Late-stage C(sp²)–H and C(sp³)–H glycosylation of C-aryl/alkyl glycopeptides: mechanistic insights and fluorescence labeling

Abstract

C(sp³)–H and C(sp²)–H glycosylations of structurally complex amino acids and peptides were accomplished through the assistance of triazole peptide-isosteres. The palladium-catalyzed peptide–saccharide conjugation provided modular access to structurally complex C-alkyl glycoamino acids, glycopeptides and C-aryl glycosides, while enabling the assembly of fluorescent-labeled glycoamino acids. The C–H activation approach represents an expedient and efficient strategy for peptide late-stage diversification in a programmable as well as chemo-, regio-, and diastereo-selective fashion.

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Introduction

Glycosylation is a biological function that regulates the structure and activity of a given peptide or protein, introducing considerable structural diversity.¹ The attachment of carbohydrates onto peptides can improve their metabolic stability, water solubility, and protect the peptide backbone from proteolytic attack, while playing key structural roles in numerous biological recognition processes.² As a consequence, glycopeptides have emerged as valuable vaccine candidates and therapeutics.³ However, their chemical and enzymatic instability under physiological conditions limited the utility of O/N-glycopeptides as drugs.⁴ In contrast, C-glycoside – stabilized isosteres of O/N-glycosides⁵ – possess improved metabolic stability towards acids, bases and enzymatic hydrolysis,⁶ thus being promising inhibitors of cell-surface recognition events and regulators of glycoside metabolism (Fig. 1a).⁷ The targeted modification of biologically active peptides is an important strategy for the elucidation of structure–activity relationships (SAR). During the past decade, the direct C–H manipulation⁸ of a peptide side-chain mediated by transition metal catalysis has emerged as a powerful paradigm,⁹ with key contributions from Lavilla/Albericio,¹⁰ Chen,¹¹ Daugulis,¹² Wang,¹³ Shi,¹⁴ Yu,¹⁵ and Ackermann¹⁶ among others.¹⁷ However, efficient methods for the synthesis of C-alkyl/aryl glycopeptides continue to be rare,¹⁸ which contrasts with numerous examples of metal-catalyzed cross-couplings for the construction of C-aryl glycoside with two prefunctionalized substrates.¹⁹ Within our program on sustainable C–H activation,²⁰ we herein disclose unprecedented C(sp³)/(sp²)–H glycosylations of amino acids, peptides and (hetero)arenes (Fig. 1b). Notable features of our findings include (1) internal peptide-isosteric click-triazole²¹ as powerful amide surrogates in various bioactive peptidomimetics, (2) modification of terminal and internal peptides by secondary C(sp³)–H alkenylation with remarkable chemo- and diastereo-selectivities, and (3) detailed mechanistic insights by experiment and computation as well as (4) versatile fluorescence labeling with structurally complex glycopeptides.

Fig. 1 (a) Selected C-aryl glycosides and glycopeptides. (b) C(sp³)–H glycosylation of labeled amino acids and peptides.

Results and discussion

Optimization of reaction conditions

We initiated our studies by exploring reaction conditions for the challenging secondary C(sp³)–H glycosylation of triazolyldimethylmethyl (TAM) amide 1a (Table 1). Preliminary optimization indicated that 60 °C was a less suitable temperature, whilst a slight increase led to the formation of product 3a in 85% yield with Pd(TFA)₂ as the catalyst, 1,4-dioxane as the solvent and AgOAc as the additive. When replacing AgOAc by other silver salts (AgTFA, Ag₂CO₃, and AgBF₄), Ag₂CO₃ stood out, providing glycopeptide 3a in 95% yield (entries 3–5). Notably, further optimization indicated that 1,4-dioxane was the solvent of choice, and DCE, PhMe, or THF provided diminished or trace amounts of the desired product 3a (entries 6–8). When 8-aminoquinoline (AQ) was employed, which was independently utilized by Liu for the synthesis of C-alkyl glycoamino acids,²² the reaction also proceeded efficiently, albeit under slightly modified reaction conditions. Under otherwise identical reaction conditions the use of 2-iodo-glycals provided as of yet unsatisfactory results.

