Dynamic sampling in autonomous process optimization.

Autonomous process optimization (APO) is a technology that has recently found utility in a multitude of process optimization challenges. In contrast to most APO examples in microflow reactor systems, we recently presented a system capable of optimization in high-throughput batch reactor systems. The drawback of APO in a high-throughput batch reactor system is the reliance on reaction sampling at a predetermined static timepoint rather than a dynamic endpoint.

Transition-Metal-Free C-N Cross-Coupling Enabled by a Multifunctional Reagent.

We report the design and development of a transition-metal-free cross-coupling reaction of phenols and primary amines using a simple and readily available multifunctional reagent. The reactions work by induced proximity and electronic activation of both the nucleophile and the electrophile for net dehydrative C-N coupling reactions. Notably, the reactions do not involve the use of a transition metal for C-N bond formation, preactivation of the phenol electrophile, or exclusion of air or moisture.

The Direct Conversion of Esters to Ketones Enabled by a Traceless Activating Group.

We report here the design and development of a method for the single-step conversion of esters to ketones with simple reagents. The selective transformation of esters to ketones, rather than tertiary alcohols, is made possible by the use of a transient sulfinate group on the nucleophile that activates the adjacent carbon toward deprotonation to form a carbanion that adds to the ester, followed by a second deprotonation to prevent further addition. The resulting dianion undergoes spontaneous fragmentation of the SO group upon quenching with water to reveal the ketone product.

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation.

A kinase-cGAS cascade to synthesize a therapeutic STING activator.

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents.

Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19.

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19.

Molnupiravir (MK-4482) is an investigational antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand and urgency for this compound, it was critical to develop a short and sustainable synthesis from simple raw materials that would minimize the time needed to manufacture and supply molnupiravir. The route reported here is enabled through the invention of a novel biocatalytic cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase.

The application of modern reactions in large-scale synthesis.

In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C-H activation, reductive coupling and flow chemistry. While these methods and technologies offer many strategic advantages in streamlining syntheses, their application on the process scale is complicated by several factors. In this Review, we discuss the challenges that arise when these reaction classes and/or flow chemistry technology are taken from a research laboratory operating at the milligram scale to a reactor capable of producing kilograms of product.

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest.

A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines.

We report the development of a multifunctional reagent for the direct conversion of pyridines to Boc-protected 2-aminopyridines with exquisite site selectivity and chemoselectivity. The novel reagent was prepared on 200-g scale in a single step, reacts in the title reaction under mild conditions without precautions toward air or moisture, and is tolerant of nearly all common functionality. Experimental and spectroscopic monitoring techniques provide detailed insights and unexpected findings for the unique reaction mechanism.

Late-Stage O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway.

A late-stage O labeling approach of sulfonamides that employs the corresponding unlabeled molecule as the starting material was developed. Upon deamination of the sulfonamide, a sulfinate intermediate was isotopically enriched using eco-friendly reagents H O and NH (aq) to afford a M+5 isotopologue of the parent compound. This degradation-reconstruction approach afforded isolated yields of up to 96 % for the stable isotope labeled (SIL) sulfonamides, and was compatible with multiple marketed therapeutics, including celecoxib, on a gram scale.

Reductive Cleavage of Secondary Sulfonamides: Converting Terminal Functional Groups into Versatile Synthetic Handles.

Sulfonamides are pervasive in pharmaceuticals and agrochemicals, yet they are typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild and general method to reductively cleave the N-S bonds of sulfonamides to generate sulfinates and amines, components which can further react to access a variety of other medicinally relevant functional groups. The utility of this platform is highlighted by the selective manipulation of several complex bioactive molecules.

Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl Bromides.

We describe the development of the first reductive cross-electrophile coupling between alkyl sulfones and aryl bromides. The use of alkyl sulfones offers strategic advantages over other alkyl electrophiles as they can be incorporated into molecules in unique ways and permit α-functionalization prior to coupling. The conditions developed here enable incorporation of a wide array of aromatic rings onto (fluoro)alkyl scaffolds with broad functional group tolerance and generality, making this a practical method for late-stage diversification.

NHC-Catalyzed Deamination of Primary Sulfonamides: A Platform for Late-Stage Functionalization.

