Synthesis Of Complex Molecules Research Articles

The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans

Integrating nutrient sensing with the synthesis of complex molecules is a central feature of metabolism. Yet the regulatory mechanisms underlying such integration are often unknown. Here, we establish that the transcription regulators Rtg1/3 are key determinants of sphingolipid homeostasis in the human fungal pathogen Candida albicans. Quantitative analysis of the C.albicans lipidome reveals Rtg1/3-dependent alterations in all complex sphingolipids and their precursors, ceramides. Mutations in the regulators render the fungus susceptible to myriocin, a sphingolipid synthesis inhibitor. Rtg1/3 exert control on the expression of several enzymes involved in the synthesis of sphingolipids' building blocks, and the regulators are activated upon engulfment of C.albicans cells by human neutrophils. We demonstrate that Rtg1p and Rtg3p are regulated at two levels, one in response to sphingolipids and the other by the nutrient sensor TOR. Our findings, therefore, indicate that the Rtg1/3 system integrates nutrient sensing into the synthesis of complex lipids.

Controllable double CF2-insertion into sp2 C-Cu bond using TMSCF3: a facile access to tetrafluoroethylene-bridged structures.

A highly efficient method for controllable double CF2-insertion into pentafluorophenylcopper species using TMSCF3 as difluoromethylene source has been developed. The newly generated fluoroalkylcopper(i) species, C6F5CF2CF2Cu, shows good reactivity towards a myriad of structurally diverse aryl, heteroaryl and alkenyl iodides. This protocol is easy to handle, ready to scale up and applicable for the synthesis of relative complex molecules, thus providing a convenient method for facile access to tetrafluoroethylene-bridged structures.

Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

Recent advances in three-component difunctionalization of gem-difluoroalkenes.

Three-component difunctionalization of alkenes is regarded as one of the most attractive strategies in synthetic chemistry, because it enables the direct synthesis of useful and complex molecules from simple and readily available starting materials in a step-economic manner. gem-Difluoroalkenes, as a class of useful and readily available fluorine-containing raw materials, have been well investigated in two-component coupling reactions. This review focuses on the progress of three-component difunctionalization reactions of gem-difluoroalkenes. On the basis of the intermediates involved in these transformations, these three-component reactions of gem-difluoroalkenes could be categorized into four types: (1) involving an α-fluoroalkylated carbanion, (2) involving an α-fluoroalkylated carbon-metal species, (3) involving an α-fluoroalkylated radical, and (4) involving an α-fluoroalkylated carbocation. The typical transformations, the substrate scope, the reaction mechanisms, and their subsequent applications in the synthesis of bioactive molecules are discussed. Owing to the rapidly increasing interest in this area, we believe that this review will present a timely and comprehensive understanding of the recent progress in three-component difunctionalization reactions of gem-difluoroalkenes.

Recent advances in oxidative allylic C-H functionalization via group IX-metal catalysis.

Allylic substitution, pioneered by the work of Tsuji and Trost, has been an invaluable tool in the synthesis of complex molecules for decades. An attractive alternative to allylic substitution is the direct functionalization of allylic C-H bonds of unactivated alkenes, thereby avoiding the need for prefunctionalization. Significant early advances in allylic C-H functionalization were made using palladium catalysis. However, Pd-catalyzed reactions are generally limited to the functionalization of terminal olefins with stabilized nucleophiles. Insights from Li, Cossy, and Tanaka demonstrated the utility of RhCpx catalysts for allylic functionalization. Since these initial reports, a number of key intermolecular Co-, Rh-, and Ir-catalyzed allylic C-H functionalization reactions have been reported, offering significant complementarity to the Pd-catalyzed reactions. Herein, we report a summary of recent advances in intermolecular allylic C-H functionalization via group IX-metal π-allyl complexes. Mechanism-driven development of new catalysts is highlighted, and the potential for future developments is discussed.

Scalable biocatalytic C-H oxyfunctionalization reactions.

