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

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.

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

References and Notes

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22

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.

23

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