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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. The overall yield is improved ten-fold, from 6.4% to 67%.

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.

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)2 and ligand-matched to the desired type of coupling, in water.

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, PhCF3 (1 equiv. vs. substrate), appears to significantly extend the scope of usable acid/alcohol combinations. Taken together, several chemo- and bio-catalyzed 1-pot, multi-step reactions can now be performed in water.

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000-2500 ppm or 0.10-0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N2Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand-Pd(0) complex more for N2Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand-Pdo complex that is more reactive in oxidative addition to aryl chlorides.

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000-2500 ppm or 0.10-0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N2Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand-Pd(0) complex more for N2Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand-Pdo complex that is more reactive in oxidative addition to aryl chlorides.

A 1 : 1 Pd : ligand complex, [t-BuXPhos(Pd-π-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, is readily scaled, and compares very favorably vs. traditional amination conditions. It has also been shown to successfully lead to key intermediates associated with several physiologically active compounds.

A stereoselective total synthesis of O,N-dimethylhamatine, an analogue of an axially chiral naphthylisoquinoline natural biaryl product from tropical Ancistrocladus lianas, is reported. The route features a late-stage atropo-diastereoselective biaryl bond formation. Generation of this especially challenging, sterically hindered tetra-ortho-substituted array was achieved by using Nolan's (IPr*NHC)PdCinCl pre-catalyst under mild Negishi coupling conditions. Discussion is offered regarding the selectivity obtained experimentally and predicted from DFT calculations on the key biaryl coupling step that leads to the desired M-diastereomer.

A newly engineered palladacycle that contains substituents on the biphenyl rings along with the ligand HandaPhos is especially well-matched to an aqueous micellar medium, enabling valued Suzuki-Miyaura couplings to be run not only in water under mild conditions, but at 300 ppm of Pd catalyst. This general methodology has been applied to several targets in the pharmaceutical area. Multiple recyclings of the aqueous reaction mixture involving both the same as well as different coupling partners is demonstrated. Low temperature microscopy (cryo-TEM) indicates the nature and size of the particles acting as nanoreactors. Importantly, given the low loadings of Pd invested per reaction, ICP-MS analyses of residual palladium in the products shows levels to be expected that are well within FDA allowable limits.

A new catalyst that derives from commercially available precursors for copper-free, Pd-catalyzed Sonogashira reactions at the sustainable ppm level of precious metal palladium under mild aqueous micellar conditions has been developed. Both the palladium pre-catalyst and ligand are commercially available, bench stable, and highly cost-effective. The catalyst is applicable to both aryl- and heteroaryl-bromides as educts. A wide range of functional groups are tolerated and the aqueous reaction medium can be recycled. An application to a key intermediate associated with an active pharmaceutical ingredient (ponatinib) is discussed.

Micellar catalysis has become an important aspect of the chemical industry's effort to "go green". However, this chemistry has yet to be fully explored in educational settings such as second-year organic chemistry laboratories. Reported herein is a discovery-based nucleophilic aromatic substitution experiment that introduces chemistry students to micellar catalysis, green chemistry, and systems thinking. The students prepare tandem reactions in water to explore how the leaving group identity affects the rate of reaction and how the reaction incorporates principles of green chemistry. The product of the fastest reaction is isolated through recrystallization, and the product's identity is verified through infrared spectroscopy and melting point analysis.

A new biaryl phosphine-containing platform can be constructed in only two steps and this complexes Pd(OAc)2 forming a precursor of a very active catalyst useful for Suzuki–Miyaura cross-couplings of functionalized substrates.

Several ppm level gold-catalyzed reactions enabled by the ligand HandaPhos can be performed at room temperature in aqueous nanoreactors composed of the surfactant Nok. Variously substituted allenes undergo cycloisomerization leading to heterocyclic products in good yields. Likewise, cyclodehydration is also illustrated under similar conditions, as is an intermolecular variant, hydration of terminal alkynes. Recycling of the catalyst and reaction medium is also illustrated. A low E factor associated with limited solvent use and therefore, waste generation, documents the greenness of this process.

The new monophosphine ligand HandaPhos has been identified such that when complexed in a 1:1 ratio with Pd(OAc)2, enables Pd-catalyzed cross-couplings to be run using ≤1000 ppm of this pre-catalyst. Applications to Suzuki-Miyaura reactions involving highly funtionalized reaction partners are demonstrated, all run using environmentally benign nanoreactors in water at ambient temperatures. Comparisons with existing state-of-the-art ligands and catalysts are discussed herein.

Nickel nanoparticles, formed in situ and used in combination with micellar catalysis, catalyze Suzuki-Miyaura cross-couplings in water under very mild reaction conditions.

Asymmetric gold-catalyzed hydrocarboxylations are reported that show broad substrate scope. The hydrophobic effect associated with in situ-formed aqueous nanomicelles gives good to excellent ee's of product lactones. In-flask product isolation, along with the recycling of the catalyst and the reaction medium, are combined to arrive at an especially environmentally friendly process.

A new, green esterification and thioesterification method has been developed based on the intermediacy of in situ-generated 2-thiopyridine esters derived from dipyridyldithiocarbamate (DPDTC). Both are formed from initial treatment of the corresponding carboxylic acid with DPDTC under neat conditions, followed by introduction of the alcohol or thiol, together with catalytic amounts of an activating group, in concentrated EtOAc or under aqueous micellar conditions. These 1-pot processes generate high yields of esters and thioesters, avoid use of traditional coupling agents, and lead to minimal waste creation as both the EtOAc and the thiol by-product are easily recycled. [ABSTRACT FROM AUTHOR]

Transition-metal-catalyzed carbon-carbon and carbon-heteroatom bond formations are among the most heavily used types of reactions in both academic and industrial settings. As important as these are to the synthetic community, such cross-couplings come with a heavy price to our environment, and sustainability. E Factors are one measure of waste created, and organic solvents, by far, are the main contributors to the high values associated, in particular, with the pharmaceutical and fine-chemical companies which utilize these reactions. An alternative to organic solvents in which cross-couplings are run can be found in the form of micellar catalysis, wherein nanoparticles composed of newly introduced designer surfactants enable the same cross-couplings, albeit in water, with most taking place at room temperature. In the absence of an organic solvent as the reaction medium, organic waste and hence, E Factors, drop dramatically.

New methodologies that enable palladium catalyzed cross-coupling reactions to be performed under environmentally benign conditions (in water and/or at room temperature) have been developed. Described approaches involve in situ activation of carbon–halogen or carbon–hydrogen bonds using zinc metal, or cationic palladium, respectively.