A Domino N-Amidoacylation/Aldol-Type Condensation Approach to the Synthesis of the Topo-I Inhibitor Rosettacin and Derivatives

Abstract

The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. The key domino procedure simply involves mixing HOBt ester as new reagent with lactam and NaH together in THF or THF/ DMF. The reaction seems to be general and led to suitable N-heterocyclic products in moderate to good yields.

Copper-Catalyzed Photoinduced Radical Domino Cyclization of Ynamides and Cyanamides: A Unified Entry to Rosettacin, Luotonin A, and Deoxyvasicinone

“…Further cleavage of the TMS group with TBAF finally gave rosettacin whose spectral data were in good agreement with previously reported ones. 36 Notably, the cyclization can also be performed with blue LEDs with a slightly reduced efficiency (67%) and desilylation of 17 prior to its cyclization resulted in extensive degradation.…”

“…32 As with the aromathecins, a series of analogues with greater antiproliferative activities, including 14-azacamptothecin (11), 27b has been developed. 33 The potency of these natural or synthetic heterocycles naturally generated immediate interest from synthetic chemists to develop efficient and divergent accesses to benzo [6,7] 34 cyclization of a pyrroloquinoleine with a chlorinated benzofuranone, 35 domino N-amidoacylation/aldol-type condensation, 36 rhodium-catalyzed intramolecular annulations of alkynyl (N-alkoxy)benzamides 37 and its intermolecular variant, 38 aryl radical cyclization into an enamide, 39 or goldcatalyzed domino intramolecular alkyne hydroamination/lactamization. 40 As for luotonin A, total syntheses reported to date 41 feature the condensation of a oxopyrroloquinoline with 2-sulfinylaminobenzoyl chloride, 42 a biomimetic cyclization of vasicinone with anthranilic acid equivalents, 43 a Friedländer condensation, 44 an intramolecular CH arylation of a quinazolinone, 45 a palladium-catalyzed cyanation/cyclization/N-arylation domino sequence, 46 and a radical cyclization of an N-benzoylcyanamide.…”

Expeditious Synthesis of the Topoisomerase I Inhibitors Isoindolo[2,1-b]isoquinolin-7(5H)-one and the Alkaloid Rosettacin Based on Aryl Radical Cyclization of Enamide Generated by Using N-Acyl­iminium Chemistry

“…In parallel to this, we were also interested in the synthesis of natural aromathecins, including rosettacin [path (iii)]. 10 The approach we used is based on an extremely simple intramolecular domino N-amidoacylation/aldol condensation as the key step from reagents IV and V. A similar process from V resulted in the formation of the C-D-E core, which, after oxidization, Friedländer reaction, and decarboxylative hydrolysis, provides the expected target 3a. A similar approach was used in 2012 by Park [path (iv)] 11 using amino-imine VI and keto-amide VII.…”

The structure–activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode

“…Although there are several routes to rosettacin and aromathecin derivatives,32,33 our route proceeds through tricyclic synthon 8 34. The previously developed route to 8 28 (See Scheme 3 for structure) proceeds in good yield from commercially available starting materials and can be scaled up readily.…”