A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions, 1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, 2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and finally 3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. A regioselective synthesis of an N-Boc-1-mesyl pyrazole fragment was achieved via a base promoted mesyl group isomerisation to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multi-kilogram deliveries, and improved the overall diastereoselectivity and efficiency of the route.

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an ␣,␤-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols. E strogen receptors (ERs) are members of the steroid hormone nuclear receptor superfamily. They are ligand-dependent transcription factors that bind to specific DNA sequences and regulate gene expression. There are two known members of the estrogen receptor family, ER␣ and ER␤, encoded by distinct genes. ER modulators are potentially useful agents for treatment or prevention of a variety of conditions related to estrogen functions, including bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence, and cancer (refs. 1-4 and references cited in ref. 4). SERMs are ER ligands that act like estrogens in some tissues, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic activity, depending on the context in which their activity is examined. Fig. 1) is a potent ER␣ SERM being evaluated as part of the selective ER antagonist program at Merck (1-4). Although there are several methods for the synthesis of the core cis-2,3-disubstituted-dihydrobenzoxathiin, the asymmetric synthesis of these compounds has not been reported (1-7). Herein, we report an enantioselective synthesis of 1. Experimental ProceduresGeneral. Chemicals were used as received from commercial sources unless otherwise noted. NMR data were collected on Bruker Avance NMR spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane. HPLC purity data are reported as area percentage of the desired peak from the total peaks. HPLC conditions are listed in supporting information, which is published on the PNAS web site. High-resolution mass spectrometer (HRMS) data were collected on a Micromass API US Ultima quadrupole time-of-flight (QTOF) mass spectrometer. Vinyl Sulfide 6.A 100-liter round-bottom flask was charged with ketone 7 (8.01 kg, 12.2 mol) and 48 liters of acetonitrile followed by phenylphosphonic dichloride (2.50 kg, 12.9 mol). The flask was fitted with a reflux condenser with off-gases vented through a caustic scrubber, and the reaction mixture was heated to reflux (75°C). After about 2 h, HPLC assay showed Ͼ99% conversion. The reaction mixture was concentrated under reduced pressure at 20-50°C to 28 liters. Diisopropylethylamine (786 g, 6.08 mol) was added, followed by 28 liters of denatured ethanol (denatured with 0.5% toluene). The solution was ...

Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti‐hepatitis C drug grazoprevir.

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...

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.

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