Practical formal total synthesis of (rac)- and (S)-camptothecin |
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Authors: | Peters René Althaus Martin Nagy Anne-Laure |
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Institution: | F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Safety and Technical Sciences, Synthesis and Process Research, Grenzacherstr. 124, CH-4070 Basel, Switzerland. peters@org.chem.ethz.ch |
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Abstract: | A practical, efficient and scalable formal total synthesis of (rac)- and (S)-camptothecin is described, which proceeds via the known DE ring building blocks 19 and (S)-19, respectively. The racemic synthesis starts from diethyl oxalate and uses straightforward carbonyl chemistry in order to generate the pyridone ring system. 19 was formed in 8.4% overall yield over 9 linear steps avoiding any chromatographic purification. The asymmetric version of this approach encompassed a diastereoselective Grignard addition to the enantiomerically pure alpha-ketoester 30 in order to generate the (S)-configured quaternary stereocenter. The auxiliary could be recycled in high yield and was successfully reused multiple times. The final steps paralleled the racemic approach. (S)-19 was thus prepared in 9.4% overall yield (er = 95 : 5) over 10 steps. |
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