Manganese-Catalyzed C ─ H Activations for Late-Stage Peptide Diversifications

Precious 4d and 5d transition metals have undeniably achieved great success in the area of peptide C─H functionalizations. However, drawbacks such as the high price and toxicity of these metals limit further applications in peptide C─H functionalizations. In recent years, 3d transition metals emerged as naturally abundant, less-toxic and user-friendly catalysts,^{[19, 100]}

with considerable contributions by manganese catalysis.[20a, 101] Ackermann and coworkers pioneered the field of late-stage peptide diversifications employing manganese-catalyzed C─H activations. Early examples by Ackermann and coworkers showed tryptophan transformations by manganese(I) catalysis, such as C–H cyanations^[102] and allylations^{[99, 103]}

in a racemization-free manner (Scheme 1.5.1).

Introduction

Scheme 1.5.1. Manganese-catalyzed tryptophan C─H activations.

Alkynes are synthetically useful for further transformations, such as 1,3-dipolar cycloadditions,^[104] Ackermann and coworkers^[105] developed manganese(I)-catalyzed chemo-selective peptide C─H alkynylations, delivering various tryptophan-based peptides bearing alkyne motifs (Scheme 1.5.2). Employing bromoalkynes as the alkynylating reagents, this late-stage peptide diversification proceeded efficiently in a racemization-free manner.

Moreover, this strategy was compatible with various functional groups, such as the native NH-free tryptophan, azide and iodide groups, thereby outcompeting palladium catalysis. A tryptophan-natural product hybrid was efficiently delivered as well. Furthermore, an intramolecular macrocyclization was conducted, delivering a 21-membered cyclic peptide under this highly chemo-selective manganese catalysis.

Introduction

35

Scheme 1.5.2. Manganese-catalyzed peptide C─H alkynylations

To get mechanistic insights into the manganese catalysis, a KIE study was performed, revealing a facile C–H metalation step with kH/kD ≈ 1.0. This result suggested a fast initiating C─H activation step for the C─Mn bond formation, further supported by the isolation of the key 5-membered manganacycle intermediate 96a, which could be used as the catalyst.

Migratory insertion further delivers intermediate 96b, which yields the desired alkynylation product through β-elimination (Scheme 1.5.3).

Introduction

Scheme 1.5.3. Proposed mechanism of manganese-catalyzed C‒H alkynylations

To further explore the manganese(I)-catalyzed peptide transformations, Ackermann and coworkers^[106] demonstrated a bioorthogonal C─H allylation reaction for late-stage peptide diversifications under racemization-free conditions, using easily accessible Morita-Baylis-Hillman adducts^[107] as the allylating reagents (Scheme 1.5.4a). The robustness of the manganese(I) catalysis was shown by tolerating various functional groups, such as iodides, esters, amides and free hydroxyl groups.^[106] Moreover, peptide-conjugates were obtained under the manganese catalysis with various steroid and drug molecules. Notably, an intramolecular allylation enabled the assembly of a 15-membered cyclic peptide (Scheme 1.5.4b), further highlighting the importance of manganese catalysis in peptide diversifications.

The pyridyl group was removed in a traceless fashion under mild conditions, delivering native allylated tryptophan 104 (Scheme 1.5.4 c).

Introduction

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Scheme 1.5.4. Peptide diversification by manganese-catalyzed C‒H allylations

Objectives

2 Objectives

The transition metal-catalyzed C─H activations have been explored as powerful strategy for sustainable organic syntheses.^[108] Prof. Dr. Lutz Ackermann and coworkers have achieved landmark progress in this field, focusing on establishing highly chemo- and site-selective C─H bond transformations of synthetically useful and valuable organic molecules, which further proved powerful in the applications to medicinal chemistry, material sciences, and electrochemistry.^[109] In this context, major efforts were made to establish novel and highly positional selective late-stage peptide diversifications by C─H activations, under palladium, rhodium and Earth-abundant manganese catalysis.

Peptides are of great importance for medicinal chemistry and drug discovery.^[34] Numerous efforts have been made in the field of peptide modifications for improved biological and pharmacokinetic properties. In the past few years, C(sp³)–H activations have been developed as powerful tools for peptide diversifications.^[48] Major advances have been limited to the alanine primary C(sp³)–H activations at the peptide N-terminus. In a sharp contrast, secondary C(sp³)–H arylations are more challenging and important due to its stereo chemistry and structural complexity. The strategy was envisioned by the assistance of peptide bond isosteric triazoles in palladium catalysis, the power of this internal triazole assistance was reflected by establishing the secondary C(sp³)–H functionalizations on terminal peptides as well as the unprecedented positional-selective C(sp³)–H functionalization of internal peptides (Scheme 2.1).

Scheme 2.1. Internal peptide diversifications by isosteric triazole.

Objectives

39

As the late-stage peptide diversifications bears potential for drug discovery and pharmaceutical industries,^[34] peptide labeling technology enabled the molecular insight into biological events and real-time therapy.^[110] Although BODIPY fluorescent dyes proved biocompatible and benign optical properties,^[111] BODIPY peptide labeling largely rely on lengthy prefunctionalizations. Internal peptide C─H activations offered direct functionalization strategy, thus the direct peptide BODIPY fluorescent labeling should be developed.

Scheme 2.2. Internal peptide BODIPY fluorescent labeling.

In the field of C(sp³)–H functionalizations, cyclobutanes are of the great importance as well as amino acids and peptides. Because cyclobutanes represent important building blocks for complex natural molecules with relevant biological activities, and are found as common motifs in several natural products.^[112] C(sp³)–H activations of cyclobutanes enabled a direct strategy for cyclobutane derivative assembly other than [2+2] photocycloaddition^[113] which is usually associated with mixtures of isomers. With the established triazole assisted C─H activations, a novel cyclobutane arylation should be established.

Objectives

Scheme 2.3. Cyclobutane BODIPY fluorescent labeling.

C─H activation proved powerful and step-economical for peptide modifications,^[48] but it is largely restricted to C─C bond formations. C─N bond formations^[114] represent established strategies for medicinal chemistry and drug discovery, but rarely employed for peptide diversifications. And late-stage tryptophan containing peptide diversifications are severely restricted to the tryptophan C2 position. In sharp contrast, highly selective C7^[115] amidation reaction should be explored by rhodium catalysis.

Scheme 2.4. Peptide sequential functionalizations by tryptophan C7/C2 double C─H activations

Objectives

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Glycopeptides and glycoproteins are largely related to key biological events.^[116] Naturally and synthetic glycopeptides serve as effective therapies against infections.^[117] However, glycopeptide assemblies are largely limited to lengthy prefunctionalizations. As C─H activation has seen its great success in peptide functionalizations, manganese(I)[20a, 101]

catalyzed late-stage peptide C─H glycoconjugation was thus of interest, enabling unprecedented direct peptide glycoconjugation in a racemization-free manner. The manganese(I) catalyst is earth abundant and non-toxic, featuring a sustainable and user friendly peptide bioconjugation process.

Scheme 2.5. Direct peptide glycoconjugation by manganese(I) catalysis

Results and Discussion

3 Results and Discussion

3.1 Position-Selective C(sp

)‒H Functionalization by Internal Triazole