Reactions of In Situ-Generated Difluorocarbene (:CF) with Aromatic/Heteroaromatic Alcohols, Thiols, Olefins, and Alkynes under Environmentally Responsible Conditions.

Environmentally respectful methods for generating and utilizing difluorocarbene (:CF) in the synthesis of a wide array of valuable difluoromethylated compounds are disclosed. In particular, the insertion of the CF moiety into aromatic/heteroaromatic alcohols, thiols, olefins, and alkynes under neat or aqueous micellar catalysis conditions is demonstrated. These methods yield both satisfactory results and significantly lower E-Factors compared to traditional synthetic approaches.

Rapid Aminations of Functionalized Aryl Fluorosulfates in Water.

Aryl fluorosulfates of varying complexities have been used in amination reactions in water using a new Pd oxidative addition complex (OAC-1) developed specifically to match the needs of the fine chemicals industry, not only in terms of functional group tolerance, but also reflecting time considerations associated with these important C-N couplings. Also especially noteworthy is that they replace both PFAS-related triflates and nonaflates, which are today out of favor due to recent government regulations. The new complex based on the BippyPhos ligand is used at low loadings and under aqueous micellar conditions.

The impact of earth-abundant metals as a replacement for Pd in cross coupling reactions.

Substitution of one metal catalyst for another is not as straightforward as simply justifying this change based on the availability and/or cost of the metals. Methodologies to properly assess options for reaction design, including multiple factors like a metal's availability, cost, or environmental indicators have not advanced at the pace needed, leaving decisions to be made along these lines more challenging. Isolated indicators can lead to conclusions being made in too hasty a fashion.

Preparation of a Key Intermediate En Route to the Anti-HIV Drug Lenacapavir.

A very efficient four-step synthesis of the main fragment of Gilead's anti-HIV drug lenacapavir is described. The route showcases a 1,2-addition to an intermediate aldehyde using an organozinc halide derived from a commercially available difluorobenzyl Grignard reagent. This sets the stage for the oxidation of the resulting secondary alcohol to the desired ketone, which relies solely on catalytic amounts of TEMPO together with NaClO as the terminal oxidant, affording the targeted ketone in 67% overall yield.

Ligated Pd-Catalyzed Aminations of Aryl/Heteroaryl Halides with Amines under Sustainable Aqueous Micellar Conditions.

Sustainable technology for constructing Pd-catalyzed C-N bonds involving aliphatic amines is reported. A catalytic system that relies on , a known and , and a are combined, leading to a newly developed procedure. This new technology can be used in ocean water with equal effectiveness.

Nanoparticles as Catalysts for ppm Pd-Catalyzed Aminations .

A general protocol employing heterogeneous catalysis has been developed that enables ppm of Pd-catalyzed C-N cross-coupling reactions under aqueous micellar catalysis. A new nanoparticle catalyst containing specifically ligated Pd, in combination with nanoreactors composed of the designer surfactant Savie, a biodegradable amphiphile, catalyzes C-N bond formations in recyclable water. A variety of coupling partners, ranging from highly functionalized pharmaceutically relevant APIs to educts from the Merck Informer Library, readily participate under these environmentally responsible, sustainable reaction conditions.

Challenging cross couplings, in water, aided by iodination of (hetero)aromatic bromides.

Palladium-catalyzed reactions that involve functionalized substrates are oftentimes problematic. Those involving aryl or heteroaryl bromides that are either resistant to, or inefficient in such couplings present challenges that are difficult to overcome and may require development of an entirely new route, or worse, no opportunity to install the desired group using a standard coupling strategy. In this report, we describe a solution that allows for the conversion of such bromo educts to transient iodide derivatives that can be made and used under environmentally responsible conditions, for subsequent reactions to highly functionalized, complex targets.

Impact of Nonionic Surfactants on Reactions of IREDs. Applications to Tandem Chemoenzymatic Sequences in Water.

The influence of added surfactant to aqueous reaction mixtures containing various IREDs has been determined. Just the presence of a nonionic surfactant tends to increase both rates and extent of conversion to the targeted amines. The latter can be as much as >40% relative to buffer alone.

A sustainable, efficient, and potentially cost-effective approach to the antimalarial drug candidate MMV688533.

A 6-step synthesis of the antimalarial drug candidate MMV688533 is reported. Key transformations carried out under aqueous micellar conditions include two Sonogashira couplings and amide bond formation. Compared with the first-generation manufacturing process reported by Sanofi, the current route features ppm levels of palladium loading, less material input, less organic solvent, and no traditional amide coupling reagents.

A Streamlined, Green, and Sustainable Synthesis of the Anticancer Agent Erdafitinib.

Erdafitinib, an anticancer drug, was synthesized in a three-step two-pot sequence involving ppm levels of Pd catalyst run under aqueous micellar conditions enabled by a biodegradable surfactant. This process features both pot- and time-economies and eliminates egregious organic solvents and toxic reagents associated with existing routes.

