A General Approach to Optically Pure, α-Methyl Non-Natural Amino Acids: Enabling Unique Peptides as Drug Candidates.

An α-methyl, non-natural amino acid (NNAA) building block equipped with an alkyl halide tail that could be readily transformed into an organozinc was prepared. This single organometallic was cross-coupled to an array of heterocyclic electrophiles using the Pd-PEPPSI-IHeptCl catalyst to produce a wide selection of optically pure α-methyl NNAAs. With these in hand, non-natural peptides are being produced for evaluation in a variety of therapeutic areas in drug discovery.

Impact of N-Aryl- and NHC Core-Substituents on the Coupling of Alkylzinc Nucleophiles: Is Bigger always Better?

Bulky Pd-N-heterocyclic carbene (NHC) catalysts (e. g., N-(di-2,6-(3-pentyl)phenyl), IPent) have been shown to have significantly higher reactivity in a wide variety of cross-coupling applications (i. e., C-C, C-S, C-N) than less hindered variants (e. g., N-(di-2,6-(isopropyl)phenyl), IPr). Further, chlorinating the backbone of the NHC ring sees an even greater increase in reactivity. In the cross-coupling of (hetero)aryl electrophiles to secondary alkyl nucleophiles, making the N-aryl groups larger reduces the amount of ß-hydride elimination leading to alkene byproducts and chlorinating the NHC core had an even greater effect, all but eliminating alkene formation. In the present study involving the cross-coupling of primary alkyl electrophiles and nucleophiles, a sharp and surprising reversal of all of the above trends was observed. Bulkier catalysts had generally slower rate of reaction and ß-hydride elimination worsened leading to extensive amounts of alkene byproducts.

Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria.

The polyprenyl lipid undecaprenyl phosphate (C55P) is the universal carrier lipid for the biosynthesis of bacterial cell wall polymers. C55P is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essential cis-prenyltransferase that is an attractive target for antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate ß-lactam antibiotics. Here, we provide a structural model for MAC-0547630's inhibition of UppS and a structural rationale for its enhanced effect on UppS from Bacillus subtilis versus Staphylococcus aureus. We also describe the synthesis of a MAC-0547630 derivative (JPD447), show that it too can potentiate ß-lactam antibiotics, and provide a structural rationale for its improved potentiation. Finally, we present an improved structural model of clomiphene's inhibition of UppS. Taken together, our data provide a foundation for structure-guided drug design of more potent UppS inhibitors in the future.

(DiMeIHeptCl)Pd: A Low-Load Catalyst for Solvent-Free (Melt) Amination.

(DiMeIHeptCl)Pd, a hyper-branched N-aryl Pd NHC catalyst, has been shown to be efficient at performing amine arylation reactions in solvent-free ("melt") conditions. The highly lipophilic environment of the alkyl chains flanking the Pd center serves as lubricant to allow the complex to navigate through the paste-like environment of these mixtures. The protocol can be used on a multi-gram scale to make a variety of aniline derivatives, including substrates containing alcohol moieties.

Sodium Butylated Hydroxytoluene: A Functional Group Tolerant, Eco-Friendly Base for Solvent-Free, Pd-Catalysed Amination.

NaBHT (sodium 2,6-di-tert-butyl-4-methylphenolate), a strong, but hindered and lipophilic base, has been effectively paired with similarly lipophilic, high-reactivity Pd-NHC (N-heterocyclic carbene) catalysts to produce an ideal combination for performing solvent-free (melt) cross-coupling amination. The mild nucleophilicity of NaBHT, coupled with the anti-oxidant properties of its conjugate acid byproduct, BHT means the process seems to have no functional group incompatibilities. Highly effective coupling of base-sensitive and redox-active functional groups was observed in all cases with only 0.1-0.2 mol percent catalyst. Comparisons using the standard base for this reaction, KOtBu, led to poor couplings or complete degradation in most applications - only NaBHT works.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing.

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine-chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self-optimization tools.

Intelligent Multidimensional Purity Analysis and Confirmation Tool for Multiple Attribute Analysis.

