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Synlett 2008(18): 2781-2784  
DOI: 10.1055/s-0028-1083539
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Subhash P. Chavan*, Abasaheb N. Dhawane, Uttam R. Kalkote
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
e-Mail: sp.chavan@ncl.res.in;
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Publication History

Received 12 April 2008
Publication Date:
15 October 2008 (online)

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Tandem Aza-Michael-Condensation-Aldol Cyclization Reaction: Approach to the Construction of DE Synthon of (±)-CamptothecinSynlett 2009; 2009(09): 1524-1524
DOI: 10.1055/s-0029-1216750

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.

Key words

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

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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).

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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).