Some Items of Interest to Process R&D Chemists ... - ACS Publications

Highlights from the Literature Cite This: Org. Process Res. Dev. XXXX, XXX, XXX-XXX

pubs.acs.org/OPRD

Some Items of Interest to Process R&D Chemists and Engineers

■

■

REMOVAL OF TRIPHENYLPHOSPHINE OXIDE BY PRECIPITATION WITH ZINC CHLORIDE IN POLAR SOLVENTS

Despite the exponential growth in the employment of small strained heterocyclic ring systems in drug discovery, there have been relatively few reports on the synthesis or application of azetines. Didier and co-workers have reported on two complementary approaches to a wide variety of disubstituted azetines in good to excellent yields (Org. Lett. 2017, 19, 5681). Both approaches start with the addition of an organometallic (Grignard or organolithium) to commercially available Bocprotected 3-azetidinone followed by methylation of the crude intermediary tertiary alcohol. Treatment with excess s-BuLi triggers a β-elimination leading to the key 4-azetinyl lithium intermediate, which can be trapped with a range of electrophiles or with B(OiPr)3 to form a stable organoboronate. The organoborate is an excellent substrate for Pd-mediated Suzuki crosscouplings. Alternatively, the 4-azetinyl lithium species can be engaged in a catalyst free cross-coupling through adaptation of a Zweifel-type olefination strategy to provide the 3,4-disubstitued azetines. Hydrogenation provides the corresponding syn-azetidines, which are difficult to access with high diastereoselectivity by alternative means.

Despite its significant utility as a reagent in synthetic chemistry, one of the main issues with the use of triphenylphosphine (TPP) is the removal of the corresponding oxide byproduct (TPPO) after reaction. To achieve this often chromatography is required, though use of alternative phosphines or a drive to develop catalytic processes have emerged as approaches to avoid this issue. Weix and co-workers have reported on a solution which exploits the insolubility in polar solvents of the complex formed between ZnCl2 and TPPO (J. Org. Chem. 2017, 82, 9931). The investigation of this complexation process led to the conclusion that 3 equiv of ZnCl2 was able to completely remove TPPO, though given the diminishing returns, 2 equiv (removes ∼97%) was selected for the subsequent optimization studies. A solvent solubility screen demonstrated that EtOH was the best although i PrOH, EtOAc, and iPrOAc were also effective. An evaluation of the compatibility of a range of functional groups indicated that further optimization would be required if this process was to be employed in reactions involving compounds with basic nitrogens. In addition, care must be exercised if there is potential for the reaction of a sensitive functional group (e.g., a lactone) with EtOH under Lewis acidic conditions. Despite these limitations, a reductive cyclization, Corey−Fuchs, and Mitsunobu reactions were all carried out on multigram scale with the ZnCl2−TPPO2 precipitation employed allowing for the desired products to be isolated without chromatography. © XXXX American Chemical Society

METHODS FOR THE SYNTHESIS OF SUBSTITUTED AZETINES

■

GRAM-SCALE SYNTHESIS OF AMINES BEARING A gem-DIFLUOROCYCLOPROPANE MOIETY Given that the incorporation of small fluorinated fragments in drug-like molecules continues to rise, this has created an onus on the synthetic community to provide robust, scalable routes to these molecules of interest. Grygorenko and co-workers have reported on a synthesis of amines featuring a gem-difluorocyclopropane moiety using the readily available Ruppert−Prakash reagent (Adv. Synth. Catal. 2017, 10.1002/adsc.201700857). Evaluating a series of olefins under the standard reaction conditions in refluxing THF indicated that only the most reactive olefins (gem-disubstituted) provided good yields of the desired cyclopropane, while other solvents proved to be ineffective. Conducting a control experiment omitting the substrate demonstrated that the key issue herein was competitive decomposition of the TMSCF3 to a series of gaseous byproducts under the reaction conditions. Whereas continuous flow provides a

A

DOI: 10.1021/acs.oprd.7b00338 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

products with TMPMgCl·LiCl then enables functionalization at the C-8 position, whereas the addition of BF3·OEt2 to the reactions leads to functionalization at the C-2 position due to the BF3-complexation enhancing the acidity of this position. Metalation of the 2,4-disubstituted naphthyridine with TMP-Li followed by trapping with electrophiles enables access to the C-8 position, while treatment with the 8-iodo species (accessed in this manner) with TMP-Li followed by trapping with an electrophile leads to the rearrangement of the iodo and functionalization at the C-8 position through a lithium-mediated “halogendance” rearrangement. DFT calculations were carried out to explain the facile nature of this rearrangement. The methodology was applied on the gram scale to several bioactive naphthyridines.

■

potential to mitigate against this, the current report demonstrated that slow addition of the reagent to the reaction mixture also provided a practical solution to this problem. Employing this approach enabled not only excellent conversions and yields to be realized but also allowed reactivity trends to be identified. In general, gem-disubstituted are the most reactive with the trend correlating with steric hindrance. For other classes of olefins, electronics are the major factor with the ability of the substituents to stabilize a positive charge in the transition state consistent with a nonsynchronous formation of the two sigma bonds in the cycloaddition the key consideration. The removal of the Bocprotecting group under standard acidic conditions provided the amines as their hydrochloride salts.