Table 1 Optimization of C(sp³)–H glycosylation^a

Entry	[Ag]	Solvents	T/°C	Yield^b/%
a Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), Pd(TFA)2 (10 mol%), Ag2CO3 (0.20 mmol), 1,4-dioxane (0.5 mL) at 80 °C for 10 h. b Yield of isolated products.
1	AgOAc	1,4-Dioxane	60	49
2	AgOAc	1,4-Dioxane	80	85
3	AgTFA	1,4-Dioxane	80	Trace
4	Ag 2 CO 3	1,4-Dioxane	80	95
5	AgBF4	1,4-Dioxane	80	Trace
6	Ag2CO3	DCE	80	45
7	Ag2CO3	PhMe	80	28
8	Ag2CO3	THF	80	<5%

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Substrate scope

With the optimized reaction conditions for the challenging C(sp³)–H glycosylation in hand, we subsequently examined its versatility. Phenylalanine derivatives 1 bearing a variety of functional groups, such as esters or aldehydes, were well tolerated, leading to the formation of products 3a–e with high diasteroselectivities (Scheme 1a). Besides the substrate 2a, the reaction of rhamnose-derived glycal 2b also occurred efficiently. In addition, primary C(sp³)–H bonds of deuterated or non-deuterated Ala-TAM [D₃]-1f and 1f were likewise converted, giving product 3g and 3h in 88% and 93% yields respectively, without racemization of the stereogenic centers (see Pages S46–S47 of the ESI‡). The optimized glycosylation proved amenable to substrate 1h with an N-aryl substituent. Similarly, we also proved the reactivity of substrates 1h–j with 8-amino quinoline as a terminal auxiliary. We were pleased to find that glycosylation of primary and secondary C(sp³)–H bonds of alanine, phenylalanine, glutamic acid and even lysine proved to viable. Interestingly, when the reaction temperature was raised to 100 °C, 1,3-diene 3j′ was isolated because of the elimination of the OTIPS group.

Scheme 1 Scope of glycosylation with TAM and AQ as auxiliaries. (a) 100 °C.

When deuterated L-α-aminobutyramide [D₃]-1l was employed as the substrate, deuterium-labeled glycopeptide 3p was obtained.

Due to the unique role of C-aryl glycosides as privileged glycomimetics,^19a we next probed the TAM-assisted C(sp²)–H glycosylation by palladium catalysis (Scheme 2). Hence, arenes 4a–c with electron-donating or electron-withdrawing substituents were compatible, furnishing the desired products 5a–5c in 92% to 97% yields. It was found that the heteroarenes furan and thiophene were likewise tolerated by the versatile palladium catalyst to deliver conjugate saccharides. Moreover, the fluorescent label pyrene could be successively attached to the glycoside 5f.

Scheme 2 Scope of C(sp²)–H glycosylation to C-aryl glycosides.

Next, we studied the bio-conjugation to form versatile glycopeptides and the hybrids derived thereof (Scheme 3). Various terminal peptides and peptide-natural product hybrids were employed, and late-stage modified peptides 7a–g were obtained by C–H glycosylation. Thereby, the possibilities for accessing structurally complex peptides for drug discovery were showcased.

Scheme 3 Scope of glycosylation of terminal peptides and hybrids.

