Total Synthesis of Darobactin A.

The collaborative total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from d-Garner's aldehyde and l-serine. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product.

Biocatalytic oxidation of alcohols using galactose oxidase and a manganese(III) activator for the synthesis of islatravir.

Galactose oxidase (GOase) is a Cu-dependent metalloenzyme that catalyzes the oxidation of alcohols to aldehydes. An evolved GOase variant was recently shown to catalyze a desymmetrizing oxidation as the first enzymatic step in the biocatalytic synthesis of islatravir. Horseradish peroxidase (HRP) is required to activate the GOase, introducing cost and protein burden to the process.

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade.

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.

Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone.

The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale.

Design of an in vitro biocatalytic cascade for the manufacture of islatravir.

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates.

Aminomethylation of Aryl Halides using α-Silylamines Enabled by Ni/Photoredox Dual Catalysis.

A protocol for the aminomethylation of aryl halides using α-silylamines via Ni/photoredox dual catalysis is described. The low oxidation potential of these silylated species enables facile single electron transfer (SET) oxidation of the amine followed by rapid desilylation. The resulting α-amino radicals can be directly funneled into a nickel-mediated cross-coupling cycle with aryl halides.

-Benzyl Xanthate Esters under Ni/Photoredox Dual Catalysis: Selective Radical Generation and Csp-Csp Cross-Coupling.

Alkyl xanthate esters are perhaps best known for their use in deoxygenation chemistry. However, their use in cross-coupling chemistry has not been productive, which is due, in part, to inadequate xanthate activation strategies. Herein, we report the use of -benzyl xanthate esters, readily derived from alcohols, as radical pronucleophiles in Csp-Csp cross-couplings under Ni/photoredox dual catalysis.

Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic Photocatalyst.

An operationally simple, mild, redox-neutral method for the photoredox alkylation of imines is reported. Utilizing an inexpensive organic photoredox catalyst, alkyl radicals are readily generated from the single-electron oxidation of ammonium alkyl bis(catecholato)silicates and are subsequently engaged in a C-C bond-forming reaction with imines. The process is highly selective, metal-free, and does not require a large excess of the alkylating reagent or the use of acidic additives.

Preparation of visible-light-activated metal complexes and their use in photoredox/nickel dual catalysis.

Visible-light-activated photoredox catalysts provide synthetic chemists with the unprecedented capability to harness reactive radicals through discrete, single-electron transfer (SET) events. This protocol describes the synthesis of two transition metal complexes, [Ir{dF(CF)ppy}(bpy)]PF (1a) and [Ru(bpy)](PF) (2a), that are activated by visible light. These photoredox catalysts are SET agents that can be used to facilitate transformations ranging from proton-coupled electron-transfer-mediated cyclizations to C-C bond constructions, dehalogenations, and H-atom abstractions.

Single-Electron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp(3)-sp(2) Cross-Coupling.

The important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chemical territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex molecule construction, contemporary protocols are not without their Achilles' heel: Csp(3)-Csp(2)/sp(3) coupling. The underlying challenge in sp(3) cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability.

Phenol Derivatives as Coupling Partners with Alkylsilicates in Photoredox/Nickel Dual Catalysis.

Photoredox/nickel dual catalysis via single electron transmetalation allows coupling of Csp(3)-Csp(2) hybridized centers under mild conditions. A procedure for the coupling of electron-deficient aryl triflates, -tosylates, and -mesylates with alkylbis(catecholato)silicates is presented. This method represents the first example of the use of phenol derivatives as electrophilic coupling partners in photoredox/nickel dual catalysis.

Engaging Alkenyl Halides with Alkylsilicates via Photoredox Dual Catalysis.

Single-electron transmetalation via photoredox/nickel dual catalysis provides the opportunity for the construction of Csp(3)-Csp(2) bonds through the transfer of alkyl radicals under very mild reaction conditions. A general procedure for the cross-coupling of primary and secondary (bis-catecholato)alkylsilicates with alkenyl halides is presented. The developed method allows not only alkenyl bromides and iodides but also previously underexplored alkenyl chlorides to be employed.

Mechanistic study of silver-catalyzed decarboxylative fluorination.

The silver-catalyzed fluorination of aliphatic carboxylic acids by Selectfluor in acetone/water provides access to fluorinated compounds under mild and straightforward reaction conditions. Although this reaction provides efficient access to fluorinated alkanes from a pool of starting materials that are ubiquitous in nature, little is known about the details of the reaction mechanism. We report spectroscopic and kinetic studies on the role of the individual reaction components in decarboxylative fluorination.

Uncovering the mechanism of the Ag(I)/persulfate-catalyzed cross-coupling reaction of arylboronic acids and heteroarenes.

The catalytic cross-coupling of arylboronic acids with pyridines through single-electron oxidation provides efficient access to substituted heterocycles. Despite the importance of this reaction, very little is known about its mechanism, and as a consequence, it is unclear whether the full scope of the transformation has been realized. Here we present kinetic and spectroscopic evidence showing a high degree of complexity in the reaction system.