Enantio- and diastereoselective synthesis of duocarmycine-based prodrugs for a selective treatment of cancer by epoxide opening.
For the enantio- und diastereoselective synthesis of the prodrug 2, the N-tert-butyloxycarbonyl-protected amine 7 was alkylated with the enantiopure epoxide 14 to give the amide 10. A regio- and facial-selective metal-mediated cyclisation by using a cuprate led to 17 with an inversion of configuration at C10. Subsequent transformation of the hydroxy group in 17 by using the Appel procedure afforded (1S,10R)-9 with an unusual double inversion owing to neighbouring-group participation of the N-tert-butoxycarbonyl group. (1S,10R)-9 is the key intermediate in the synthesis of the prodrug 2, which has been developed for a selective treatment of cancer based on the antibody-directed enzyme prodrug therapy as an analogue of the natural antibiotic duocarmycine SA (1).
Tietze
Lutz F
LF
Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany. ltietze@gwdg.de
Schuster
Heiko J
HJ
Hampel
Sonja M
SM
Rühl
Stephan
S
Pfoh
Roland
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D003500:Cyclization; D000080890:Duocarmycins; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D000080890:Duocarmycins; D004852:Epoxy Compounds; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; C058289:duocarmycin A