Catalytic C-H oxyfunctionalization reactions have garnered significant attention in recent years with their ability to streamline synthetic routes toward complex molecules. Consequently, there have been significant strides in the design and development of catalysts that enable diversification through C-H functionalization reactions. Enzymatic C-H oxygenation reactions are often complementary to small molecule based synthetic approaches, providing a powerful tool when deployable on preparative-scale. This review highlights key advances in scalable biocatalytic C-H oxyfunctionalization reactions developed within the past decade.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis.

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.

Selective C-C Bond Scission of Ketones via Visible-Light-Mediated Cerium Catalysis

Summary Here, we report a general catalytic manifold for the selective C–C bond scission of ketones via the exploitation of the ligand-to-metal charge transfer (LMCT) excitation mode. Through a cooperative utilization of Lewis acid catalysis and LMCT catalysis, the C–C bond of ketones could be selectively and effectively cleaved, enabling the installation of different functionalities at each carbon of the cleaved C–C bond through a sequential and orthogonal manner. This reaction manifold serves as a photocatalytic alternative to the Norrish type I reaction with the combination of visible light and inexpensive cerium salts. Under operationally simple conditions, a wide range of acyclic and cyclic ketones, from simple strained cyclobutanones to complex androsterone with less strained cyclopentanone moiety, could be successfully transformed into versatile chemical building blocks.

Enhanced Catalysis from Multienzyme Cascades Assembled on a DNA Origami Triangle.

Developing reliable methods of constructing cell-free multienzyme biocatalytic systems is a milestone goal of synthetic biology. It would enable overcoming the limitations of current cell-based systems, which suffer from the presence of competing pathways, toxicity, and inefficient access to extracellular reactants and removal of products. DNA nanostructures have been suggested as ideal scaffolds for assembling sequential enzymatic cascades in close enough proximity to potentially allow for exploiting of channeling effects; however, initial demonstrations have provided somewhat contradictory results toward confirming this phenomenon. In this work, a three-enzyme sequential cascade was realized by site-specifically immobilizing DNA-conjugated amylase, maltase, and glucokinase on a self-assembled DNA origami triangle. The kinetics of seven different enzyme configurations were evaluated experimentally and compared to simulations of optimized activity. A 30-fold increase in the pathway's kinetic activity was observed for enzymes assembled to the DNA. Detailed kinetic analysis suggests that this catalytic enhancement originated from increased enzyme stability and a localized DNA surface affinity or hydration layer effect and not from a directed enzyme-to-enzyme channeling mechanism. Nevertheless, the approach used to construct this pathway still shows promise toward improving other more elaborate multienzymatic cascades and could potentially allow for the custom synthesis of complex (bio)molecules that cannot be realized with conventional organic chemistry approaches.

XszenFHal, a novel tryptophan 5-halogenase from Xenorhabdus szentirmaii

Flavin-dependent halogenases (FHals) catalyse the halogenation of electron-rich substrates, mainly aromatics. Halogenated compounds have many applications, as pharmaceutical, agrochemicals or as starting materials for the synthesis of complex molecules. By exploring the sequenced bacterial diversity, we discovered and characterized XszenFHal, a novel FHal from Xenorhabdus szentirmaii, a symbiotic bacterium of entomopathogenic nematode. The substrate scope of XszenFHal was examined and revealed activities towards tryptophan, indole and indole derivatives, leading to the formation of the corresponding 5-chloro products. XszenFHal makes a valuable addition to the panel of flavin-dependent halogenases already discovered and enriches the potential for biotechnology applications by allowing access to 5-halogenated indole derivatives.

Blue LED Irradiation of Iodonium Ylides Gives Diradical Intermediates for Efficient Metal‐free Cyclopropanation with Alkenes

AbstractA facile and highly chemoselective synthesis of doubly activated cyclopropanes is reported where mixtures of alkenes and β‐dicarbonyl‐derived iodonium ylides are irradiated with light from blue LEDs. This metal‐free synthesis gives cyclopropanes in yields up to 96 %, is operative with cyclic and acyclic ylides, and proceeds with a variety of electronically‐diverse alkenes. Computational analysis explains the high selectivity observed, which derives from exclusive HOMO to LUMO excitation, instead of free carbene generation. The procedure is operationally simple, uses no photocatalyst, and provides access in one step to important building blocks for complex molecule synthesis.