■

MANGANESE-BASED PHOTOREDOX CATALYSIS FOR C−H ALKYLATION OF HETEROARENES: APPLICATIONS AND MECHANISTIC STUDIES

The Minisci reaction provides a powerful method for the C−H functionalization through the addition of alkyl radicals to heteroaromatic bases, and although photomediated versions have been disclosed, they all suffer from drawbacks such as expensive catalysts or limited scope. Fadeyi, Frenette, and co-workers have reported on a Mn-mediated visible-light initiated Minisci-type reaction, which relies on the photochemical homolysis of the Mn−Mn bond in Mn2(CO)10 to initiate the reaction (Angew. Chem., Int. Ed. 2017, 10.1002/anie.201707958). Optimization studies demonstrated that two equivalents of the alkyl iodide (alkyl bromides were unsuccessful substrates) were sufficient, while 15 mol % of the catalyst and a catalytic amount of a Brønsted acid led to the best yields. From a scope perspective, a wide range of primary, secondary and tertiary alkyl iodides were tolerated, while an array of heterocyclic cores proved to be effective substrates including relatively complex drug-like molecules such as saguinavir. The reaction was also demonstrated in an array format leading to a 97% success rate, with the scope being significantly expanded through in situ generation of the alkyl iodides by treatment of the corresponding alcohols with the iodo-Ghosez reagent. Mechanistic studies demonstrate the intermediacy of the Mn(CO)5 radical with the stronger bond dissociation energy of the C−Br bond being proposed for the lack of reactivity of these substrates.

Zn-, Mg-, AND Li-TMP BASES FOR THE SUCCESSIVE REGIOSELECTIVE METALATIONS OF THE 1,5-NAPHTHYRIDINE SCAFFOLD (TMP = 2,2,6,6TETRAMETHYLPIPERIDYL)

■

The ability to regioselectively functionalize heterocyclic scaffolds represents a powerful methodology in organic synthesis. Knochel and co-workers have reported on the utility of Zn-, Mg-, and Li-TMP bases for the reliable, sequential synthesis of tetra-substituted 1,5-naphthyridines (Chem. Eur. J. 2017, 23, 13046). Initial treatment with TMP2Mg·2LiCl leads to precomplexation and subsequent functionalization at the C-4 position. Treatment of the B

DIRECT SYNTHESIS OF AMIDES BY DEHYDROGENATIVE COUPLING OF AMINES WITH ALCOHOLS OR ESTERS CATALYZED BY A MANGANESE PINCER COMPLEX



■

UNRAVELING COMPLEXITY IN THE SOLID FORM SCREENING OF A PHARMACEUTICAL SALT: WHY SO MANY FORMS? WHY SO FEW? Because of technical and intellectual property considerations, one of the most important strategic decisions made in the evolution of a solid dosage form API is the definition of the polymorph to be developed. During the past two decades, methods to establish the solid form landscape of an API went through a number of transformations, from low to high, and then to medium throughput. With the advancement of crystal structure predictions methods, an “ideal” polymorph screening includes a creative combination of both computational and experimental techniques. An example of such an approach, emphasizing the value of the computational/experimental synergy, was published by a team from Lilly, University College London, Massachusetts Institute of Technology, Eurofins Lancaster, and the University of Innsbruck (Braun, D. E.; Reutzel-Edens, S. M., et al. Cryst. Growth Des. 2017, 17, 5349). The model compound discussed is a 5-HT2a agonist, 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)2,2-dimethylpropanoic acid hydrochloride (B5HCl). The experimental program comprised more than 450 experiments; however due to practical considerations, automated screening platforms using preprogrammed routines had to be abandoned in favor of manual methods, where suitable process modifications could be made effectively. The paper reiterates that there are no standard recipes to carry out effective solid form screens. The study revealed that B5HCl exhibits at least 14 forms: two anhydrous polymorphs (I and II), a dehydrate, 9 alcohol monosolvates (1:1) from 9 monoalcohols, and 2 hemisolvates (2:1) from ethylene glycol and propylene glycol. Extensive solid-state characterization was executed for all of the forms identified. The half of a century old McCrone statement is mentioned, showing that it stood the test of time: “...the number of forms known for each compound is proportional to the time and money spent in the research on that compound”. This paper has 68 references, and the Supporting Information has 76 pages.

Amide bond formation still represents a key challenge from a sustainability perspective in the pharmaceutical industry. Dehydrogenative coupling between alcohols and amines mediated by base−metal complexes represents a method to achieve this goal, and although some progress has been reported, significant challenges still exist particularly in the case of primary alcohols given their propensity for imine formation. Milstein and co-workers have reported on the synthesis of a Mn-based PPhNNH pincer complex and its ability to mediate the formation of amides (Angew. Chem., Int. Ed. 2017, 10.1002/anie.201709180). Evaluation of the new complex in the reaction between hexan-1-ol and 4-methylbenzylamine revealed high levels of amide formation in the presence of KOtBu. From a scope perspective, amides were formed in good to excellent yields for a range of linear and branched alcohols with a number of benzylamines. Aliphatic amines provided lower yields due to competing self-dehydrogenative coupling, while benzylic alcohols gave high levels of imine formation. Extending the reaction to symmetrical esters provided two equivalents of the desired amide. From a mechanistic perspective, treatment with base allowed an active Mn-catalyst species to be isolated featuring a hemilabile pincer amine “arm” which allows an amine attack on the Mn-coordinated intermediary aldehyde.

