Tandem Aza-Michael-Condensation-Aldol Cyclization Reaction: Approach to the Construction of DE Synthon of (±)-Camptothecin

Abstract

An efficient synthesis of the DE ring of camptothecin, employing a Reformatsky and a tandem one-pot, three-step transformation involving aza-Michael reaction, condensation with ethyl malonyl chloride followed by intramolecular ‘aldol’ reaction to furnish the dihydropyridone derivative from commercially available starting materials, has been achieved.

natural products - alkaloids - antitumor - Aldol cyclizations - Reformatsky reaction

References and Notes

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14

All compounds were characterized by IR, ^¹H NMR, ^¹³C NMR, and MS analysis.
Spectral Data
Compound 8: ^¹H NMR (200 MHz, CDCl₃): δ = 0.90 (t, J = 7.4 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.70-1.81 (m, 1 H), 1.92-2.04 (m, 1 H), 3.5 (t, J = 7.4 Hz, 1 H), 4.13 (q, J = 7.1, 2 H), 4.45 (q, J = 7.3 Hz, 2 H), 5.09 (d, J = 14.4 Hz, 1 H), 5.17 (d, J = 14.4 Hz, 1 H), 6.28 (d, J = 7.2 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.29-7.35 (s, 5 H).
Compound 9: ^¹H NMR (200 MHz, CDCl₃): δ = 0.92 (t, J = 7.4 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.35 (t, J = 7.3 Hz, 3 H), 1.51-1.71 (m, 2 H), 1.82-1.96 (m, 1 H), 2.21-2.50 (m, 1 H), 3.22-3.42 (m, 2 H), 3.60-3.73 (m, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.36 (q, J = 7.3 Hz, 2 H), 4.49 (d, J = 14.7 Hz, 1 H), 4.66 (d, J = 14.7 Hz, 1 H), 7.24-7.30 (m, 5 H).
Compound 14: ^¹H NMR (200 MHz, CDCl₃): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.60-1.77 (m,
1 H), 1.92-2.10 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.96 (t, J = 7.3 Hz, 1 H), 5.13 (s, 2 H), 6.30 (d, J = 7.2 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.31-7.38 (m, 5 H), 10.52 (s, 1 H).
Compound 6: ^¹H NMR (400 MHz; CD₃OD): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.86 (q, J = 7.2 Hz, 2 H), 5.22 (d, J = 16.2 Hz, 1 H), 5.41 (d, J = 16.2 Hz, 1 H), 6.63 (d, J = 6.8 Hz,
1 H), 7.46 (d, J = 6.8 Hz, 1 H).

15

Typical Procedure for Compound 9
To a stirred solution of keto compound 10 (5 g, 29.4 mmol) in dry CH₂Cl₂ benzyl amine (3.21 mL, 29.4 mmol) was added dropwise at r.t. and allowed to stir for 20 min. After the completion of the reaction (TLC), K₂CO₃ (14.2 g, 102.9 mmol) was added followed by dropwise addition of ethyl malonyl chloride (4.89 mL, 38.22 mmol) at 0 ˚C. The mixture was stirred at r.t. until completion (1 h, TLC), and then was filtered, and the residue was washed with CH₂Cl₂ (3 × 30 mL). The organic layer was washed with H₂O, brine, dried over anhyd Na₂SO₄, filtered, and concentrated on a rotary evaporator under diminished pressure. The resulting residue was purified by flash column chromatography (silica gel) using EtOAc-PE (3:7) as an eluent, affording the dihydropyridone 9 as a colorless liquid (7.6 g, 70% yield).