Blue LED Irradiation of Iodonium Ylides Gives Diradical Intermediates for Efficient Metal-free Cyclopropanation with Alkenes.

A facile and highly chemoselective synthesis of doubly activated cyclopropanes is reported where mixtures of alkenes and β-dicarbonyl-derived iodonium ylides are irradiated with light from blue LEDs. This metal-free synthesis gives cyclopropanes in yields up to 96 %, is operative with cyclic and acyclic ylides, and proceeds with a variety of electronically-diverse alkenes. Computational analysis explains the high selectivity observed, which derives from exclusive HOMO to LUMO excitation, instead of free carbene generation. The procedure is operationally simple, uses no photocatalyst, and provides access in one step to important building blocks for complex molecule synthesis.

Transformation of Racemic Azlactones into Enantioenriched Dihydropyrroles and Lactones Enabled by Hydrogen‐Bond Organocatalysis

Azlactones, a potent building block for the synthesis of complex molecules, have been explored in an organocatalytic Mannich reaction with protected imines. In this study, azlactones containing a propargyl substituent were employed for the first time in organocatalysis so far. The catalytically active species responsible for high enantioselectivity with substrate containing such a small linear substituent is assembled in situ from a bifunctional thiourea, prone to dimerization, and an organic acid, as evidenced by DOSY NMR. The resulting α,β‐diamino acid derivatives were subjected to further derivatization: as an example, gold‐catalyzed intramolecular hydroamination of alkynes gave chiral spirocyclic dihydropyrrole. Alternatively, related squaramide catalyst enabled a Mannich reaction of azlactones with N‐aryl or alkyl glyoxylate imines. Reduction of these adducts gave access to 2,3‐diaminobutyrolactones or 2,3‐diamino‐1,4‐diol with a tertiary and a quaternary stereocenter.

Total Synthesis as a Vehicle for Collaboration.

"Collaboration" is not the first word most would associate with the field of total synthesis. In fact, the spirit of total synthesis is all-too-often reputed as being more competitive, rather than collaborative, sometimes even within individual laboratories. However, recent studies in total synthesis have inspired a number of collaborative efforts that strategically blend synthetic methodology, biocatalysis, biosynthesis, computational chemistry, and drug discovery with complex molecule synthesis. This Perspective highlights select recent advances in these areas, including collaborative syntheses of chlorolissoclimide, nigelladine A, artemisinin, ingenol, hippolachnin A, communesin A, and citrinalin B. The legendary Woodward-Eschenmoser collaboration that led to the total synthesis of vitamin B12 is also discussed.

Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile

While reductive cross-electrochemical coupling is an attractive approach for the synthesis of complex molecules at both small and large scale, two barriers for large-scale applications have remaine...

Gold(I)-Catalyzed Synthesis of Furopyrans: Insight into Hetero-Diels-Alder Reactions.

We report herein the synthesis of complex molecules containing furopyran cores through a gold(I)-catalyzed hetero-Diels-Alder cascade reaction. During this process, the diene and the dienophile are produced concomitantly by the action of a single catalyst from a single starting material. Moreover, six bonds, four heterocycles, and four controlled stereogenic centers are formed in a one-step operation. DFT calculations provide the mechanistic basis of this unprecedented reaction.

Studies Targeting Ryanodol Result in an Annulation Reaction for the Synthesis of a Variety of Fused Carbocycles.

An annulation reaction is described to access a range of polycyclic and highly oxygenated carbocycles. First developed in an approach to the synthesis of ryanodol, metallacycle-mediated annulative diketone-alkyne coupling defines a framework for realization of new retrosynthetic relationships for complex molecule synthesis. In addition to demonstrating this reaction in the context of forging distinct carbocyclic systems, including those featuring a seven-membered ring, the choice of quenching reagent leads to unique reaction outcomes.

Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands.

The catalytic, asymmetric synthesis of complex molecules has been a core focus of our research program for some time because developments in the area can have an immediate impact on the identification of novel strategies for the synthesis of value-added molecules. In concert with this central interest, we have emphasized the design of ligand scaffolds as a tactic to discover and develop novel chemistry and overcome well-recognized synthetic challenges. Based on our group's work on chiral pool-derived diolefin ligands, we designed and implemented a class of hybrid (phosphoramidite,olefin) ligands, which combines the properties of both phosphoramidite and olefin motifs to impact, fine-tune, and even override the inherent reactivity of the metal center. Specifically, we have utilized these unique modifying ligands to address several recognized limitations in the field of iridium-catalyzed, asymmetric allylic substitution. The methods we have documented typically employ branched, unprotected allylic alcohols as substrates and obviate the need forrigorous exclusion of air and moisture. Following Takeuchi's seminal report demonstrating the high aptitude of Ir(I)-phosphite catalysts for branch-selective allylic substitution, concerted efforts from numerous research laboratories have led to a broadening of the synthetic utility of this reaction class. The first section of this Account outlines the process leading to our discovery of an unprecedented (phosphoramidite,olefin) ligand and its validation in the first iridium-catalyzed amination of branched, unprotected allylic alcohols. This section continues with our work involving heteroatom-based nucleophiles within inter- and intramolecular etherification, thioetherification and spiroketalization processes. The second section highlights the use of readily available carbon nucleophiles possessing sp, sp2, and sp3 hybridization in a series of enantioselective carbon-carbon bond-forming reactions. We describe how alkylzinc, allylsilane, and several classes of organotrifluoroborate nucleophiles can be coupled enantioselectively to enable construction of several key motifs including 1,5-dienes, 1,4-dienes, and 1,4-enynes. Since the unique electronic and steric properties of this class of ligands renders the (η3-allyl)-Ir(III) intermediate highly electrophilic, even weak nucleophiles such as alkyl olefins can be used. We also show that more nucleophilic alkene motifs such as enamines and in situ generated ketene acetalssmoothly participate in substitution reactions with allylic alcohols to yield valuable piperidines and γ,δ-unsaturated esters, respectively. The concept of stereodivergent dual catalysis, which synergistically combines chiral amine catalysiswith iridium catalysis to furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. This process has enabled the independent, stereoselective synthesis of all four possible product stereoisomers from a single set of starting materials, and was highlighted in the stereodivergent synthesis of Δ9-tetrahydrocannabinol. This Account concludes with an overview of our organometallic mechanistic studies regarding relevant intermediates within the catalytic cycle of this class of allylic substitution. These studies have allowed us to better understand the origin of the unique characteristics exhibited by this catalyst in comparison to related systems.

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances.

Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional "on demand" analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.

Gold(I)-Catalyzed Chloroalkynylation of 1,1-Disubstituted Alkenes via 1,3-Chlorine Shift: A Combined Experimental and Theoretical Study.

The haloalkynylation reaction is of great interest for the synthesis of complex molecules as it represents a carbon-carbon bond-forming reaction where the reactive halide reappears in the product. The latter enables further chemical transformations. However, only a few examples of haloalkynylations have been described so far. By using alkenes as reactant, this reaction is strictly limited to norbornene systems proceeding via a nonclassical carbocation. Herein, we show by means of quantum chemical calculations and experiments that the chloroalkynylation of 1,1-disubstituted alkenes can be successfully achieved via gold(I) catalysis. The key step in the reaction mechanism is a 1,3-chlorine shift to a cationic center, leading selectively to the corresponding homopropargyl chlorides. As this gold(I)-catalyzed addition can be conducted on a preparative scale and tolerates a broad substrate scope of both alkyne and alkene reactants, the presented chloroalkynylation reaction is an attractive method en route to complex alkynes and their congeners.