Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation–Fischer indole synthesis

Abstract

Combination of enantioselective allylation reactions with a tandem hydroformylation-Fischer indole synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and homologues was explored. This modular approach allows the substituents at C3 of the indole core, the type of the amine moiety, and the distance of the amine moiety to the indole core in the final synthetic step to be defined. The starting materials required for the hydroformylation step were synthesized via iridium catalyzed enantioselective allylic substitution reactions in high yields and excellent enantioselectivities. The Rh catalyzed hydroformylation step in the presence of phenyl hydrazine, allows the in situ formed aldehyde to be trapped as the hydrazone. Subsequent acid catalyzed indolization furnishes the desired indole structures in moderate to good yields.

Phosphoramidites: Privileged Ligands in Asymmetric Catalysis

“…The allylic amination was the key step in the synthesis of branched allylic amines 209 in good yield and excellent enantioselectivity (Scheme 66). [327] Allylamines 209 could be converted into substituted indoles 210 by a hydroformylation/Fischer indole synthesis to provide the indole derivatives 210.…”

Phosphoramidite: privilegierte Liganden in der asymmetrischen Katalyse

“…[305,321,323] Durch Ir-katalysierte allylische Substitution konnten auch chirale substituierte Indole synthetisiert werden. So war eine allylische Aminierung der wichtigste Schritt in der effizienten und enantioselektiven Synthese der verzweigten Allylamine 209 (Schema 66), [327] die über eine Hydroformylierung/Fischer-Indolsynthese in die substituierten Indole 210 überführt werden konnten.…”

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

“…While addition of LiO t ‐Bu provided only a slight enhancement in enantioselectivity to 81 % ee (entry 2), we were delighted to find that the amine base DABCO afforded product 3 in 92 % yield and an excellent 95 % ee (entry 3). At this time, the specific role of DABCO remains unknown; however, owing to the additive's drastic effect on enantioselectivity, we hypothesize that DABCO allows for increased equilibration between diastereomers of an iridium π‐allyl complex by slowing the rate of nucleophilic attack . Moreover, while we observed the highest yield for the allylic alkylation reaction using a 1:2 nucleophile/electrophile ratio, the nucleophile/electrophile stoichiometry can be varied (1:1 or 2:1) without affecting reaction selectivity, though yields are diminished (entries 4 and 5)…”