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The development of multikilogram scale green and economical synthetic route of enantiomerically pure cis-4-amino-3-fluoro-1-methylpiperidine 1 is described. The synthesis features a highly regio-, ...

The deformation induced atomic-scale stick-slip behaviors are unique and prominent friction characteristics of atomically thin two-dimensional (2D) materials. Here, the deformation induced atomic-scale frictional characteristics of atomically thin 2D materials under different load were explored at different velocity using atomic force microscopy. The evolution of contact quality and puckering forming play important role in atomic-scale frictional characteristics of 2D materials. The critical load was proposed for the strengthening effect at transient period of atomic-scale friction. The velocity-dependent evolution of contact quality affects the strengthening effect when the normal load is less than the critical load. Strengthening degree and distance increase with the increase of the normal load because of high puckering and strong interfacial bonding when the load exceeds the critical load. The suspended 2D materials on asperities of rough substrate possess stronger strengthening effect than smooth substrate because of large deformation space and flexibility. The stick time in stick-slip behavior elongated with the increase of load as the lattice of 2D materials on rough substrate is locally distorted by large deformation under high load. The correlation between the strengthening effect and friction of 2D materials could potentially provide deep insights into the tribological behavior of atomically thin 2D materials.

Copper catalyzed regioselective and stereospecific coupling between aziridines and

The atomic-scale steps are ubiquitous on graphene. The frictional behavior of graphene at atomic-scale steps under different relative humidity (RH) is very important for application of graphene as solid lubricant in complicated environment. Frictional properties at atomic-scale graphene steps were investigated using calibrated atomic force microscopy (AFM) in various RH. Lateral force at uncovered atomic step decreased with the increase of RH, while lateral force at covered step were independent of RH. Uncovered steps possessed higher work function than graphene plane from the scanning Kelvin probe microscopy (SKPM) measurement due to the existence of dangling bonds and oxygen-containing functional groups. Then the adsorption of water molecule on hydrophilic oxygen containing functional groups at uncovered step decreased the work function and reduced the lateral force under high RH. Also, lateral force at steps increased even fast than plane after plasma treatment, because dangling bonds is easier to be oxide functionalization. The studies provide a further understanding of frictional properties at atomic scale steps and could be helpful in the applications of graphene as solid lubricant in humid environment.

Graphene and molybdenum disulfide (MoS2) are promising solid lubricants to deal with the interfacial friction and adhesion concerns in silver nanowires (Ag NWs)-based nanodevices, but their difference in friction performance is seldom considered. Here, the difference in friction performance between graphene and MoS2 has been comparatively studied by manipulating the Ag NWs on graphene and MoS2 surfaces through atomic force microscopy (AFM) tip-on-side and tip-on-top manipulations. The tip-on-side and tip-on-top manipulations demonstrate the atomically thin MoS2 has better friction performance than graphene. The tip-on-top manipulation further shows the shear strength in NW–MoS2 interface is smaller than in NW–graphene interface. The underlying mechanism for the friction difference between the two interfaces is attributed to the different interfacial adhesion interactions. The relatively small adhesion interaction in NW–MoS2 interface leads to a small interfacial shear strength, resulting in a small friction when the NW slides on MoS2 surface. The measured water contact angles, calculated work of adhesion and the adhesion force directly measured by AFM tip confirm the relatively small adhesion interaction in NW–MoS2 interface. These findings suggest that MoS2 may be more appropriate as lubricants for application in the NW-based nanodevices.

DBU as base is key in a practical modified Guareschi–Thorpe cyclization of β-keto esters and 2-cyanoacetamide to allow the synthesis of substituted pyridones in good to excellent yields. The chlorination of DBU salts of pyridones with POCl3 in the presence of a quaternary ammonium salt under standard atmospheric reflux conditions as opposed to the typical pressure equipment led to high yields of substituted 2,6-dichloropyridines.

Nanotribological characteristics of silver nanowires (Ag NWs) are of great importance for the reliability of their applications where involving mechanical interactions. The frictional behaviors of the Ag NWs with different lengths on SiO2/Si substrate have been investigated directly by atomic force microscopy (AFM) nanomanipulation. The relatively short and long Ag NWs behave like the rigid rods and flexible beams, respectively, and the critical aspect ratio of NWs for the two cases is found to be about 20. The relatively short NWs demonstrates three forms of motion with different frictional behaviors. The friction of the relatively long NWs increases with the bend of the NWs. The long Ag NWs display extraordinary flexibility that can be folded to different shapes, and the folded NWs show a similar frictional behavior with the rigid rods. Different simplified mechanical models are established to match the frictional behaviors of the corresponding Ag NWs. The adhesion between the Ag NWs and substrate is calculated by an indirect method based on the van der Waals force equation to assess their adhesive attraction. These findings may provide insight into the frictional characteristics of Ag NWs and contribute to the quantitative interface design and control for their applications.

