Construction of Natural-Product-Like Cyclophane-Braced Peptide Macrocycles via sp³ C–H Arylation

Abstract

Cyclic peptides have provided one of the most important platforms for exploration of biorelevant chemical space between small molecules and biologics. However, in comparison with the design and synthesis of small molecules, chemists' ability to fine-tune the three-dimensional structures and properties of cyclic peptides lag far behind. Intrigued by cyclophane peptide natural products, we wondered whether the rigid, planar, and hydrophobic cyclophane motif could provide a new design element for the synthesis of cyclic peptides with well-behaved 3D structures. Herein, we report a generally applicable method for synthesis of natural-product-like cyclophane-braced peptide macrocycles via Pd-catalyzed intramolecular C(sp 3 )−H arylation with aryl iodides at the remote γ position of various N-terminal aliphatic amino acid units using a simple picolinamide directing group. Products of high structural and stereochemical complexity were quickly assembled from easily accessible peptide precursors prepared by standard solid phase peptide synthesis. Many of these peptide macrocycles show highly ordered structures as revealed by X-ray crystallography. Remarkably, the PA-directed C(sp 3 )−H cyclization reaction of unprotected peptide substrates carrying various free polar side chains proceeded with high efficiency and selectivity in aqueous media. This demonstrates not only the synthetic utility of Pd-catalyzed C(sp 3 )−H functionalization reactions, but also offers a valuable new orthogonal reactivity for peptide chemistry.

Total Synthesis of C-α-Mannosyl Tryptophan via Palladium-Catalyzed C–H Glycosylation

“…37,38 These Pd-catalyzed reactions start with C-H palladation at the ortho position of arene to form a fiveor six-membered Pd II palladacycle intermediate. [43][44][45][46][47][48][49][50][51] Due to the stabilizing effect of the auxiliary, this Pd II palladacycle intermediate reacts with chloro glycosyl donors via oxidative addition (OA) and reductive elimination (RE) to give C-glycosylated product. 30 Reactions of arylcarboxamides through kinetically favored five-membered palladacycle intermediates exhibited higher reactivity than 2-arylacetamides through six-membered palladacycle intermediates.…”

“…To our delight, C-H mannosylation of N 1 -benzyl-protected tryptophan 20 equipped with a picolinamide (PA) auxiliary under the standard conditions gave the desired product 21 in 82% yield and with exclusive α selectivity (Scheme 3a). 31, [45][46][47][48][49][50][51] The reaction likely proceeds through a six-membered palladacycle intermediate 20-0. C-H glycosylation of the C 4 position of indole was not observed.…”

Peptide Cyclization at High Concentration

“…Some of the approaches include the use of bidentate directing groups, innate directing groups, or targeting aromatic amino acids with weaker C(sp 2 )-H bonds. [23][24][25][26] Albericio and Lavilla achieved this by reacting iodo-phenylalanine or iodo-tyrosine with tryptophan in the presence of palladium as a C-H activation catalyst (Figure 1, C). 27 They were able to achieve cyclization at a concentration of 3 mM with low levels of cyclodimerization.…”

Late-stage stitching enabled by manganese-catalyzed C─H activation: Peptide ligation and access to cyclopeptides

“…As a consequence, latestage diversification of amino acids and peptides (8,9) via noble metalcatalyzed C─H activation was developed by Lavilla/Albericio (10,11), , Ackermann (15)(16)(17)(18), and Yu (19)(20)(21)(22), among others (23)(24)(25)(26)(27). While this regime enabled the assembly of challenging cyclic peptides, toxic and costly palladium catalysts were required, which, among others, prove detrimental because of their costs and trace metal impurities (28)(29)(30)(31)(32). In contrast, 3d transition metal-catalyzed C─H activation has gained considerable recent attention, with major advances by Earth-abundant, nontoxic manganese (33,34).…”