Green Chemistry has become a priority for conducting chemistry in both academia and industry. When advanced processes are developed in the area, chemists not only are concerned with the efficiency of the processes but also the impact on the environment. One of the major criteria of green chemistry, which is the focus of this thesis, is the replacement of organic solvents with an environmentally friendly reaction medium: water. Micellar catalysis facilitates organic reactions in water by self-assembling of surfactants, creating on organic environment for substrates and catalyst in which to perform reactions. The development of a surfactant, which serves as a solvent, is crucial for achieving syntheses under micellar catalysis conditions.

A third-generation designer surfactant, “Nok” (SPGS-550-M), commercially available from Aldrich, can be prepared in two-steps, both involving esterification using a naturally abundant plant feedstock β-sitosterol together with succinic anhydride and PEG-550-M. To evaluate this surfactant, various side-by-side transition metal-catalyzed reactions have been tested relative to TPGS-750-M (the second-generation surfactant). It has been shown that with lower cost, Nok usually affords yields that are as good as, or better than those typically obtained with TPGS-750-M.

Additionally, lowering the amount of precious metal-containing catalysts and costly ligands is preferable according to the 12 Principles of Green Chemistry and from the standpoint of economics as well. Ligand-free dehalogenation of aryl halides in water is an example of applying green chemistry principles by avoiding use of ligands and organic solvents in an important organic reaction. These mild and efficient conditions achieved via in-situ generation of dihydrogen from PdCl2/TMDS in water, subsequent dehalogenation of various functionalized aryl halides. The technology can be further expanded to include an application to multi-step synthesis, as well as showing an ability to recycle catalysts and the reaction medium.

Finally, utilizing the highly effective ligand HandaPhos for ppm gold-catalyzed reactions has been successfully performed in nanomicelles. Several cycloisomerizations of allenes have been performed giving various types of heterocyclic products in good yields. The scope of reaction also allows for intermolecular reactions such as hydration of alkynes. Although catalyst loadings are very low, this work demonstrates an ability to recycle catalysts as well as the reaction medium with consistent reactivity.

I. A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by aqueous micellar reaction medium is presented. 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 destabilize the 2:1 ligand-Pd0 complex for N2Phos then previously described ligands, and thereby favoring the formation of the 1:1 ligand-Pd0 complex that is more reactive in the oxidative addition of aryl chlorides.

II. Previous studies have shown that aqueous solutions of designer surfactants enable a wide verity of valuable transformations in synthetic organic chemistry. Since reactions take place within the inner hydrophobic cores of the aggregate nanoreactors, and products made therein are in dynamic exchange between micelles through in water, opportunities exist to use enzymes to participate in multi-step chemo- and bio-catalytic processes. Herein, studies conducted utilizing the oxidoreductase class of enzymes are presented. Most noteworthy is the finding that aqueous micelles present in the water appear to function not only as a medium for both chemo- and bio-catalysis, but as a reservoir for substrates, products and catalysts, decreasing noncompetitive enzyme inhibition.

III. Two new methods for selective deprotection of diphenylmethylsilyl (DPMS) ethers are described. Unmasking can be achieved with either catalytic amounts of perfluoro-1-butanesulfonyl fluoride (a SuFEx reagent) under mild, aqueous conditions, or using stoichiometric amounts of 18-crown-6 ether in aqueous ethanol.

The world of modern organic chemistry, a very traditional but unsustainable 200-year-old discipline, relies heavily on the use of environmentally harmful chemicals. From the 12 Principles of Green Chemistry it is evident that waste-generating and toxic organic solvents must be eliminated and replaced by the greenest solvent, recyclable water. New surfactants were developed by the Lipshutz lab which forms nano-micelles in water to serve as organic reaction vessels. Micellar catalysis has been advantageous by enabling a myriad of synthetic organic reactions. Recent advancements utilize enzymes such as lipases for bio-catalytic processes that benefit significantly when run in the presence of these nanomicelles, offering an advantageous and unprecedented “reservoir effect” that minimizes textbook enzymatic inhibition. In addition, the study of substrate promiscuity for lipases that catalyze esterification reactions, focuses on the use of a simple, economical and commercially available additive. The common aqueous micellar reaction medium provides the synergy between chemo- and bio-catalytic processes giving rise to the blossoming field of “chemoenzymatic catalysis” that can now occur sequentially in 1-pot in various permutations and combinations. These cascade reactions abide by many principles of green chemistry such as time- and pot-economy and illustrate the potential of conducting sequential organic transformations including industrial drug development, under ambient condition with low levels of precious metal catalyst loadings. One such example is the synthesis of an anticancer drug, erdafitinib which is achieved in a 3-step, 2-pot sequence under aqueous micellar conditions enabled by a biodegradable surfactant, Savie.  