BI 187004, an 11β-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite [N-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N-methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro-α-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation.

Interfacial friction is of crucial importance to ensure the friction-reducing and anti-wear properties of mechanical microstructures in micro/nanoelectromechanical systems (MEMS/NEMS). An ultra-low frictional interface combining hydrophobic 1H,1H,2H,2H-perfluorodecyltrichlorosilane (FDTS) self-assembled monolayers (SAMs) coated on an AFM tip with mechanically exfoliated molybdenum disulfide (MoS2) nanosheets deposited on a planar Si/SiO2 substrate was achieved. The FDTS SAMs/MoS2 interface between the FDTS SAMs and the MoS2 nanosheets exhibits an ultra-low friction force that is independent of the relative humidity. The incommensurate contact with ultra-low energy dissipation between FDTS and MoS2 nanosheets and hydrophobic surface properties lead to this ultra-low frictional FDTS SAMs/MoS2 interface. Also, the MoS2 nanosheets have a high elastic modulus, which gives them a smaller contact area than the FDTS SAMs and contributes to the low friction. The excellent hydrophobic properties of both the FDTS SAMs and MoS2 enable them to be unaffected by the relative humidity by preventing the capillary interaction. This study paves the way for extensive applications in reducing the friction of nanoscale contact interfaces.

High-performance composite films based on ionic liquids (ILs) and two-dimensional MoS2 have attracted considerable attention because of their unique structure and properties, especially in the field of lubrication. Ultrathin MoS2 nanosheets obtained via a liquid exfoliation process exhibited good dispersion in the organic solution of 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) without the addition of any other additives. A series of uniform composite films with different amounts of MoS2 were spin-coated onto the hydroxylated Si/SiO2 wafers, and the tribological performance of the composite films was studied. The load-carrying capacity and anti-wear properties of the IL films were greatly improved with the addition of MoS2 nanosheets, and the enhanced tribological properties of the composite films were attributed to the synergistic effect of the IL and MoS2. The low-friction composite films may provide a kind of reference and be useful for the design of ultralow friction films for practical lubrication applications.

Graphene is one of the key building blocks for a broad range of flexible/stretchable electronics and has great potential as a solid lubricant in flexible micro/nanoelectromechanical systems, soft robot and microfluidic devices due to their excellent electrical, mechanical and tribological properties. The nanotribological properties of graphene on soft elastic substrate were studied using the calibrated atomic force microscopy (AFM). The nanotribological properties of graphene on soft elastic substrate were enhanced by the elastic deformation compared with the hard SiO2/Si substrate. Also the friction force of graphene on soft elastic substrate decreases with the increase of the thickness and shows a sub-linear dependence on the indentation depth. A novel model of the elastic deformation enhancing puckering effect was proposed to explain the nanotribological properties of graphene on soft elastic substrate. The atomic-scale frictional behaviors of graphene on soft elastic substrate confirmed the mechanism of the elastic deformation enhanced puckering effect. These studies can provide a fundamental understanding of graphene as a solid lubricant on soft elastic substrate for graphene-based flexible MEMS/NEMS devices.

A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.

Graphene as a well-known solid lubricant is widely used in micro- and nano-scale mechanical devices, decreasing the friction of graphene as far as possible is a perpetual task to improve the performance of these devices. A novel approach was proposed to decrease the friction of graphene against atomic force microscopy (AFM) tip by plasma treatment of the substrate. The plasma treatment of the substrate enhances the adhesive attraction between graphene and SiO 2 substrate by generating stronger van der Waals attraction. Enhancing the adhesive attraction can indeed decrease the friction of graphene, regardless of the thickness of graphene and the kinds of AFM tip. Longer time of plasma treatment results in stronger adhesive attraction, leads to smaller friction. The decreased friction is mainly due to the combined action of the suppressed puckering of graphene and the reduced ability of graphene to adjust its atomic configuration. This novel approach will promote the engineering application of graphene and other related 2D materials as lubricants in MEMS/NEMS.