■


RAPID METHOD DEVELOPMENT IN HYDROPHILIC INTERACTION LIQUID CHROMATOGRAPHY FOR PHARMACEUTICAL ANALYSIS USING A COMBINATION OF QUANTITATIVE STRUCTURE−RETENTION RELATIONSHIPS AND DESIGN OF EXPERIMENTS

Quality by Design (QbD) has found a special niche in analytical chemistry, and the term “Analytical QbD”, or “AQbD”, is becoming more and more popular. In general, AQbD refers to the use of statistical design of experiments (DoE) in the development of an analytical method (often UPLC, or HPLC), or in the robustness assessment of such a method. A collaboration among Pfizer, the University of Tasmania, Thermo Fisher Scientific, and LC Resources describes the use of DoE for the rapid method development in a hydrophilic interaction liquid chromatography (HILIC) application (Taraji, M.; Haddad, P. H., et al. Anal. Chem. 2017, 89, 1870). The DoE methodology was used in synergy with a quantitative structure−retention relationship (QSRR) analysis with the former providing optimized chromatographic conditions for a given analyte and the latter allowing for retention time predictions for several analytes. After preliminary risk analysis and probably a screening DoE, a central composite design (CCD) DoE was executed including three factors: amount of acetonitrile in the mobile phase, pH, and buffer concentration in the mobile phase. The type of the stationary phase was identified to be a high impact factor and was studied separately. 38 Compounds belonging to three classes were investigated: 15 β-adrenergic agonists, 13 benzoic acids, and 10 nucleosides. An optimized set of 321 molecular descriptors was used for QSRR simulation purposes. Monte Carlo simulations were executed to quantify the risk associated with the execution of the processes in the proposed design spaces. Excellent agreement was obtained between the predicted and the experimental chromatograms. This paper has 59 references, and the Supporting Information is quite detailed (13 pages).

■

ANGLE-DIRECTED NUCLEATION OF PARACETAMOL ON BIOCOMPATIBLE NANOIMPRINTED POLYMERS Inspired by the success with crystal growth control in the field of semiconductors, using imprinted geometrical patterns on amorphous surfaces (glass, polymers) crystallization scientists have evaluated the possibility of nucleation and growth control for active pharmaceutical ingredients as well. As a continuation of their work in this field, the groups of Professors Myerson and Trout at the Massachusetts Institute of Technology reported their recent finding on nucleation control using biocompatible nanoimprinted polymers (Stojakovic, J.; Trout, B. L., et al. Cryst. Growth Des. 2017, 17, 2955). The model compound used was paracetamol, and the polymer used was 2-hydroxyethyl cellulose. The imprinted polymer films were prepared using nanopatterned silicon “masters”, which in turn were fabricated using a relatively sophisticated process allowing for five different patterns to be imprinted. Computational methods were used to analyze the paracetamol crystal faces and their interaction with the nanoimprinted polymer. The crystallization experiments were conducted in carefully cleaned vials, using 6 mm polymer pieces to control nucleation, and a microscope to observe crystal formation. The fastest crystallization rate was observed with the polymer imprinted with 40° angle nanopatterns: 4 h vs 16 h in the absence of the nanoimprinted polymer. Atomic force microscopy C




allow the reaction to occur at reasonable temperatures and in good yields. However, the nuances of the reaction’s catalytic cycle are still being understood, and numerous catalyst deactivation pathways exist, requiring relatively high catalyst and ligand loadings. Moreover, when insoluble inorganic bases are used, the reaction is often plagued by poor reproducibility and scalability, making it unappealing for industrial use. A recent publication from a team led by researchers at the University of Leeds (Chem. Sci. 2017, 8, 7203−7210) delves into the mechanistic origins of these requirements through detailed experimental studies. Surprisingly, when the morphology and particle size of the inorganic base were investigated, it was found that a larger induction period and worse reproducibility were observed for finely milled bases, a counterintuitive observation explained by the greater formation of the catalytically inactive Cu-bis(amido) species when the more deprotonated amine is able to form.

imaging was used to study crystal formation and growth. Insights into understanding of the observed nucleation acceleration were developed; it is postulated that the concentration of the solute is increased near the polymer surface due to favorable solute− polymer interactions, with the nanoimprints providing geometrical confinement facilitating orientational ordering of the solute. This technology can prove to be valuable for difficult-tonucleate crystals. The computational methods developed are expected to be used in the design of optimal polymer patterns, eliminating the experimental need for screening various angular patterns.

■

COMPLEXATION-ASSISTED CONTINUOUS CRYSTALLIZATION OF ISOMERIC SYSTEMS WITH NANOFILTRATION RECYCLE The formation of API isostructural impurities leads to the need of API purification, often conducted by recrystallization at the expense of yield. A better strategy was developed by Professor Myerson’s group at the Massachusetts Institute of Technology, based on selective impurity complexation (Vartak, S.; Myerson, A. S., et al. Cryst. Growth. Des. 2017, 17, 5506). Because of their larger molecular volume, selectively formed complexes are prevented from incorporation into the API host lattice and can be effectively separated from the desired API using a nanofiltration membrane. The use of this nanofiltration method allows for a yield increase through mother liquor recirculation without the undesired increase of impurity concentration. Two model systems were used for proof of concept: 4-nitrophenol with 3-nitrophenol impurity, and acetaminophen API with 3-acetamidophenol impurity. On the basis of structural considerations, the complexing agents selected were 3-aminobenzoic acid for the 4-nitrophenol system and 3-nitrobenzoioc acid for the acetaminophen system. A 24-PBI-DBX membrane was used [prepared using 24% wt. polybenzimidazol (PBI) dissolved in dibromoxylene (DBX)]. An evaporation step is used to ensure suitable throughput. Certain yield improvements were observed; however in the acetaminophen case, the continuous process was capable to reduce the amount of the 3-acetamidophenol impurity to 0.12%, compared with the level of 1.18% obtained in the batch recrystallization (in two cycles). The experimental system is depicted in the schematic below. A picture of the membrane setup is included in the Supporting Information. Additional examples of this technology were reported by the same group in Org. Process Res. Dev. 2017, 21, 253.

