Where Chemocatalysis Meets Biocatalysis: In Water.

Chemoenzymatic catalysis, by definition, involves the merging of sequential reactions using both chemocatalysis and biocatalysis, typically in a single reaction vessel. A major challenge, the solution to which, however, is associated with numerous advantages, is to run such one-pot processes in water: the majority of enzyme-catalyzed processes take place in water as Nature's reaction medium, thus enabling a broad synthetic diversity when using water due to the option to use virtually all types of enzymes. Furthermore, water is cheap, abundantly available, and environmentally friendly, thus making it, in principle, an ideal reaction medium. On the other hand, most chemocatalysis is routinely performed today in organic solvents (which might deactivate enzymes), thus appearing to make it difficult to combine such reactions with biocatalysis toward one-pot cascades in water. Several creative approaches and solutions that enable such combinations of chemo- and biocatalysis in water to be realized and applied to synthetic problems are presented herein, reflecting the state-of-the-art in this blossoming field. Coverage has been sectioned into three parts, after introductory remarks: (1) Chapter 2 focuses on historical developments that initiated this area of research; (2) Chapter 3 describes key developments post-initial discoveries that have advanced this field; and (3) Chapter 4 highlights the latest achievements that provide attractive solutions to the main question of compatibility between biocatalysis (used predominantly in aqueous media) and chemocatalysis (that remains predominantly performed in organic solvents), both Chapters covering mainly literature from ca. 2018 to the present. Chapters 5 and 6 provide a brief overview as to where the field stands, the challenges that lie ahead, and ultimately, the prognosis looking toward the future of chemoenzymatic catalysis in organic synthesis.

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.

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.

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 (0.25 mol %). Highly functionalized aromatic and heteroaromatic bromides readily participate, including examples taken from the Merck Informer Library indicative of the functional group tolerance associated with these couplings. Direct comparisons with existing literature routes are made. Very low residual levels of Pd in newly formed products are to be expected, as determined by ICP-MS. The reagent involved has been extensively characterized via DLS, TEM, cryo-TEM, and EDX measurements.

Water-Sculpting of a Heterogeneous Nanoparticle Precatalyst for Mizoroki-Heck Couplings under Aqueous Micellar Catalysis Conditions.

Powdery, spherical nanoparticles (NPs) containing ppm levels of palladium ligated by t-Bu3P, derived from FeCl3, upon simple exposure to water undergo a remarkable alteration in their morphology leading to nanorods that catalyze Mizoroki-Heck (MH) couplings. Such NP alteration is general, shown to occur with three unrelated phosphine ligand-containing NPs. Each catalyst has been studied using X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), and cryogenic transmission electron microscopy (cryo-TEM) analyses. Couplings that rely specifically on NPs containing t-Bu3P-ligated Pd occur under aqueous micellar catalysis conditions between room temperature and 45 °C, and show broad substrate scope. Other key features associated with this new technology include low residual Pd in the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a member of the Hancock family of alkaloids, is suggestive of potential industrial applications.

Safe, Scalable, Inexpensive, and Mild Nickel-Catalyzed Migita-Like C-S Cross-Couplings in Recyclable Water.

A new approach to C-S couplings is reported that relies on nickel catalysis under mild conditions, enabled by micellar catalysis in recyclable water as the reaction medium. The protocol tolerates a wide range of heteroaromatic halides and thiols, including alkyl and heteroaryl thiols, leading to a variety of thioethers in good isolated yields. The method is scalable, results in low residual metal in the products, and is applicable to syntheses of targets in the pharmaceutical area. The procedure also features an associated low E Factor, suggesting a far more attractive entry than is otherwise currently available, especially those based on unsustainable loadings of Pd catalysts.

Mild and Robust Stille Reactions in Water using Parts Per Million Levels of a Triphenylphosphine-Based Palladacycle.

An inexpensive and new triphenylphosphine-based palladacycle has been developed as a pre-catalyst, leading to highly effective Stille cross-coupling reactions in water under mild reaction conditions. Only 500-1000 ppm of Pd suffices for couplings involving a variety of aryl/heteroaryl halides with aryl/hetaryl stannanes. Several drug intermediates can be prepared using this catalyst in aqueous nanoreactors formed by 2 wt % Brij-30 in water.

Nickel Nanoparticle Catalyzed Mono- and Di-Reductions of gem-Dibromocyclopropanes Under Mild, Aqueous Micellar Conditions.

Mild mono- and di-hydrodehalogenative reductions of gem-dibromocyclopropanes are described, providing an easy and green approach towards the synthesis of cyclopropanes. The methodology utilizes 0.5-5 mol % TMPhen-nickel as the catalyst, which, when activated with a hydride source such as sodium borohydride, cleanly and selectively dehalogenates dibromocyclopropanes. Double reduction proceeds in a single operation at temperatures between 20-45 °C and at atmospheric pressure in an aqueous designer surfactant medium. At lower loading and either in the absence of ligand or in the presence of 2,2'-bipyridine, this new technology can also be used to gain access to not only monobrominated cyclopropanes, interesting building blocks for further use in synthesis, but also mono- or di-deuterated analogues. Taken together, this base-metal-catalyzed process provides access to cyclopropyl-containing products and is achieved under environmentally responsible conditions.

Recent advances in Cu-catalyzed C(sp3)-Si and C(sp3)-B bond formation.

Numerous reactions generating C-Si and C-B bonds are in focus owing to the importance of incorporating silicon or boron into new or existing drugs, in addition to their use as building blocks in cross-coupling reactions en route to various targets of both natural and unnatural origins. In this review, recent protocols relying on copper-catalyzed sp3 carbon-silicon and carbon-boron bond-forming reactions are discussed.