Atomic-scale steps generally presented in 2-dimensional materials have important influence on the overall nanotribological properties of surface. Frictional properties at atomic-scale steps of two types of 2-dimensional materials are studied using calibrated atomic force microscopy (AFM) tip sliding against the steps. The lateral force at uncovered step is larger than covered step due to the bending of step edge. The lateral force at monolayer uncovered step edge of h-BN is lower than graphene because h-BN possesses higher interlayer bonding strength than graphene and the bending of h-BN step edge is suppressed to some extent. The high uncovered step exhibits much larger lateral force than low uncovered step, which could be mainly induced by increased bending stiffness of step edge rather than increased step height. The results revealed that interlayer bonding strength and bending stiffness have great influence on the lateral force at atomic-scale steps. The studies can provide a further understanding of frictional properties at atomic scale steps and could be helpful for the applications of 2-dimensional materials as lubricant coating.

The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.

Graphene and functionalized graphene are promising candidates as ultrathin solid lubricants for dealing with the adhesion and friction in micro- and nanoelectromechanical systems (MEMS and NEMS). Here, the dynamic friction and adhesion characteristics of pristine graphene (PG), graphene oxide (GO), and fluorinated graphene (FG) were comparatively studied using atomic force microscopy (AFM). The friction as a function of load shows nonlinear characteristic on GO with strong adhesion and linear characteristic on PG and FG with relatively weak adhesions. An adhesion enhancement phenomenon that the slide-off force after dynamic friction sliding is larger than the pull-off force is observed. The degree of adhesion enhancement increases with the increasing surface energy, accompanied by a corresponding increase in transient friction strengthening effect. The dynamic adhesion and friction enhancements are attributed to the coupling of dynamic tip sliding and surface hydrophilic properties. The atomic-scale stick-slip behaviors confirm that the interfacial interaction is enhanced during dynamic sliding, and the enhancing degree depends on the surface hydrophilic properties. These findings demonstrate the adhesive strength between the contact surfaces can be enhanced in the dynamic friction process, which needs careful attention in the interface design of MEMS and NEMS.

Graphene shows great potential applications as a solid lubricant in micro- and nanoelectromechanical systems (MEMS/NEMS). An atomic-scale friction strengthening effect in a few initial atomic friction periods usually occurred on few-layer graphene. Here, velocity dependent friction strengthening was observed in atomic-scale frictional behavior of graphene by atomic force microscopy (AFM). The degree of the friction strengthening decreases with the increase of velocity first and then reaches a plateau. This could be attributed to the interaction potential between the tip and graphene at high velocity which is weaker than that at low velocity, because the strong tip-graphene contact interface needs a longer time to evolve. The subatomic-scale stick-slip behavior in the conventional stick-slip motion supports the weak interaction between the tip and graphene at high velocity. These findings can provide a deeper understanding of the atomic-scale friction mechanism of graphene and other two-dimensional materials.

The nanotribological characteristics of silver nanowires (Ag NWs) are of great importance for the reliability of their applications in flexible nanodevices involving mechanical interactions. The frictional behaviors of Ag NWs on graphite substrate were directly investigated by atomic force microscopy (AFM) nanomanipulation. The relatively short NWs demonstrate three forms of motion-rotation, translation and a combination of the two-whose frictional behaviors behave like rigid rods. The relatively long Ag NW shows characteristics of a flexible beam, whose friction increases with an increase in the bending angle of the NW. The friction between the NW and substrate increases linearly with an increase in the length of the NW. The long Ag NW displays extraordinary flexibility that can be folded to different shapes, and the friction of the folded NW becomes smaller due to the decreased bending deformation. The critical aspect ratio of the Ag NW on graphite substrate for two different frictional behaviors between the relatively long and short NWs is found to be 12-15. These findings can deepen the understanding of the frictional characteristics of Ag NWs and contribute to their quantitative interface design.

An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

A practical process was developed for the synthesis of 2-difluoromethylpyridines via a Cu-mediated Reductive Coupling-Hydrolysis-Decarboxylation sequence. The process employed 2-bromopyridines with a variety of functional groups on the pyridine as substrates and used readily available and inexpensive starting materials. For operational safety DMSO shall not be considered as solvent and the use of DMF is recommended.

