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α-heteroaryl acetaldehydes have become important building blocks in the synthesis of synthetic nucleosides. Novel organocatalytic cascades have enabled the rapid generation of nucleosides, which are valuable building blocks in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies, obviating the need for laborious synthetic routes relying on chiral pool starting materials and inefficient synthetic routes. This manuscript describes a robust and scalable protocol to α-heteroaryl acetaldehydes from readily available building blocks.

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (low density lipoprotein cholesterol). Results: MK-0616 displayed high affinity ( K i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84–103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple–oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43–85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

The total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from ᴅ-Garner’s aldehyde and ʟ-serine. Scalable routes towards three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product.

The transition-metal-catalyzed α-arylation of secondary amides remains a synthetic challenge due to the presence of a free N-H bond. We report a strategy to synthesize secondary α-aryl amides via a Ni-catalyzed reductive arylation of redox-active

A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refrac...

Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists. Finally, we calculated medicinal chemistry properties of benzenoid containing APIs that are often used by practitioners as design elements, including "druglikeness", shape, complexity, and similarity/diversity and discuss these properties in the context of synthesis.

The gap between fundamental academic research and the applied industrial research that is necessary to ensure real-world applications can be bridged by engaging in well-defined collaborative academia–industry projects and fostering better communication between the scientists involved in them.

Nucleoside analogs are valuable commodities in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies. Syntheses of nucleoside analogs are typically challenged by a reliance on chiral pool starting materials and inefficient synthetic routes that are not readily amenable to diversification. The novel methodology described in this protocol addresses several longstanding challenges in nucleoside analog synthesis by enabling flexible and selective access to nucleoside analogs possessing variable nucleobase substitution, D- or L-configuration, selective protection of C3'/C5' alcohols and C2' or C4' derivatizations. This protocol provides direct access to C3'/C5' protected nucleoside analogs in three steps from simple, achiral starting materials and is described on both research (2.8 g) and process (30 g) scales for the synthesis of C3'/C5'-acetonide protected uridine. Using this protocol, proline catalyzes the fluorination of simple heteroaryl-substituted aldehyde starting materials, which are then directly engaged in a one-pot enantioselective aldol reaction with a dioxanone. Reduction, followed by intramolecular annulative fluoride displacement, forges the nucleoside analog. The three-step parent protocol can be completed in ~5 d by using simple mix-and-stir reaction procedures and standard column chromatographic purification techniques.

An important metric for gauging the impact a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step PMI for a given synthesis from a process description is more and more common across the pharmaceutical industry, especially in process chemistry departments. Our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with eight EPA Green Chemistry Challenge Awards in the last 15 years and we show how these routes help define aspirational PMI tar-gets. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what a ‘good’ PMI for a molecule looks like given its structure alone. An existing tool chemists have at their disposal to predict PMI requires the synthetic route be provided or proposed (e.g., via retrosynthetic analysis) which then enables practitioners to compare predicted PMIs between routes. We have developed SMART-PMI (in-Silico MSD Aspirational Research Tool) to fill the gap in predicting PMI from molecular structure alone. Using only a 2D chemical structure, we can generate a predicted SMART-PMI from a measure of molecular complexity. We show how these predictions correlate with historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges which we termed “Successful”, “World Class”, and “Aspirational” PMI. The goal of this range is to set the floor for what is a “good” PMI for a given molecule and provide ambitious targets to drive innovative green chemistry. Using this model, chemists can develop synthetic strategies that make the biggest impact on PMI. As innovation in chemistry and processes lead to better and better PMIs , in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI to set industry-wide aspirational PMI tar-gets is discussed.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Glycomimetics are structural mimics of carbohydrates that can replicate their biological activity but have improved drug-like properties. Here, using proline-catalysed α-halogenation/aldol cascades, carbohydrate building blocks are readily assembled and then diversified into glycomimetics including imino- and carbasugars.

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

A nickel-catalyzed reductive cross-coupling of redox-active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in pharmaceutical sciences. Mechanistic studies reveal that decarboxylation of the NHP ester to the reactive radical intermediate is accomplished by a combination of a chlorosilane additive and Zn dust. The reaction exhibits a broad scope as many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents.