Fe-Catalyzed Reductive Couplings of Terminal (Hetero)Aryl Alkenes and Alkyl Halides under Aqueous Micellar Conditions.

The combination of a vinyl-substituted aromatic or heteroaromatic and an alkyl bromide or iodide leads, in the presence of Zn and a catalytic amount of an Fe(II) salt, to a net reductive coupling. The new C-C bond is regiospecifically formed at rt at the ß-site of the alkene. The coupling only occurs in an aqueous micellar medium, where a radical process is likely, supported by several control experiments. A mechanism based on these data is proposed.

Atroposelective Total Synthesis of the Fourfold ortho-Substituted Naphthyltetrahydroisoquinoline Biaryl O,N-Dimethylhamatine.

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.

The Hydrophobic Effect Applied to Organic Synthesis: Recent Synthetic Chemistry "in Water".

Recent developments over the past few years in aqueous micellar catalysis are discussed. Applications to problems in synthesis are highlighted, enabled by the use of surfactants that self-aggregate in water into micelles as nanoreactors. These include amphiphiles that have been available for some time, as well as those that have been newly designed. Reactions catalyzed by transition metals, including Pd, Cu, Rh, and Au, are of particular focus.

Structure of Nanoparticles Derived from Designer Surfactant TPGS-750-M in Water, As Used in Organic Synthesis.

Using density functional theory and the COSMO-RS implicit solvent model, we predict the structure and physical chemical properties of nanomicelles derived from the designer surfactant TPGS-750-M used in organic synthesis. We predict that the influence of chain length of the PEG region is low, while the termination of the PEG chain (-OH vs.-OCH3 ) plays a very large role. The interfacial tension is considerably lower between the micellar and water phases for the -OH than the -OCH3 terminated surfactant, and our calculations reproduce the large difference observed in average particle size as a function of PEG chain termination. We propose a structure for the nanoparticles formed by TPGS-750-M in water that is consistent with a ≈50 nm average diameter, which is significantly larger than a single micelle. According to the calculations, each nanoparticle would consist of 30-40 aggregated TPGS-750-M micelles forming a compartmentalized nanoparticle, with considerable amounts of water in the PEG region. The whole particle is stabilized by vitamin E succinate at the nanoparticle-water interface. In the presence of Zn dust or powder, the surfactant collides with the Zn surface, and by interactions with the hydrophobic inner cores, form organozinc species that are protected from the surrounding water. This explains why highly moisture-sensitive Negishi-like couplings take place in surfactant-water systems.

When Does Organic Chemistry Follow Nature's Lead and "Make the Switch"?

The case is made for transitioning organic chemistry from a developed discipline that remains highly dependent upon organic solvents to one that will be sustainable, based on water as the reaction medium. Processes in hand that today achieve the same bond constructions characteristic of traditional organic synthesis, but can be accomplished under environmentally responsible conditions, are discussed as representative of the potential that lies ahead.

Molecularly Smooth Self-Assembled Monolayer for High-Mobility Organic Field-Effect Transistors.

Despite the need for molecularly smooth self-assembled monolayers (SAMs) on silicon dioxide surfaces (the most common dielectric surface), current techniques are limited to nonideal silane grafting. Here, we show unique bioinspired zwitterionic molecules forming a molecularly smooth and uniformly thin SAM in "water" in <1 min on various dielectric surfaces, which enables a dip-coating process that is essential for organic electronics to become reality. This monomolecular layer leads to high mobility of organic field-effect transistors (OFETs) based on various organic semiconductors and source/drain electrodes. A combination of experimental and computational techniques confirms strong adsorption (Wad > 20 mJ m-2), uniform thickness (∼0.5 or ∼1 nm) and orientation (all catechol head groups facing the oxide surface) of the "monomolecular" layers. This robust (strong adsorption), rapid, and green SAM represents a promising advancement toward the next generation of nanofabrication compared to the current nonuniform and inconsistent polysiloxane-based SAM involving toxic chemicals, long processing time (>10 h), or heat (>80 °C).

Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium-Catalyzed Cross-Couplings of Substituted Allenoates.

A mild method for the synthesis of highly functionalized [3]-[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp2 -, and sp3 -substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology.

Safe and Selective Nitro Group Reductions Catalyzed by Sustainable and Recyclable Fe/ppm Pd Nanoparticles in Water at Room Temperature.

As a result of a unique synergy between ligand-free Fe/ppm Pd nanoparticles and PEG-containing designer surfactants, a facile and selective reduction of nitro-containing aromatics and heteroaromatics can be effected in water at room temperature in the presence of NaBH4 . This new nanotechnology involves low catalyst loadings, is highly chemoselective, and tolerates a wide variety of functional groups. The process, which includes recycling of the entire aqueous medium, offers a general, environmentally responsible, and notably safe approach to highly valued reductions of nitro-containing compounds.

HandaPhos: A General Ligand Enabling Sustainable ppm Levels of Palladium-Catalyzed Cross-Couplings in Water at Room Temperature.

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.

Cationic Pd(II)-catalyzed C-H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies.

Cationic palladium(II) complexes have been found to be highly reactive towards aromatic C-H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C-H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C-H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C-H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied.

Reductions of aryl bromides in water at room temperature.

Micellar nanoreactors derived from commercially available 'Nok' (SPGS-550-M), in the presence of Fu's catalyst and a mild hydride source (NaBH4), are useful for facile debromination of functionalized aromatic derivatives. This mild and environemntally responsible process is utlized in water at room temperature, and the reaction mixtures can be smoothly recycled.