c: ¹H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 4.96 (d, J = 15.3 Hz, 1 H), 3.86 (d, J = 15.6 Hz, 1 H), 3.77 (s, 3 H), 2.85 (t, J = 6.6 Hz, 2 H), 2.41-2.65 (m, 2 H), 2.21-2.29 (m, 1 H), 1.83-1.94 (m, 1 H), 1.53 (p, J = 7.8 Hz, 2 H), 1.39 (p, J = 7.2 Hz, 2 H), 1.36 (s, 3 H), 0.92 (t, J = 7.5 Hz, 3 H). Compound 5d: ¹H NMR (300 MHz, CDCl3): δ = 7.18 (d, J = 8.7 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 6.74-6.86 (m, 4 H), 6.05 (br s, 1 H), 4.36 (q, J = 13.8 Hz, 2 H), 4.26 (dd, J = 6.3, 14.4 Hz 1 H), 3.91 (dd, J = 5.1, 14.4 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 2.26-2.45 (m, 3 H), 1.84-2.04 (m, 1 H), 1.44 (s, 3 H). Compound 5e: ¹H NMR (300 MHz, CDCl3): δ = 9.04 (s, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 2 H), 4.60 (d, J = 15.0 Hz, 1 H), 4.13 (d, J = 14.7 Hz, 1 H), 3.74 (s, 3 H), 2.47 (t, J = 7.5 Hz, 2 H), 2.07-2.16 (m, 1 H), 1.77 (td, J = 8.7, 13.8 Hz, 1 H), 1.31 (s, 3 H). Compound 8: ¹H NMR (400 MHz, CDCl3): δ = 7.38-7.21 (m, 10 H), 6.59 (s, 1 H), 5.18 (s, 2 H), 4.64 (t, J = 6.4 Hz, 1 H), 2.94 (br s, 1 H), 2.73 (d, J = 2.0 Hz, 1 H), 2.71 (s, 1 H), 1.88 (s, 3 H). Compound 9: ¹H NMR (400 MHz, CDCl3): δ = 7.31-7.39 (m, 5 H), 5.17 (d, J = 12.4 Hz, 1 H), 5.13 (d, J = 12.4 Hz, 1 H), 4.39 (q, J = 4.8, 10.8 Hz, 1 H), 3.77 (d, J = 5.2 Hz, 1 H), 2.93 (dd, J = 4.4, 16.8 Hz, 1 H), 2.79 (dd, J = 6.0, 16.4 Hz, 1 H), 2.26 (s, 3 H). Compound 10: ¹H NMR (400 MHz, CDCl3): δ = 5.61 (br s, 1 H), 4.39 (dd, J = 4.0, 6.4 Hz, 1 H), 2.93 (dd, J = 4.4, 16.8 Hz, 1 H), 2.79 (dd, J = 6.4, 16.8 Hz, 1 H), 2.27 (s, 3 H). Compound 11a: ¹H NMR (400 MHz, CDCl3): δ = 8.96 (br s, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.10-7.24 (m, 5 H), 6.78 (d, J = 8.4 Hz, 2 H), 4.94 (d, J = 15.2 Hz, 1 H), 4.41-4.46 (m, 2 H), 4.10-4.18 (m, 1 H), 3.74 (s, 3 H), 3.38 (s, 3 H), 3.36 (s, 3 H), 2.74-2.94 (m, 3 H), 2.45 (dd, J = 2.8, 17.2 Hz, 1 H), 1.37 (s, 3 H). Compound 18: ¹H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 4.78 (t, J = 4.0 Hz, 1 H), 4.72 (d, J = 14.8 Hz, 1 H), 4.38 (d, J = 15.2 Hz, 1 H), 3.78 (s, 3 H), 2.88 (d, J = 3.6 Hz, 2 H), 1.50 (s, 3 H).