Herein we describe the development and application of a method for the mild, late-stage conversion of primary sulfonamides to several other other functional groups. These reactions occur via initial reductive deamination of sulfonamides to sulfinates via an NHC-catalyzed reaction of transiently formed N-sulfonylimines. The method described here is tolerant of nearly all common functional groups, as exemplified by the late-stage derivatization of several complex pharmaceutical compounds.

S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds.

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H, C, and N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of S.

A Bifunctional Reagent Designed for the Mild, Nucleophilic Functionalization of Pyridines.

Herein is reported the design and application of a reagent for the direct functionalization of pyridines. These reactions occur under mild conditions and exhibit broad functional group tolerance, enabling the late-stage functionalization of drug-like molecules. The reagent can be easily prepared on large scale from inexpensive reagents, and reacts in the title reaction with acetonitrile, sodium chloride, and sodium methanesulfonate as the sole byproducts.

Reagent Design and Ligand Evolution for the Development of a Mild Copper-Catalyzed Hydroxylation Reaction.

Parallel synthesis and mass-directed purification of a modular ligand library, high-throughput experimentation, and rational ligand evolution have led to a novel copper catalyst for the synthesis of phenols with a traceless hydroxide surrogate. The mild reaction conditions reported here enable the late-stage synthesis of numerous complex, druglike phenols.

Synthesis of Complex Phenols Enabled by a Rationally Designed Hydroxide Surrogate.

The conversion of aryl halides to phenols under mild reaction conditions is a longstanding and formidable challenge in organic chemistry. Herein, we report the rational design of a broadly applicable Pd-catalyzed method to prepare phenols with benzaldehyde oxime as a hydroxide surrogate. These reactions occur under mildly basic conditions and enable the late-stage hydroxylation of several functionally-dense drug-like aryl halides.

An Atom-Economical Method To Prepare Enantiopure Benzodiazepines with N-Carboxyanhydrides.

The development of a rapid, one-pot synthesis of diazepinones with simple reagents is described. N-Carboxyanhydrides (NCAs) are employed as amino acid building blocks that react with o-ketoanilines sequentially as electrophiles and nucleophiles to form diazepinones with water and carbon dioxide as byproducts. Notably, these reactions enable the coupling of stereodefined amino acid derived NCAs without racemization.

Direct Conversion of Haloarenes to Phenols under Mild, Transition-Metal-Free Conditions.

A high-yielding and practical method for the synthesis of phenols from electron-deficient haloarenes and heteroarenes has been developed. The products are formed from acetohydroxamic acid as the hydroxide source via a novel SNAr reaction/Lossen rearrangement sequence. Notably, these reactions employ inexpensive and air-stable reagents, require no special handling, occur under mildly basic conditions, and form products in high yields in the presence of electrophilic and protic functionality.

Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution.

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride.

Copper-mediated perfluoroalkylation of heteroaryl bromides with (phen)CuRF.

The attachment of perfluoroalkyl groups onto organic compounds has been a major synthetic goal over the past several decades. Previously, our group reported phenanthroline-ligated perfluoroalkyl copper reagents, (phen)CuRF, which react with aryl iodides and aryl boronates to form the corresponding benzotrifluorides. Herein the perfluoroalkylation of a series of heteroaryl bromides with (phen)CuCF3 and (phen)CuCF2CF3 is reported.

Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction.

Fluorinated heterocycles are prevalent in pharmaceuticals, agrochemicals, and materials. However, reactions that incorporate fluorine into heteroarenes are limited in scope and can be hazardous. We present a broadly applicable and safe method for the site-selective fluorination of a single carbon-hydrogen bond in pyridines and diazines using commercially available silver(II) fluoride.

Copper-mediated fluorination of arylboronate esters. Identification of a copper(III) fluoride complex.

A method for the direct conversion of arylboronate esters to aryl fluorides under mild conditions with readily available reagents is reported. Tandem reactions have also been developed for the fluorination of arenes and aryl bromides through arylboronate ester intermediates. Mechanistic studies suggest that this fluorination reaction occurs through facile oxidation of Cu(I) to Cu(III), followed by rate-limiting transmetalation of a bound arylboronate to Cu(III).