On the Elucidation of the Mechanism of Vinca Alkaloid Fluorination in Superacidic Medium

Abstract

Detailed investigations on one of the key steps of the superacidic fluorination of Vinca alkaloids that is the origin of C20' activation are reported. While two different pathways can be envisioned for the emergence of the transient secondary carbocationic intermediate, isotopic labeling experiments unambiguously revealed the involvement of a 1,2-hydride shift mechanism.

Modifications on the Basic Skeletons of Vinblastine and Vincristine

“…Ngo et al [17] synthesized vinorelbine (33) in two steps from anhydrovinblastine (32), prepared by the coupling of vindoline (4) and catharanthine (3) (Scheme 13). This derivative is a potent antitumor agent in the treatment of non-small cell lung cancer [18].…”

“…This derivative is a potent antitumor agent in the treatment of non-small cell lung cancer [18]. In addition vinorelbine (33) and anhydrovinblastine (32) were hybridized through the 17-hydroxy group of the vindoline part with colchicine, podophyllotoxine and baccatine III to investigate the effect of the new molecules on the polymerisation of tubuline [19].…”

“…Superacids were used in some cases to carry out the fluorination reactions [32], and the mechanism of the superacidic fluorination was investigated in detail [33]. The preparation of the vinflunine (58) was also elaborated directly by fluorination of vinorelbine (33) or by fluorination of anhydrovinblastine (32) and then with C′-ring contraction [34].…”

“…The preparation of the vinflunine (58) was also elaborated directly by fluorination of vinorelbine (33) or by fluorination of anhydrovinblastine (32) and then with C′-ring contraction [34].…”

Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity

“…Following a known 3-step synthesis, 21 intermediate 11 was prepared from the free base of catharanthine ( 4, $ 16/g) by indole protection (2.5 equiv KH, THF, 0 °C; 2.5 equiv ClCO 2 Me, 0–23 °C, 15 h, 90%), single-step conversion of 9 to the lactam 10 (4.5 equiv I 2 , 9 equiv Na 2 CO 3 , THF/H 2 O, 0–23 °C, 22 h, 82%) and subsequent allylic oxidation (2 equiv SeO 2 , THF, 65 °C, 18 h, 60%) under modified reaction conditions (THF vs EtOH) that substantially reduced the amount of required SeO 2 (2 vs 11 equiv) (Scheme 1). Starting with 11 , acid-catalyzed elimination of the secondary allylic alcohol (0.6 equiv TsOH, toluene, 110 °C, Dean–Stark trap, 2.5 h, 97%) cleanly provided the diene 12 poised for introduction of the fused unsaturated six-membered ring by a Diels–Alder reaction.…”