Synthesis of Functionalized
Pyroglutamic Acids, Part 2: The Stereoselective Condensation of
Multifunctional Groups with Chiral Levulinic Acids

Cynthia B. Gilley; Matthew J. Buller; Yoshihisa Kobayashi

doi:10.1055/s-2008-1078211

LETTER

Synthesis of Functionalized Pyroglutamic Acids, Part 2: The Stereoselective Condensation of Multifunctional Groups with Chiral Levulinic Acids

Cynthia B. Gilley, Matthew J. Buller, 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

All articles of this category

Abstract

A general procedure to access 3-hydroxy-4-oxopentanoic acid derivatives is described. A key feature is an aldol reaction with an enal as a masked pyruvic aldehyde. Chiral levulinic acid derivatives are provided as precursors for isocyanide-mediated condensation of multifunctional groups, which affords functionalized pyroglutamic acids. The stereoselectivity in the Ugi 4C-3C reaction with the chiral keto acids is examined.

Key words

pyroglutamic acid - Ugi reaction - levulinic acid - aldol reaction - Amadori rearrangement

Full Text

References

References and Notes

<A NAME="RS04308ST-1">1</A> See the preceding paper: Buller MJ. Gilley CB. Nguyen B. Olshansky L. Fraga B. Kobayashi Y. Synlett 2008, 2244

For γ-lactam synthesis, see:

<A NAME="RS04308ST-2A">2a</A> Short KM. Mjalli AMM. Tetrahedron Lett. 1997, 38: 359

<A NAME="RS04308ST-2B">2b</A> Harriman GCB. Tetrahedron Lett. 1997, 38: 5591

<A NAME="RS04308ST-2C">2c</A> Hanusch-Kompa C. Ugi I. Tetrahedron Lett. 1998, 39: 2725

<A NAME="RS04308ST-2D">2d</A> Tye H. Whittaker M. Org. Biomol. Chem. 2004, 2: 813

<A NAME="RS04308ST-2E">2e</A> For γ-lactone synthesis, see: Passerini M. Gazz. Chim. Ital. 1923, 53: 331

For recent reviews on multicomponent condensation reactions, see:

<A NAME="RS04308ST-2F">2f</A> Ramon DJ. Yus M. Angew. Chem. Int. Ed. 2005, 44: 1602

<A NAME="RS04308ST-2G">2g</A> Dömling A. Chem. Rev. 2006, 106: 17

Database search on the reported synthesis of levulinic acid derivatives by MDL CrossFire Commander was conducted on April 25, 2008.

<A NAME="RS04308ST-4">4</A> For a recent example in the literature, see: Mahajan VA. Borate HB. Wakharkar RD. Tetrahedron 2006, 62: 1258

<A NAME="RS04308ST-5A">5a</A> For compound 1, see: Lueoend RM. Walker J. Neier RW. J. Org. Chem. 1992, 57: 5005

<A NAME="RS04308ST-5B">5b</A> For an ester of compound 4, see: Kende AS. Kawamura K. Orwat MJ. Tetrahedron Lett. 1989, 30: 5821

<A NAME="RS04308ST-6">6</A> Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc. 2002, 124: 392

<A NAME="RS04308ST-7">7</A> Abiko A. Liu J.-F. Masamune S. J. Org. Chem. 1996, 61: 2590

The anti isomer was also isolated in 18% yield.

<A NAME="RS04308ST-9">9</A> Enantioselective synthesis of 4 would be achieved by Mulzer’s procedure: Kögl M. Brecker L. Warrass R. Mulzer J. Angew. Chem. Int. Ed. 2007, 46: 9320

<A NAME="RS04308ST-10A">10a</A> Gilley CB. Buller MJ. Kobayashi Y. Org. Lett. 2007, 9: 3631

<A NAME="RS04308ST-10B">10b</A> Isaacson J. Loo M. Kobayashi Y. Org. Lett. 2008, 10: 1461

<A NAME="RS04308ST-10C">10c</A> Isaacson J. Gilley CB. Kobayshi Y. J. Org. Chem. 2007, 72: 3913

<A NAME="RS04308ST-10D">10d</A> Vamos M. Ozboya K. Kobayashi Y. Synlett 2007, 1595

<A NAME="RS04308ST-10E">10e</A> Kreye O. Westermann B. Wessjohann LA. Synlett 2007, 3188

<A NAME="RS04308ST-11">11</A> The stereochemistry of compound 23 was not determined. For a recent application of the Amadori rearrangement in natural product synthesis, see: Guzi TJ. Macdonald TL. Tetrahedron Lett. 1996, 37: 2939