Mechanistic studies

As shown in Fig. 2, a minor deuterium kinetic isotope effect (KIE) with deuterated and non-deuterated Ala-TAM [D₃]-1f and 1f (k_H/k_D = 1.0) indicated that the C(sp³)–H bond cleavage is not likely a kinetically relevant step of the palladium catalysis. In order to gain further insights into the mechanism of the palladium-catalyzed C–H glycosylation DFT calculations were hence performed at the ωB97X-D/6-311++G(d,p), SDD(Pd, I, Ag) + SMD(1,4-dioxane)//ωB97X-D/6-31G(d), LANL2DZ(Pd, I, Ag) level of theory.²³ The calculated barrier for the initial C–H activation is 19.4 kcal mol⁻¹ (see Fig. S1 of the ESI‡), which is in good agreement with our previous studies.^16f Subsequent to the C–H activation, the dissociation of acetic acid and association of substrate 2a lead to the intermediate I1′, which could be further stabilized by Ag₂CO₃ to afford the stable intermediate I1.²⁴ This process is highly exergonic by 36.8 kcal mol⁻¹, thus making the step irreversible. In I1 as shown in Fig. 3, C–I bond cleavage occurs with the assistance of silver via the transition state TS1–2 to afford the oxidized palladium(IV) intermediate I2, with a barrier of 19.3 kcal mol⁻¹ with respect to I1. In this transition state, it is possible to observe attractive dispersive interactions between the imide of the substrate and Ag₂CO₃, which subsequently becomes evident by the bond distances between both moieties as shown in Fig. 4. This could be further confirmed by visualizing the NCI (non-covalent interactions) plot. The reaction continues with the reductive elimination via the transition state TS2–3 with a barrier of 18.8 kcal mol⁻¹ to finalize the C–C formation process, followed by subsequent protonation to release the desired product.

Fig. 2 H/D exchange and KIE experiments.

Fig. 3 Calculated Gibbs free energy profiles for the oxidative addition and reductive elimination steps in kcal mol⁻¹ at the ωB97X-D/6-311++G(d,p), SDD(Pd, I, Ag) + SMD(1,4-dioxane)//ωB97X-D/6-31G(d), LANL2DZ(Pd, I, Ag) level of theory.

Fig. 4 The 3D structures and the non-covalent interactions visualized through NCI-plots of the transition state TS1–2 (strong and weak attractive interactions are given in blue and green, respectively, while red corresponds to strong repulsive interactions).

In order to illustrate the robustness of our C(sp³)–H activation, we explored the unprecedented late-stage glycosylation of internal peptides (Scheme 4). With the sterically congested gem-disubstituted substrates 8a–8e various peptides 9a–9e were converted into value-added glycopeptides under exceedingly mild reaction conditions. When unprotected peptide Phth-Ala-Tzl-Tyr-OMe was employed, only trace amounts of product 9f were observed. Here, the peptidomimetic Tzl scaffold set the stage for expedient site-selective peptide late-stage glycosylations.

Scheme 4 Scope of glycosylation of terminal peptides.

Intrigued by the unique potential of BODIPYs as bio-compatible fluorescent probes,^16e,25 glycosylation of different BODIPY labeled amino acids was explored for our C(sp³)–H activation process (Scheme 5). Hence, the C–H activation enabled the unprecedented preparation of BODIPY labeled glycoamino acids (11a–11e).

Scheme 5 Scope of BODIPY labeled glycoamino acids.

Conclusion

In summary, we have reported a versatile C(sp³)–H/C(sp²)–H glycosylation strategy enabled by peptide isosteric click-triazoles. Thus, the de novo synthesis of structurally complex C-alkyl glycoamino acids, glycopeptides and C-aryl glycosides was achieved by palladium-catalyzed C(sp³)–H/C(sp²)–H activation with excellent levels of regio-, chemo- and diastereoselectivities. The synthetic utility of our strategy was reflected inter alia by the assembly of BODIPY fluorescent labeled glycoamino acids and the racemization-free late-stage diversification of structurally complex molecules. Our approach holds major potential for the preparation of C-alkyl and C-aryl glycosyl amino acid building blocks for their subsequent use in glycopeptide assembly and molecular labeling.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Generous support by the DFG (Gottfried-Wilhelm-Leibniz award to L. A. and SPP1807), the CSC (fellowship to J. W.) and the Onassis Foundation (fellowship to N. K.) is gratefully acknowledged.

Notes and references

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23. For detailed information, see the ESI.‡.
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Footnotes

† Dedicated to the memory of Prof. Kilian Muñiz.

‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/d0sc01260b

§ These authors contributed equally.

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