C-H activation methods for peptide macrocyclization have the potential to provide peptidomimetics and cyclic peptides with expanded structural diversity. Now, a highly versatile peptide macrocyclization strategy via late-stage palladium-catalyzed δ-C(sp )-H olefination of phenylalanine residues has been developed. This method utilizes peptide backbone amides as internal directing groups and allows facile macrocyclization of peptides in the N-to-C direction. Combined with the previously developed β-C(sp )-H arylation method for peptide macrocyclization in the C-to-N direction, a pair of palladium-catalyzed reactions were obtained that are directionally orthogonal, and the first example of one-pot synthesis of bicyclic peptides via Pd-catalyzed β-C(sp )-H and δ-C(sp )-H activation is demonstrated.

C À Ha ctivation methods for peptide macrocyclization have the potential to provide peptidomimetics and cyclic peptides with expanded structural diversity.N ow,ahighly versatile peptide macrocyclization strategy via late-stage palladium-catalyzed d-C(sp 2 )ÀHo lefination of phenylalanine residues has been developed. This method utilizes peptide backbone amides as internal directing groups and allows facile macrocyclization of peptides in the N-to-C direction. Combined with the previously developed b-C(sp 3 )ÀHa rylation method for peptide macrocyclization in the C-to-N direction, apair of palladium-catalyzed reactions were obtained that are directionally orthogonal, and the first example of one-pot synthesis of bicyclic peptides via Pd-catalyzed b-C(sp 3 ) À Hand d-C(sp 2 ) À Ha ctivation is demonstrated.

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Spirocyclic hexadienones with multiple stereogenic centers are frequently found in natural products but remain challenging targets to synthesize. Herein, we report the enantioselective desymmetrization of bisphenol derivatives via Ir-catalyzed allylic dearomatization reactions, affording spirocyclic hexadienone derivatives with up to three contiguous stereogenic centers in good yields (up to 90%) and excellent enantioselectivity (up to 99% ee). The high efficiency of this reaction is exemplified by the short reaction time (30 min), low catalyst loading (down to 0.2 mol %), and ability to perform the reaction on a gram-scale. The total syntheses of (+)-tatanan B and (+)-tatanan C were also realized using this Ir-catalyzed allylic dearomatization reaction as a key step.