I. A sustainable method for reductive aminations using shelf-stable bisulfite addition compounds of aldehydes under aqueous micellar catalysis is presented. Using α-picolineborane as a readily available stoichiometric hydride source, we successfully synthesized highly valued compounds, inclusive of those pertinent to the pharmaceutical domain. Moreover, this method allows for straightforward recycling of the aqueous reaction medium, emphasizing its environmental benefits.

II. Under micellar catalysis conditions, an eco-friendly nitro group reduction has been developed using readily accessible Pd/C as a catalyst with a minimal Pd loading of 0.4 mol %. This methodology efficiently facilitates the transformation of a diverse range of nitro compounds into their corresponding amines, yielding notable results. The robustness of this process is further showcased through the one-pot synthesis of specific pharmaceutical intermediates. Notably, both the catalyst and the surfactant have demonstrated consistent recyclability without any decrease in effectiveness.

III. The introduction of nonionic surfactant to aqueous reaction systems with varied IREDs significantly enhances both the reaction rate and the yield of the target amines, with improvements reaching more than 40% in comparison to buffer only. Moreover, these findings underscore the potential of combining chemocatalysis and biocatalysis into a 1-pot sequence under aqueous micellar environments. Multiple 1-pot procedures integrating the use of IREDs with diverse chemo-catalytic methods were shown.

IV. Ketones, both aromatic and heteroaromatic, possessing an α-methine proton, have been demonstrated to undergo deprotonation and subsequent mono-allylation rapidly and exclusively in the absence of any solvent. This process consistently delivers the targeted products with excellent isolated yields. The versatility and applicability of this novel method are further highlighted through its successful application to the synthesis of notable compounds such as MK-7, MK-9, and coenzyme Q9 (CoQ9).

Two Methods for Selective Deprotection of Diphenylmethylsilyl Protecting Group under Aqueous Conditions

By

Joshua A. Lieberman

Two, new, methods for chemo-selective deprotection of diphenylmethylsilylether of allylic, benzylic, and alkyl alcohols is achieved. Catalytic amounts of Perfluoro-1-butanesulfonyl fluoride or stoichiometric amounts of 18-crown-6 ether are employed for successful deprotection. All selective deprotection can be attained under mild aqueous conditions.

Copper hydride (CuH) has been shown to enable a number of selective 1,2- and 1,4-reductions when complexed with the appropriate ligand, yet the allylic substitution chemistry of CuH has been much less studied. This dissertation describes the further study of CuH to perform sequential reductions on Morita-Baylis-Hillman (MBH) adducts. Specifically: I) Selectivity in the SN2’ reduction of MBH adducts was shown to be highly dependant on the nature of the ligand used. II) The reaction of MBH alcohols was shown to involve an initial dehydrogenative silylation with PMHS, where both the oligomeric nature and electronics of the initially formed trialkoxysilyl ether intermediate are important in determining both the observed stereoselectivity, and efficiency of the substitution. III) MBH ketones could be employed in tandem SN2’/1,2-reduction sequences to arrive at stereodefined allylic alcohols with central chirality.

Vinylsilanes are versatile intermediates in organic synthesis owing to numerous methods for their transformation into other functional groups that proceed with high stereoretention. While there are numerous methods to synthesize stereodefined vinylsilanes from alkynes, many existing methods require the use of highly reactive moisture intolerant reagents and harsh reaction conditions, features that limit the functionality that can be accommodated. Even fewer of these existing methods are conducted under environmentally responsible conditions. The use of Suginome’s reagent as a moisture tolerant source of nucleophilic silicon, small catalytic quantities of a simple copper(I) salt, and an aqueous solution of TPGS-750-M as an environmentally benign nonionic surfactant, is described herein as a highly effective combination of reagents that allows for the stereoselective silylcupration of conjugated alkynes giving access to a variety of (E)-β-silyl-substituted carbonyl derivatives under environmentally responsible conditions.

