Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin |
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| Authors: | Tatsuya Watanabe Yasunori Tsuboi Dr. Sumihiro Nomura |
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| Affiliation: | 1. Chemistry Department I Medicinal Chemistry Research, Laboratory Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida‐cho, Aobaku, Yokohama, 227‐0033 (Japan);2. Chemistry Department II Medicinal Chemistry Research, Laboratory Mitsubishi Tanabe Pharma Corporation, 2‐2‐50 Kawagishi, Toda, Saitama, 335‐8505 (Japan), Fax: +81‐48‐433‐2611 |
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| Abstract: | A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps). |
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| Keywords: | camptothecin chiral auxiliaries diastereoselectivity natural products total synthesis |
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