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Synlett 2008(15): 2249-2252  
DOI: 10.1055/s-2008-1078211
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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;
Further Information

Publication History

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

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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

    References and Notes

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3

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

8

The anti isomer was also isolated in 18% yield.

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).