A Simple Biomimetic Route to Nonsymmetric Pyrazines

Abstract

The condensation of enaminoketone 8 to α-hydroxyketones gives rise to nonsymmetric pyrazines. This may be of relevance for the biosynthesis of this heterocycle in the cephalostatins and ritterazines.

Key words

hydroxyketones - pyrazine synthesis - cephalostatins - biosynthesis - pyrylium salts

References

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25

The low yield observed may well be due to methanolysis of the O-acetate under the reaction conditions.

26

It is mentioned in passing that the well-known oxidative degradation of the furan ring [28] to a carboxylic acid could lead to pyrazine bis-carboxylic acids and derivatives thereof.

27

Reaction Procedure to Form Nonsymmetric Pyrazine 29: Enaminoketone 13 ⁹ (80 mg, 0.18 mmol) and NH₄OAc (35 mg, 0.45 mmol) were dissolved in moist MeOH (5 mL, <0.1% H₂O) and refluxed for 30 min. A solution of α-hydroxyketone 28 (80 mg, 0.18 mmol) in CH₂Cl₂ (0.6 mL) was added and the resulting suspension was refluxed for additional 90 min. The mixture was quenched with H₂O, extracted with CH₂Cl₂, and the organic layer was washed with brine and dried over MgSO₄. After removal of the solvent, the residue was purified by column chromatography on silica gel to give 29 (43 mg, 28%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 5.48 (s br, 1 H), 4.78 (dd, J = 7.9 Hz, 2.0 Hz, 1 H), 4.40-4.34 (m, 1 H), 3.56-3.47 (m br, 2 H), 3.44-3.33 (m, 2 H), 1.33 (s, 3 H), 1.09 (s, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 0.92 (s, 3 H), 0.89 (s, 3 H), 0.81 (d, J = 6.1 Hz, 3 H), 0.79 (d, J = 6.1 Hz, 3 H). ¹³C NMR (100 MHz, DEPT, CDCl₃): δ = 212.88 (s), 210.61 (s), 154.27 (s), 148.52 (s), 148.33 (s), 148.27 (s), 148.09 (s), 121.54 (d), 109.28 (s), 107.04 (s), 83.92 (d), 79.13 (d), 67.10 (t), 66.89 (t), 62.27 (s), 55.65 (d), 55.01 (s), 54.79 (d), 53.53 (d), 53.08 (d), 49.73 (d), 45.25 (t), 45.11 (t), 44.19 (d), 42.22 (d), 41.59 (d), 41.23 (d), 37.62 (t), 37.18 (t), 36.34 (s), 36.12 (s), 35.28 (t), 35.22 (t), 34.18 (d), 33.92 (d), 31.42 (t), 31.24 (t), 31.17 (2 t), 30.30 (d), 30.18 (d), 29.69 (t), 29.12 (t), 28.78 (t), 28.08 (t), 27.86 (t), 20.73 (q), 17.15 (q), 17.13 (q), 15.92 (q), 13.76 (q), 13.22 (q), 11.69 (q), 11.47 (q). MS-FAB (NBA matrix): m/z (%) = 846 (100)[M⁺], 828 (19), 732 (20), 154 (33) [NBA matrix].