^¹H NMR data of the selected compounds are shown below. Compounds 1 and 19 are reported as compounds 10 and 11a, respectively, in the preceding paper.^¹ Compound 2: ^¹H NMR (400 MHz, CDCl₃): δ = 5.01 (br s, 1 H), 4.10 (br s, 1 H), 3.11 (d, J = 4.8 Hz, 1 H), 2.20 (br s, 4 H), 1.34 (d, J = 6.8 Hz, 3 H). Compound 3: ^¹H NMR (400 MHz, CDCl₃): δ = 7.02 (br s, 1 H), 4.53 (br s, 1 H), 2.95 (br s, 1 H), 2.13 (br s, 4 H), 1.05 (br s, 3 H). Compound 4: ^¹H NMR (400 MHz, CDCl₃): δ = 4.76 (br s, 1 H), 4.05 (s, 1 H), 1.91 (s, 3 H), 1.27 (s, 3 H), 1.22 (s, 3 H). Compound 5: ^¹H NMR (300 MHz, CDCl₃): δ = 5.97 (br s, 1 H), 2.99 (d, J = 12.3 Hz, 1 H), 2.66 (d, J = 12.3 Hz, 1 H), 2.25 (s, 3 H), 1.32 (s, 3 H). Compound 8: ^¹H NMR (400 MHz, CDCl₃): δ = 7.24-7.35 (m, 10 H), 6.56 (s, 1 H), 4.69-4.76 (m, 1 H), 4.16-4.37 (m, 4 H), 3.34 (dd, J = 3.2, 13.6 Hz, 1 H), 2.78 (dd, J = 9.6, 13.6 Hz, 1 H), 1.96 (s, 3 H), 1.18 (d, J = 6.8 Hz, 3 H). Compound 9: ^¹H NMR (400 MHz, CDCl₃): δ = 7.21-7.36 (m, 10 H), 6.52 (s, 1 H), 5.21 (d, J = 12.4 Hz, 1 H), 5.17 (d, J = 12.4 Hz, 1 H), 4.30 (d, J = 8.4 Hz, 1 H), 2.84 (quin, J = 7.6 Hz, 1 H), 1.86 (s, 3 H), 1.16 (d, J = 7.2 Hz, 3 H). Compound 16: ^¹H NMR (300 MHz, CDCl₃): δ = 7.28-7.36 (m, 5 H), 5.13 (s, 2 H), 3.67 (s, 1 H), 3.32 (s, 3 H), 3.24 (s, 3 H), 2.73 (d, J = 14.1 Hz, 1 H), 2.40 (d, J = 14.1 Hz, 1 H), 1.30 (br s, 6 H). Compound 17: ^¹H NMR (300 MHz, CDCl₃): δ = 7.32-7.38 (m, 5 H), 5.14 (d, J = 12.3 Hz, 1 H), 5.09 (d, J = 12.3 Hz, 1 H), 3.05 (d, J = 16.5 Hz, 1 H), 2.69 (d, J = 16.5 Hz, 1 H), 2.29 (s, 3 H), 1.32 (s, 3 H). Compound 20 (major diastereomer, anti): ^¹H NMR (400 MHz, CDCl₃): δ = 8.97 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.13-7.26 (m, 5 H), 6.79-6.83 (m, 2 H), 5.15 (d, J = 15.6 Hz, 1 H), 4.46-4.49 (m, 2 H), 4.03-4.12 (m, 2 H), 3.77 (s, 3 H), 3.42 (s, 3 H), 3.37 (s, 3 H), 2.77-2.85 (m, 3 H), 1.42 (s, 3 H), 1.28-1.36 (m, 3 H). Compound 21 (major diastereomer, anti): ^¹H NMR (300 MHz, CDCl₃): δ = 9.14 (s, 1 H), 7.69-7.73 (m, 2 H), 7.11-7.22 (m, 5 H), 6.77-6.84 (m, 2 H), 5.36 (d, J = 15.3 Hz, 1 H), 4.40-4.45 (m, 1 H), 4.00 (d, J = 15.3 Hz, 1 H), 3.77 (s, 3 H), 3.41 (s, 3 H), 3.36 (s, 3 H), 2.81-3.00 (m, 3 H), 1.46 (s, 3 H), 1.28 (s, 3 H), 1.24 (s, 3 H). Compound 22 (major diastereomer, anti): ^¹H NMR (400 MHz, CDCl₃): δ = 8.94 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.09-7.28 (m, 5 H), 6.79-6.88 (m, 2 H), 4.76 (d, J = 15.2 Hz, 1 H), 4.41-4.45 (m, 1 H), 4.22 (d, J = 15.2 Hz, 1 H), 4.08-4.13 (m, 1 H), 3.74 (s, 3 H), 3.41 (s, 3 H), 3.39 (s, 3 H), 2.74 (m, 3 H), 2.92 (m, 1 H), 1.47 (s, 3 H), 1.41 (s, 3 H). Compound 23: ^¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 8.3 Hz, 2 H), 6.83 (d, J = 8.3 Hz, 2 H), 3.74-3.77 (m, 5 H), 3.60 (q, J = 8.8 Hz, 1 H), 3.11 (br s, 1 H), 2.53 (dd, J = 7.2, 17.6 Hz, 1 H), 2.37 (dd, J = 7.6, 17.6 Hz, 1 H), 1.21 (d, J = 6.8 Hz, 3 H), 1.04 (d, J = 7.2 Hz, 3 H).