Total synthesis of velbanamine

Abstract

The oncolytic agents vinblastine and vincristine1-2 are "dimeric" alkaloids containing a pentacyclic indoline and a tetracyclic indole moiety. Fragmentation into these structural units is brought about readily by reduction in acidic media which in the case of vinblastine gives desacetylvindoline3 and velbanamine (14).4 These fragments are obvious intermediates in a synthesis of vinblastine, and we now describe the first total synthesis5 of velbanamine ( 14).Oxygenation6 of the isoquinuclidine V in Z-butyl alcohol-monoglyme saturated with potassium t-butoxide at -20°g ave the hydroxy ketone 2,8 mp 156-158°. The corresponding diol 3, mp 182-183°, prepared by reduction of the hydroxy ketone with sodium borohydride, was cleaved with sodium metaperiodate in aqueous methanol to give the ketone 4, mp 109-112°( ethyl acetate solvate). The latter was transformed to the ketal 5, mp 163-165°, by treatment with a mixture of methyl orthoformate and methanol in the presence of p-toluenesulfonic acid at reflux (1)

Chemistry of Bridged Lactams and Related Heterocycles

“…The approach by Büchi relied on retroaldol cleavage of the β-hydroxyketone 644 to reveal the bridged lactam 645 embedded in a [6.3.1] ring system (Scheme 182a). 180,181 This intermediate was converted into velbamine in five more steps. In contrast, Narisada showed that the analogous bridged lactam 650 could be obtained via fragmentation of 649 under oxidative conditions using Pb(OAc) 4 in comparable yield (Scheme 182b).…”

Pharmacology of some metabolites of triazolam, alprazolam, and diazepam prepared by a simple, one-step oxidation of benzodiazepines

“…respectively, less potent than alprazolam (8) in the same two assays. Somewhat less marked potency differences were noted for the 4-hydroxytriazole derivatives 9a-lla vs. 9 11.…”

“…1-Demethylation and 3-hydroxylation of diazepam produce several metabolites which retain much of the parent compound's activity. Temazepam (3), demethyldiazepam (2), and oxazepam (4) are quite active and unquestionably contribute to diazepam's biologic effect.la,b Triazolobenzodiazepines such as triazolam (7) and probably alprazolam (8) are primarily metabolized by «or 4-hydroxylation or both.19'20 «-Hydroxylation of these triazolo compounds reduces activity slightly (7 vs. 10 and 8 vs. 11). However, hydroxylation of triazoloand imidazobenzodiazepines at position 4 reduces potency considerably (see Results and Table II).…”

“…In this paper we describe a direct, one-step oxidation procedure which cleanly converts diazepam (1), triazolobenzodiazepines such as triazolam (7) and alprazolam (8), and imidazo analogue 13 to the corresponding hydroxy derivatives (3,7a, 8a, and 13). We also describe the animal pharmacology of the triazolobenzodiazepine metabolites whose structure-activity relationship differs considerably from the parent diazepam metabolites.…”

Study on the total synthesis of velbanamine: Chemoselective dioxygenation of alkenes with PIFA via a stop-and-flow strategy

“…Since the first racemic synthesis of velbanamine ( 2 ) was disclosed by Büchi and co-workers in 1968, four racemic syntheses and two enantioselective syntheses have been reported in spite of several synthetic efforts toward the core structure [17–24]. The practical synthesis of velbanamine ( 2 ) and a general approach toward structurally related alkaloids remain an intriguing task in the synthetic community.…”