Synthesis of <i>Adagrasib</i> (MRTX849), a Covalent KRAS^G12C Inhibitor Drug for the Treatment of Cancer

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRASG12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyrido­pyrimidine core was accomplished via two sequential SNAr reactions. Extensive reaction optimization led to a robust, transition-metal-free oxidation of the sulfide intermediate. A judicious choice of the leaving group with favorable steric and electronic characteristics at the 4-OH position of the tetrahydropyrido­pyrimidine core enabled a facile SNAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of adagrasib from readily available starting materials obviated the palladium catalysis and protecting group manipulations in the current commercial route and significantly improved the efficiency of the process in 45% overall yield

A Concise and Atom-Economical Suzuki–Miyaura Coupling Reaction Using Unactivated Trialkyl- and Triarylboranes with Aryl Halides

A concise and atom-economical Suzuki–Miyaura coupling of trialkyl- and triarylboranes with aryl halides is described. This new protocol represents the first general, practical method that efficiently utilizes peralkyl and peraryl groups of the unactivated trialkyl- and triarylboranes for the Suzuki–Miyaura coupling reaction

Synthesis of α-Hydroxyacetophenones

A general method for the preparation of α-hydroxyacetophenones is presented. Functionalized arylmagnesium species are transmetalated to the corresponding arylzinc intermediates, which undergo Cu­(I)-catalyzed reaction with acetoxyacetyl chloride. Acidic hydrolysis of the acetate group releases the target α-hydroxyacetophenones with minimal production of undesired polymeric degradates that are often observed under alternative conditions

A Synthesis of 1<i>H</i>‑Indazoles via a Cu(OAc)₂‑Catalyzed N–N Bond Formation

A facile synthesis of 1<i>H</i>-indazoles featuring a Cu­(OAc)₂-catalyzed N–N bond formation using oxygen as the terminal oxidant is described. The reaction of readily available 2-aminobenzonitriles with various organometallic reagents led to <i>o</i>-aminoaryl N–H ketimine species. The subsequent Cu­(OAc)₂-catalyzed N–N bond formation in DMSO under oxygen afforded a wide variety of 1<i>H</i>-indazoles in good to excellent yields

Synthesis of Quinazolines via an Iron-Catalyzed Oxidative Amination of N–H Ketimines

An efficient synthesis of quinazolines based on an iron-catalyzed C­(sp³)-H oxidation and intramolecular C–N bond formation using <i>tert</i>-BuOOH as the terminal oxidant is described. The reaction of readily available 2-alkylamino benzonitriles with various organometallic reagents led to 2-alkylamino N–H ketimine species. The FeCl₂-catalyzed C­(sp³)-H oxidation of the alkyl group employing <i>tert</i>-BuOOH followed by intramolecular C–N bond formation and aromatization afforded a wide variety of 2,4-disubstituted quinazolines in good to excellent yields

Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Strategy

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M

Asymmetric Synthesis of Cyclic Indole Aminals via 1,3-Stereoinduction

A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups

Enantioselective Synthesis of an HCV NS5a Antagonist

A concise, enantioselective synthesis of the HCV NS5a inhibitor MK-8742 (<b>1</b>) is reported. The features of the synthesis include a highly enantioselective transfer hydrogenation of an NH imine and a dynamic diastereoselective transformation. The synthesis of this complex target requires simple starting materials and nine linear steps for completion

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 (<b>1</b>) 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

Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (<b>1</b>) 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 <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (<b>1</b>) has been achieved