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Synlett 2006(16): 2636-2640  
DOI: 10.1055/s-2006-950433
LETTER
© Georg Thieme Verlag Stuttgart · New York

Introduction of the Acetate Unit to the 2-Pyridinone Ring System and Its Application to the Synthesis of (20S)-Camptothecin DE Ring System

Kou Hiroya*a, Kei Kawamotoa, Takao Sakamotoa,b
a Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
b Tohoku University, 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation’, Sendai 980-8578, Japan
Fax: +81(22)7956864; e-Mail: hiroya@mail.tains.tohoku.ac.jp;
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Publication History

Received 15 July 2006
Publication Date:
22 September 2006 (online)

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Abstract

The DE ring system of (20S)-camptothecin had been ­prepared from commercially available nicotinic acid in six steps ­utilizing the nucleophilic addition reaction of the silyl ketene acetal to the pyridinone ring as a key step.

Key words

anti-tumor agents - asymmetric synthesis - Lewis acids - nucleophilic additions - regioselectivity

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Asymmetric Hydroxylation of 19 by 20c (Table [3] , entry 3): KHMDS (0.79 mL, 0.59 mmol, 0.75 M solution in toluene) was slowly added to a solution of 19 (152 mg, 0.536 mmol) in anhyd THF (6.0 mL) at -78 °C. After stirring for 30 min, a solution of 20c (240 mg, 0.829 mmol) in anhyd THF (6.0 mL) was slowly added to the reaction mixture at -78 °C and stirred for 5 h at the same temperature. A sat. aq solution of NH4Cl and THF were added successively to the mixture and the dry ice-acetone bath was removed. H2O was added to the mixture and the aqueous phase was extracted with EtOAc. The combined organic solution was washed with a sat. aq solution of Na2SO3 and brine, dried over anhyd MgSO4, and concentrated. The residue was purified by silica gel chromatography [EtOAc-hexane (2:3)] to afford (S)-21 (133 mg, 83%, 72% ee) as a white solid; mp 140 °C (benzene); [α]D 23 +107.2 (c 1.01, CHCl3, 91% ee). IR (film): 3362, 1747, 1651, 1593, 1564, 1229, 1139, 1047, 880, 748, 702 cm -1. 1H NMR (400 MHz, CDCl3): δ = 0.96 (3 H, t, J = 7.2 Hz), 1.71-1.87 (2 H, m), 3.65 (1 H, s), 5.11 (1 H, d, J = 14.4 Hz), 5.18 (2 H, m), 5.61 (1 H, d, J = 16.0 Hz), 6.50 (1 H, d, J = 7.2 Hz), 7.20-7.45 (6 H, m). 13C NMR (100 MHz, CDCl3): δ = 7.7, 31.6, 52.3, 66.6, 72.1, 102.9, 119.0, 128.2, 128.3, 128.9, 135.5, 137.4, 148.3, 158.6, 173.7. MS: m/z (%) = 299 (M+, 88.8), 270 (20.6), 164 (17.8), 91 (100.0). HRMS: m/z calcd for C17H17NO4: 299.1157; found: 299.1138. Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.07; H, 5.79; N, 4.59.

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The ee was determined by chiral HPLC (Daicel, Chiralcel OD-H, EtOH-hexane, 1:9).