Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C–H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C–H bond, especially the C(sp3)–H bond of methyl groups, as functional groups in organic synthesis.

We report a unified photoredox-catalysis strategy for both hydroxylation and amidation of tertiary and benzylic C–H bonds. Use of hydroxyl perfluorobenziodoxole (PFBl–OH) oxidant is critical for efficient tertiary C–H functionalization, likely due to the enhanced electrophilicity of the benziodoxole radical. Benzylic methylene C–H bonds can be hydroxylated or amidated using unmodified hydroxyl benziodoxole oxidant Bl–OH under similar conditions. An ionic mechanism involving nucleophilic trapping of a carbocation intermediate by H2O or CH3CN cosolvent is presented.

α-Amino acids (αAA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups on side chains (e.g., serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure αAAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these “conventional” strategies, a strategy based on the selective functionalization of side chain C–H bonds, particularly sp3 hybridized C–H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs. However, many hurdles related to the low reactivity of C(sp3)–H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C–H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C–H functionalization reactions for αAA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of αAA substrates, to exert complementary regio- and stereocontrol on C–H functionalization reactions through palladacycle intermediates. A variety of αAA precursors can undergo multiple modes of C(sp3)–H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the β, γ, and even δ positions to form new αAA products with diverse structures. In addition to transforming αAAs at previously unreachable positions, these palladium-catalyzed C–H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. This approach reduces the synthetic difficulty for many αAAs by bypassing the requirement for stereocontrol at Cα and relies on straightforward and convergent single-bond coupling transformations at the β-methyl position of alanine to access a wide range of β-monosubstituted αAAs. Moreover, these β-monosubstituted αAAs can undergo further C–H functionalization at the β-methylene position to generate various β-branched αAAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging αAAs and may facilitate the efficient total synthesis of complex peptide natural products.

The mannopeptimycins are a class of glycopeptide natural products with unusual structures and potent antibiotic activity against a range of Gram-positive multidrug-resistant bacteria. Their cyclic hexapeptide core features a pair of unprecedented β-hydroxyenduracididines (l- and d-βhEnd), an O-glycosylated d-Tyr carrying an α-linked dimannose, and a β-methylated Phe residue. The d-βhEnd unit also carries an α-linked mannopyranose at the most hindered N of its cyclic guanidine ring. Herein, we report the first total synthesis of mannopeptimycin α and β with fully elaborated N- and O-linked sugars. Critically, a gold-catalyzed N-glycosylation of a d-βhEnd substrate with a mannosyl ortho-alkynylbenzoate donor enabled the synthesis of the most challenging N-Man-d-βhEnd unit with excellent efficiency and stereoselectivity. The l-βMePhe unit was prepared using a Pd-catalyzed C–H arylation method. The l-βhEnd, d-Tyr(di-Man), and l-βMePhe units were prepared in gram quantities. A convergent assembly of the cyclic peptide scaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β.

A highly tunable radical-mediated reaction system for the functionalization of tertiary aliphatic C–H bonds was developed. Reactions of various substrates with the Zhdankin azidoiodane reagent 1, Ru(bpy)3Cl2, and visible light irradiation at room temperature gave C–H azidated or halogenated products in an easily controllable fashion. These reactions are efficient, selective, and compatible with complex substrates. They provide a potentially valuable tool for selectively labeling tertiary C–H bonds of organic and biomolecules with tags of varied chemical and biophysical properties for comparative functional studies.

•Design and synthesis of new click-compatible alkynyl sugar probes.•Expanding the toolbox of click-compatible alkynyl sugar probes.•Efficient and scalable synthesis strategy.Metabolic labeling based on the click chemistry between alkynyl and azido groups offers a powerful tool to study the function of carbohydrates in living systems, including plants. Herein, we describe the chemical synthesis of six alkynyl-modified sugars designed as analogs to D-glucose, D-mannose, L-rhamnose and sucrose present in plant cell walls. Among these new alkynyl probes, four of them are the 6-deoxy-alkynyl analogs of the corresponding sugars and do not possess any 6-OH groups. The other two are based on a new structural design, in which an ethynyl group is incorporated at the C-6 position of the sugar and the 6-OH group remains. The synthetic routes for both types of probes share common aldehyde intermediates, which are derived from the corresponding 6-OH precursor with other hydroxy groups protected. The overall synthesis sequence of these probes is efficient, concise, and scalable.