A series of efficient ruthenium catalysts has been developed for the asymmetric hydrogenation and transfer hydrogenation of ketones with high reactivities and selectivities. The new chiral bisdihydrobenzooxaphosphole (BIBOP)/diamine-ruthenium complexes catalyzed the enantioselective hydrogenation of substrates such as aryl and heteroaryl cyclic and alkyl ketones with substrate/catalyst (S/C) ratios of up to 100,000. The opposite sense of enantioselectivity can be obtained by proper selection of a diamine with a given chirality of the phosphine. The usefulness of the new system has been demonstrated in the asymmetric hydrogenation of a complex synthetic intermediate towards cholesteryl ester transfer protein (CETP) inhibitors at S/C 20,000 on large-scale operation.

Graphene as one type of well-known solid lubricants possesses different nanotribological properties, due to the varied surface and structural characteristics caused by different preparation methods or post-processes. Graphene nanosheets with controllable surface wettability and structural defects were achieved by plasma treatment and thermal reduction. The nanotribological properties of graphene nanosheets were investigated using the calibrated atomic force microscopy. The friction force increases faster and faster with plasma treatment time, which results from the increase of surface wettability and the introduction of structural defects. Short-time plasma treatment increasing friction force is due to the enhancement of surface hydrophilicity. Longer-time plasma treatment increasing friction force can attribute to the combined effects of the enhanced surface hydrophilicity and the generated structural defects. The structural defects as a single factor also increase the friction force when the surface properties are unified by thermal reduction. The surface wettability and the nanotribological properties of plasma-treated graphene nanosheets can recover to its initial level over time. An improved spring model was proposed to elaborate the effects of surface wettability and structural defects on nanotribological properties at the atomic-scale.

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C–H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

A novel trans-diastereoselective reductive amination of 4-substituted cyclohexanones is described using 9-BBN as reducing agent in the presence of FeCl3. The method permits efficient synthesis of structurally diverse 4-trans-alkoxycyclohexylamines.

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.

Enantiomeric separation of two aromatic α-substituted alanine esters was achieved on two commercially available polysaccharide-based chiral stationary phases (CSPs): amylose tris(3,5-dimethylphenylcarbamate) (ADMPC) and cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC). The interactions between enantiomeric analytes and the CSPs were investigated using chromatographic methods and vibration circular dichroism (VCD). The two analytes differ on the aromatic portion of the molecules where one analyte has a π-acceptor aromatic ring (1) while the other has a π-donor aromatic ring (2). When an ADMPC CSP was employed, an increase in the polarity of the mobile phase leads to a reversal of the elution order for the two enantiomers of 1. The elution order of compound 2 was not affected by the polarity of the mobile phase. In order to gain an understanding of these phenomena, the enantiomeric separation of 1 and 2 was also performed on the CDMPC CSP. Interestingly, no reversal of elution order was observed upon the chromatographic separation of both pairs of enantiomers of compounds 1 and 2 upon increasing the solvent polarity when a CDMPC CSP was utilized. To understand the underlying mechanism governing these chiral separations, VCD was applied to study the structure of the ADMPC and CDMPC polymers and their conformational behaviors under chromatographic conditions. For the first time the conformations of the side chains of both polymers were revealed based on the VCD spectra along with DFT calculations. Furthermore, the interactions between the two analytes and the two CSPs were directly probed by VCD. By comparing the spectral differences of the two CSPs in the presence of the two analytes, the detailed interactions involving different functional groups associated with the chiral recognition were elucidated and thus explained the unusual reversal of elution order associated with increasing solvent polarity.

We describe the Ru-catalyzed ring-closing metathesis (RCM) reaction of a densely functionalized diene leading to the 15-membered ring of HCV protease inhibitor BILN 2061. The evaluation of several catalysts led us to the discovery of a new epimerization reaction which plagued our initial attempts to scale-up the reaction. A mechanistic study of this side reaction is described. Factors that may contribute to render our RCM sub-optimal were identified in the low initiation rate of the best catalyst (first-generation Hoveyda), to yield what seems to be a highly stabilized and perhaps catalytically inactive intermediate. Preliminary efforts to affect the initiation site by substrate modification are also discussed.

Diisobutylaluminium hydride has been found to be an excellentreducing agent for phosphinites, phosphinates, and chlorophosphines.By performing reductions in situ, direct synthesis of secondaryphosphine boranes from Grignard reagents has been achieved withoutisolation or purification of any intermediates.