■

ANTI-MARKOVNIKOV ALKENE OXIDATION BY METAL−OXO-MEDIATED ENZYME CATALYSIS A recent report from the Arnold group (Science 2017, 358, 215) describes the enzyme-catalyzed anti-Markovnikov oxidation of alkene feedstocks using a modified cytochrome P450 enzyme and oxygen as the terminal oxidant. Impressively, directed evolution was used to steer the enzyme away from the competing epoxidation reaction toward direct oxo transfer, resulting in the net anti-Markovnikov oxidation of styrenes through enantioselective 1,2-hydride migration. Intriguingly, the anti-Markovnikov oxygenase (aMOx) could be combined with a second enzyme an alcohol dehydrogenase (ADH)to enable a formal one-pot enantioselective hydration of alkenes, a transformation that is not easily accomplished catalytically using chemical means. Unfortunately, for the most interesting cases where substituted alkenes are used to generate new stereogenic centers, side reactions such as epoxidation and allylic oxidation become more competitive,

■

ORIGINS OF HIGH CATALYST LOADING IN COPPER(I)-CATALYZED ULLMANN−GOLDBERG C−N COUPLING REACTIONS On the surface, the Ullmann−Goldberg C−N coupling reaction appears almost ideal for use in a process setting; aryl halides and amines can be coupled using an inexpensive and nontoxic copper catalyst, and recent developments in ligand design now often D




10.1039/C7GC02190a) and shows the importance of thinking beyond mass-based metrics in evaluating the environmental impact of a chemical step or process.

resulting in lower yields and suggesting that further evolution may be required to increase efficiency for these systems.

■

■

POTASSIUM ISOPROPYL XANTHATE (PIX): AN ULTRA-EFFICIENT PALLADIUM SCAVENGER Despite several known drawbacks, palladium-catalyzed reactions remain a mainstay of carbon−carbon and carbon−heteroatom bond-forming reactions in the pharmaceutical industry. The popularity of these reactions in drug manufacture combined with the potential toxicity of palladium residues has created a need for ultraefficient palladium scavengers that are capable of reducing the palladium content of reaction products to ppm levels. A recent publication from Reng and Maloney et al. at Merck & Co. (Green Chem. 2017, 19, 4002) describes the use of potassium isopropyl xanthate (PIX) as a new palladium solubilizing agent to assist in the rejection of residual palladium during API recrystallization. Although numerous methods for palladium removal have been described, it was found that these were not effective when applied to the highly polar compound of interest under the acidic conditions of the crude reaction stream. In contrast, PIX was shown to exhibit improved stability at low pH compared to other common scavengers, and just 5 mol % could reduce palladium content to 0.1 ppm in the case shown. Although this publication only describes the use of this scavenger in a single case, it was demonstrated to be effective on 30 kg scale in the pilot plant, showing that it can viably be incorporated into a commercial drug synthesis.

ELECTROCHEMICALLY ENABLED, NICKEL-CATALYZED AMINATION A recent report from the Baran laboratory details a new electrochemical nickel-catalyzed amination reaction (Angew. Chem., Int. Ed. 2017, 56, 13088). This cross-coupling protocol overcomes a number of common limitations of nickel catalyst systems for C−N bond formation, allowing aryl halides to undergo coupling with a range of amine partners at room temperature. Primary and secondary amines are tolerated, even when alpha-branching is present, and the reaction works well for electron-poor and electron-neutral aryl halides. Helpfully, the new conditions are compared to literature yields for alternative palladium-, copper-, and nickel-catalyzed systems in order to show where this reaction system can offer an improvement over the current state of the art. The potential scalability of the reaction is demonstrated through a 100 mmol (22.5 g) example. Unusually for nickel, the system has the advantage of being able to employ chlorides, bromides, iodides, and triflates as substrates and inexpensive electrodes (reticulated vitreous carbon (RVC) and nickel) and electrolyte materials are used. However, the low concentration required, the need for 3 equiv of amine coupling partner, and the inability to use anilines may prove drawbacks in a process setting.

