Enabling C7 Methylation and Arylation of the Indolyl Core via P(III)-Directed C-H Functionalization

Peripheral editing of complex molecules via C-H functionalization removes the pervasive retrosynthetic bias toward pre-functionalization and taps into the innate, often subtle, stereoelectronic differences between C-H linkages. Using this approach, bioactive molecules and residues can be modified without being beholden to lengthy sequences, thus allowing biochemical hypotheses to be interrogated on accelerated timelines. Herein, the C-H functionalization paradigm is leveraged to tackle C7 C-H functionalization of the biologically important tryptophan core. The devised process, which was expanded to indolyl (and related) systems, utilizes an N-bound unsymmetrical "designer" phosphine to direct C-H functionalization to the desired position while maintaining operational ease of directing group installation/removal. Quantum mechanically calculated steric properties and activation free energies suggest that this phosphine is hindered enough for favoring C-H functionalization over deactivation pathways but is still easily cleaved by nucleophiles. In addition, the process enables the direct C-H methylation, cyclopropanation, and arylation of tryptophan to yield unnatural amino acid (UAA) building blocks. As a testament to the versatility of this method, a solid phase peptide synthesis (SPPS)-ready phosphinated tryptophan was incorporated into a pentapeptide and the C-H functionalization/dephosphination sequence was executed with ease. The utility of "on-peptide" editing was exhibited through the late-stage functionalization of several pentapeptides with a diverse set of C7 substituents on- and off-resin. image