UC Santa Barbara

I. Efficient and mild reductions of carboxylic acids to aldehydes or alcohols can be accomplished through a two-step process involving the conversion of these acids into their corresponding S-2-pyridyl thioesters. When these S-2-pyridyl thioesters are subjected to treatment with a commercially available and air-stable nickel pre-catalyst, along with a silane acting as a stoichiometric reductant, the desired aldehydes are generated in yields that range from moderate to high. Alternatively, the methodology allows for a one-pot procedure where carboxylic acids can be directly reduced to the alcohols. In this approach, after the formation of the thioester, a reduction step is performed using sodium borohydride. The applicability of this methodology is notably broad, covering a diverse array of starting materials. It is suitable for highly functionalized carboxylic acids as well as substrates derived from the Merck Informer Library. Moreover, the process is conducted in environmentally friendly reaction media, enhancing its sustainability and reducing the environmental impact typically associated with chemical transformations. This method, therefore, represents a versatile and eco-friendly approach to the reduction of carboxylic acids.

II. 2-Sustainable routes to the SARS-CoV-2 MPro inhibitor nirmatrelvir, the key ingredient in Paxlovid, are described. The first route describes a 7-step, 3-pot synthesis of nirmatrelvir, arriving at the targeted compound in 70% overall yield. The second route features a 4-step one-pot synthesis of nirmatrelvir as its MTBE-solvate, achieving 64% overall yield. Additionally, these routes feature several newly developed green methodologies, including the Pd-catalyzed amide-dehydration, in water, thereby avoiding use of the Burgess reagent and chlorinated solvents. Also featured are several amide bond-forming reactions that no longer rely on traditional (environmentally egregious) coupling reagents.

III. A comprehensive protocol utilizing heterogeneous catalysis has been devised, enabling ppm Pd-catalyzed C–N cross-coupling reactions with aromatic amines in an aqueous micellar environment. A novel nanoparticle catalyst, featuring specifically ligated Pd in combination with nano-reactors composed of the designer surfactant Savie, a biodegradable amphiphile, facilitates C–N bond formations in recyclable water. Simultaneously, a sustainable methodology for C–N bond formation involving aliphatic amines has also been developed. This catalytic system leverages low levels of precious metal, a commercially available ligand, and a recyclable aqueous medium, leading to a newly developed procedure. Notably, this technology is equally effective when deployed in ocean water. Both approaches accommodate a diverse array of coupling partners, including highly functionalized APIs pertinent to the pharmaceutical industry, and compounds from the Merck Informer Library, that readily participate under these environmentally responsible, sustainable reaction conditions. Other notable features of this report include the minimal residual Pd levels in the products, the recyclability of the aqueous medium, the feasibility of using ocean water as an alternative reaction medium, and the exploration of pseudohalides as alternative reaction partners with associated low E-factors. Moreover, an unprecedented 5-step, one-pot sequence is described, highlighting several of the most widely-used transformations within the pharmaceutical industry, alongside a concise yet efficient synthesis of the drug naftopidil, underscoring its potential industrial applications.

IV. Aryl fluorosulfates with varying complexities have been effectively utilized in amination reactions in water using a novel Pd-containing oxidative addition complex (OAC-1). This complex was specifically developed to meet the needs of the fine chemicals industry, offering excellent functional group tolerance and efficiency in C–N couplings. Significantly, it serves as an eco-friendly alternative to PFAS-related triflates and nonaflates, which are currently disfavored due to new government regulations. The OAC-1 complex, based on the BippyPhos ligand, operates at low loadings and under aqueous micellar conditions, and it is both easily prepared and stable for long-term storage. DFT calculations on the OAC precatalyst correlate well with the X-ray crystallographic data, showing π-complexation to the aromatic system of the ligand. These calculations also support NMR data that reveal a mixture of conformers in solution, differing from the X-ray structure in the rotation of the phenyl and t-butyl ligand substituents. The complex efficiently facilitates coupling reactions with a wide range of partners, including pharmaceutically relevant APIs, under mild and environmentally sustainable conditions.

V. A highly efficient six-step synthesis of the antimalarial drug candidate MMV688533 is presented, showcasing significant advancements in both sustainability and process optimization. Key transformations within this route include two Sonogashira couplings and an amide bond formation, all performed under environmentally benign aqueous micellar conditions. Compared to the first-generation manufacturing process developed by Sanofi, this novel approach is far superior in several aspects. Notably, it employs only ppm levels of palladium, drastically reduces material inputs, minimizes the use of organic solvents, and entirely eliminates the need for traditional amide coupling reagents. As a result, the overall yield of the synthesis is dramatically improved from 6.4% to 64%, marking a ten-fold increase in efficiency. This new route not only enhances the yield but also offers a greener and more cost-effective solution for the large-scale production of MMV688533.