Practical formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via asymmetric acetate aldol additions to pyridine ketone substrates.
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.
Peters
René
R
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
Althaus
Martin
M
Diolez
Christian
C
Rolland
Alain
A
Manginot
Eric
E
Veyrat
Marc
M
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
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