Highly Enantioselective Iridium(I)-Catalyzed Hydrocarbonation of Alkenes: A Versatile Approach to Heterocyclic Systems Bearing Quaternary Stereocenters

Abstract

We report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five-, six- and seven-membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non-covalent interactions as key factors to control the enantioselectivity.

Keywords: C-H activation; enantioselective; heterocycles; hydrocarbonation; iridium.

Scheme 1

Transition‐Metal Catalyzed Hydrocarbonations of Alkenes via C−H Bond Activations.

Figure 1

Natural Products Bearing Pyrrole or Indole Cores.

Scheme 2

Preliminary exploration of the synthetic versatility of the carboxamide group in a model product. Conditions: a) MeLi (excess); b) Et₃O⋅BF₄, Na₂HPO₄; c) LiAlH₄, 50 °C.

Figure 2

Energy Profile ΔG ^solv (kcal mol⁻¹) for the Hydrocarbonation of 1 g′ (R′=Me, R=Bn; [Ir]=[Ir(Binapine)]⁺); B3LYP/6‐31G(d) (LANL2DZ for Ir) // M06/6‐311++g(d,p) (SDD for Ir). Binapine ligand is mostly simplified in the 3D representations (aryl rings omitted) for clarity. Stationary points are truncated, for their full representations see the Supporting Information.

Scheme 3

Mechanistic outline.

Figure 3

Optimized geometries of stationary points I‐3 ^S, I‐3 ^R, TS‐3 ^S and TS‐3 ^R highlighting: (a) key interatomic contacts at I‐3 ^S and I‐3 ^R (blue lines a–g), which correspond to non‐covalent interactions (NCI′s) for which bond paths and bond critical points were found by AIM formalism. The type of each interatomic interaction and the distance (Å) associated to them at I‐3 ^R and I‐3 ^S are tabulated; (b) NCIs obtained by NCIPLOT of I‐3^S , I‐3 ^R and their corresponding transition states TS‐3 ^S and TS‐3 ^R indicating the bond paths found by AIM (blue lines). Iridium bonds are depicted with dot lines for clarity. Only selected fractions of the whole stationary points are shown.