A nickel-catalyzed reductive cross-coupling of redox-active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in pharmaceutical sciences. Mechanistic studies reveal that decarboxylation of the NHP ester to the reactive radical intermediate is accomplished by a combination of a chlorosilane additive and Zn dust. The reaction exhibits a broad scope as many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents.

A nickel-catalyzed reductive cross-coupling of redox-active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted a-aryl nitriles, an important scaffold in pharmaceutical sciences. Mechanistic studies reveal that decarboxylation of the NHP ester to the reactive radical intermediate is accomplished by a combination of a chlorosilane additive and Zn dust. The reaction exhibits a broad scope as many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides., An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield.

Aziridines — three-membered nitrogen-containing heterocycles — are important synthetic targets, but N-alkyl aziridines are difficult to synthesize. Now, an electrochemical method, involving a dicationic intermediate, enables the coupling of alkenes and amines.

Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists. Finally, we calculated medicinal chemistry properties of benzenoid containing APIs that are often used by practitioners as design elements, including "druglikeness", shape, complexity, and similarity/diversity and discuss these properties in the context of synthesis.

Cross-coupling reactions, which were discovered almost 50 years ago, are widely used in both industry and academia. Even though cross-coupling reactions now represent mature technology, there is still a significant amount of research in this area that aims to improve the scope of these reactions, develop more efficient catalysts, and make reactions more practical. In this tutorial, a brief background to cross-coupling reactions is provided, and then the major advances in cross-coupling research over the last 20 years are described. These include the development of improved ligands and precatalysts for cross-coupling and the extension of cross-coupling reactions to a much wider range of electrophiles. For example, cross-coupling reactions are now common with sp(3)-hybridized electrophiles as well as ester, amide, ether, and aziridine substrates. For many of these more modern substrates, traditional palladium-based catalysts are less efficient than systems based on first-row transition metals such as nickel. Conventional cross-coupling reactions have also inspired the development of a range of related reactions, such as cross-electrophile and decarboxylative couplings as well as couplings based on metallaphotoredox chemistry. The development of these new reactions is probably at the same stage as traditional cross-coupling reactions 30 years ago, and this tutorial highlights how many of the same strategies used to improve cross-coupling reactions may also be applicable to making the new reactions more practical.

obtained his PhD degree in 2008 with the late Professor Keith Fagnou at the University of Ottawa in Canada as an NSERC Doctoral Fellow. He then joined Merck Research Laboratories at Merck-Frosst in Montreal in 2007, making key contributions to the discovery of Doravirine (MK-1439) for which he received a Merck Special Achievement Award. In 2010, he moved from Quebec to New Jersey, where he has served in roles of increasing responsibility with Merck ever since. L.-C. is currently Executive Director and the Head of Process Chemistry and Discovery Process Chemistry organizations, leading a team of smart creative scientists developing innovative chemistry solutions in support of all discovery, pre-clinical and clinical active pharmaceutical ingredient deliveries for the entire Merck portfolio for small-molecule therapeutics. Over his tenure at Merck, L.-C. and his team have made important contributions to >40 clinical candidates and 4 commercial products to date. Tom Rovis was born in Zagreb in former Yugoslavia but was largely raised in southern Ontario, Canada. He earned his PhD degree at the University of Toronto (Canada) in 1998 under the direction of Professor Mark Lautens. From 1998–2000, he was an NSERC Postdoctoral Fellow at Harvard University (USA) with Professor David A. Evans. In 2000, he began his independent career at Colorado State University and was promoted in 2005 to Associate Professor and in 2008 to Professor. His group’s accomplishments have been recognized by a number of awards including an Arthur C. Cope Scholar, an NSF CAREER Award, a Fellow of the American Association for the Advancement of Science and a ­Katritzky Young Investigator in Heterocyclic Chemistry. In 2016, he moved to Columbia University where he is currently the Samuel Latham Mitchill Professor of Chemistry.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science , this issue p. 426

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C–N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide–Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(II) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.

A convergent three-step method for the synthesis of 2-substituted chromans is described. These results have been accomplished via the Heck coupling of readily accessible allylic alcohols and 2-iodophenols, followed by reduction and Mitsunobu cyclization. The utility and generality of this method is demonstrated through the synthesis of a series of 2-aryl-, 2-heteroaryl- and 2-alkylchromans, as well as an azachroman derivative. The asymmetric version of this approach via a Noyori-catalyzed ketone reduction and subsequent cyclization is likewise highlighted.

