Organometallics in Process Chemistry

The importance of organometallic chemistry for developing organic processes is briefly reviewed with a historical perspective, for the readers to appreciate the contents of this special volume. In addition to highlighting popular name reactions, a section was devoted to emerging technologies with a hope that some of these technologies might mature into real-world applications within a few years. Examples include photocatalysis, flow chemistry, electroorganic synthesis, and computational predictions.

Within the field of process chemistry, all available methods of synthesis are typically considered for the preparation of complex targets. Early in development, speed and flexibility are paramount, but as larger quantities of clinical candidates are required later in development, a route is typically chosen based on process robustness, product quality, and its overall efficiency with respect to several metrics. In this chapter we will highlight the preparation of active pharmaceutical compounds and intermediates containing [3.1.0] bicycles for which stoichiometric main group or catalytic transition metals were utilized to construct C–C bonds. We will focus on four broad classes of reactions: Intermolecular metallocarbenoid cyclopropanation, Michael-initiated ring closures, intramolecular metallocarbenoid cyclopropanation, and those utilizing nucleophilic displacements. A comparative method assessment is presented to illustrate which targets are most amenable to a particular chemistry for obtaining high yields and controlling stereochemistry.

In this review, we focus on synthetic applications of asymmetric transfer hydrogenation (ATH) of structurally complex ketone and imine substrates towards the synthesis of biologically active molecules and natural products with high levels of diastereo- and enantioselectivity. This approach should be interesting to a large scientific community from both academic and industrial assets, and specially life-science businesses. Commercial supply of catalysts is key for industrial groups aiming to implement this technology in their production campaigns. Thus, relevant examples of industrial use of ATH are described.

Inherent creativity in synthetic organic chemists is hallucinogenic and found to have potential to impact global healthcare industry incredibly by executing contemporary organometallic strategies to manufacture the products of varied interest. Application of organometallics in chemical industry has intensely perfected the manufacturing of the materials right from trade goods to very personalized medicines without generating significant amount of waste. In pursuit of drug development, two types of challenges are encountered. The first one is related to design of the molecules, and the second is related to the manufacturing of these at commercial scale. Contemporary organometallics in the context of drug development and process research have advanced the toolbox of enabling technologies for addressing these challenges posed during drug development.

Up to and beyond the 2010 Nobel Prize in Chemistry, Pd-based cross coupling has seen a boom in industrial applications and scientific research. These efforts have yielded a wealth of information on Pd-based catalyst technology that can be separated into two broad categories: pre-catalysts and in situ generated catalysts. Proper selection of the catalyst system, i.e., in situ vs pre-catalyst is although process dependent, herein we provide an in-depth look into the often overlooked benefits of the pre-catalyst technology for maximizing the process economics. Although ligands play a crucial role in catalysis, it is not “all about ligands” alone. To improve the efficiency of the process one may need to precisely generate the active catalytic species for that particular reaction. In this chapter, we highlighted this concept by providing industrial case studies where switching from in situ generated to pre-catalyst technology yielded significant process economic benefits. We also provided process chemists with a methodology to properly evaluate catalyst technology and make recommendations on potential benefits by weighing the pros and cons of using in situ vs preformed.

During our search for sustainable alternatives for reprotoxic polar aprotic solvents, the high-impact and long-term potential of surfactant technology was identified. Based on aqueous micellar catalysis, various synthetic methodologies have been developed and implemented on scale that rely on a variety of transition-metal-catalyzed transformations, as well as other reaction types that are also amenable to this chemistry in water. Implementation typically results in significant benefits across our entire portfolio; that is, in addition to the environmental benefits, from the economic and productivity perspectives, there are also advances to be realized. Representative benefits include reduction in organic solvent consumption, water use, and cycle time, milder reaction conditions, and improved yields and selectivities, which all contribute to improved process performance and lower manufacturing costs.

These surfactant-enabled reactions can be upscaled in the already existing multipurpose facilities of pharmaceutical or other chemical organizations, using a catalytic amount of a combination of a nonionic designer surfactant (e.g., TPGS-750-M) in water and a well-chosen organic cosolvent, instead of traditional and undesirable organic solvents.

Further mechanistic insight gained in the course of our efforts in the field led us to the development of new and always more effective catalytic systems, of both a homogeneous and heterogeneous nature, specifically tailor-made for the medium. The potential of even more appealing synergistic effects has been clearly demonstrated. Taken together, these advances pave the way for an overall transformational, and yet environmentally responsible, approach to catalysis.

Metal-catalysed transformations are essential for the synthesis of the increasingly complex structures required in the pharmaceutical industry and allow chemists to be more inventive and efficient with their synthetic routes. More than 90% of chemicals involve the use of metal catalysts in their manufacture, yet the perceived challenge of metal removal can still be a deterrent to their use in the pharmaceutical industry. Any remaining metal can interfere with subsequent steps and, importantly, should never reach the patient. To ensure this, strict regulations are in place. The technologies available for the separation of transition metals from APIs have improved greatly in recent years, allowing the efficient removal of the catalyst, recovery of the metal and further improvement of the sustainability of catalytic processes. This chapter will provide an overview, with examples, of the methods for effective metal removal. The scale-up of metal removal processes including a consideration of the environmental impact and the cost of metal removal steps at scale is presented.

Sodium acrylate is a valuable monomer for the synthesis of superabsorbents and produced industrially on large scale. Currently, sodium acrylate is made by the oxidation of propene to acrylic acid followed by neutralization with NaOH. The synthesis of sodium acrylate from CO₂, ethylene, and NaOH would be very attractive due to lower raw material costs but was for many years only a “dream reaction.” Significant progress has been made since the first report in 2012 on a catalytic system for this synthesis. Different nickel and palladium catalysts were identified. In addition, the influence of the base in this reaction was evaluated. The use of solvents fulfilling certain criteria is necessary for the design of continuous process concepts. To date, two process concepts have resulted: one using phenolate bases and the other utilizing alkoxide bases.

Generation of highly Lewis acidic metal center in a catalytic system has been one of the key challenges in olefin polymerization. Highly acidic metal center can easily bind with a nucleophilic monomer and starts the polymerization process. With this objective in mind, we categorically designed and synthesized catalysts containing enhanced Lewis acidic metal centers of catalytically active metal centers with enhanced Lewis acidity. We have developed a carefully designed synthetic approach of introducing oxygen between two different metal centers to produce multimetallic systems. The attachment of the oxygen between the two metal centers also brings the metals into close proximity at the molecular level, resulting in a pronounced chemical communication between the metals. The compounds containing covalently bridged metal centers have often modified the fundamental properties of the individual metal atoms and exhibit “cooperativity” that is difficult to achieve. The synthetic strategy involves the isolation of different hydroxides as precursors for multimetallic systems. By taking the advantage of oxophilicity of Group-4 metals and Bronsted acidic character of M(O–H) species, new class of heterometallic complexes have been assembled. Many of these isolated complexes demonstrated excellent catalytic activity in olefin and styrene polymerization. Computational studies reveal that the improvement in the catalytic properties is a result of the presence of a more electrophilic metal center, which is essential for the catalysis.