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Paper | Special issue | Vol 72, No. 1, 2007, pp.255-273
Published online, 17th November, 2006
DOI: 10.3987/COM-06-S(K)10
Practical Racemic and Asymmetric Formal Total Syntheses of the Homocamptothecin Derivative and Anticancer Agent Diflomotecan via Tertiary Homoallylic Alcohols as Masked Aldol Equivalents

René Peters,* Christian Diolez, Alain Rolland, Eric Manginot, and Marc Veyrat

*Synthesis and Process Research, Safety & Technical Sciences, Pharmaceuticals Division, F.Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland


An efficient and scalable racemic as well as an asymmetric approach to the key building block for the synthesis of homocamptothecin and derivatives thereof such as the potent anticancer agent diflomotecan (4) are described. In the asymmetric route, the pyridone ring was assembled applying straightforward carbonyl chemistry. The selective generation of the quaternary stereocenter was accomplished by self reproduction of chiral information starting from (S)-2-hydroxybutyric acid (22) utilizing an allyl moiety to act as a masked carbonyl group. The optically pure DE building block (7) (er > 99.95 : 0.05) was obtained in 9.0% overall yield over 10 steps (two chromatographic purifications). The asymmetric “de novo pyridone approach” has the potential to serve as the basis for a technical synthesis of diflomotecan.