title: Practical formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via asymmetric acetate aldol additions to pyridine ketone substrates.
abstract: Two practical, efficient, and scalable asymmetric routes to DE ring fragment 7, a key building block in the synthesis of the homocamptothecin derivative diflomotecan 4, are described. The "acetal route" starts from 2-chloro-4-cyanopyridine 8 and represents an enantioselective and optimized modification of the original racemic discovery chemistry synthesis. The inefficient optical resolution procedure was replaced by an efficient asymmetric acetate aldol addition (dr 87:13) to a ketone substrate as the key step generating the (R)-configured quaternary stereocenter with high stereoselectivity. 7 was finally obtained in 8.9% overall yield (er 99.95:0.05) over nine steps, avoiding chromatographic purifications and comparing favorably with the initial procedure. In the related "amide route" starting from 2-chloroisonicotinic acid 41, a secondary amide directing group was used to facilitate the ortho lithiation of the pyridine 3-position. The key step of this protocol again consists of a practical asymmetric acetate aldol addition (dr = 87:13). The DE ring building block 7 was thus obtained in 11.1% overall yield (er > 99.95:0.05) over nine steps requiring only one chromatographic purification.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Safety & Technical Sciences, Synthesis and Process Research, Grenzacherstr. 124, CH-4070 Basel, Switzerland. peters@org.chem.ethz.ch
authors.forename: René
authors.initials: R
authors.lastname: Peters
authors.forename: Martin
authors.initials: M
authors.lastname: Althaus
authors.forename: Christian
authors.initials: C
authors.lastname: Diolez
authors.forename: Alain
authors.initials: A
authors.lastname: Rolland
authors.forename: Eric
authors.initials: E
authors.lastname: Manginot
authors.forename: Marc
authors.initials: M
authors.lastname: Veyrat
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis*; D007659:Ketones / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007659:Ketones; D011725:Pyridines; C116609:3-hydroxybutanal; C120029:homocamptothecin; C023666:pyridine; C424962:diflomotecan; D002166:Camptothecin