The ring-closing metathesis (RCM) step, a key reaction in our process to BILN 2061, was dramatically improved from the first-generation process by the selection of a more appropriate substrate as well as the use of a more effective catalyst. The two RCM reactions are compared in detail using criteria that are of high significance to the process chemist.

Through unflooded mulching in field plots and 15nitrogen microplot tracer experiments, nitrogen (N) uptake of rice and N utilization have been studied compared with normal irrigation cultivation. The results showed that N uptake of unflooded rice and N derived from fertilizer (NDFF) of root, stem, and grain under mulching cultivation were lower than that under cultivation without mulching. However, the NDFF of rice under unflooded cultivation was higher than that under normal irrigation cultivation. The N utilization has been greatly enhanced under unflooded cultivation without mulching and unflooded plastic film cultivation with mulching as compared with normal irrigation. At the same time, there was no significant difference on the N uptake of unflooded rice among different ways of mulching cultivations. During the growth period of rice, no prominent differences were found in the soil residue, recovery, and N losses of fertilizer except the N uptake of rice between unflooded mulching and normal...

A novel ruthenium carbene-catalyzed epimerization of vinylcyclopropanes is reported. The reaction rate strongly depends on the presence of ruthenium ligands in solution. When the first-generation Grubbs catalyst is employed, a 5.3:1 equilibrium ratio of epimers is established quickly, but when a first-generation Hoveyda catalyst is employed, epimerization is observed only if an additional phosphine or nitrogen ligand is added. NMR and kinetic studies suggest that the isomerization reaction occurs through the intermediacy of a ruthenacyclopentene. The observation suggests that cyclopropylmethylidene ruthenium carbenes of synthetic utility may be accessible via ruthenacyclopentenes obtained via other routes.

Efficient access to dioxo-tetrasubstituted 2,4 E , E -dienes is developed in three steps from commercially available starting materials via sequential transhalogenation and Heck reaction, which provides potentially useful synthons for the synthesis of a tetrasubstituted conjugated diene structure in complex molecules. Thereby, segment C1–C6 of apoptolidin is synthesized.

A very convenient method for the synthesis of unsymmetrical ureas is described, based on isopropenyl carbamates. The synthetic efficiency of traditional methods for urea formation, such as use of phosgene or alkyl and aryl carbamates, is limited by the formation of symmetrical urea side products or reaction reversibility. Isopropenyl carbamates react with amines cleanly and irreversibly and give unsymmetrical ureas in high yield and purity. This method is ideal for the rapid synthesis of compound libraries.

trans-Selective (≥98%) monoalkynylation of 1,1-dibromo-1-alkenes and 1,1-dichloro-1-alkenes catalyzed by Cl2Pd(DPEphos) followed by stereospecific methylation with Me2Zn or MeZnX (X= Cl or Br) catalyzed by Pd(tBu3P)2 provides an efficient and stereoselective (≥98%) route to 5, convertible to a wide variety of enynes and conjugated dienes. In the cases of 1,1-dibromo-1-alkenes, the Sonogashira alkynylation may also be satisfactory, but it is distinctly less satisfactory than the alkynylzinc reaction in cases where 1,1-dichloro-1-alkenes are used.

The new method for the title reaction features the unprecedented use of [Cu(MeCN)]PF6/LIG and (Z)-nitroalkenes.

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.

An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

Ferrocene Tetrahydrofuran Potassium tert-butoxide tert-Butyllithium Di-tert-butylchlorophosphine Tetrafluoroboric acid Di-tert-butylphosphinoferrocene Keywords: Di-tert-butyl-phosphinoferrocene; Hazardous chemical disposals; Aminocarbonylation; Aryl halides

A scalable de novo synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1–0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

The leading HVC protease inhibitors have tested and extended the frontiers of synthetic chemistry. The discovery and development of these anti-HCV drugs presented numerous synthetic challenges which required unmet innovation and implementation of new reactions into large scale production. In this chapter, the syntheses of the leading HCV protease inhibitors not only demonstrated the tremendous creativity exhibited by medicinal chemists in designing such structurally complex molecules, but also exemplified the innovation by process chemists in developing simple solutions to the challenging issues encountered during the scale-up of these syntheses. These synthetic endeavors have furnished the fruit of two revolutionary therapies for HCV to change the dire prognosis and achieve cure rates in three-quarters of the patients.