Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents

• Published in: Nature chemistry 2014-05, Vol.6 (5), p.448-452
• Main Authors: Wender, Paul A., Fournogerakis, Dennis N., Jeffreys, Matthew S., Quiroz, Ryan V., Inagaki, Fuyuhiko, Pfaffenbach, Magnus
• Format: Article
• Language: English
• Subjects: 639/638/309/2420; 639/638/403/933; 639/638/406/910; 639/638/549/933; Alkynes - chemical synthesis; Alkynes - chemistry; Analytical Chemistry; Biochemistry; Carbon; Chemistry; Chemistry/Food Science; Cyclization; Inorganic Chemistry; Metals; Molecular Structure; Organic Chemistry; Physical Chemistry; Reagents; Temperature
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.1917

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH 2 C≡CCH 2 OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions—the homologous Diels–Alder and Diels–Alder cycloadditions—through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles. Cascade reactions allow step-economical generation of molecular complexity. Now, a butatriene equivalent, TMSCH 2 C ≡ CCH 2 OH, is used to couple two powerful and convergent cycloadditions — the homologous Diels–Alder ([5 + 2]) and the Diels–Alder ([4 + 2]) reactions –– through a vinylogous Peterson elimination, en route to a series of kinase inhibitors inspired by staurosporine.