Showing papers by "Gong Chen published in 2016"

Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp3 C–H Functionalization

Abstract: 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 sp(3) 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(sp(3))-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(sp(3))-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.

Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine

Abstract: A photoredox-mediated Minisci C–H alkylation reaction of N-heteroarenes with alkyl boronic acids is reported. A broad range of primary and secondary alkyl groups can be efficiently incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent substrate scope and functional group tolerance, and offers a broadly applicable method for late-stage functionalization of complex substrates. Mechanistic experiments and computational studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate might play a key role in this reaction system.

A visible-light-promoted radical reaction system for azidation and halogenation of tertiary aliphatic C-H bonds

Abstract: 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.

An Enantioselective Bidentate Auxiliary Directed Palladium-Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

Abstract: A new enantioselective palladium(II)-catalyzed benzylic C−H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ-C−H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′-dihydroxy-1,1′-binaphthyl (BINOL) phosphoric acid ligand, Cs2CO3, and solvent-free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C−H palladation step.

Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination

Abstract: Hampered by a lack of practical syntheses, benzazetidines are one of the few rarely explored compounds in N-heterocyclic chemical space. An efficient synthesis of various benzazetidines by Pd-catalysed intramolecular C−H amination of N-benzyl picolinamides is now reported. Reagent-controlled reductive elimination of a Pd intermediate is a key aspect of this particular method.

Total Synthesis of Mannopeptimycins α and β

Abstract: 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...

Palladium-catalyzed arylation of β-methylene C(sp3)–H bonds at room temperature: desymmetrization of simple cycloalkyl carboxylic acids

Abstract: A new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides at room temperature is reported. The β methylene C–H bonds of symmetrical cycloalkylcarboxamides of varied ring size can be arylated in moderate to good yields and monoselectivity with excellent diastereoselectivity. This mono-selective β methylene C–H arylation reaction enabled the rapid synthesis of complex carbocycle products from easily accessible symmetrical cycloalkyl carboxylic acids via sequential C–H functionalization.

Palladium-catalyzed β-C(sp3)–H arylation of phthaloyl alanine with hindered aryl iodides: synthesis of complex β-aryl α-amino acids

Abstract: An efficient protocol for palladium-catalyzed β-C(sp(3))-H arylation of aliphatic carboxamides equipped with a 2-(2-pyridyl) ethylamine (PE) auxiliary was developed. The PE auxiliary is uniquely effective at facilitating the arylation of primary C(sp(3))-H bonds with sterically hindered aryl iodides. A variety of aryl iodides bearing alkoxyl, carbonyl, nitro and halogen groups on the ortho position can react with the PE-coupled phthaloyl alanine substrate in moderate to excellent yield. These reactions offer a useful solution for preparing complex β-aryl α-amino acid products from readily accessible starting materials.

Palladium-catalyzed picolinamide-directed iodination of remote ortho-C−H bonds of arenes: Synthesis of tetrahydroquinolines

Abstract: A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of e-C(sp(2))-H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp(3))-H arylation, Pd-catalyzed e-C(sp(2))-H iodination, and Cu-catalyzed C-N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

Correction: Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine

Abstract: Correction for ‘Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine’ by Guo-Xing Li et al., Chem. Sci., 2016, DOI: 10.1039/c6sc02653b.

Chemical reprogramming of human glial cells into neurons with small molecule cocktail

Abstract: Provided are compositions, articles and methods that relate to promoting neurogenesis or neuroregeneration in mammalian nervous system. Embodiments relate to use of groups of compounds that contain Crizotinib (Cri), Flurbiprofen, Lithium Chloride (Li), Vitamin C (VC), Ceritinib (Cer) or Pirfenidone (PFD). In certain implementations glial cells are converted into functional neurons.

Syntheses of Nitrogen-Containing Heterocycles via Palladium-Catalyzed Intramolecular Dehydrogenative C—H Amination

Abstract: This article traces the development of catalytic, intramolecular dehydrogenative C–H amination (IDCA) reactions. Over the last 10 years, effective syntheses of carbazoles, indolines and oxindoles via palladium-catalyzed sp2 intramolecular dehydrogenative C–H amination reactions have been realized. While the corresponding amination reactions of sp3 C–H bonds are more challenging, syntheses of pyrrolidines, azetidines, β-lactams and even aziridines via this manifold have been reported. 1 Introduction 2 Intramolecular Aminations of C(sp2)–H Bonds 3 Intramolecular Aminations of C(sp3)–H Bonds 4 Conclusion

Palladium-Catalyzed Arylation of β-Methylene C(sp3)-H Bonds at Room Temperature: Desymmetrization of Simple Cycloalkyl Carboxylic Acids.

Abstract: A new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides at room temperature is reported. The β methylene C–H bonds of symmetrical cycloalkylcarboxamides of varied ring size can be arylated in moderate to good yields and monoselectivity with excellent diastereoselectivity. This mono-selective β methylene C–H arylation reaction enabled the rapid synthesis of complex carbocycle products from easily accessible symmetrical cycloalkyl carboxylic acids via sequential C–H functionalization.

Palladium-Catalyzed Picolinamide-Directed Iodination of Remote ortho-C-H Bonds of Arenes: Synthesis of Tetrahydroquinolines.

Abstract: A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of e-C(sp(2))-H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp(3))-H arylation, Pd-catalyzed e-C(sp(2))-H iodination, and Cu-catalyzed C-N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

Palladium‐Catalyzed Alkylation of Unactivated C(sp3)—H Bonds with Primary Alkyl Iodides at Room Temperature: Facile Synthesis of β‐Alkyl α‐Amino Acids.

Abstract: 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.