•6-Deoxy-alkynyl glucose was synthesized as a sugar analog to study wall biosynthesis.•6dAG incorporates into growth-arrested root hairs in Arabidopsis seedlings.•6dAG incorporation is metabolism-, time-, and concentration-dependent.•Induced callose colocalizes with the site of 6dAG incorporation.Plant cell walls are dynamic structures whose polysaccharide components are rearranged and recycled during growth and morphogenesis. Covalent fluorescent tagging of these polysaccharides following a metabolic labeling approach can help elucidate these changes. Herein reported are the synthesis and seedling-incorporation of a plant polysaccharide chemical reporter, 6-deoxy-alkynyl glucose (6dAG), that is modeled on d-glucose. Whereas fucose-alkyne, a previously reported chemical reporter for pectin, incorporates diffusely throughout growing cell walls, 6dAG incorporated specifically into root hair tips. This incorporation occurs in a time- and concentration-dependent manner. 6dAG exposure both induces and colocalizes with callose deposition in this tissue, and arrests both root hair and root growth. These results show that plants can incorporate an additional alkynyl-modified sugar analog into their metabolism, and into a discrete subcellular location.Arabidopsis root epidermal cells incorporate the click-compatible sugar analog, 6-deoxy-alkynyl glucose, specifically into root hair tip cell walls where it arrests root hair growth.

β-Di-substituted α-amino acids (AAs) contain adjacent carbon stereogenic centers and pose considerable synthetic challenge. Complementary to the conventional synthesis strategies based on the transformation of existing functional groups, we envisioned these molecules could be quickly accessed via selective functionalization of sp3 hybridized C-H bonds on the side chains of common α-AA precursors. We report a readily applicable method to prepare β-alkynyl α-amino acids via Pd-catalyzed diastereoselective C(sp3)-H alkynylation of common α-amino acids precursors with acetylene bromide.

We report a method for the monoselective alkylation of ortho-C–H bonds of N-quinolyl benzamides with both primary and secondary alkyl halides under palladium catalysis. With promotion by NaHCO3 and (BnO)2PO2H or (PhO)2PO2H, symmetric benzamide substrates can be selectively ortho-alkylated to give either mono- or dialkylated products by simply adjusting the amount of NaHCO3 applied. The use of phosphate notably improves the alkylation yield, although it may not be directly involved in C–H palladation or the subsequent functionalization step. Kinetic isotope effect studies indicate that C–H palladation is not the rate-limiting step. Examination of the reactions of an isolated palladacycle intermediate with both cis- and trans-4-methylcyclohexyl iodides revealed surprising stereoretentive couplings of these alkyl iodides. This evidence strongly suggests that the functionalization of the palladacycle with secondary alkyl iodides proceeds via a rarely precedented concerted oxidative addition pathway.

We report a highly efficient and practical protocol for palladium-catalyzed N-quinolylcarboxamide (AQ)-directed arylation of the unactivated β-C(sp3)–H bonds of alanine with aryl iodides at room temperature. For the first time, a broad range of easily accessible aryl iodides can be installed onto the β-methyl group of AQ-coupled phthaloyl alanine mono-selectively, providing both natural and unnatural aromatic α-amino acids. Access to these mono-arylated compounds enables subsequent AQ-directed diastereoselective C–H functionalization, allowing the preparation of various β-disubstituted aromatic α-amino acids in a programmable manner.

To access the key Ile-Hpa pseudodipeptide motif in hibispeptins, a series of bidentate carboxamide-based auxiliary groups have been explored to facilitate the palladium-catalyzed arylation of unactivated γ-C(sp3)–H bonds of Ile precursor with aryl iodides. A new pyridylmethylamine-based auxiliary group PR is introduced, which permits the use of more sterically hindered ortho-substituted aryl iodide substrates and can be removed under mild conditions. Pd-catalyzed PR-directed γ-C(sp3)–H arylation enabled the first total synthesis of hibispeptin A.

A method is reported for palladium-catalyzed N-quinolyl carboxamide-directed olefination of the unactivated C(sp3)–H bonds of phthaloyl alanine with a broad range of vinyl iodides at room temperature. This reaction represents the first example of the stereoretentive installation of multisubstituted terminal and internal olefins onto unactivated C(sp3)–H bonds. These methods enable access to a wide range of challenging β-vinyl α-amino acid products in a streamlined and controllable fashion, beginning from simple precursors.

In this report, a highly efficient method for the room temperature installation of alkyl amino motifs onto the ortho position of anilines via Cu-catalyzed carboxamide-directed amination with alkylamines is described. This method offers a practical solution for the rapid synthesis of complex arylamines from simple starting materials and enables new planning strategies for the construction of arylamine-containing pharmacophores. A single electron transfer (SET)-mediated mechanism is proposed.

We report an efficient method for the alkylation of γ-C(sp3)–H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag2CO3 and dibenzyl phosphate, (BnO)2PO2H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors.

We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp3)–H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C–H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.

A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote C–H bonds is reported. This method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp3)–H arylation, metal-free ε-C(sp2)–H iodination, and Cu-catalyzed intramolecular C–N cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.

Mannose-6-phosphate (M6P)-containing N-linked glycans are essential signaling molecules for sorting hydrolases in eukaryotic cells. Their receptors, especially the cation-independent M6P receptors (CI-MPRs), have emerged as promising protein targets for targeted drug delivery for the treatment of lysosomal storage disease and liver fibrosis. In this Letter, we describe the design and synthesis of novel bivalent mimetic ligands for CI-MPRs. We report that for the first time, a newly-discovered binding motif, GlcNAc-M6P, has been incorporated in mimetic ligands. M6P- and GlcNAc-M6P-containing building blocks, equipped with NH2 and CO2H handles, have been prepared and assembled with an ornithine linker through amide coupling reactions. Efficient global deprotection protocols have also been developed which have been showcased in the synthesis of our novel bivalent mimetic ligands.

