Practical formal total synthesis of (rac)- and (S)-camptothecin.
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.
Peters
René
R
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
Althaus
Martin
M
Nagy
Anne-Laure
AL
D002166:Camptothecin / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure
D002166:Camptothecin