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Synlett 2004(14): 2509-2512  
DOI: 10.1055/s-2004-834810
LETTER
© Georg Thieme Verlag Stuttgart · New York

20-Deoxy-20-fluorocamptothecin: Design and Synthesis of Camptothecin Isostere

Norio Shibata*, Takehisa Ishimaru, Mai Nakamura, Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
Fax: +81(52)7355442; e-Mail: nozshiba@nitech.ac.jp; e-Mail: toru@nitech.ac.jp;
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Publication History

Received 2 September 2004
Publication Date:
20 October 2004 (online)

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Abstract

20-Deoxy-20-fluorocamptothecin (2) has been synthesized as an isosteric analogue of camptothecin (1). The use of selectfluor or N-fluorobenzenesulfonimide for the electrophilic fluorination of 20-deoxycamptothecin (3) yields the target compound. Enantioselective fluorination of 3 was also achieved using our previously described cinchona alkaloids/selectfluor combination to provide both enantiomers of 2 with 88% ee and 81% ee, ­respectively.

Key words

fluorine - antitumor agent - asymmetric synthesis - camptothecin - topoisomerase I

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General Experimental Procedure: A solution of 3 (82.5 mg, 0.25 mmol) in CH2Cl2 (15.0 mL) was added to a stirred solution of NF-(DHQ)2PHAL [prepared in situ from (DHQ)2PHAL (232.0 mg, 0.30 mmol) and Selectfluor (105.5 mg, 0.30 mmol) in CH2Cl2 (15.0 mL) at r.t. for 30 min] at r.t. under nitrogen atmosphere. After the mixture was stirred for 1-2 d, H2O was added to the reaction mixture and extracted with CH2Cl2. The organic phase was washed with 3% HCl, sat. NaHCO3, and brine and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by silica gel column chromatography eluting with 1% MeOH in CHCl3 to give 2 (85.5 mg, 98%) as yellow powders. The ee was determined to be 81% by HPLC analysis (at a wavelength of 224 nm) using a CHIRALCEL OD-H (250 mm, 4.6 mm) eluting with EtOH at a flow rate of 1.0 mL/min. t R [20 (R)-FluoroCPT (2)] = 11.5 min, t R [20(S)-FluoroCPT (2)] = 14.5 min. 1H NMR (270 MHz, CDCl3): δ = 8.43 (s, 1 H), 8.25 (d, J = 8.6 Hz, 1 H), 7.96 (d, J = 7.6 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.55 (s, 1 H), 5.51 (AB q, J = 16.5 Hz, 2 H, Δν = 106.4 Hz), 5.33 (s, 2 H), 2.14 (dq, J = 21.3, 7.3 Hz, 2 H), 1.13 (t, J = 7.3 Hz, 3 H). 19F NMR (254 MHz, CDCl3): δ = -163.16 (t, J = 21.3 Hz). ESI-MS: m/z = 350 [M+]; found: 351 [M+ + 1]. IR (KBr): 1765, 1659, 1609 cm-1. Anal. Calcd for C20H15FN2O3: C, 68.57; H, 4.32; N, 8.00. Found: C, 68.68; H, 4.23; N, 7.97.
20(S)-FluoroCPT (2, 92% ee, recrystallized from MeOH-CHCl3): mp 256-258 °C (MeOH-CHCl3). [a]D 26 +71.6 (c 0.153, CHCl3). CD (c 0.054 mmol dm-3, MeOH, 26 °C) Δε/dm3 mol-1 cm-1 (λ/nm): 0 (402.0), -1.24 (357.0), 0 (312.3), +0.46 (304.2), +0.17 (290.2), +16.2 (231.6), +5.12 (221.0).
20(R)-FluoroCPT (2, 98% ee, recrystallized from MeOH-CHCl3): mp 257-259 °C (MeOH-CHCl3). [a]D 26 -75.8 (c 0.172, CHCl3). CD (c 0.054 mmol dm-3, MeOH, 26 °C) Δε/dm3 mol-1 cm-1 (λ/nm) +0.02 (402.0), +1.36 (354.2), 0 (311.9), -0.48 (302.8), -0.13 (287.8), -17.4 (231.8), -8.47 (221.0).
CPT 1: CD (c 0.054 mmol dm-3, MeOH, 26 °C) Δε/dm3 mol-1 cm-1 (λ/nm) -0.06 (402.0), -1.88 (360.8), 0 (309.3), +0.32 (304.2), 0 (291.3), -0.08 (288.8), 0 (284.5), +18.2 (232.8), +6.10 (221.0).

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In initial cytotoxicity study, both 20(S)- and 20(R)-fluoroCPT (2) were evaluated on three human cancer cell lines (KB, A549 and HT-29) and they appeared to be less active than CPT (1). Further biological study using pure enantiomer of 2 is now under considerations.