We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp3- and sp2-hybridized C–H bonds. In the Pd(OAc)2-catalyzed, PhI(OAc)2-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the γ or δ positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C–H bonds, particularly the C(sp3)–H bond of methyl groups, as functional groups in organic synthesis.

An efficient functionalization of ortho-C(sp2)–H bonds of picolinamide (PA)-protected benzylamine substrates with a range of vinyl iodides as well as acetylenic bromide is reported. ortho-Phenyl benzoic acid (oPBA) acts as an effective promoter in this reaction system. This method provides a practical strategy to access highly functionalized benzylamine compounds for organic synthesis.

Isoquinoline-3-carboxylic acid (2) was modified with amino acid benzylesters and 18 novel N-isoquinoline-3-carbonylamino acid benzylesters (3a–r) were provided. The IC50 values of 3a–r against the proliferation of HL-60 and Hela cells were less than 1 × 10−8 M and 6 × 10−7 M, respectively. On S180 mice model 100 μmol/kg of 3a–r effectively inhibited the growth of the tumors. Using MFA based Cerius2 QSAR module, two equations (r, 0.989 and 0.987) were established to correlate the structure with the in vitro and in vivo activities. The benefit of this modification was supported with both the in vitro membrane permeation test and the in vivo anti-tumor assay. The in vitro membrane permeability of N-isoquinoline-3-carbonyl-l-threonine benzylester (3n) and N-isoquinoline-3-carbonyl-l-leucine benzylester (3q) was 2.5 fold higher than that of 2, and the in vivo anti-tumor activity of 3n, q was 4.4-fold higher than that of 2.Highlights► Design, evaluation, topoisomerse I inhibition and 3D QSAR of novel N-isoquinoline-3-carbonyl-l-amino acid benzylesters were investigated as the potential intercalators. ► On S180 mouse model the oral effective dose was 1 μmol/kg. ► At the dose of 1 mmol/kg the healthy mice had no neurotoxic and acute toxic response. ► The LD50 value of N-isoquinoline-3-carbonyl-l-amino acid benzylesters is more than 540 mg/kg.

Mannose-6-phosphate (M6P) containing N-linked glycans are the essential targeting signals for hydrolases sorting in eukaryotic cells. To facilitate their structural and binding analyses, a highly efficient and convergent method has been developed to prepare complex N-linked glycans with well-defined M6P and N-acetylglucosamine (GlcNAc)-M6P motifs, a newly identified binding element for M6P receptors. The GlcNAc-M6P motif was stereoselectively installed at the late stage of the synthesis. Sequential deprotection of benzyl and acetate groups provided the fully deprotected N-glycans in excellent yield.

A practical synthetic method for the annulation of benzo-rings by the intramolecular coupling of an aryl iodide and a methylene C−H bond is described. The palladium-catalyzed C−H functionalization is directed by an aminoquinoline carboxamide group, which can be easily installed and removed. High yields and broad substrate scope were achieved. An additive of ortho-phenyl benzoic acid, identified from a systematic screening, functions as a critical ligand for the catalytic process under mild condition, even at near room temperature.

Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C–H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C–H bond, especially the C(sp3)–H bond of methyl groups, as functional groups in organic synthesis.

An efficient protocol for the synthesis of β-alkyl α-amino acids via palladium-catalyzed β-C(sp3)–H alkylation of aminoquinoline-coupled phthaloyl alanine is developed. The new TFA-promoted reaction conditions provide excellent C–H alkylation reactivity with alkyl iodides bearing moderately electron-withdrawing groups at room temperature. A range of β-alkyl α-amino acid products, including some difficult to access by other means, can be quickly prepared from readily available primary alkyl iodides and alanine precursors.

A highly tunable radical-mediated reaction system for the functionalization of tertiary aliphatic C–H bonds was developed. Reactions of various substrates with the Zhdankin azidoiodane reagent 1, Ru(bpy)3Cl2, and visible light irradiation at room temperature gave C–H azidated or halogenated products in an easily controllable fashion. These reactions are efficient, selective, and compatible with complex substrates. They provide a potentially valuable tool for selectively labeling tertiary C–H bonds of organic and biomolecules with tags of varied chemical and biophysical properties for comparative functional studies.

We report a highly efficient and practical protocol for palladium-catalyzed N-quinolylcarboxamide (AQ)-directed arylation of the unactivated β-C(sp3)–H bonds of alanine with aryl iodides at room temperature. For the first time, a broad range of easily accessible aryl iodides can be installed onto the β-methyl group of AQ-coupled phthaloyl alanine mono-selectively, providing both natural and unnatural aromatic α-amino acids. Access to these mono-arylated compounds enables subsequent AQ-directed diastereoselective C–H functionalization, allowing the preparation of various β-disubstituted aromatic α-amino acids in a programmable manner.