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DOI: 10.1055/s-2008-1078211
Synthesis of Functionalized Pyroglutamic Acids, Part 2: The Stereoselective Condensation of Multifunctional Groups with Chiral Levulinic Acids
Publikationsverlauf
Publikationsdatum:
28. August 2008 (online)
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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References and Notes
Database search on the reported synthesis of levulinic acid derivatives by MDL CrossFire Commander was conducted on April 25, 2008.
8The anti isomer was also isolated in 18% yield.
12¹H 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).