Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles

Abstract

We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.

The Ugi Three‐Component Reaction; a Valuable Tool in Modern Organic Synthesis

“…Reactions of a very similar fashion can also be obtained by employing tryptamine-derived isocyanides. [154,155] Dömling et al [156] used L-glutamine (Gln), as a primary amine, cyclic ketones, aliphatic and aromatic aldehydes and isocyanides to synthesize iminopyrrolidines 72, via an U-3CR type using nanoscale synthesis. A nano dispensing instrument was employed, based on the immediate drop-on-demand technology (I-DOT, a non-contact, pressure-based dispensing technology) in ethanol/H 2 O (1:1) at room temperature for 16 h (Scheme 43).…”

“…Reactions of a very similar fashion can also be obtained by employing tryptamine‐derived isocyanides. [ 154,155 ]…”

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

“…[48] After in situ condensation of aldehydes with malonitrile, an ucleophilic addition of isocyanide 173 generatesn itrilium ion 174.T he indole C3 position subsequently intercepts the nitrilium ion to form spiroindolenine 175.L ike the interrupted Bischler-Napieralski reaction of 144,t his intermediate is trapped by aM annich-typec yclization to afford tetracycles 176.I na ddition to Michael acceptors, other electrophiles proveds uitable in similarc ascade processes. [49] We have reported N-iodosuccinimide( NIS) as ac ompatible electrophile in iodospirocyclization reactions. [49c] The resulting products,e specially regarding the imidoyli odide moiety,a re remarkably flexible and can undergo ar ange of post cyclization modifications.…”

Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

“…3‐(2‐Isocyanoethyl)indoles, which possess several reactive sites, are known to readily undergo cascade cyclization reactions with Michael acceptors,– imines– or isocyanates, leading to the formation of [6,5,5,5] tetracyclic spiroindoline skeleton (Scheme a). However, all of these cascade processes work with only a single reaction mode involving the electrophilic nitrilium ion intermediate.…”