Direct formation of amide/peptide bonds from carboxylic acids: no traditional coupling reagents, 1-pot, and green.

Technology for generating especially important amide and peptide bonds from carboxylic acids and amines that avoids traditional coupling reagents is described. The 1-pot processes developed rely on thioester formation, neat, using a simple dithiocarbamate, and are safe and green, and rely on Nature-inspired thioesters that are then converted to the targeted functionality.

Simplified Preparation of ppm Pd-Containing Nanoparticles as Catalysts for Chemistry in Water.

A protocol has been developed that not only simplifies the preparation of nanoparticles (NPs) containing ppm levels of ligated palladium that affect heterogeneous catalysis but also ensures that they afford products of cross-couplings reproducibly due to the freshly prepared nature of each reagent. Four different types of couplings are studied: Suzuki-Miyaura, Sonogashira, Mizoroki-Heck, and Negishi reactions, all performed under mild aqueous micellar conditions. The simplified process relies on the initial formation of stable, storable Pd- and ligand-free NPs, to which is then added the appropriate amount of Pd(OAc) and ligand-matched to the desired type of coupling, in water.

Introducing Savie: A Biodegradable Surfactant Enabling Chemo- and Biocatalysis and Related Reactions in Recyclable Water.

Savie is a biodegradable surfactant derived from vitamin E and polysarcosine (PSar) developed for use in organic synthesis in recyclable water. This includes homogeneous catalysis (including examples employing only ppm levels of catalyst), heterogeneous catalysis, and biocatalytic transformations, including a multistep chemoenzymatic sequence. Use of Savie frequently leads to significantly higher yields than do conventional surfactants, while obviating the need for waste-generating organic solvents.

An Efficient and Sustainable Synthesis of the Antimalarial Drug Tafenoquine.

An 11-step, 8-pot synthesis of the antimalarial drug tafenoquine succinate was achieved in 42% overall yield using commercially available starting materials. Compared to the previous manufacturing processes that utilize environmentally egregious organic solvents and toxic reagents, the current route features a far greener (as measured by Sheldon's E Factors) and likely more economically attractive sequence, potentially expanding the availability of this important drug worldwide.

A 1-Pot Synthesis of the SARS-CoV-2 M Inhibitor Nirmatrelvir, the Key Ingredient in Paxlovid.

A newly devised route to the Pfizer drug nirmatrelvir is reported that reduces the overall sequence to a 1-pot process and relies on a commercially available, green coupling reagent, T3P. The overall yield of the targeted material, isolated as its MTBE solvate, is 64%.

A sustainable synthesis of the SARS-CoV-2 M inhibitor nirmatrelvir, the active ingredient in Paxlovid.

Pfizer's drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield.

ppm Pd-Containing Nanoparticles as Catalysts for Negishi Couplings … in Water.

New technology is reported that enables Negishi couplings to be run under sustainable, far greener conditions. Thus, ppm Pd-containing nanoparticles (NPs) have been developed that catalyze couplings in recyclable water under very mild conditions. These heterogeneous reactions involve loadings of Pd of typically only 2500 ppm (0.

A Randomized, Triple-Blind, Comparator-Controlled Parallel Study Investigating the Pharmacokinetics of Cannabidiol and Tetrahydrocannabinol in a Novel Delivery System, Solutech, in Association with Cannabis Use History.

An oral route of administration for tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ-THC, 11-OH-THC, and 11-nor-9-carboxy-Δ-THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design.

Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine.

Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield.

Lipase-catalyzed esterification in water enabled by nanomicelles. Applications to 1-pot multi-step sequences.

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors. The presence of only 2 wt% designer surfactant, TPGS-750-M, assists in a 100% selective enzymatic process in which only primary alcohols participate (in a 1 : 1 ratio with carboxylic acid). An unexpected finding is also disclosed where the simple additive, PhCF (1 equiv.

Nanomicelle-enhanced, asymmetric ERED-catalyzed reductions of activated olefins. Applications to 1-pot chemo- and bio-catalysis sequences in water.

Bio-catalytic reactions involving ene-reductases (EREDs) in tandem with chemo-catalysis in water can be greatly enhanced by the presence of nanomicelles derived from the surfactant TPGS-750-M. Transformations are provided that illustrate the variety of sequences now possible in 1-pot as representative examples of this environmentally attractive approach to organic synthesis.

High Turnover Pd/C Catalyst for Nitro Group Reductions in Water. One-Pot Sequences and Syntheses of Pharmaceutical Intermediates.

Commercially available Pd/C can be used as a catalyst for nitro group reductions with only 0.4 mol % Pd loading. The reaction can be performed using either silane as a transfer hydrogenating agent or simply a hydrogen balloon (∼1 atm pressure).

Bisulfite Addition Compounds as Substrates for Reductive Aminations in Water.

Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend.

A review presenting water as the logical reaction medium for the future of organic chemistry. A discussion is offered that covers both the "on water" and "in water" phenomena, and how water is playing unique roles in each, specifically with regard to its use in organic synthesis.