Enantioselective Rh-catalyzed addition of indoles to enones and the key role of the free N-H group with acyclic enones.

The protection of N-H groups is often essential to harness highly valuable metal-catalyzed C-C coupling protocols. However, the avoidance of protecting groups has enormous advantages in terms of atom- and step-economy and can, on occasion, be required. Herein, we report a Rh-catalyzed asymmetric conjugate addition using free N-H indole boronic acids and esters with enones. Excellent yields (up to 96%) and e.r. values (up to >99 : 1) were obtained. Each position on the carbocyclic backbone of the indole is accessible. Two sets of conditions involving two sets of chiral ligands (a chiral sulfinamide (S-ligand) and BINAP) were optimized for cyclic and acyclic enones, respectively. The origin of success and failure for each ligand family was investigated using DFT calculations. For example, the calculations suggested that using the chiral S-ligand and an acyclic enone allows for ligation of two enone units, which scuppers catalytic activity. Secondly, using the BINAP ligand with acyclic enones, specifically at the C7 position of indole, allows for an H-bond between the indole (N-H) and the enone, which is critical for high yields and enantioselectivities. In certain cases, a subsequent one-pot process ensues where the indole product undergoes an intramolecular addition (:NH) to the newly tethered ketone (C[double bond, length as m-dash]O), to form unusual tetracyclic hemiaminals, with two chiral centers. As expected, in cyclic enone systems, the cyclization in step 2 occurs with an excellent d.r. However, remarkably, when flexible acyclic enones are used, excellent d.r. values are retained. DFT calculations were again employed which suggest that both product diastereoisomers are of similar thermodynamic energy values, so a high kinetic barrier is expected. Finally, the methodology was also extended to 1,2-addition reactions to form quaternary centers with excellent e.r.