A direct asymmetric reductive amination (DARA) of α,α-disubstituted β-amino esters and amides has been developed to access a key β-amino amide intermediate for the commercial synthesis of a COVID protease inhibitor. High-throughput experimentation was utilized to identify a commercial ruthenium BINAP complex as an optimal catalyst for this transformation and counterion effects were critical for enabling the chemoselective reduction in this DARA strategy. The protocol was employed to synthesize a variety of highly substituted noncanonical β-amino esters and amides in good yields and excellent enantioselectivities. An intermolecular functional group tolerance study revealed that many Lewis basic functionalities are tolerated under reaction conditions and mechanistic insight was gained from reaction profile monitoring, isotopic labeling experiments, precatalyst poisoning studies, and ketone/imine equilibrium experiments.

We report the development of a selective and scalable Shono oxidation process of Boc-l-proline methyl ester (Boc-l-Pro-OMe) using flow electrosynthesis. A key feature of the reaction is the preferential methoxylation of Boc-l-Pro-OMe at its C5 carbon over oxidation at its C2 carbon. Different forms of carbon-based materials (porous graphite, resin-filled graphite, graphite foil, and graphite felts) were explored for the anode material in a Shono oxidation of Boc-l-Pro-OMe, and their impact on selectivity was characterized. Ultimately, an inexpensive carbon-based anode that is able to accommodate high current density was identified, thus enabling high productivity for the formation of the N,O-acetal product. We demonstrate the electrochemical process on two different scales using a parallel plate electrochemical reactor operating in a recirculating mode. A lab-scale setup with a footprint fitting within a standard fume hood was used to process ca. 0.7 kg of Boc-l-Pro-OMe per day. The use of a pilot-scale parallel plate reactor equipped with 0.4 m2 anode surface area of inexpensive electrode materials enabled deca-kilogram scale deployment of the process suitable to electrolyze 13 kg of Boc-l-Pro-OMe per day.

A scalable electrochemical process to synthesize iminophosphorane ligands is reported. The application of these iminophosphoranes was recently reported in Ni-catalyzed cross-electrophile and C–N cross-couplings. The use of parallel plate flow electrochemical reactors enables the synthesis of these iminophosphorane ligands on a multigram scale, with selected examples reported on up to 0.6 kg scale. Direct crystallization from the end of reaction mixture for selected ligands provides facile isolation processes. This article also details improvements in our electrochemical capabilities across scales, including addressing material compatibility issues, increasing accessible range of flow rates, and integration of process analytical technology tools.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals. Electrosynthetic oxidations often may be performed "reagent-free", generating H2 derived from the substrate as the sole byproduct at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications, but more sustainable options are needed at large scale. Anodic water oxidation is an especially appealing option, but many reductions require anhydrous, air-free reaction conditions. This constraint motivates the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions. Here, we report a mediated H2 anode that achieves indirect electrochemical oxidation of H2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H2 anode is used to support nickel-catalyzed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption within the pharmaceutical industry. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H2 anode technology disclosed here offers a general strategy to support H2-driven electrosynthetic reductions.

Here we report the fluorination–dynamic kinetic resolution (DKR) process for the commercial supply of belzutifan (MK-6482). Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed on the basis of increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of the fluorodiol product with low process mass intensity.

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; (iii) isocyanates as alternative electrophiles for direct C-H amidation; (iv) and the use of the developed chemistry in a 24 × 12 parallel synthesis workflow with a 90% library success rate. Fundamentally, the reported protocol expands the use of heterocycle C-H functionalization from late-stage functionalization applications toward its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot diversification.

A novel application of the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters promoted by aluminum-based Lewis acids is described. In the multikilogram synthesis of uprifosbuvir (MK-3682, 1), a clinical candidate for the treatment of hepatitis C, this methodology provided >100:1 diastereoselectivity at the phosphorus stereocenter and >100:1 selectivity for the 5′-mono phosphorylation over undesired bisphosphorylation side products. The high diastereoselectivity and mono/bis ratio achieved enabled elimination of the tedious workup associated with the tert-butyl magnesium chloride protocol commonly used to install this functionality in similar nucleotide prodrugs, achieving a near doubling of the isolated yield from 45% to 81%. The process development and purity control strategy of MK-3682, as well as handling of the pyrophoric reagent on scale, will also be discussed.

We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldol-glycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.

Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK 7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.

A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.

Although diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs were discovered over 50 years ago, the current methodology is not safe, has a limited substrate scope, and is not amenable to large-scale production. For example, a recent investigation utilizing the standard methodology to prepare DAZDs resulted in two unexpected explosions, highlighting the need for safer and more practical chemistry. Recently, we have reported a general, scalable, safer, and high-yielding methodology adaptable to large-scale synthesis of diazeniumdiolates in water using a calcium hydroxide base. Herein, we report the full account for the development of the reaction. The merit of this strategy is evidenced by the highly efficient and safer preparation of a key DAZD intermediate, on the kilogram scale, needed for the preparation of MK-8150 (1), a novel O2-alkylated diazeniumdiolate NO donor under investigation as a potent and significant blood-pressure-lowering drug candidate.

The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors; however, synthetic challenges have hampered their use. O2-alkylation or arylation of diazeniumdiolates form stable pro-drugs which have found application in hypertension, cancer, and as antimicrobial agents. The synthesis of sodium diazeniumdiolates has proven to be challenging due to hazardous reaction conditions (high N2O concentrations, and flammable solvents), which can lead to detonation and suffered from limited scope. We have previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible and a comparison of their reactivity in comparison to sodium diazeniumdiolate.

We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity of the reaction and the heat removal, which were critical for the development of the process. Our goal was to improve the yield and purity of this pharmaceutical intermediate (2-fluoroadenine) and develop a more robust process.

Synthetic diazeniumdiolate (DAZD)-based nitric oxide is utilized to modulate the nitric oxide (NO) concentration in cellular environments and to control physiological processes, yet chemists are still struggling to find efficient and scalable methodologies that will enable them to access sufficient quantities of the high-energy diazeniumdiolate intermediates for biological studies. Now, a general, scalable, safer, and high-yielding new methodology adaptable to the large-scale synthesis of DAZDs has been developed.

NMR studies of the catalyst, deuteration experiments, mass spectrometry, and isolation and characterization of intermediates, allow us to propose an outer-sphere mechanism for the Iridium-catalyzed asymmetric hydrogenation of N-alkyl-2-arylpyridinium salts.

Previous methods to prepare a bicyclic N-hydroxyl urea intermediate in the synthesis of the potent β-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an in situ protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of O-benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of O- and N-benzyl-containing substrates was demonstrated.

A mechanistic study of a rhenium catalyzed monoalkylation of phenols is described. Reaction kinetics reveals a zero-order dependence on both alkene and phenol and a half order dependence on catalyst. Isotopic labeling studies, competition experiments, kinetic isotope effects, and Hammett analysis together afford experimental data consistent with a reversible C–H activation step and an irreversible hydrometalation process. The turnover-limiting step is identified as catalyst deaggregation. NMR studies of binary mixtures of catalyst and a single substrate (alkene or phenol) as well as those of reaction mixtures identify potential intermediates and off-cycle species. Despite the numerous Re complexes formed in these mixtures, the overall reaction is both high yielding and highly selective for monoalkylation of phenols.

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.