Chiral active pharmaceutical ingredients (APIs) are known to bind to chiral biological targets with better on-target specificity than achiral ones. However, the methods of synthesizing such APIs stereoselectively require the exhaustive optimization of multiple quality attributes of an asymmetric synthesis, wherein all critical quality attributes (for example, chemical and stereochemical purity of the API) are to be optimized in parallel and ideally from the beginning of the drug development program. A multidimensional liquid chromatographic tool capable of simultaneously measuring multiple quality attributes from a single analytical injection is reported. The tool is designed for the recirculation of chromatographic eluent bearing an analyte of interest through one or more stationary phases using a new and uniquely designed heart-cut valve. The iterative measurement of a target analyte from just one single injection will help scientists identify whether an unknown impurity is formed during reaction or during analysis. This chromatographic tool is particularly useful in the discovery of on-analysis artifacts, which is a resource-intensive exercise involving the identification, synthesis, and injection of impurity standards, all of which delay the drug development program.

Experimental and Computational Study on the Anti-Markovnikov Hydrofunctionalization of Olefins Using Glycine-Extended AQ-Auxiliaries.

Two similar tridentate directing groups derived from glycine and 8-aminoquinoline were shown to enable the palladium-catalyzed anti-Markovnikov hydrofunctionalization of 4-pentenylamine with drastically different efficiencies. A computational investigation into the origin of the reactivity difference between these isomeric, carbonyl-transposed auxiliaries suggests that protonation state, thus charge of the substrate-metal complex prior to nucleopalladation is key. These investigations have culminated in a directing group design that can undergo Pd-catalyzed hydrofunctionalization under relatively mild conditions, as low as room temperature.

Salt to Taste: The Critical Roles Played by Inorganic Salts in Organozinc Formation and in the Negishi Reaction.

The first cross-coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.e. one with salt and one without) provided drastically different results. Since this finding, the exact role of salt additives in cross-coupling has been debated in the catalysis community. In this Review we highlight all the major discoveries regarding the influence of salt additives on the formation of organozinc reagents and their use in the Negishi reaction. These effects include solubilizing key intermediates, the formation of higher-order zincates, product inhibition, catalyst protection, and solvent effects.

The Synthesis of Warfarin Using a Reconfigurable-Reactor Platform Integrated to a Multiple-Variable Optimization Tool.

Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug-flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart-cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high-level of confidence in analytical measurements, which are obtained without operator intervention.

A Path to More Sustainable Catalysis: The Critical Role of LiBr in Avoiding Catalyst Death and its Impact on Cross-Coupling.

The role that LiBr plays in the lifetime of Pd-NHC complexes has been investigated. A bromide ion is proposed to coordinate to Pd thereby preventing beta hydride elimination (BHE) (to form NHC-H+ ) of the reductive elimination (RE) intermediate that normally completes with the desired cross-coupling catalytic cycle. Coordinating groups, such as anilines, are able to bind suitably well to Pd to prevent this pathway from occurring, thus reducing the need for the added salt. The metal hydride formed from BHE is very unstable and RE of the hydride to the NHC ligand occurs very rapidly giving rise to the corresponding hydrido-NHC (i.e., NHC-H+ ). The use of the per deuterated dibutylzinc shows a significant deuterium isotope effect, shutting down catalyst death almost completely. The use of bis-neopentylzinc, now possessing no hydrides, eliminates catalyst death all together leading to a very long-lived catalytic cycle and confirming the untoward role of BHE.

Discovery of an antivirulence compound that reverses ß-lactam resistance in MRSA.

Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses ß-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in Galleria mellonella larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.

Rate and Computational Studies for Pd-NHC-Catalyzed Amination with Primary Alkylamines and Secondary Anilines: Rationalizing Selectivity for Monoarylation versus Diarylation with NHC Ligands.

The relative rates of arylation of primary alkylamines with different Pd-NHC catalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attempt to understand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increase in size, selectivity for monoarylation increases and this is further enhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycle of this transformation in order to understand the selectivity obtained with the different catalysts.

The Role of LiBr and ZnBr2 on the Cross-Coupling of Aryl Bromides with Bu2 Zn or BuZnBr.

