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. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Scalable Asymmetric Synthesis of MK-8998, a T-Type Calcium Channel Antagonist.

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Highly Diastereoselective Synthesis of a HCV NS5B Nucleoside Polymerase Inhibitor.

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether.

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin.

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides.

Direct C7-amination of N-pivaloylindoles has been achieved using a combination of [Cp*IrCl2]2, AgNTf2, and AgOAc as the catalyst and sulfonoazides as the nitrogen source. The reaction proceeded at room temperature to 80 °C to afford 7-sulfonamidoindoles in good to excellent yields. The reaction is broadly applicable to the C7-amination of a wide variety of 3-, 4-, 5-, and 6-substituted N-pivaloylindoles with either alkyl or aryl sulfonoazides.

Promotion of a Ti-Mediated Mannich Reaction by a Proton Source.

Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields.

Rhodium-Catalyzed Regioselective C7-Functionalization of N-Pivaloylindoles.

An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,ß-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.

A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold.

Herein, we present a strategy for the preparation of 3'-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2'-ketonucleosides. Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

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.

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties.

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.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

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.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931).

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.

An efficient and scalable synthesis of substituted phenanthrenequinones by intramolecular Friedel-Crafts reaction of imidazolides.

An efficient synthesis of 9,10-phenanthrenequinones is described. The two carbonyl groups were introduced by an orthoselective intermolecular Friedel-Crafts reaction of 3-methoxyphenol with ethyl chlorooxoacetate. The formation of a biaryl bond by Suzuki-Miyaura coupling reaction, followed by the hydrolysis of the ester, gave a biaryloxoacetic acid. Treatment of this acid with CDI gave the corresponding imidazolide. The ring closure to the desired phenanthrenequinone was accomplished by intramolecular Friedel-Crafts reaction of the imidazolide promoted by TiCl(4).

Enantioselective Synthesis of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) via Enzymatic Desymmetrization.

An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired ß-anomer from the glycosylation step.

Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease.

Verubecestat is an inhibitor of ß-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation.

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction.

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp²-sp³ Suzuki-Miyaura coupling and ring closing metathesis.

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp(2)-sp(3) Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.

A Novel, Highly Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides.

Kilogram-scale synthesis of the HIV reverse transcriptase inhibitor efavirenz was achieved by means of a highly enantioselective alkynylation of prochiral ketones 1 with alkynyllithium or alkynylmagnesium reagents in the presence of chiral zinc aminoalkoxides as mediators. With the achiral auxiliary 2,2,2-trifluoroethanol (R3 =CF3 CH2 ), the efavirenz precursor 2 (R1 =H, R2 =cyclopropyl) was obtained with an ee of 99.2%.