Chiral Phosphathiahelicenes: Improved Synthetic Approach and Uses in Enantioselective Gold(I)-Catalyzed [2 + 2] Cycloadditions of N-Homoallenyl Tryptamines

Abstract

A chiral phosphathiahelicene scaffold displaying a phosphole and a thiophene unit as the terminal rings of the helical sequence has been synthesized and characterized by spectroscopic methods and X-ray diffraction studies. The phosphine oxides (HelPhos-V oxides) have been obtained following a robust and scalable synthetic approach, based on a nickel-promoted alkynes cyclotrimerization reaction. Then, late-stage functionalization has been carried out via a bromination/palladium coupling reaction sequence. The HelPhos-V gold(I) complexes have been used as catalysts in the unprecedented enantioselective [2+2] cyclization of N-homoallenyl tryptamine derivatives, to afford indolenine-fused cyclobutanes in good isolated yields, with enantiomeric excesses up to 93%.

Recent Advances in the Development of Chiral Gold Complexes for Catalytic Asymmetric Catalysis

“…In 2020, Guinchard and Voituriez [35] improved a synthetic approach of phosphathiahelicenes, enabling gram scale synthesis and structure fine tuning. The obtained phosphathiahelicenes was successfully used as chiral ligand in enantioselective gold(I)‐catalyzed [2+2] cycloadditions of N − homoallenyl tryptamines, affording polycyclic indole derivatives with high good enantioselectivity (up to 93% ee) (Scheme 24).…”

Gold-catalyzed enantioselective functionalization of indoles

“…One of the first examples of enantioselective gold-catalyzed functionalization for the synthesis of polycyclic indoles was demonstrated by Bandini in 2012 (Scheme 1). 27 Indoles tethered to alkyne functions are known to undergo goldcatalyzed spirocyclizations [28][29][30][31][32][33][34][35][36] with concomitant indole dearomatization. Compounds 1 (X= NTs or diester moiety) undergo hydroindolination of the carbon-carbon triple bond followed by iminium trapping of the alkenyl-gold intermediate.…”

“…2). 53 Newly designed HelPhos chiral ligands Lj were used as their chiral gold complexes ensuring high enantioselectivities in a range of compounds. Interestingly, the replacement of the unsubstituted catalyst (R= H) by an alkyne substitution (R=-C≡C-Ph) led to an increase of the enantioselectivities, as previously observed in other enantioselective gold-catalyzed processes.…”

When Indoles Meet Allene and its Derivatives

“…[ 41b ] A similar result was described by Voituriez using C3‐indolylallenes 83 in a gold‐catalyzed strategy and phosphathiahelicenes as chiral ligands to obtain products 84 in a complementary approach to the photocatalyzed reaction (Scheme 18b). [ 42 ]…”