■

■

SYNTHETIC ORGANIC ELECTROCHEMICAL METHODS SINCE 2000: ON THE VERGE OF A RENAISSANCE Although electrochemistry is frequently used on ton-scale in bulk chemical manufacture, its applicability to the large-scale synthesis of fine chemicals such as pharmaceutical ingredients has yet to be demonstrated. However, given the number of useful new electrochemical methods that have appeared in the chemical literature in recent years, this seems surely set to change in the future. This review from Baran and co-workers (Chem. Rev. 2017, 10.1021/acs.chemrev.7b00397) summarizes new developments in synthetic organic electrochemical methods over the past two decades as well as providing a useful introduction and brief history of the field of organic electrochemistry. As much of the early electrochemical literature is often not written for a general organic audience, this review provides a valuable compendium of useful organic reactions that can be accomplished

DESIGN AND EVOLUTION OF THE BMS PROCESS GREENNESS SCORECARD Within the pharmaceutical industry, a green chemistry mindset can lead to processes that are not only better for the environment, but also more sustainable, cost-effective, safer, and profitable. Given the obvious benefits, chemists have devised numerous metrics to assess the “greeness” of a given reaction or process, the most popular being the mass-based E factor and product mass intensity (PMI). However, these simple metrics often miss other important considerations such as the nature and number of solvents used (and if they can be recycled), the hazards of chemical intermediates, the number of isolations, and the nature of the waste streams generated. As such, companies and researchers have attempted to develop more holistic scoring systems that better encapsulate these less tangible factors. The evolution of Bristol−Myers Squibb’s “Greenness Scorecard” is detailed in a recent publication (Green Chem. 2017, E



■

electrochemically and makes a strong case for the wide use of these green, economical, and scalable methods. This article contains 914 references.

■

OXIDATIVE ANNULATIONS INVOLVING DMSO AND FORMAMIDE: K2S2O8 MEDIATED SYNTHESES OF QUINOLINES AND PYRIMIDINES

ARTIFICIAL BIOCATALYTIC LINEAR CASCADES FOR THE PREPARATION OF ORGANIC MOLECULES

The use of chemical cascades, where the product of one chemical step is subject to subsequent transformations in the same pot without isolation of intermediates, is highly desirable in a process setting. Enzymes are uniquely suited to use in these types systems owing to their exquisite substrate specificity that prevents them from acting on the wrong substrate at the wrong time and allows them to peacefully coexist in the same reaction vessel. A review by Kroutil and co-workers at the University of Graz (Chem. Rev. 2017, 10.1021/acs.chemrev.7b00033) provides a snapshot of the power of artificial biocatalytic cascades over the past decade. The article covers both purely biocatalytic processes, where all steps in the cascade are enzyme-mediated (or spontaneous after initiation by the enzyme), as well as systems that combine biocatalysis with unnatural catalysts and reagents. This overview will be extremely useful to those interested in biocatalysis or incorporating enzymatic steps into a larger chemical process. The review contains 434 references.

■


DMSO has been employed as a one-carbon homologation source to generate a variety of heterocycles and useful motifs but generally requires preassembly of a structure that can intercept the sulfenium ion in an intramolecular fashion. Jadhav and Singh from the Indian Institute of Technology Kanpur have described one of the few examples of a three-component, intermolecular annulation using DMSO as a one-carbon source to provide useful heterocycles (Org. Lett. 2017, 19, 5673). Sulfenium ions can be generated by the mixture of DMSO with K2S2O8 and reacted with various nucleophiles. When acetophenones and anilines are used as nucleophiles, quinolines are generated. The increased nucleophilicity of aniline versus acetophenone can lead to aniline dimer byproducts, but the addition of FeCl3 as additive can limit these side products for electron-rich acetophenones by assisting with enolization. FeCl3 is not required with electron-deficient acetophenones. Only para-substituted anilines are suitable for this reaction, possibly due to oxidative modification/degradation of unsubstituted substrates. Under similar conditions with formamide instead of DMSO, pyrimidines are formed. A variety of substituted acetophenones react with two equivalents of formamide to generate 4-substituted pyrimidines in low to moderate yield.

OXIDATIVE SYNTHESIS OF BENZIMIDAZOLES, QUINOXALINES, AND BENZOXAZOLES FROM PRIMARY AMINES BY ORTHO-QUINONE CATALYSIS

■

Catalytic and metal-free synthetic methods to access heterocycles such as benzimidazoles and benzoxazoles are very valuable. Luo and co-workers at the Chinese Academy of Sciences in Beijing have described the use of an ortho-quinone catalyst to promote the oxidative synthesis of a variety of heterocycles with primary amines under mild conditions (Org. Lett. 2017, 19, 5629). The ortho-quinone catalyst is available in 1−2 steps from commercially available materials and promotes the oxidation of primary and secondary amines, activating them for cyclization with o-amino anilines, or o-aminophenol, to make benzimidazoles and benzoxazoles, respectively. An acid additive is required for benzimidazole synthesis, to activate the in situ generated imine, while base additive is required for benzoxazole synthesis. Without catalyst, no product is formed. Benzylamines provide the best results for both heterocycles; however, alkylamines can also be used in moderate to excellent yields in the synthesis of benzimidazoles. Interestingly, when 2-phenethylamine was used as a substrate, quinoxaline formation was favored. Regioisomers are formed if monosubstituted o-aminoanilines are used with 2-phenylethylamines in ∼1:1 selectivities. The reaction is run under oxygen to oxidize the cyclized adducts to the heterocycles, as well as to regenerate the catalyst. The use of other oxidizing reagents in place of oxygen was not described.

STEREOSELECTIVE TANDEM BIS-ELECTROPHILE COUPLINGS OF DIBORYLMETHANE

1,1-Diborylalkanes have become versatile reagents for the stereoselective synthesis of a variety of structural motifs due to their ability to be selectively cross coupled and used as a carbon nucleophile due to the relatively acidic C−H bond. Meek and co-workers at the University of North Carolina have expanded upon the utility of 1,1-diboryl methane by developing a coppercatalyzed three-component coupling with epoxides and allyl electrophiles (J. Am. Chem. Soc. 2017, 139, 14061). After deprotonation with LTMP, lithiated diborylmethane reacts regioselectively with terminal and internal epoxides at the sterically least hindered center. NMR studies showed the addition to be poorly stereoselective, providing cyclic boronates in 56:44 dr after reaction with styrene oxide. But upon addition of CuCl and an allyl bromide, the antihomoallylic boronate is isolated in useful diastereoselectivity and yield. It was observed that both diastereomers F




sciences involved in bringing C−H functionalization to main stream science.

that arise from the epoxide opening react with copper at similar rates, suggesting that the antiselectivity arises from the kinetic selectivity of the Cu-alkyl species generated via transmetalation. The boronate products are useful intermediates, participating in selective oxidation, amination, cross-coupling, and isomerization/ allylation reactions.

■

COPPER-CATALYZED ENANTIOSELECTIVE HYDROBORATION OF UNACTIVATED 1,1-DISUBSTITUTED ALKENES

■

TOTAL SYNTHESIS OF (−)-NAHUOIC ACID Ci(Bii) The enzyme histone lysine monomethyltransferase SETD8 is an epigenetic regulator of essential cellular functions. Nahuoic acid A, a polyketide, is the first known selective SAM-competitive inhibitor of SETD8. Consequently, there is considerable interest in the synthesis of the highly functionalized polyol. The Smith Research Group at the University of Pennsylvania have reported the first total synthesis of (−)-nahuoic acid Ci(Bii) (J. Am. Chem. Soc. 2017, 139, 13668). The group initiated the synthesis by using the readily accessible starting materials 1−3, employing anion relay chemistry (ARC), a protocol developed by the group to construct the 1,3,5-triol functionality. In addition, Ti-catalyzed asymmetric Diels−Alder reaction generated the cis-decalin skeleton with high enantioselectivity. The late stage union of the highly functionalized fragments led to the synthesis of the (−)-nahuoic acid Ci(Bii) in 16 linear steps. This report may lead to the rapid development of a variety of analogues for biological evaluations.

While enantioselective hydroboration of alkenes has been thoroughly studied, obtaining high yields and enantioselectivities with alkyl 1,1-disubsituted alkenes remain a challenge. Yun and co-workers at Sungkyunkwan University have developed an exceptionally high yielding and enantioselective copper-catalyzed hydroboration of 1,1-disubstituted alkenes (J. Am. Chem. Soc. 2017, 139, 13660). Utilizing cheap and commercially available catalyst, CuCl, and hydroborating agent, pinacolborane (HB(pin)), the ligand selection proved critical for not only enantioselectivity, but reactivity with alkyl 1,1-disubstituted alkenes. Several phosphine and NHC ligands were screened but showed no reactivity. However, the use of commercially available DTBM-Segphos, and KOtBu as base, provided the hydroboration product in excellent yield and enantioselectivity for a variety of alkenes with broad functional group tolerance. The reaction is run at room temperature with 5% catalyst loading and was shown to be first order in catalyst and HB(pin).

■

CATALYTIC, ENANTIOSELECTIVE SYNTHESIS OF POLYCYCLIC NITROGEN, OXYGEN, AND SULFUR HETEROCYCLES VIA Rh-CATALYZED ALKENE HYDROACYLATION The efficient synthesis of heterocycles remain relevant as these motifs are present in many biological active natural products, pharmaceuticals, agrochemicals, and so forth. Stanley et al. have disclosed the enantioselective synthesis of polycyclic heterocycles via catalytic rhodium-catalyzed alkene hydroacylation (Org. Lett. 2017, 19, 5054). The team found a catalyst generated from [Rh(cod)Cl2, (R)-MeO-Biphep, and NaBARF gave moderate to high yields (65−99%) and good to excellent enantioselectivities (84−99%). A variety of structurally complex heterocycles were synthesized, which contained alkyl, electron-rich, and electron-poor substrates, indoles, thiophenes, furan, and so forth.

■

COLLECTIVE APPROACH TO ADVANCING C−H FUNCTIONALIZATION Davies and Morton at the Emory University have given an interesting perspective on the collective approach in bringing the once obscure C−H functionalization that have now become an important tool in synthetic and computational methodology, physical organic, enzymology, and so forth (ACS Cent. Sci. 2017, 3, 936). Key to the advancement of C−H functionalization they pointed out was the creation of the Center for Selective C−H Functionalization (CCHF) by the National Science Foundation Center for Chemical Innovation, which facilitated extensive collaboration between researchers of diverse backgrounds. In addition, the CCHF addressed the issue of selectivity in three main categories; catalyst/reagent control, prior coordination of the catalyst to the substrate, and bioinspired site selective control. As illustrated below for the catalyst/reagent controlled selectivity, the dirhodium catalyst controlled the functionalization of the most accessible methylene group. This outlook brought to light the systematic and dedicated efforts in the breakthrough

G




synthesis of acid 1. The team quickly identified a scalable route, which enabled the coupling of 1 and 2, which provided over 100 g of BMS-986097.

This report may spur the rapid asymmetric construction of complex heterocyclic compounds.

■

■

QUANTIFICATION AND THEORETICAL ANALYSIS OF THE ELECTROPHILICITIES OF MICHAEL ACCEPTORS The rapid evaluation of electrophilic reactivity is an essential tool in synthetic and applied chemistry. Mayr and co-workers at the University of München in Germany have disclosed the quantification and theoretical analysis of the electrophilicity of Michael acceptors such as substituted ethylenes and styrenes (J. Am. Chem. Soc. 2017, 139, 13318). The team measured the kinetics of the reactions with nucleophiles such as pyridinium ylides, sulfonium ylide, and sulfonyl-substituted chloro-methyl anion. The method described determined the electrophilic parameters E, which was used to calculate the rates of reaction of ethylenes and styrenes with any known nucleophilic parameter N and nucleophilic-specific susceptibility parameter sN. In addition, quantum chemical calculations elucidated the origin of the observed electrophilicity. A good correlation between the calculated and the electrophilic reactivities in DMSO was found. These findings may be useful in evaluating the toxicological profile of a variety of Michael acceptors.

BUCHWALD−HARTWIG AMINATION OF NITROARENES Nitroarenes are generally cheap and stable starting materials compared to the corresponding anilines. The use of nitroarenes as pseudohalides circumvent the undesired contamination when halides are used as coupling partners. Nakao et al. have disclosed the use of nitroarenes as coupling partners in a Buchwald− Hartwig amination reaction (Angew. Chem., Int. Ed. 2017, 56, 13307). After some experimentation, the team obtained optimal reaction conditions using 5.0 mol % of Pd(acac)2, BrettPhos ligand (15 mol %), K3PO4 in n-heptane or toluene at 130 °C. The coupling reaction was tolerant of functional groups such as cyclic ketal, fluoro, esters, sulfones, and so forth. In addition, the team proposes a plausible mechanism for the reaction, supported by experimental data.

■

ENANTIOSELECTIVE CONJUGATE ADDITION WITH ALKENYLBORONIC ESTER NUCLEOPHILES

■

DEVELOPMENT OF THE LARGE-SCALE SYNTHESIS OF TETRAHYDROPYRAN GLYCINE, A PRECURSOR TO THE HCV NS5A INHIBITOR BMS-986097 The progress made in the treatment of chronic hepatitis C virus (HCV) has accelerated in the past few years. Collaborative work between the Phil Baran’s research Group at the Scripps Research Institute and researchers at the Bristol-Myers Squibb has led to the development of a scalable synthesis of tetrahydropyran glycine, which is a precursor to the HCV NS5A inhibitor BMS986097 (J. Org. Chem. 2017, 82, 10376). The key features of their strategy were the pursuit of three independent routes in the

Meng and colleagues reported an enantioselective C−C bond forming reaction that involves conjugate addition of alkenyl boronates to arylidene or alkylidene malonates (ACS Catalysis 2017, 7, 5693). Enantioselectivity is controlled by a chiral copper(I)-N-heterocyclic carbene catalyst which is generated in situ from air-stable imidazolinium salts. A mechanism involving Cu−B transmetalation and π-coordination of the alkenyl copper intermediate to the malonate substrate is proposed. The origins of enantioselectivity were elucidated through DFT calculations.

■

METAL TRIFLATES CAN ACCELERATE THE PALLADIUM CATALYZED CROSS-COUPLING OF (HETERO)ARYL BROMIDES AND AMIDES

Dobereiner and Becica reported that certain metal triflates can accelerate palladium-catalyzed amide N-arylation reactions H




(ACS Catalysis 2017, 7, 5862). The substrates that were evaluated included phenyl and pyridyl bromides as well as substituted benzamides and acetamides. Primary and secondary carboxylic acid amides and secondary sulfonamides gave moderate to good yields in the coupling reaction. Kinetic and mechanistic studies supported a mechanism in which amide-halogen ligand exchange was turnover-limiting. It was proposed that the metal triflates examined in the study facilitate this exchange reaction.

■

in analytical science will unearth impurities that are presently undetectable.

■

PROCESS INTENSIFICATION THROUGH CONTINUOUS SPHERICAL CRYSTALLIZATION USING AN OSCILLATORY FLOW BAFFLED CRYSTALLIZER Researchers at Purdue, with support from Eli Lilly, have reported on their use of continuous spherical crystallization of benzoic acid from aqueous ethanol in an oscillatory flow baffled crystallizer (OFBC) (Z. K. Nagy et al. Cryst. Growth Des 2017, 17, 4776). The study looked at the impact of variation in the initial supersaturation concentration and relative amount of wetting agent (toluene) that was present in order to encourage agglomeration, as well as mixing conditions. The setup produced agglomerates of consistent quality and appeared to be suitable for operation at a variety of different productivity levels, without needing to change the volume of the tubular crystallizer. However, the agglomerate size distributions were greater than expected. Thus, at least in this case, the ability of the technology to produce agglomerates with specific particle and material properties, a benefit that was targeted at the outset of the study, was compromised.

PHOTOORGANOCATALYTIC SYNTHESIS OF LACTONES

Heeres and colleagues reported an atom-economical photocatalytic method for lactone synthesis (Green Chem. 2017, 19, 4451). The method featured the use of glyoxylic acid derivatives in substoichiometric quantities to promote the reaction. Based on spectroscopic investigations, it was postulated that the reaction proceeds through excimer formation, generation of a carbon-centered radical in the alcohol, addition across the double bond of the maleate ester, proton transfer, and cyclization.

■

■

PHARMACEUTICAL ASPECTS OF SALT AND COCRYSTAL FORMS OF APIS AND CHARACTERIZATION CHALLENGES Researchers at the University of Torino have reviewed characterization challenges when the form of an API selected for development is a salt, solvate/hydrate, or cocrystal (Adv. Drug Deliv. Rev. 2017, 10.1016/j.addr.2017.07.001). The article starts by briefly summarizing pharmaceutical and business drivers that influence the selection of the solid state form of an API as well as design approaches to crystal engineering. The bulk of the article deals with the role of different experimental and computational techniques that can be used to provide understanding about form, including approaches that can be leveraged when a single crystal X-ray determination does not afford accurate proton positions. The article finishes with detailed discussion around how specific characterization challenges have been solved for a number of cocrystals (ionic and salt) and salts. The article provides 246 references.

GREENER PEPTIDE SYNTHESIS

Lipshutz and colleagues reported a mild synthesis of oligopeptides using a tandem deprotection-coupling strategy under aqueous micellar conditions (Green Chem. 2017, 19, 4263). The scope of the method was tested with respect to several functionalized amino acid side chains. The method was utilized to efficiently synthesize a ten amino acid residue oligopeptide. No epimerization was detected under the reported experimental conditions.

■

■

CHROMATOGRAPHIC APPROACHES FOR THE CHARACTERIZATION AND QUALITY CONTROL OF THERAPEUTIC OLIGONUCLEOTIDE IMPURITIES Scientists supporting phosphorothioate oligonucleotide drugs in clinical development will be interested in a review that pulls together information on the formation and analysis of impurities associated with their manufacture on a solid phase (M. G. Bartlett et al. Biomed. Chromatogr. 2017, 10.1002/bmc.4088). The structural complexity, size, and potential presence of diastereomers at each stereogenic phosphorus center, together with the polycharged nature of the oligonucleotide means impurities are treated in groups, rather than individually. Impurity groups covered include 4,4′-dimethoxytrityl adducts, acrylonitrile adducts, “shortmers”, “longmers”, phosphodiester analogues, and those arising from depurination. While ion-pair reversed-phased highperformance liquid chromatography coupled with MS detection is reported as remaining a versatile workhorse for the separation and identification of impurities, it is likely that future developments

A REDUCTIVE AMINASE FROM Aspergillus oryzae

The reductive amination of a broad set of carbonyl compounds by a reductive aminase found in koji has been reported (Grogan, G.; Turner, N. J., et al. Nat. Chem. 2017, 9, 961). While such activity is well-known where ammonia is acting as the amine donor, there are only limited examples of the use of alkylamines as an intermolecular coupling partner. Unlike imine reductases, this enzyme shows high activity for both imine formation and reduction. The study yielded a predictive matrix of the relative specific activity that might be expected for a particular amine or I




ketone, based on its structural features. Notably some of the examples quote the use of equimolar amounts of the two coupling partners, an obvious boon where the amine coupling partner is expensive. Results from the use of two variants of the wild type enzyme developed by site-directed mutagenesis are reported as achieving enantioselective outcomes that are stereodivergent and high.

■

John Knight*

■

JKonsult Ltd., Meadow View, Cross Keys, Hereford, HR1 3NT, U.K.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

HYDROGENATION OF FLUOROARENES: DIRECT ACCESS TO ALL-cis-(MULTI)FLUORINATED CYCLOALKANES

Alan Steven: 0000-0002-0134-0918 Robert Kargbo: 0000-0002-5539-6343 Christopher C. Nawrat: 0000-0003-4550-9954 Arjun Raghuraman: 0000-0002-9843-0441 Notes

E-mail: [email protected]; paul.f.richardson@pfizer.com; [email protected]; Alan.Steven@astrazeneca. com; [email protected]; [email protected]; [email protected].

The Glorius group have disclosed a method for the production of fluorinated aliphatic heterocycles from the hydrogenation of the corresponding (hetero)arenes (Science 2017, 357, 908). The method uses an air-stable rhodium catalyst bearing a strongly σ-donating cyclic (amino)(alkyl)carbene ligand. Given that the utility of previous attempts to hydrogenate fluoroarenes has been hampered by a competing hydrodefluorination pathway, the work is notable. Lowering the polarity of the solvent was found to translate into a means of discouraging this pathway, explaining the use of hexane as reaction solvent. The method is used to make fluorine-bearing analogues of the chemotherapeutic agent lomustine and the mucolytic agent bromhexine. The method is also shown to be applicable to multifluorinated substrates.

Robert Ely Achaogen, Inc., 1 Tower Place, Suite 300 South San Francisco, 94080, United States

Paul Richardson Pfizer, Chemistry, 10578 Science Center Drive, San Diego, California 09121, United States

Andrei Zlota The Zlota Company, LLC, 15 Fairbanks Road, Sharon, Massachusetts 02067-2858, United States

Alan Steven AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, SK10 2NA, U.K.

Robert Kargbo Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401, United States

Christopher C. Nawrat Merck & Co. Inc., Rahway, New Jersey 07065, United States

Arjun Raghuraman Polyurethane Process R&D, The Dow Chemical Co., Freeport, Texas 77541, United States J


Some Items of Interest to Process R&D Chemists ... - ACS Publications

Recommend Documents