This dissertation also describes the application of substituted allenoates as electrophilic butadienyl coupling partners under palladium catalysis in aqueous micellar media. The substituted allenoates could then be transformed by the methods developed herein into a variety of 2-substituted butadienes, where the methods were then extended to provide entry into a variety of substituted [3]-[6]dendralenes. Specifically: I) Application of an additive based screen allowed for evaluation of functional group tolerance in the Pd-catalyzed coupling of substituted allenoates with boronic acids. II) Curiosity driven investigations to identify boron based sp3 coupling reagents compatible with the conditions of micellar catalysis led to the identification of OBBD alkylborinate reagents as stable and isolable coupling reagents, which was the applied to the synthesis of 2-alkyl 1,3-butadienes. III) An analogous vinylallenyl coupling partner that functions formally as an electrophilic [3]dendralene synthon was proposed, and a number of synthetic routes were examined to access this molecule. Optimization of the synthetic route allowed for access to multigram quantities of this material, where it was applied to the synthesis of variously substituted [3]-[6]dendralenes.

Efforts to understand the marine mussels mechanism of strong wet adhesion has been a subject of intense scientific investigation. Analysis of the peptide sequence of mfp-5, a mussel foot protein most correlated with interactions at the interface, revealed a high proportion of charged, hydrophobic, and catechol containing residues. Described in this dissertation is the synthesis of small molecule underwater adhesives by incorporation of these key features of mfp-5. These newly designed molecules formed adhesive bilayers underwater, and were shown to replicate and even exceed mfp-5’s strong wet adhesive energy, while also being orders of magnitude smaller than both the native mussel proteins or existing biomimetic adhesive platforms. By systematically varying key portions of these small molecular adhesives, the adhesive bilayers could be transformed into molecularly uniform monolayers which were applied to the nanofabrication of organic electronic devices.

ABSTRACT

I. A greener and sustainable technology for Negishi coupling reactions in water is reported. This work demonstrates the efficacy of palladium-containing nanoparticles (NPs) with low palladium loadings, typically ca. 2500 ppm (0.25 mol %), as robust catalysts that operate in water under remarkably mild conditions. The water serves not only as a green reaction medium but is also recyclable, further reinforcing the green aspects of this methodology. A board substrate scope of highly functionalized aromatic and heteroaromatic bromides, including select examples from the Merck Informer Library, readily underwent coupling, thereby underscoring the excellent functional group tolerance associated with this approach. Furthermore, residual palladium levels in the resulting products are found to be particularly low, as confirmed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Comprehensive characterization of these catalytically active nanoparticles has been carried out using techniques such as Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), cryogenic-TEM (cryo-TEM), and Energy-Dispersive X-ray Spectroscopy (EDX).

II. An optimized methodology had been developed that not only streamlines the preparation of nanoparticles (NPs) featuring ppm levels of palladium loading but also ensures reliable outcomes in cross-coupling reactions due to the utilization of freshly added ligand and palladium catalyst. The scope of this research encompasses four types of coupling reactions: Suzuki–Miyaura, Sonogashira, Mizoroki–Heck, and Negishi, all executed under aqueous micellar conditions. The novelty of this approach lies in the initial generation of storable, shelf-stable nanoparticles that, without either palladium or ligand can be subsequently converted to active NPs. This conversion involves the simple addition of precise quantities of palladium salt and the corresponding ligand, tailored to catalyze the specific type of coupling reaction being targeted, all in an aqueous medium.

III. Ketones plays an important role in the field of organic chemistry. They are present in various molecules like pharmaceuticals, fragrances, and polymers. Moreover, they serve as precursors in synthesizing heterocycles and natural products. Traditional ketone synthesis methods, such as oxidation of alcohols or Friedel-Crafts acylation, have limitations like low regioselectivity and environmental concerns. The Fukuyama reaction, noted for its chemoselectivity and mild conditions, still faces challenges like the need for intermediate thioester synthesis, organozinc reagent synthesis and the use of odorous ethanethiol. Our group developed a new reagent, dipyridyldithiocarbonate (DPDTC), for converting carboxylic acids into thioesters, offering odorless alternatives. We also pioneered a Negishi reaction in water using organozinc reagents, overcoming their typical sensitivity to water. This development paves the way for a more sustainable, efficient Fukuyama reaction approach.

