We disclose a pair of ortho-sulfinylaniline auxiliaries for palladium-catalyzed β–C-H arylation of alkyl carboxamides. Together, these auxiliaries offer a means to effect efficient β-methyl and methylene C–H bond arylation with sterically hindered aryl iodides. ortho-Methylsulfinylaniline (MSOA) enables efficient β-methyl C–H arylation of propanamide substrates with aryl iodides bearing various ortho-substituents including alkyl groups. ortho-Tosylsulfinylaniline (TSOA) enables β-methylene C–H arylation with ortho-substituted aryl iodides. Both amide-linked MSOA and TSOA auxiliaries can be easily removed to give ester products under relatively mild conditions.Keywords: hindered aryl iodide; methylene C−H; palladium; sp3 C−H arylation; sulfinylaniline auxiliary;

An iridium-catalyzed ortho-C(sp2)–H amidation reaction of benzaldehydes with organic azides has been developed. A catalytic amount of 3,5-di(trifluoromethyl)aniline was used to promote the Ir-catalyzed directed C–H amination reaction through a transient aldimine intermediate. This reaction tolerates a broad scope of benzaldehyde substrates and works well with a range of aryl- and alkylsulfonyl azides.

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.

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.