The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth's crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield.

The asymmetric hydrogenation of cyclic alkenes lacking coordinating functionality with a C1-symmetric bis(imino)pyridine cobalt catalyst is described and has been applied to the synthesis of important substructures found in natural products and biologically active compounds. High activities and enantioselectivities were observed with substituted benzo-fused five-, six-, and seven-membered alkenes. The stereochemical outcome was dependent on both the ring size and exo/endo disposition. Deuterium labeling experiments support rapid and reversible 2,1-insertion that is unproductive for generating alkane product but accounts for the unusual isotopic distribution in deuterated alkanes. Analysis of the stereochemical outcome of the hydrogenated products coupled with isotopic labeling, stoichiometric, and kinetic studies established 1,2-alkene insertion as both turnover limiting and enantiodetermining with no evidence for erosion of cobalt alkyl stereochemistry by competing β-hydrogen elimination processes. A stereochemical model accounting for the preferred antipodes of the alkanes is proposed and relies on the subtle influence of the achiral aryl imine substituent on the cobalt catalyst.

α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.

Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic hemiaminal center under most standard oxidation conditions. To address this issue, a novel visible light photoredox process for indoline oxidation was developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction was discovered through a high-throughput experimentation campaign and the optimized process was demonstrated on 100 g scale in flow to afford a key intermediate towards the target compound. A battery of kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective HAT from the substrate by an alkoxy radicals. Notably, isotope effects were used to validate the chain mechanism when quantum yield data proved ambiguous.

Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki–Miyaura, cyanation and Buchwald–Hartwig amination.

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

The non-nucleophilic organic superbase P2Et phosphazene can enable a broad range of palladium-catalyzed cross-coupling reactions, including C-C, C-N, and C-O couplings of aryl chlorides, bromides, and iodides at room temperature. The mildness and substrate compatibility of this chemistry can deliver immediate synthetic utility for the preparation of complex molecules.

Breaking through the milligram floor When chemists synthesize compounds, the threshold for success is at least a milligram of product. This has been true for decades—even though biochemical assays have long since descended into microgram territory—and results in part from the constraints of characterization methods. Buitrago Santanilla et al. present an automated dosing and characterization protocol for optimizing chemical reaction conditions on the microgram scale. This allowed them to screen numerous base and ligand combinations for catalytic C-N bond-forming reactions between complex pairs of compounds, in short supply, that resisted standard coupling conditions. Science , this issue p. 49

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a mainstay of therapy for treating human immunodeficiency type 1 virus (HIV-1)-infected patients. MK-1439 is a novel NNRTI with a 50% inhibitory concentration (IC 50 ) of 12, 9.7, and 9.7 nM against the wild type (WT) and K103N and Y181C reverse transcriptase (RT) mutants, respectively, in a biochemical assay. Selectivity and cytotoxicity studies confirmed that MK-1439 is a highly specific NNRTI with minimum off-target activities. In the presence of 50% normal human serum (NHS), MK-1439 showed excellent potency in suppressing the replication of WT virus, with a 95% effective concentration (EC 95 ) of 20 nM, as well as K103N, Y181C, and K103N/Y181C mutant viruses with EC 95 of 43, 27, and 55 nM, respectively. MK-1439 exhibited similar antiviral activities against 10 different HIV-1 subtype viruses (a total of 93 viruses). In addition, the susceptibility of a broader array of clinical NNRTI-associated mutant viruses (a total of 96 viruses) to MK-1439 and other benchmark NNRTIs was investigated. The results showed that the mutant profile of MK-1439 was superior overall to that of efavirenz (EFV) and comparable to that of etravirine (ETR) and rilpivirine (RPV). Furthermore, E138K, Y181C, and K101E mutant viruses that are associated with ETR and RPV were susceptible to MK-1439 with a fold change (FC) of in vitro combination study indicated that MK-1439 acts nonantagonistically in the antiviral activity with each of 18 FDA-licensed drugs for HIV infection. Taken together, these in vitro data suggest that MK-1439 possesses the desired properties for further development as a new antiviral agent.

MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.

A highly enantioselective hydrogenation of cyclic and 1,1-disubstituted alkenes, including substructures of natural products and biologically active compounds, is examined.