Hydrogenation catalyst generates cyclic peptide stereocentres in sequence

Abstract

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.

Figure 1. Unidirectional peptide synthesis is catalyzed by enzymes and synthetic catalysts.

a, Sequence recognition by ribosomes enables peptide synthesis (in nature). b, Synthetic rotaxane enables directional peptide synthesis (Leigh, 2013). c, Molecular recognition of dehydrophenylalanine enables unidirectional cascade reduction (this work).

Figure 2. Synthesizing cyclic dehydropeptides using dehydroamino acids.

a, Synthesis and elongation of linear dehydropeptide is enabled using oxazolones and (±)-β-phenylserine. b, Macrocyclization of linear dehydropeptides proceeds at high concentration. Boc, t-butyloxycarbonyl; TFA, trifluoroacetic acid; DMAP, 4-dimethylaminopyridine; rt, room temperature.

Figure 3. Examining the hydrogenation of cyclic dehydropeptide 5a’ gives mechanistic insight.

Pictured on the left is the hydrogenation of cyclic dehydropeptide 5a’ using heterogeneous catalysis. Shown on the right is the hydrogenation of cyclic dehydropeptide 5a’ using achiral rhodium catalysis. cod, 1,5-cyclooctadiene; dppp, 1,3-bis(diphenylphosphino)propane; atm, atmosphere. The inclusion of a prime in the compound number indicates it is the fluorinated analog. E.g. 5a = cyclo(Gly-ΔPhe-ΔPhe-ΔPhe-ΔPhe) 5a’ = cyclo(Gly-ΔPhe-ΔPhe-ΔPhe-ΔPhe(4-F)), ΔPhe, dehydrophenylalanine.

Figure 4. Mechanistic experiments support a unidirectional hydrogenation.

a, ¹⁹F-NMR time trace supports sequential reduction. b, Subjecting the synthesized intermediates to standard hydrogenation conditions yields cyclic peptide 6a’ with high diastereoselectivity.

Figure 5. Computational support for a sequential and unidirectional cascade reduction (Non-reacting hydrogens have been hidden and phenyls on the ligand are shown transparent for clarity).

a, Lowest energy transition structure 7_s^‡ for hydrogenation at ΔPhe₂ leading to the anti diastereoselectivity. b, Lowest energy transition structure 7_s^‡ for hydrogenation at ΔPhe₂ leading to the syn diastereoselectivity. c, Predicted selectivities for hydrogenation supports sequential reduction. d, Predicted selectivities support second diastereoselective reduction occurring at ΔPhe₂ while a reduction occuring at ΔPhe₃ or ΔPhe₄ would lead to diminished diastereoselectivity. 5b = cyclo(Gly-ΔPhe-ΔPhe-ΔPhe-Phe)

Figure 6. Cascade hydrogenation of cyclic dehydropeptide 5a and 8 using chiral Rh catalysis yields a different result.

a, Duanphos ligand overcomes substrate control to generate homochiral peptide with high selectivity via cascade hydrogenation. b, Cascade hydrogenation is extended to cyclic dehydropeptide 8.