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

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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

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Referenzen

References and Notes

1 See the preceding paper: Buller MJ. Gilley CB. Nguyen B. Olshansky L. Fraga B. Kobayashi Y. Synlett 2008, 2244

For γ-lactam synthesis, see:

2a Short KM. Mjalli AMM. Tetrahedron Lett. 1997, 38: 359

2b Harriman GCB. Tetrahedron Lett. 1997, 38: 5591

2c Hanusch-Kompa C. Ugi I. Tetrahedron Lett. 1998, 39: 2725

2d Tye H. Whittaker M. Org. Biomol. Chem. 2004, 2: 813

2e For γ-lactone synthesis, see: Passerini M. Gazz. Chim. Ital. 1923, 53: 331

For recent reviews on multicomponent condensation reactions, see:

2f Ramon DJ. Yus M. Angew. Chem. Int. Ed. 2005, 44: 1602

2g Dömling A. Chem. Rev. 2006, 106: 17

3

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

4 For a recent example in the literature, see: Mahajan VA. Borate HB. Wakharkar RD. Tetrahedron 2006, 62: 1258

5a For compound 1, see: Lueoend RM. Walker J. Neier RW. J. Org. Chem. 1992, 57: 5005

5b For an ester of compound 4, see: Kende AS. Kawamura K. Orwat MJ. Tetrahedron Lett. 1989, 30: 5821

6 Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc. 2002, 124: 392

7 Abiko A. Liu J.-F. Masamune S. J. Org. Chem. 1996, 61: 2590

8

The anti isomer was also isolated in 18% yield.

9 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

10a Gilley CB. Buller MJ. Kobayashi Y. Org. Lett. 2007, 9: 3631

10b Isaacson J. Loo M. Kobayashi Y. Org. Lett. 2008, 10: 1461

10c Isaacson J. Gilley CB. Kobayshi Y. J. Org. Chem. 2007, 72: 3913

10d Vamos M. Ozboya K. Kobayashi Y. Synlett 2007, 1595

10e Kreye O. Westermann B. Wessjohann LA. Synlett 2007, 3188

11 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

12

^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).