Traditional Sonogashira coupling reactions require high loadings of both palladium(II) and copper(I) catalysts. A copper-free, ppm palladium approach was discovered by using a combination of novel ligand and palladium pre-catalyst. A wide range of (hetero)aryl bromides and terminal alkynes can be tolerated under standard reaction condition in water at 45 oC without any organic solvent. In many cases solid crude products can be obtained by simple filtration, and the filtrate can be recycled. No more than 1 ppm of palladium residue was detected in ICP-MS analysis. A key internal alkyne precursor of commercially available tyrosine-kinase inhibitor ponatinib (Iclusig®) was prepared by using this methodology. This reaction is efficient, greener and cost-effective compared with currently used ones.

Fe/ppm Pd nanoparticles are highly useful catalysts used in Suzuki-Miyaura coupling reactions. However, the relatively long reaction time at 45 oC limits their applications in time-sensitive reactions. Modifications of the original nanoparticles were conducted by adding another earth abundant metal (Ni, Co, Mn) and screening different types of ligands. The original nanoparticles were used in a newly designed continuous flow reactor to synthesize key pharmaceutical intermediates. The sartan precursor, JAK inhibitor precursor and BRAF inhibitor precursor were prepared in this continuous flow platform. This approach gives an idea of how to perform large scale Suzuki-Miyaura coupling reactions in water using Fe/ppm Pd nanoparticles.

Diaryl ethers are common structures in drugs. These compounds are usually prepared by copper catalyzed Ullmann-type reactions under harsh conditions in organic solvents. Different types of ligands were tested with copper(I) or palladium(II) salts in water. These reactions give a hint of ligands and co-solvents used under aqueous micellar condition.

I. A mild and affordable method for C–S couplings under environmentally responsible micellar aqueous conditions with low nickel loadings is presented. The scope includes various heterocycles and API-related structures. Moreover, the practicability was demonstrated by a gram-scale synthesis with low residual nickel in the products detected after standard purification. Opportunities to use the aqueous medium for tandem, 1-pot applications are also demonstrated.

II. Introducing the use of nanomicelles in transaminase-catalyzed chemoenzymatic reactions enables a faster reaction rate and minimizes enzymatic inhibition. Furthermore, it allows chem- and bio-catalytic reactions to run in a single reaction vessel without switching solvents. An anti-dementia drug (S)-rivastigmine is synthesized efficiently with this new technology.

III. A green chemistry-based synthesis of lapatinib was developed. A streamlined 5- step synthesis in 3 pots was carried out in water and ethanol as the only solvents. This unprecedented method represents an opportunity for shifting from petroleum-based solvents to green solvents. Additionally, a less precious metal catalyst was involved using mild reaction conditions with less reaction time.

IV. Fluorinated compounds are one of the most important categories in pharmaceuticals. A convenient method has been developed for the synthesis of difluorocyclopropenes and difluorocyclopropanes using commercially available TMSCF2Br in the absence of solvents. Complex alkenes and alkynes can readily undergo [2+1] cycloaddition to difluorocarbene with extraordinarily low E Factors.

There currently exists a need for more extensive mild and greener bond forming reactions that allow for construction of sophisticated carbon frameworks. Vinylsilanes have proven themselves to be valuable intermediates in organic synthesis. Traditionally, these educts have been difficult to access requiring stoichiometric metals which often precudes their use on scale. Herein, we investigated the use of Suginome’s reagent, PhMe2SiBpin, in a commercially available surfactant TPGS-750-M to afford isomerically pure (E)-β-silyl-substituted carbonyl derivatives by way of a copper catalyzed silylcupration in water at room temperature.

Copper hydride has seen extensive use as both an asymmetric and achiral source of hydride for many decades. We were interested in investigating copper hydride’s application toward Morita-Baylis-Hillman adducts given their possession of multiple electrophilic sites. We discovered that CuH could be used for tandem reductions of racemic MBH ketones lacking defined olefin geometry into valuable chiral allylic alcohol derivatives with defined stereochemistry.