The impact of LiBr and ZnBr2 salts on the Negishi coupling of alkylZnBr and dialkylzinc nucleophiles with both electron-rich and -poor aryl electrophiles has been examined. Focusing only on the more difficult coupling of deactivated (electron-rich) oxidative addition partners, LiBr promotes coupling with BuZnBr, but does not have such an effect with Bu2 Zn. The presence of exogenous ZnBr2 shuts down the coupling of both BuZnBr and Bu2 Zn, which has been shown before with alkyl electrophiles. Strikingly, the addition of LiBr to Bu2 Zn reactions containing exogenous ZnBr2 now fully restores coupling to levels seen without any salt present. This suggests that there is a very important interaction between LiBr and ZnBr2 . It is proposed that Lewis acid adducts are forming between ZnBr2 and the electron-rich Pd0 centre and the bromide from LiBr forms inorganic zincates that prevent the catalyst from binding to ZnBr2 . This idea has been supported by catalyst design as chlorinating the backbone of the NHC ring of Pd-PEPPSI-IPent to produce Pd-PEPPSI-IPentCl catalyst now gives quantitative conversion, up from a ceiling of only 50 % with the former catalyst.

Sodium Butylated Hydroxytoluene (NaBHT) as a New and Efficient Hydride Source for Pd-Catalysed Reduction Reactions.

NaBHT (sodium butylated hydroxytoluene), a hindered and soluble base for the efficient arylation of various base-sensitive amines and (hetero)aryl halides has been found to have an unanticipated role as a hydride donor to reduce (hetero)aryl halides and allylic acetates. Mechanistic studies have uncovered that NaBHT, but not BHT, can deliver multiple hydrides through oxidation of the benzylic methyl group in NaBHT to the aldehyde. Further, performing the reduction with NaBHT-d20 has revealed that the redox-active benzylic position is not the only hydride donor site from NaBHT with one hydride in three coming, presumably, from the tert-butyl groups. The reduction works well under mild conditions and, incredibly, only consumes 20 percent of the NaBHT in the process; the remaining 80 percent can be readily recovered in pure form and reused. This, combined with the low cost of the material in ton-scale quantity, makes it practical and attractive for wider use in industry at scale.

Murahashi Cross-Coupling at -78 °C: A One-Pot Procedure for Sequential C-C/C-C, C-C/C-N, and C-C/C-S Cross-Coupling of Bromo-Chloro-Arenes.

The coupling of organolithium reagents, including strongly hindered examples, at cryogenic temperatures (as low as -78 °C) has been achieved with high-reactivity Pd-NHC catalysts. A temperature-dependent chemoselectivity trigger has been developed for the selective coupling of aryl bromides in the presence of chlorides. Building on this, a one-pot, sequential coupling strategy is presented for the rapid construction of advanced building blocks. Importantly, one-shot addition of alkyllithium compounds to Pd cross-coupling reactions has been achieved, eliminating the need for slow addition by syringe pump.

One-Pot Sequential Kumada-Tamao-Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl.

We report a general and rapid chemoselective Kumada-Tamao-Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPentCl (C4). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo-chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.

Cross-Coupling of Primary Amides to Aryl and Heteroaryl Partners Using (DiMeIHeptCl)Pd Promoted by Trialkylboranes or B(C6F5)3.

Boron-derived Lewis acids have been shown to effectively promote the coupling of amide nucleophiles to a wide variety of oxidative addition partners using Pd-NHC catalysts. Through a combination of NMR spectroscopy and control studies with and without oxygen and radical scavengers, we propose that boron-imidates form under the basic reaction conditions that aid coordination of nitrogen to Pd(II), which is rate limiting, and directly delivers the intermediate for reductive elimination.

Pd-PEPPSI-IPent-SiO2 : A Supported Catalyst for Challenging Negishi Coupling Reactions in Flow.

A silica-supported precatalyst, Pd-PEPPSI-IPent-SiO2 , has been prepared and evaluated for its proficiency in the Negishi cross-coupling of hindered and electronically deactivated coupling partners. The precatalyst Pd-PEPPSI-IPent loaded onto packed bed columns shows high catalytic activity for the room-temperature coupling of deactivated/hindered biaryl partners. Also for the first time, the flowed Csp3 -Csp2 coupling of secondary alkylzinc reagents to (hetero)aromatics has been achieved with high selectivity with Pd-PEPPSI-IPent-SiO2 . These couplings required residence times as short as 3 minutes to effect completion of these challenging transformations with excellent selectivity for the nonrearranged product.

Designing Pd-N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications.

Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 °C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing ß-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl-substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, α-amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications.