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A new undergraduate organic laboratory experiment has been developed for amide bond formation between biorenewable 2-furoic acid and either of two substituted piperazines to prepare medicinally relevant amide products using a procedure with industrial significance. The reactions proceeded smoothly under ambient conditions using the combination of

As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.

Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for

Research on the development of scalable routes to pharmaceutical intermediates typically proceeds from explorations of the chemistry to the identification of robust procedures for isolation. Althou...

The utility of peroxides in synthetic organic chemistry is tied to significant safety risks posed by their handling, storage, and disposal. Although guidelines exist, a lack of reliable methods for...

In the pharmaceutical industry, H2O2-mediated oxidation reactions are commonly used in chemical syntheses but they can also introduce unexpected safety hazards. Our labs recently reported on the di...

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The process development and the kilogram-scale synthesis of linrodostat (BMS-986205, 1) are described. The synthesis features several highly efficient telescoped processes and the use of Evans auxi...

To succeed in the development of a mechanistic model for the Vorbruggen reaction of thymine with an advanced furanose intermediate, a range of spectroscopic techniques were applied and found essent...

The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C–N coupling is enabled by the use of a uniq...

The use of LiOH/H2O2 for cleavage of Evans oxazolidinones is an essential but often overlooked part of using these ubiquitous chiral auxiliaries in synthetic routes. These conditions were disclosed in the literature more than 30 years ago and have found widespread use with little change. During studies focused on the synthesis of a drug candidate, we discovered the evolution of oxygen under the LiOH/H2O2 conditions for cleavage of an Evans auxiliary. We find this phenomenon to be general and tied to the fact that the initially formed peracid is not stable under the reaction conditions. The peracid is rapidly reduced by the excess H2O2 present in the reaction mixture, leading to the release of a stoichiometric amount of oxygen. This can present a significant risk for maintaining proper inertion in the presence of the flammable organic solvent, and we propose options for safely executing this chemistry at multikilogram scale.

The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3.

Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.

A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.

During exploration of the nickel(0)-catalyzed reaction of isocyanates and isatoic anhydrides, it was found that changes in the substitution pattern of the isocyanate led to constitutionally isomeric quinazolinediones [quinazoline-2,4(1H,3H)-diones] or benzoxazinone imines [2-imino-1,2-dihydro-4H-3,1-benzoxazin-4-ones]. Ligand and solvent screening experiments allowed for identification of conditions that could lead to each constitutional isomer in good to excellent levels of selectivity and yield. Comprehensive characterization of the previously poorly characterized benzoxazinone imines is also provided.

The discovery, development, and optimization of an Ullmann–Goldberg–Buchwald coupling reaction is described. This complex process represents a key transformation in the development of a commercially viable synthesis of the HIV attachment inhibitor prodrug BMS-663068. In this reaction, high regioselectivities were obtained for the coupling of a 1,2,4-triazole and a 7-bromoazaindole, preparing BMS-626529, the antepenultimate in good yield and quality. Key challenges associated with developing commercially viable conditions for this copper-mediated coupling include achieving the desired level of regiochemical control, identifying robust isolation conditions and controlling residual copper levels in the isolated product.

The reaction optimization of an alkylation to enable the production of the penultimate intermediate of an HIV-attachment inhibitor candidate is described. To address the challenges associated with the reactivity and stability of di-tert-butyl (chloromethyl) phosphate (2), and the poor solubility and reactivity of the starting BMS-626529-Li salt (1), strategic selection of Et4NI and 325 mesh K2CO3 as additives, and wet CH3CN as solvent were required. An aqueous workup protocol was also developed to selectively remove an undesired N-6 alkylation isomer. The final processing conditions resulted in the isolation of the penultimate compound 3 in 70% yield with high purity.

During the development of a Friedel–Crafts acylation for the preparation of a key pyrrole intermediate in the synthesis of the HIV attachment inhibitor, BMS-663068-03, a significant scale dependence was found. A precipitous drop in yield was observed for the acylation of a protected pyrrole with chloroacetyl chloride upon scale-up. Spectroscopic studies to mitigate this scale dependence led to the identification of the complex effect of dissolved hydrogen chloride (HCl) as well as the poor reactivity of the acylating agent, chloroacetyl chloride. At this point, the counterintuitive choice to switch to a longer, but scale-independent, three-step route was made. By changing the acylating agent to acetyl chloride, a more robust process was obtained. Rapid development of a high yielding α-chlorination then provided the common α-chloroketone intermediate required to generate the desired α-amide ketopyrrole. The improved yield and scalability of this three-step process supported the addition of one linear step ...

A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C–H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.

During efforts to employ a Claisen rearrangement in the synthesis of a complex nucleoside, a highly functionalized, protected vinyl ether was required as a key intermediate. The optimal route to this vinyl ether was found to be a remarkably selective ring opening of a cyclic acetal with TMSOTf and NEt3. In this paper we describe factors affecting the selectivity of this vinyl ether synthesis as well as the scope of the reaction for preparation of highly functionalized nucleoside vinyl ethers.

Zinc salts have been shown to promote the Buchwald–Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.

Herein we report a novel heterogeneous pyrrole nitration that can be run on a large scale in batch mode. Activation of sodium nitrate by SO3–pyridine in acetonitrile leads to the formation of an insoluble nitronium sulfate intermediate that effects a high-yielding reaction. These conditions allow for a safer and practical nitration reaction with unique thermal stability that appears to be a function of the low solubility of the proposed nitronium ion carrier. Mechanistic insights gained from reaction kinetics as well as 1H and 15N NMR studies are presented to support this analysis.

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.

The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.

Die Mukaiyama-Aldolreaktion, die 1973 erstmals beschrieben wurde, ist eine regio-, diastereo- und enantioselektive Reaktion, die den seltenen Rang einer Namensreaktion von strategischer Bedeutung erlangt hat. Die Bedeutung der Mukaiyama-Reaktion fur die stereoselektive Synthese organischer Verbindungen (Naturstoffe sowie vollsynthetische) kann kaum uberschatzt werden. Ihr Einfluss auf das Gebiet der Synthesechemie reicht uber die blose Anwendung in der Synthese hinaus, denn sie hat sich als Inspiration fur neue Konzepte und Methoden der Stereokontrolle und der Katalyse erwiesen. Dieser Kurzaufsatz soll aufzeigen, wie die Suche nach einer regio-, diastereo- und enantioselektiven Katalysereaktion zur Entwicklung der Lewis-Base-katalysierten Aldolreaktion gefuhrt hat. Die Entwicklungsgeschichte dieses Verfahrens wird anhand der Studien aus den Arbeitsgruppen der Autoren und von Teruaki Mukaiyama nachgezeichnet.

A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an improved procedure is described which was safely demonstrated at multikilogram scale.

The development of practical and efficient syntheses of the potent non-nucleoside reverse transcriptase inhibitors 1 and 2 is described. The preparation of 1 proceeded in four synthetic steps and in 48% overall yield from 3. The long-term synthesis of 2 proceeded in nine synthetic steps and in 47% overall yield from commercially available 2,6-diflurorpyridine. The route to 2 was highlighted by the three-step synthesis of intermediate 22 and the high yielding coupling between 18 and phenol 8. The overall sequence required no chromatography and has successfully been utilized for the manufacture of 2 on large scale.

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.

4-Hydroxyquinolinone esters are a common motif for many medicinal agents. Several methods exist for preparation of these compounds, generally involving the use of sodium hydride, which raises significant safety issues and limits their application to large-scale synthesis. In this note a practical, safe, and general method that employs a combination of diisopropylethylamine and sodium tert-butoxide is described. This allows for the synthesis of 4-hydroxyquinolinone esters and amides in good yields.

The enantioselective ring opening of meso- epoxides (from both cyclic and acyclic olefins) with silicon tetrachloride under catalysis by chiral phos- phoramides affords enantiomerically enriched chloro- hydrins in excellent yields. Experiments designed to elucidate the mechanistic foundation and origins of enantioselectivity are described. From studies on the loading and stoichiometry of the reagent (SiCl4) and the catalyst ((R)-1) it was established that only one chloride per SiCl4 is delivered and that the nature of reactive species does not change over the course of the reaction. Kinetic studies together with asymmet- ric amplification experiments have suggested that more than one catalyst molecule may be bound to SiCl4 in the stereochemistry-determining transition structure.

Title compound (IX*) is prepared from racemic lactol (I) using small-molecule-mediated dynamic kinetic resolution and a selective pyranose-to-furanose ring contraction as the key steps.

The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a ∼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).

Described herein is the synthesis of BMS-986001 by employing two novel organocatalytic transformations: 1) a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2) an unprecedented small-molecule-mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography-free synthesis of BMS-986001. The synthesis required five chemical transformations and resulted in a 44 % overall yield.

The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2H-pyran-3(6H)-one (3), proceeds cleanly in the presence of tert-butyl hydroperoxide (TBHP, 2) using low loadings of VO(O(i)Pr)3 as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product 3 and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO(O(i)Pr)3), and a negative dependence on the 2-methyl-2-propanol (4) concentration. (51)V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (4) competes with substrates for binding to the metal center, rationalizing its inhibitory effect.

In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the pi system of a carbon-carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing "extended" dienol ethers derived from gamma-enolizable alpha,beta-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.

Im Jahre 1935 formulierte R. C. Fuson das Prinzip der Vinylogie, um zu erklaren, wie sich der Einfluss einer funktionellen Gruppe an einer entfernten Position im Molekul bemerkbar macht, wenn diese uber konjugierte Doppelbindungen mit der Gruppe verbunden ist. In polaren Reaktionen ermoglicht dieses Konzept die Erweiterung des elektrophilen oder nucleophilen Charakters einer funktionellen Gruppe uber das π-System einer Kohlenstoff-Kohlenstoff-Doppelbindung. Diese vinyloge Erweiterung fuhrt im Fall der Aldolreaktion zum Einsatz “erweiterter” Dienolether, die von γ-enolisierbaren α,β-ungesattigten Carbonylverbindungen abgeleitet sind. Seit 1994 sind einige Methoden fur die katalytische enantioselektive vinyloge Aldolreaktion beschrieben worden, mit denen man unterschiedliche Regio- (Orts-), Enantio- und Diastereoselektivitaten erzielen kann. In diesem Aufsatz werden die Bandbreite und die Einschrankungen dieser Transformation sowie ihre Anwendung in der Naturstoffsynthese diskutiert.

Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo-, and enantioselective aldol reaction has been elevated to the rarefied status of being both a named and a strategy-level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors’ laboratories as well as in those of Professor Teruaki Mukaiyama.

In order to rapidly screen and select lead candidates for in vivo evaluation of lipid nanoparticles (LNPs) for systemic small interfering RNA (siRNA) delivery, an in vitro assay amenable to high-throughput screening (HTS) is developed. The strategy is to mimic the in vivo experience of LNPs after systemic administration, such as interactions with serum components, exposure to endosomal pH environments, and interactions with endosomal membrane lipids. It is postulated that the amount of siRNA released from LNPs after going through these treatments can be used as a screening tool to rank order the effectiveness of siRNA delivery by lipid nanoparticles in vivo. LNPs were incubated with 50% serum from different species (i.e. mouse, rat, or rhesus) at 37°C. The resulting samples were then reacted with anionic, endosomal-mimicking lipids at different pHs. The amount of siRNA released from LNPs was determined using spectrophotometry employing the fluorescent indicator SYBR Gold. Our results indicated that the amount of siRNA liberated was highly dependent upon the species of serum used and the pH to which it was exposed. LNPs treated with mouse serum showed higher levels of siRNA release, as did those subjected to endosomal pH (6.0), compared to physiological pH. Most interestingly, a good correlation between the amount of siRNA released and the in vivo efficacy was observed. In conclusion, an in vitro siRNA release assay was developed to screen and rank order LNPs for in vivo evaluation.

Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo-, and enantioselective aldol reaction has been elevated to the rarefied status of being both a named and a strategy-level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors’ laboratories as well as in those of Professor Teruaki Mukaiyama.

This chapter chronicles the evolution of a paradigm shift in the conceptualization and development of chiral Lewis base catalysis of carbonyl addition reactions with organosilicon nucleophiles. Prior to 2000, these reactions were exclusively practiced through the agency of highly electrophilic silicon species such as allyltrichlorosilanes and enoxytrichlorosilanes derived from aldehydes, ketones, and esters. However, a serendipitous discovery made during the development of these processes led to a fundamentally new insight, namely, that silicon tetrachloride could be activated by chiral Lewis bases (primarily phosphoramides) and the resulting chiral silicenium ion could serve as a general and effective catalyst for the addition of many different enoxysilane nucleophiles derived from aldehydes, ketones, esters, nitriles, protected cyanohydrins, conjugated esters and amides, and isocyanides. In addition to providing high generality, high yield, and high stereoselectivity, the new family of Lewis base-catalyzed reactions could be investigated mechanistically, and the foundations of reactivity and selectivity could be revealed. An analysis of how this paradigm shift occurred and the circumstances that led to discovery are described.

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl ketene acetal of methyl acetate adds nearly instantaneously to aromatic and olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene acetal of tert-butyl propanoate adds with nearly exclusive anti diastereoselectivity to a similar range of aldehydes also with excellent enantioselectivity. The origin of the slower reaction rate with aliphatic aldehydes is revealed to be the formation of chlorosilyl ether adducts.

A Rapid Injection NMR (RINMR) apparatus has been designed and constructed to allow the observation of fast chemical reactions in real time by NMR spectroscopy. The instrument was designed to allow the rapid (