Total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization.

(-)-Cylindrocyclophane A is a 22-membered C-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (-)-cylindrocyclophane A that uses 10 C-H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps).

Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of -Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear.

A C-H Functionalization Strategy Enables an Enantioselective Formal Synthesis of (-)-Aflatoxin B.

An enantioselective formal synthesis of (-)-aflatoxin B from 4-methoxyphenylacetic acid has been achieved by an approach that produces a key carbon-carbon bond, a benzylic stereocenter, and two arene carbon-oxygen bonds in the course of three site-selective C-H functionalizations. The carbonyl-directed acetoxylation of two arene C-H bonds described herein is unprecedented in natural product synthesis and occurs under mild conditions that preserve the configuration of a sensitive benzylic stereocenter.

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp)-H Activation.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction.

Ligand-Enabled, Palladium-Catalyzed β-C(sp)-H Arylation of Weinreb Amides.

We report the development of Pd(II)-catalyzed C(sp)-H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp)-H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development.

Utilizing Carbonyl Coordination of Native Amides for Palladium-Catalyzed C(sp )-H Olefination.

Pd -catalyzed C(sp )-H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp )-H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α-H-containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp )-H activation. The method enables direct C(sp )-H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time.

Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp)-H fluorination.

The development of a Pd(II)-catalysed enantioselective fluorination of C(sp)-H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp)-H bonds through Pd(II)-insertion, as well as the sluggish reductive elimination involving Pd-F bonds. Here, we report the development of a Pd(II)-catalysed enantioselective C(sp)-H fluorination using a chiral transient directing group strategy.

Methylene C(sp)-H Arylation of Aliphatic Ketones Using a Transient Directing Group.

Palladium-catalyzed methylene β-C(sp)-H arylation of aliphatic ketones using a transient directing group is developed. The use of α-benzyl β-alanine directing group that forms a six-membered chelation with palladium is crucial for promoting the methylene C(sp)-H bond activation.

Diverse ortho-C(sp)-H Functionalization of Benzaldehydes Using Transient Directing Groups.

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates.

Organic chemistry. Functionalization of C(sp3)-H bonds using a transient directing group.

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C-H bonds.