Iron-Catalyzed Enantioselective Multicomponent Cross-Couplings of α-Boryl Radicals.

Despite recent interest in the development of iron-catalyzed transformations, methods that use iron-based catalysts capable of controlling the enantioselectivity in carbon-carbon cross-couplings are underdeveloped. Herein, we report a practical and simple protocol that uses commercially available and expensive iron salts in combination with chiral bisphosphine ligands to enable the regio- and enantioselective (up to 91:9) multicomponent cross-coupling of vinyl boronates, (fluoro)alkyl halides, and Grignard reagents. Preliminary mechanistic studies are consistent with rapid formation of an α-boryl radical followed by reversible radical addition to monoaryl bisphosphine-Fe(II) and subsequent enantioselective inner-sphere reductive elimination. From a broader perspective, this work provides a blueprint to develop asymmetric Fe-catalyzed multicomponent cross-couplings via the use of alkenes as linchpins to translocate alkyl radicals, modify their steric and electronic properties, and induce stereocontrol.

Next-Generation Diprovocims with Potent Human and Murine TLR1/TLR2 Agonist Activity That Activate the Innate and Adaptive Immune Response.

The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR agonists, act through a well-defined mechanism (TLR1/TLR2 agonist), exhibit exquisite structure-activity relationships, and display in vivo adjuvant activity. They possess potent and efficacious agonist activity toward human TLR1/TLR2 but modest agonism toward the murine receptor. A manner by which diprovocims can be functionalized without impacting hTLR1/TLR2 activity is detailed, permitting future linkage to antigenic, targeting, or delivery moieties. Improvements in both potency and its low efficacy in the murine system were also achieved, permitting more effective use in animal models while maintaining the hTLR1/TLR2 activity. The prototypical member diprovocim-X exhibits the excellent potency/efficacy of diprovocim-1 in human cells, displays substantially improved potency/efficacy in mouse macrophages, and serves as an adjuvant in mice when coadministered with a nonimmunogenic antigen, indicating stimulation of the adaptive as well as innate immune response.

Connecting remote C-H bond functionalization and decarboxylative coupling using simple amines.

Transition metal-catalysed C-H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C-H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements 'C-H activation' strategies that convert inert C-H bonds into C-metal bonds prior to C-C bond formation. Instead, this reaction exploits an inverted sequence and promotes C-C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C-H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of the reaction conditions.

Palladium Catalysis Enables Benzylation of α,α-Difluoroketone Enolates.

A palladium-catalyzed decarboxylative benzylation reaction of α,α-difluoroketone enolates is reported, in which the key C(α)-C(sp(3) ) bond is generated by reductive elimination from a palladium intermediate. The transformation provides convergent access to α-benzyl-α,α-difluoroketone-based products, and should be useful for accessing biological probes.

Metal-catalyzed Decarboxylative Fluoroalkylation Reactions.

Metal-catalyzed decarboxylative fluoroalkylation reactions enable the conversion of simple O-based substrates into biologically relevant fluorinated analogs. Herein, we present decarboxylative methods that facilitate the synthesis of trifluoromethyl- and difluoroketone-containing products. We highlight key mechanistic aspects that are critical for efficient catalysis, and that inspired our thinking while developing the reactions.

Ligand-controlled regiodivergent palladium-catalyzed decarboxylative allylation reaction to access α,α-difluoroketones.

α,α-Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. To access the α-allyl-α,α-difluoroketone substructure, complementary palladium-catalyzed decarboxylative allylation reactions were developed to provide linear and branched α-allyl-α,α-difluoroketones. For these orthogonal processes, the fluorination pattern of the substrate enabled the ligands to dictate the regioselectivity of the transformations.

Metal-free trifluoromethylation of aromatic and heteroaromatic aldehydes and ketones.

The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl ß,ß,ß-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing ß,ß,ß-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.

Preparation of fluoroalkenes via the Shapiro reaction: direct access to fluorinated peptidomimetics.

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.