Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization

Abstract

5-Endo-trig cyclizations are generally considered to be kinetically unfavourable, as described by Baldwin's rules. Consequently, observation of this mode of reaction under kinetic control is rare. This is usually ascribed to challenges in achieving appropriate approach trajectories for orbital overlap in the transition state. Here, we describe a highly enantio- and diastereoselective route to complex indanes bearing all-carbon quaternary stereogenic centres via a 5-endo-trig cyclization catalysed by a chiral ammonium salt. Through computation, the preference for the formally disfavoured 5-endo-trig Michael reaction over the formally favoured 5-exo-trig Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group, which outweigh the importance of the approach trajectory as embodied by Baldwin's rules. Our experimental and theoretical findings demonstrate that geometric and stereoelectronic constraints may not be decisive in the observed outcome of irreversible ring-closing reactions.

Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling

“…Moreover, these enantioenriched drug-like scaffolds contain synthetically versatile functional groups (unreacted aryl bromide, malonate, anilines) that can be easily modified to generate pharmaceutically-related motifs such as N -heterocycles 23 and aryl halides. 24 …”

The Cation–π Interaction in Small‐Molecule Catalysis

“…[60] Paton, Smith, and coworkers recently reported unusual tetraalkylammonium-enabled 5- endo-trig intramolecular Michael reactions in the synthesis of substituted indanes ( 60 ). [61] When simple α-benzyl esters ( 57 ) are treated with base in the presence of achiral tetraalkylammonium ions, Dieckmann-type cyclization affords the traditional 5- exo-trig product ( 58 ). However, α-benzyl malonates ( 59 ) subjected to the same conditions undergo exclusively 5- endo-trig cyclization (Scheme 17A).…”

Carbocyclic Amino Ketones by Bredt's Rule‐Arrested Kulinkovich–de Meijere Reaction

“…[13,14] Homologous ketone 23 b under identical conditions yields bicyclics 43 and 44,favouring quaternary 43. Microwave heating of aminocyclohexanone 23 a with paraformaldehyde resulted in ah igh yield of Mannich products 41 and 42 (Scheme 6), despite the inherently poor orbital overlap of a5 -endo-trig cyclization.…”