Development of a Bio-Inspired Acyl-Anion Equivalent Macrocyclization and Synthesis of a trans-Resorcylide Precursor

Abstract

Studies on the macrocyclization of alpha,omega-dialdehydes have revealed a strong dependence on ring size with respect to the ultimate efficiency of the reaction. Strong catalyst dependence was observed, as thiazolium salts led to no detectable product formation, whereas electron-deficient triazolium salts served as precatalysts for the cyclization. Surprisingly, the N-pentafluorophenyl triazolium variant led to cyclization at room temperature within a short 90-min reaction time. These findings were applied to a range of substrates, including the synthesis of a key intermediate in a rapid synthesis of trans-resorcylide.

Five‐Membered Heterocycles with Three Heteroatoms: Triazoles

“…1,2,4-Triazolium salts 247 have been identified as a new family of stable annulated Nheterocyclic carebenes that found applications in catalytic benzoin condensations and transesterifications at ambient temperature [292]. N-Pentafluorophenyl triazolium tetrafluoroborate salts 248 were found to be useful catalysts in the macrocyclization of a,v-dialdehydes to a-hydroxyketones [293] and in the synthesis of 1,2-amino alcohols via azidation of epoxy aldehydes (where modest asymmetric induction was achieved) [294]. N-Pentafluorophenyl triazolium tetrafluoroborate salt 249 was found to be useful catalyst in the asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates [295].…”

Rate and Equilibrium Constants for the Addition of N‐Heterocyclic Carbenes into Benzaldehydes: A Remarkable 2‐Substituent Effect

“…[5] For example, Miller and Mennen reported the intramolecular cross-benzoin reaction between an arylaldehyde and a tethered aliphatic aldehyde to effect macrocyclization. [5b Connon and co-workers found that N -C 6 F 5 triazolium NHC precatalyst 3 catalyzes intermolecular cross-benzoin reactions between 2-substituted benzaldehydes and aliphatic aldehydes with high levels of chemoselectivity (Scheme 1 a). [5c A selective cross-benzoin reaction between two benzaldehydes catalyzed by thiamine diphosphate dependent benzaldehyde lyase (BAL) was reported by Müller et al., with one 2-substituted benzaldehyde a prerequisite for good chemoselectivity.…”

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

“…Acyl anion equivalent macrocyclization. Recently, Miller's group reported a novel acyl anion equivalent macrocyclization based on proposed biosynthetic pathways in their work toward trans-resorcylide.In this method, the dialdehyde 225 was reacted with DBU and a carbene precursor 226 to produce lactone 227 in 21% yield (Scheme 8d) 129. …”