A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

Abstract

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.

Synthesis of Antiproliferative Cephalotaxus Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

“…Several elegant syntheses of 1 have been reported over the past three decades. The racemic approaches have embodied several key transformations, including Nazarov cyclization, [19] photo-stimulated S RN 1 cyclization, [20] Claisen rearrangement, [21,22] oxidative ring contraction, [23] acylnitroso Diels-Alder cycloaddition, [24,25] transannular N-conjugate addition, [26,27] intramolecular alkyne hydroamination, [28] and reductive ring expansion of tetrahydrosioquinoline intermediates. [29,30] Non-racemic routes have featured electrophilic aromatic substitution, [31] Heck arylation, [32,33] Pummerer-electrophilic aromatic substitution cascade, [34][35][36] and acid catalyzed ring expansion of cyclobutanol derivatives.…”

5,6-Dihydro-4H-1,2-oxazines in Organic Synthesis: Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates to Methyl 7-Oxo-1-oxa-6-azaspiro[4.4]nonane-8-carboxylates

“…17 However, literature approaches [16][17][18] towards the synthesis of spiranes of type 12 seem to be less efficient owing to a greater number of steps and lower yields of the target compounds.…”

Ethyl 12b-allyl-1-hydroxy-3,6,7,12b-tetrahydro-4H-1,3-dioxolo[4,5-g]pyrido[2,1-a]isoquinoline-2-carboxylate

“…Homoharringtonine is also a potent agent against strains of the chloroquinine-resistant Plasmodium f. malaria parasite in vitro (Whaun & Brown, 1990). The unique structure and therapeutic potential of this group of alkaloids have stimulated much synthetic research, which has produced several elegant total syntheses of CET (Tietze & Schirok, 1999;Koseki et al, 2002;Suga et al, 2002), and numerous studies of the construction of the pentacyclic ring system.…”